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A number sign (#) is used with this entry because of evidence that Jervell and Lange-Nielsen syndrome-2 (JLNS2) is caused by homozygous or compound heterozygous mutation in the KCNE1 gene (176261) on chromosome 21q22.
Long QT syndrome-5 (LQT5; 613695) is caused by heterozygous mutation in the KCNE1 gene.
Description
The Jervell and Lange-Nielsen syndrome is an autosomal recessive syndrome of abnormal cardiac ventricular repolarization with prolonged QT interval and bilateral congenital deafness.
For a general description and a discussion of genetic heterogeneity of Jervell and Lange-Nielsen syndrome, see 220400.
Mapping
In a small consanguineous British family with JLNS, Tyson et al. (1997) excluded linkage to KCNQ1 (607542), and found that the affected children were homozygous by descent for markers on chromosome 21, in a region containing the KCNE1 gene (176261). Tyson et al. (1997) found that most of the families they studied showed linkage consistent with mutation at the KCNQ1 gene.
Molecular Genetics
In a small consanguineous British family in which the JLNS phenotype had been mapped to chromosome 21, Tyson et al. (1997) detected a homozygous mutation in the KCNE1 gene (176261.0001). The KCNE1 gene encodes a transmembrane protein that associates with KCNQ1 to form the delayed rectifier potassium channel.
Schulze-Bahr et al. (1997) found compound heterozygosity for mutations in the KCNE1 gene (176261.0002, 176261.0003) in affected members of a Lebanese family with JLNS.
Duggal et al. (1998) reported a family in which a young girl with JLNS was homozygous for a mutation in the KCNE1 gene (176261.0003), whereas her heterozygous first-degree relatives showed a milder phenotype with partial hearing loss and QT prolongation more in keeping with LQT1.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Congenital sensorineural hearing loss CARDIOVASCULAR Heart \- Prolonged QT interval on EKG \- Syncope \- Torsades de pointes \- Sudden cardiac death MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, Isk-related subfamily, member 1 gene (KCNE1, 176261.0001 ) ▲ Close
| JERVELL AND LANGE-NIELSEN SYNDROME 2 | c0022387 | 0 | omim | https://www.omim.org/entry/612347 | "2019-09-22T16:01:47" | {"doid": ["2842"], "mesh": ["D029593"], "omim": ["612347"], "orphanet": ["90647", "768"], "genereviews": ["NBK1405"]} |
Ethanol is the type of alcohol found in alcoholic beverages. It is a volatile, flammable, colorless liquid that acts as a central nervous system depressant.[1] Ethanol can impair different types of memory.
Ethanol
Alcoholic beverages
## Contents
* 1 Mode of actions
* 1.1 Effects on the hippocampus
* 1.2 Molecular effects on GABA and NMDA receptors
* 1.3 Effects on other brain regions
* 2 Long-term memory
* 2.1 Explicit memory
* 2.2 Implicit memory
* 3 Short-term memory
* 3.1 Brain areas affected by alcohol
* 3.2 Tasks and intoxication findings
* 4 Effects on working memory
* 4.1 In the short term
* 4.2 In the long term
* 5 Prospective memory
* 6 In popular culture
* 7 See also
* 8 References
## Mode of actions[edit]
### Effects on the hippocampus[edit]
Alcohol acts as a general central nervous system depressant, but it also affects some specific areas of the brain to a greater extent than others. Memory impairment caused by alcohol has been linked to the disruption of hippocampal function — particularly affecting gamma-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) neurotransmission which negatively impacts long-term potentiation (LTP).[2] The molecular basis of LTP is associated with learning and memory.[3] Particularly, damage to hippocampal CA1 cells adversely affects memory formation,[4] and this disruption has been linked to dose-dependent levels of alcohol consumption.[5] At higher doses, alcohol significantly inhibits neuronal activity in both the CA1 and CA3 pyramidal cell layers of the hippocampus.[6][7][8] This impairs memory encoding,[9] since the hippocampus plays an important role in the formations of new memories.
A Hippocampal Pyramidal Cell
### Molecular effects on GABA and NMDA receptors[edit]
A GABAA Receptor
Alcohol also acts as a positive allosteric modulator of GABA receptors, specifically type GABAA.[10] Upon activation, these GABA receptors conduct Cl-, resulting in neuronal hyperpolarization. This hyperpolarization decreases the chance of an action potential occurring and thus, it has an inhibitory effect on neurotransmission in the central nervous system. GABAA receptor subtypes vary in their sensitivities to dosage of alcohol consumed. Furthermore, acute alcohol intake promotes GABAergic neurotransmission via the presynaptic release of GABA, the dephosphorylation of GABAA receptors (increasing GABA sensitivity), and the elevation of endogenous GABAergic neuroactive steroids.[11] Protein kinase C (PKC) has been implicated in differentially modulating the response of the GABAA receptor to alcohol, with effects depending on the PKC isozyme.[12] Alcohol effects have also implicated protein kinase A in affecting GABAA receptor function, such as promoting sensitivity.[13] Enhancement of GABAergic transmission due to alcohol consumption can also be brought about by neuroactive steroids, such as allopregnanolone, which act as GABAA receptor agonists.[11][14] Both chronic alcohol consumption and alcohol dependence are correlated with the altered expression, properties, and functions of the GABAA receptor that may contribute to alcohol tolerance.[11] There is still much yet to be discovered about alcohol's specific and varying effects on both the GABAA receptor and its subtypes.
At higher doses, ethanol also affects NMDA receptors (NMDARs) by inhibiting the ion current induced by NMDA, a glutamate receptor agonist.[15] This inhibition of synaptic excitation by alcohol has been shown to be dose-dependent (up to a certain point, after which it did not differ by much).[16] Alcohol appears to produce this inhibition by using a site of the NMDAR that is accessible from the extracellular environment.[17] Therefore, this inhibition of an ion current usually produced by NMDAR activation leads to decreased LTP in hippocampal areas.[18] Alcohol negatively affects LTP to a greater degree in immature versus mature animals.[19] In adolescents, alcohol decreases the expression of both the NMDAR NR2A subunit in the hippocampus and the NR1 subunit in the prefrontal cortex.[20] Studies have also found that a decrease in phosphorylation of 2B subunit in the prefrontal cortex, the hippocampus, the nucleus accumbens, and the striatum.[21] NMDARS may be affected by PKA regulation due to the actions of alcohol.[22] Alcohol's effects on GABAA neurotransmission may indirectly inhibit the activity of the NMDAR, and they may contribute to its blockade of LTP induction; however, alcohol's direct effects on NMDAR alone are sufficient for the inhibition of LTP.[23] The varying dose-dependent response to alcohol relies on the combined interactions and responses of the GABAA receptors, NMDARs, and metabotropic glutamate receptors subtype 5 (mGluR5).[24][25][26] These changes prevent excitatory synaptic transmissions from occurring, affecting synaptic plasticity and, in turn, memory and learning. However, there is still much yet to be elucidated concerning specific molecular mechanisms of how alcohol affects memory formation.
### Effects on other brain regions[edit]
Alcohol also impairs and alters the functioning in the cerebellum, which affects both motor function and coordination.[27] It has a notable inhibitory effect on the neurons of the cerebral cortex, affecting and altering thought processes, decreasing inhibition, and increasing the pain threshold. It also decreases sexual performance by depressing nerve centers in the hypothalamus.[28][29] Alcohol also has an effect on urine excretion via inhibition of anti-diuretic hormone (ADH) secretion of the pituitary gland. Lastly, it depresses breathing and heart rate by inhibiting neuronal functioning of the medulla.[30]
## Long-term memory[edit]
Long-term memory (LTM) has both a long duration and a large capacity.[31] Memories that are stored in LTM can last from a few days to a lifetime.[31] LTM consists of both explicit memory (requiring conscious awareness) and implicit memory (unconscious awareness).[31] Information selected for LTM goes through three processes. First of all, in the encoding stage, information from the senses is incorporated into mental activity in the form of a memory.[31] Secondly, storage involves taking this information and holding it indefinitely in memory.[31] Lastly, retrieval is the ability to recall information from the long-term memory storage. Each of these processes can be affected by alcohol.[31]
Animation: Hippocampus (red)
### Explicit memory[edit]
Explicit memory requires conscious and intentional effort for recall.[31] It includes both episodic memory (for specific events, such as a party) and semantic memory (for general information, such as one's name).[31]
Alcohol impairs episodic encoding, specifically for cued recall, recognition of completed word fragments, and free recall.[32] A blackout is an example of a difficulty in encoding episodic memories due to alcohol. Blackouts are caused by a rapid increase in blood alcohol concentration (BAC) which in turn distorts the neurons in the hippocampus.[33] This distortion impairs a person's ability to form new episodic memories.[33]
High doses of alcohol severely disrupt the storage process of semantic memories.[34] Alcohol was found to impair the storage of novel stimuli but not that of previously learned information.[34] Since alcohol affects the central nervous system, it hinders semantic storage functioning by restricting the consolidation of the information from encoding.[34]
Retrieval of explicit memory is significantly impaired by alcohol. When compared to sober participants, intoxicated participants performed quite poorly on a recall task for everyday events (i.e., episodic memory).[35] Intoxicated participants are also slower to respond in reaction time tasks.[36] Alcohol also impairs retrieval in word recognition tasks.[32] When both encoding and retrieval take place during intoxication, there are surprisingly more impairments for cued recall than for free recall.[32] In terms of gender differences in retrieval processes, females tend to score lower than males on recall tasks when intoxicated.[36]
### Implicit memory[edit]
Implicit memory does not require conscious effort or intention for recall.[31] It occurs when previous experience influences performance on a certain task.[31] This is evident in priming experiments. Implicit memory includes procedural memory, which influences our everyday behaviours, such as riding a bike or tying shoes.[31] People can perform these abilities without even thinking about them, which means procedural memory functions automatically. While retrieval of explicit memory is severely impaired by alcohol, retrieval of implicit memory is not.[35] Intoxicated subjects score higher on recognition tasks (involving implicit memory) than they can on recall tasks (involving explicit memory).[35]
## Short-term memory[edit]
Short-term memory refers to the temporary storage of small amounts of information over short delays.[31] Digit span refers to the proposed number of pieces of information (5-9) that can be held in short-term memory. This is also referred to as the magic number seven – plus or minus two. Any more pieces of information than this, and newer items replace previous items.[37] Alcohol intoxication has been found to have dissociative effects on both short-term memory and cognitive functioning.[38][39]
Anterior Cingulate Cortex (yellow)
Animation: Parietal Lobe (red)
### Brain areas affected by alcohol[edit]
Alcohol affects the functioning of the brain. Neurochemical changes occurring in the anterior cingulate are correlated with altered short-term memory functions in the brains of young alcoholic men.[40] fMRIs of alcohol-dependent women displayed significantly less blood oxygen in the frontal and parietal regions, especially in the right hemisphere.[41] This is supported by findings of short-term memory impairment by lesions of both the parietal lobe[42] and the prefrontal cortex.[43] Associations between Third ventricle volume and cognitive performance on memory tests have been found in alcoholics.[44] Specifically, increases in third ventricular volume correlate with a decline in memory performance.[44]
### Tasks and intoxication findings[edit]
Short-term memory is commonly tested with visual tasks. Short-term memory, especially for non-verbal and spatial material, are impaired by intoxication.[44] Alcohol decreases iconic memory (a type of visual short-term memory).[45] With BACs between 80–84 mg/dl, more intrusion errors occur in a delayed recall task compared to a control group.[46] Intrusion errors, which represent reflective cognitive functioning, occur when irrelevant information is produced. Alcoholics have less control of inhibiting intrusions.[46] Acute alcohol intoxication in social drinkers caused more intrusion errors in delayed recall tasks than in immediate free recall tasks.[46] Acute alcohol intoxication increases the susceptibility to interference, which allows for more intrusion errors when there is a short delay.[46] Free recall (given list of words then asked to recall list) is significantly lower and therefore impaired by alcohol intoxication.[47][48] Encoding deficits were found in verbal free recall and recognition tasks under the influence of alcohol.[49] A discrimination task found significant alcohol-related impairments both in depth perception and in visual short-term memory.[50] State-dependent learning and relearning studies in male heavy drinkers demonstrate that the condition of intoxication while learning and sobriety when tested caused a performance deficit in free recall tasks.[51] These findings are supportive of alcohol-induced storage deficits (not retrieval deficits).[51] The effects of acute alcohol consumption on visual short-term memory, stereoscopic depth perception, and attention were all studied. A 33% alcohol condition showed significant impairments both in depth perception and in visual short-term memory (assessed by the vernier discrimination task).[52]
Working Memory Model. Alcohol intoxication can disrupt rehearsal strategies which may involve the phonological loop and/or the visuospatial sketchpad.
## Effects on working memory[edit]
Working memory allows one to keep things in mind while simultaneously performing complex tasks.[31] It involves a system for both the temporary storage and the manipulation of information, subsequently forming a crucial link between perception and controlled action.[53] Evidence suggests that working memory involves three components: the central executive which controls attention, the visuo-spatial sketchpad which holds and manipulates spatial information, and the phonological loop which performs a similar function for auditory and speech-based information.[53]
### In the short term[edit]
Alcohol consumption has substantial, measurable effects on working memory, although these effects vary greatly between individual responses. Not much is really known about the neural mechanisms that underlie these individual differences.[54] It is also found that alcohol impairs working memory by affecting mnemonic strategies and executive processes rather than by shrinking the basic holding capacity of working memory. Isolated acute-moderate levels of alcohol intoxication do not physically alter the structures that are critical for working memory function, such as the frontal cortex, the parietal cortex, the anterior cingulate, and parts of the basal ganglia.[38] One finding regarding the effects of alcohol on working memory points out that alcohol reduces working memory only in individuals with a high baseline working memory capacity,[55] which suggests that alcohol might not uniformly affect working memory in many different individuals. Alcohol appears to impair the capacity of working memory to modulate response inhibition.[55] Alcohol disinhibits behaviour, but it only does so in individuals with a low baseline working memory capacity.[55] An interesting finding is that the incentive to perform well with working memory measurement tasks while under the influence of alcohol 'does, in fact, have some effect on working memory, as it boosts scores in the rate of mental scanning and reaction time to stimulus; however, it did not reduce the number of errors as opposed to subjects with no incentive to perform well.[56] Even acute alcohol intoxication (a blood alcohol concentration of 0.08-0.09%) produces a substantial impairment of working memory processes that require mnemonic rehearsal strategies.[38] It is less likely for alcohol to impair a working memory task that does not rely on memory rehearsal or associated mnemonic strategies.[38] Because of this, working memory is very susceptible to falter when an individual participates in tasks involving retention concerning both auditory and visual sequences.[38] An interesting example of this is the failure of guitarists or other musicians performing concerts to cue in on auditory patterns and make it known that their performance is hindered by intoxication, whereas professional basketball (a less sequence-heavy activity for working memory) standout Ron Artest recently admitted in an interview with Sporting News to drinking heavily during half-time early in his career and the fact that it had little — if not any recognizable — effect on his working memory. His former coach Fran Fraschilla has gone on record saying:[citation needed]
> "It's a surprise because every day at practice, he came out in a mood to play. He came out in a basketball rage. He was fully committed; he wanted to let our upperclassmen know that he was the alpha male. It never came up that he had any sort of a problem with alcohol. This is the first I've heard of it."
### In the long term[edit]
This article needs more medical references for verification or relies too heavily on primary sources, specifically: primary sources should be replaced; consider using PMID 23905882 and PMID 28470828. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed.
Find sources: "Effects of alcohol on memory" – news · newspapers · books · scholar · JSTOR (July 2017)
Alcohol has been shown to have just some long-term effects on working memory. Findings have shown that in order for working memory to be substantially affected, long-term heavy drinking must be sustained over a long period of time, as up to one drink per day does not impair any cognitive function and may actually decrease the risk of a cognitive decline.[57] Furthermore, chronic alcoholism is associated with the impairment in both sustained attention and visual working memory. As a result, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks. This is assumed to be subserved by regions of the prefrontal cortex.[58] While it may not serve as a surprise that chronic alcoholism is linked to any decreased cognitive function such as working memory, one surprising finding is not only that even moderate levels of alcohol consumption during pregnancy were shown to have an adverse effect on the child's working memory when tested at 7.5 years of age, but also that working memory may be the most important aspect of attention that is adversely affected by prenatal alcohol exposure.[59]
## Prospective memory[edit]
Prospective memory involves remembering to carry out an intended action in the future without an explicit reminder.[31] Alcohol has been found to impair this ability. Chronic heavy alcohol users report significantly more prospective forgetting compared to low-dose and alcohol-free controls.[60] The Prospective Memory Questionnaire assesses short-term habitual prospective memory, long-term episodic prospective memory, and internally cued prospective memory.[60] Chronic heavy alcohol users reported significantly greater deficits for all three aspects of prospective memory.[60] Individuals that report heavy alcohol use report 24% more difficulties with prospective memory than those who report that they are light drinkers and 30% more difficulties than those who report that they never drink.[61] The effects of alcohol on prospective memory can also be assessed in the laboratory by simulating prospective memory tasks that individuals face in everyday life. Individuals who are given 0.6 g/kg alcohol prior to performing prospective memory tasks do significantly poorer than a placebo group.[62] Alcohol can damage the prefrontal and frontal areas of the brain, and this may be responsible for prospective memory impairments since prospective memory performance is highly correlated with frontal executive functions.[60]
## In popular culture[edit]
The memory inhibiting effects of alcohol are often a prominent topic in popular culture. It appears in movies, books, and television shows. Several movies show characters drinking alcohol to the point of memory loss and awakening the next morning with a host of problems due to actions they performed while intoxicated.
One example is The Hangover, where three groomsmen lose the groom during a bachelor party in Las Vegas, so they retrace their steps to find him.[63] The characters still had functioning implicit/procedural memory, which allowed them to carry out the many acts they performed that night, but their episodic memory was impaired and thus they had no recollection of the events occurring. In addition to alcohol the characters were also under the influence of flunitrazepam.
Another movie is What Happens in Vegas. After an intoxicated night in "Sin City," two people wake-up to find they got married.[64]
Songs such as Waking Up in Vegas by Katy Perry[65] and Last Name by Carrie Underwood[66] also depict characters waking up and not remembering the night before due to alcohol consumption.
By some accounts, popular culture makes light of the memory problems that can result from alcohol consumption.
The court case R. v. Daviault [1994] concerned the viability of a legal defense based on intoxication.
Law and Order: Special Victims Unit; in season 11 episode 4, Hammered, a recovering alcoholic was coerced to drink by a business partner and later wakes up to a dead woman in his bed.
## See also[edit]
* Confabulation
* Wernicke–Korsakoff syndrome
## References[edit]
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38. ^ a b c d e Saults, J.S.; Cowan, N.; Sher, K.J.; Moreno, M.V. (2007). "Differential short Term effects of Alcohol on Working Memory: Distinguishing Multiple Processes". Experimental and Clinical Psychopharmacology. 15 (6): 576–587. doi:10.1037/1064-1297.15.6.576. PMC 2658822. PMID 18179311.
39. ^ Bates, M. E. (2006). "Acute alcohol effects on repetition priming and word recognition memory with equivalent memory cues". Brain Cogn. 60 (2): 118–127. doi:10.1016/j.bandc.2005.07.009. PMID 16377048. S2CID 41154421.
40. ^ Eun, L.; Dong-Pyo, J.; Jae-Jin, K.; Suk Kyoon, A.; Sangjin, P.; In-Young, K.; Sun, I.K.; Kang-Jun, Y.; Kee, N. (2007). "Alteration of brain metabolites in young alcoholics without structural changes". NeuroReport. 18 (14): 1511–1514. doi:10.1097/WNR.0b013e3282ef7625. PMID 17712285. S2CID 20409183.
41. ^ Tapert, S.F.; Brown, G.G.; Kindermann, S.S.; Cheung, E.H.; Frank, L.R.; Brown, S.A. (2006). "fMRI measurement of brain dysfunctions in alcohol-dependent young women". Alcoholism: Clinical and Experimental Research. 25 (2): 26–245.
42. ^ Warrington, E. K.; James, M.; Maciejewski, C. (1986). "The WAIS as a lateralizing and localizing diagnostic instrument: A study of 656 patients with unilateral cerebral lesions". Neuropsychologia. 24 (2): 223–239. doi:10.1016/0028-3932(86)90055-2. PMID 3714027. S2CID 33190123.
43. ^ Goldman-Rakic, P. S. (1992). "Working memory and the mind". Scientific American. 267 (3): 110–117. Bibcode:1992SciAm.267c.110G. doi:10.1038/scientificamerican0992-110. PMID 1502513.
44. ^ a b c Sullivan, E.V.; Rosenbloom, M.J.; Lim, K.O.; Pfefferbam, A. (2000). "Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: relationships to changes in brain structure". Neuropsychology. 14 (2): 178–188. doi:10.1037/0894-4105.14.2.178. PMID 10791858.
45. ^ Subhan (1983). "The effects of midazolam in conjunction with alcohol in iconic memory and free recall". Neuropsychobiology. 9 (4): 230–234. doi:10.1159/000117970. PMID 6646395.
46. ^ a b c d Ray, S.; Bates, M.E. (2007). "Acute effects of alcohol on intrusion errors in free recall tasks". International Journal on Disability and Human Development. 6 (2): 201–205. doi:10.1515/ijdhd.2007.6.2.201. S2CID 147314783.
47. ^ Hashtroudi, S.; Parker, DeLisi; Wyatt, R.J.; Mutter, S.A. (1984). "Intact retention in acute alcohol amnesia". Journal of Experimental Psychology: Learning, Memory, and Cognition. 10 (1): 156–163. doi:10.1037/0278-7393.10.1.156. PMID 6242732.
48. ^ Tracy, J.I.; Bates, M.E. (1999). "The selective effects of alcohol on automatic and effortful memory processes". Neuropsychology. 13 (2): 282–290. doi:10.1037/0894-4105.13.2.282. PMID 10353377.
49. ^ Williams, H.L.; Rundell, U.H. (1984). "Effect of alcohol on recall and recognition as functions of processing levels". Journal of Studies on Alcohol. 45 (1): 10–15. doi:10.15288/jsa.1984.45.10. PMID 6700218.
50. ^ Wegner, A.J.; Fahle, M. (1999). "Alcohol and visual performance". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 23 (3): 465–482. doi:10.1016/S0278-5846(99)00009-3. PMID 10378230. S2CID 24469283.
51. ^ a b Miller, M.E.; Adesso, V.J.; Fleming, J.P.; Gino, A.; Lauerman, R. (1978). "Effects of alcohol on the storage and retrieval processes of heavy social drinkers". Journal of Experimental Psychology: Human Learning and Memory. 4 (3): 246–255. doi:10.1037/0278-7393.4.3.246. PMID 660094.
52. ^ Wegner, A.J.; Fahle, M. (1999). "Alcohol and visual performance". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 23 (3): 465–482. doi:10.1016/S0278-5846(99)00009-3. PMID 10378230. S2CID 24469283.
53. ^ a b Baddeley, A. (1998) Comptes Rendus de l'Académie des Sciences – Série III, 321(2-3), 167-173.
54. ^ Paulus, Martin P, Tapert, Susan F, Pulido, Carmen, & Schuckit, Marc A. (2006). Alcohol attenuates load-related activation during a working memory task: Relation to level of response to alcohol. Dept of Psychiatry, University of California. PP 2
55. ^ a b c Finn, P.R.; Justus, A.; Mazas, C.; Steinmetz, J.E. (1999). "Working memory, executive processes and the effects of alcohol on Go/No-Go learning: testing a model of behavioral regulation and impulsivity". Psychopharmacology. 146 (4): 465–472. doi:10.1007/pl00005492. PMID 10550497. S2CID 23894568.
56. ^ Grattan-Miscio, K.E. and Vogel-Sprott, M. (2005) Effects of alcohol and performance incentives on immediate working memory. Springer Berlin / Heidelberg, 188-196
57. ^ Stampfer MJ, Kang JH, Chen J, Cherry R, Grodstein F (2005). "Effects of moderate alcohol consumption on cognitive function in women". N Engl J Med. 352 (3): 245–253. doi:10.1056/NEJMoa041152. PMID 15659724.
58. ^ Pfefferbaum A, Desmond JE, Galloway C, Menon V, Glover GH, Sullivan EV (July 2001). "Reorganization of frontal systems used by alcoholics for spatial working memory: an fMRI study". NeuroImage. 14 (1 pt 1): 7–20. doi:10.1006/nimg.2001.0785. PMID 11525339. S2CID 508770.
59. ^ Burden MJ, Jacobson SW, Sokol RJ, Jacobson JL (March 2005). "Effects of prenatal alcohol exposure on attention and working memory at 7.5 years of age". Alcohol Clin Exp Res. 29 (3): 443–52. doi:10.1097/01.ALC.0000156125.50577.EC. PMID 15770121.
60. ^ a b c d Heffernan, T.M.; Moss, M; Ling, J. (2002). "Subjective Ratings of Prospective Memory Deficits in Chronic Heavy Alcohol Users". Alcohol and Alcoholism. 37 (3): 269–271. doi:10.1093/alcalc/37.3.269. PMID 12003916.
61. ^ Ling, J.; Heffernan, T.M.; Buchanan, T.; Rodgers, J.; Scholey, A.B.; Parrot, A.C. (2003). "Effects of Alcohol on Subjective Ratings of Prospective and Everyday Memory Deficits" (PDF). Alcoholism: Clinical and Experimental Research. 27 (6): 970–974. doi:10.1097/01.alc.0000071741.63467.cb. PMID 12824818.
62. ^ Leitz, J.R.; Morgan, C. A. J.; Bisby, J.A.; Rendell, P.G.; Curran, V.H. (2009). "Global impairment of prospective memory following acute alcohol". Psychopharmacology. 205 (3): 379–387. doi:10.1007/s00213-009-1546-z. PMID 19440700. S2CID 21923512.
63. ^ "The Hangover" (2009). Retrieved from https://www.imdb.com/title/tt1119646/.
64. ^ "What Happens in Vegas" (2008). Retrieved from https://www.imdb.com/title/tt1033643/plotsummary.
65. ^ "YouTube – Waking Up in Vegas Lyrics – Katy Perry" (2009). Retrieved from https://www.youtube.com/watch?v=06Qf7GdAF70
66. ^ "YouTube – Carrie Underwood – Last Name" (2009). Retrieved from https://www.youtube.com/watch?v=f27zNlmRMWU
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| Effects of alcohol on memory | c0001940 | 1 | wikipedia | https://en.wikipedia.org/wiki/Effects_of_alcohol_on_memory | "2021-01-18T18:59:58" | {"mesh": ["D000425"], "umls": ["C0001940"], "wikidata": ["Q5347361"]} |
Argentine hemorrhagic fever
SpecialtyInfectious disease
Argentine hemorrhagic fever (AHF) or O'Higgins disease, also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus[1] (an arenavirus, closely related to the Machupo virus, causative agent of Bolivian hemorrhagic fever). Its vector is the drylands vesper mouse, a rodent found in Argentina and Paraguay.
## Contents
* 1 Epidemiology
* 2 Clinical aspects
* 2.1 Vaccine
* 3 Weaponization
* 4 References
* 4.1 Notes
* 4.2 Bibliography
* 5 External links
## Epidemiology[edit]
The disease was first reported in the town of O'Higgins [es] in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known.[2] Various theories about its nature were proposed: it was Weil's disease, leptospirosis, caused by chemical pollution.[2] It was associated with fields containing stubble after the harvest, giving it another of its names.
The endemic area of AHF covers approximately 150,000 km², compromising the provinces of Buenos Aires, Córdoba, Santa Fe and La Pampa, with an estimated risk population of 5 million.
The vector, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus), suffers from chronic asymptomatic infection, and spreads the virus through its saliva and urine. Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age.
## Clinical aspects[edit]
AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks.
If untreated, the mortality of AHF reaches 15–30%. The specific treatment includes plasma of recovered patients, which, if started early, is extremely effective and reduces mortality to 1%.[3]
Ribavirin also has shown some promise in treating arenaviral diseases.
The disease was first detected in the 1950s in the Junín Partido in Buenos Aires, after which its agent, the Junín virus, was named upon its identification in 1958. In the early years, about 1,000 cases per year were recorded, with a high mortality rate (more than 30%). The initial introduction of treatment serums in the 1970s reduced this lethality.
### Vaccine[edit]
This section needs to be updated. Please update this article to reflect recent events or newly available information. (August 2011)
The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. The Junín vaccine has also shown cross-reactivity with Machupo virus and, as such, has been considered as a potential treatment for Bolivian hemorrhagic fever.
Candid #1 has been applied to adult high-risk population and is 95.5% effective.[4] Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005).
On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine.[5] Details of the vaccine were published in 2011,[4] and a protocol for production of the vaccine was published in 2018.[6] Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug; the Argentine government committed itself to manufacture and sponsor C#1 vaccine.[4]
## Weaponization[edit]
Argentine hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program.[7] The Soviet Union also conducted research and developing programs on the potential of the hemorragic fever as a biological weapon.[8]
## References[edit]
### Notes[edit]
1. ^ Grant, A.; Seregin, A.; Huang, C.; Kolokoltsova, O.; Brasier, A.; Peters, C.; Paessler, S. (2012). "Junín Virus Pathogenesis and Virus Replication". Viruses. National Institutes of Health. 4 (10): 2317–2339. doi:10.3390/v4102317. PMC 3497054. PMID 23202466. "Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality."
2. ^ a b Graciela Agnese: “Una rara enfermedad alarma a la modesta población de O’Higgins” Análisis del discurso de la prensa escrita sobre la epidemia de Fiebre Hemorrágica Argentina de 1958, Revista de Historia & Humanidades Médicas Vol. 3 Nº 1, Julio 2007, www.fmv-uba.org.ar/histomedicina(in Spanish)
3. ^ van Griensven, Johan; De Weiggheleire, Anja; Delamou, Alexandre; Smith, Peter G.; Edwards, Tansy; Vandekerckhove, Philippe; Bah, Elhadj Ibrahima; Colebunders, Robert; Herve, Isola; Lazaygues, Catherine; Haba, Nyankoye; Lynen, Lutgarde (2015). "The Use of Ebola Convalescent Plasma to Treat Ebola Virus Disease in Resource-Constrained Settings: A Perspective From the Field". Clinical Infectious Diseases. 62 (1): 69–74. doi:10.1093/cid/civ680. ISSN 1058-4838. PMC 4678103. PMID 26261205.
4. ^ a b c Ambrosio A, Saavedra M, Mariani M, Gamboa G, Maiza A (2011). "Argentine hemorrhagic fever vaccines". Hum Vaccin. 7 (6): 694–700. doi:10.4161/hv.7.6.15198. PMID 21451263.CS1 maint: multiple names: authors list (link)
5. ^ Enria DA1, Ambrosio AM, Briggiler AM, Feuillade MR, Crivelli E (2010). "Vacuna contra la fiebre hemorrágica argentina Candid#1 producida en la Argentina. Inmunogenicidad y seguridad" [Candid#1 vaccine against Argentine hemorrhagic fever produced in Argentina. Immunogenicity and safety]. MEDICINA (Buenos Aires). 70: 215–222.CS1 maint: uses authors parameter (link) Article in Spanish with abstract in English.
6. ^ Ambrosio, Ana María; Mariani, Mauricio Andrés; Maiza, Andrea Soledad; Gamboa, Graciela Susana; Fossa, Sebastián Edgardo; Bottale, Alejando Javier (2018). "Protocol for the Production of a Vaccine Against Argentinian Hemorrhagic Fever". Hemorrhagic Fever Viruses. Methods in Molecular Biology. 1604. pp. 305–329. doi:10.1007/978-1-4939-6981-4_24. ISBN 978-1-4939-6980-7. ISSN 1064-3745. PMID 28986845.
7. ^ "Chemical and Biological Weapons: Possession and Programs Past and Present", James Martin Center for Nonproliferation Studies, Middlebury College, April 9, 2002, accessed November 14, 2008.
8. ^ Wheelis, Mark; Rózsa, Lajos & Dando, Malcolm: Deadly cultures: biological weapons since 1945. Harvard University Press, 2006. Page 141. ISBN 0-674-01699-8
### Bibliography[edit]
* Argentine Ministry of Health and Environment, 8 October 2006. Argentina fabricará vacuna contra la fiebre hemorrágica.
* Clarín, 29 September 2006. La vacuna contra el mal de los rastrojos ya se puede elaborar en el país.
* TodoAmbiente \- Infectious diseases.
* ANLIS. Fiebre hemorrágica argentina.
## External links[edit]
Classification
D
* ICD-10: A96.0
* ICD-9-CM: 078.7
* MeSH: D018051
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| Argentine hemorrhagic fever | c0019097 | 2 | wikipedia | https://en.wikipedia.org/wiki/Argentine_hemorrhagic_fever | "2021-01-18T18:30:10" | {"mesh": ["D006478"], "umls": ["C0019097"], "icd-9": ["078.7"], "icd-10": ["A96.0"], "orphanet": ["319223"], "wikidata": ["Q2583514"]} |
Bilateral frontalparietal polymicrogyria
Other namesBFPP
Bilateral frontoparietal polymicrogyria is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyri have an increase number of folds and smaller folds than usual.[1] Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow sulci and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity.[2] It is also found that GPR56 plays a role in cortical pattering.[3]
## Contents
* 1 Presentation
* 1.1 Associated conditions
* 2 Genetics
* 2.1 Mode of inheritance
* 3 Diagnosis
* 3.1 Methods/tests
* 4 Treatment
* 5 Prognosis
* 6 See also
* 7 References
* 8 External links
## Presentation[edit]
Left:Normal Middle:polymicrgyria Right:Lissencephaly
* Symptoms: Developmental delay, Psychomotor delay, Mental retardation - moderate to severe, Exaggerated reflexes and Seizures (epilepsy)
### Associated conditions[edit]
BFPP is a cobblestone-like cortical malformation of the brain. Disruptions of cerebral cortical development due to abnormal neuronal migration and positioning usually lead to cortical disorders, which includes cobblestone lissencephaly. Cobblestone lissencephaly is typically seen in three different human congenital muscular dystrophy syndromes: Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease.[4] In cobblestone lissencephaly, the brain surface actually has a bumpy contour caused by the presence of collections of misplaced neurons and glial cells that have migrated beyond the normal surface boundaries of the brain. Sometimes regions populated by these misplaced cells have caused a radiologic misdiagnosis of polymicrogyria. However, the presence of other abnormalities in these cobblestone lissencephaly syndromes, including ocular anomalies, congenital muscular dystrophy, ventriculomegaly, and cerebellar dysplasia, usually distinguishes these disorders from polymicrogyria.[5] There are no anatomopathologic studies that have characterized the pattern of cortical laminar alterations in patients with GPR56 gene mutations, but it has been suggested that the imaging characteristics of BFPP, including myelination defects and cerebellar cortical dysplasia, are reminiscent of those of the so-called cobblestone malformations (muscle-eye-brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain.[6]
Lissencephaly ("smooth brain") is the extreme form of pachygyria. In lissencephaly, few or no sulci are seen on the cortical surface, resulting in a broad, smooth appearance to the entire brain. Lissencephaly can be radiologically confused with polymicrogyria, particularly with low-resolution imaging, but the smoothness and lack of irregularity in the gray-white junction, along with markedly increased cortical thickness, distinguishes lissencephaly.
GPR56 mutation also can cause a severe encelphalopathy which is associated with electro clinical features of the Lennox-Gastaut syndrome. Lennox-Gastaut syndrome can be cryptogenic or symptomatic, but the symptomatic forms have been associated with multiple etiologies and abnormal cortical development. BFPP caused by GPR56 mutations is a manifestation of a malformation of cortical development that causes Lennox-Gastaut Syndrome.[7]
Polymicrogyria is often confused with pachygyria; therefore, it needs to be distinguished from pachygyria, a distinct brain malformation in which the surface folds are excessively broad and sparse. Pachygyria and polymicrogyria may look similar on low-resolution neuroimaging such as CT because the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth in both conditions. This is why higher resolution neuroimaging, such as an MRI, is necessary for proper diagnosis.[5]
Lissencephaly:Brain MRI, T1 weighted, transverse plane, that shows lyssencephaly, manifested as scarce and wide circumvolutions, mostly in the occipital, parietal and temporal lobes. As aggregated findings, there is ventriculomegaly, no true Sylvian fissure, too thick gray matter and ectopic gray matter in the white matter.
## Genetics[edit]
The GPR56 is grouped in the B family of GPCRs. This GPCR group have long N termini characterized by an extracellular “cysteine box” and hydrophilic, potentially mucin-rich. The cysteine box contains four conserved cysteines and two tryptophans arranged in a specific fashion (C-x2-W-x6-16-W-x4-C-x10-22-C-x-C) just before the first transmembrane domain and serves as a cleavage site in some members of this group of G protein–coupled receptors.[8] Although, the molecular and cellular mechanisms of how GPR56 regulates brain development remain largely unknown.[9] These types of receptors play an essential role in biological processes including embryonic development, central nervous system (CNS), immune system, and tumorigenesis.[10]
GPCR classification
### Mode of inheritance[edit]
Parents of a proband
* The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
* Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
* At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
* Once an at-risk sibling is known to be unaffected, the risk of his/her being a carrier is 2/3.
* Heterozygotes (carriers) are asymptomatic.
Offspring of a proband
* Offspring of a proband are obligate heterozygotes and will therefore carry one mutant allele.
* In populations with a high rate of consanguinity, the offspring of a person with GPR56-related BFPP and a reproductive partner who is a carrier of GPR56-related BFPP have a 50% chance of inheriting two GPR56 disease-causing alleles and having BFPP and a 50% chance of being carriers.
Other family members of a proband.
* Each sibling of the proband's parents is at a 50% risk of being a carrier[5]
## Diagnosis[edit]
Diagnostic criteria for a BFPP patient entails a heterozygous genotype for a deletion of chromosome 16q12.1-q21 region, including GPR56 gene.[11] To date the only gene known to be associated with polymicrogyria is GPR56. Testing for GPR56-related bilateral frontoparietal polymicrogyria is available clinically. Mutations in GPR56 hinders Collagen III, its specific ligand, to bind in a developing brain. To date, a total of fourteen BFPP-associated mutations have been identified, including one deletion, two splicing, and eleven missense mutations. Two mutations in the GPCR proteolytic site (GPS) domain, C346S and W349S, cause a brain malformation through trapping the mutated proteins in the endoplasmic reticulum.[12]
GPR56 are a part of the B class of the GPCR family, the largest cell surface gene family in the human genome. Within this family there are different types of bio-active molecules that transduce their signal to the intracellular compartment via interaction with this type of receptor. Children often present with developmental delay, spasticity, or seizures; they are also often microcephalic. Some patients with polymicrogyria go undiagnosed until they produce children with the disorder who have more severe manifestations. Retrospectively, these patients will often report some difficulty in their medical or educational history.[13] BFPP patients demonstrate mental retardation, language impairment, motor developmental delay, and seizure disorders such as epilepsy.[14] The association of epilepsy is in approximately 50% to 85% of affected BFPP patients.
The clinical manifestations of polymicrogyria are stable neurologic deficits:
In the mildest form, polymicrogyria is unilateral with only one small region of the brain involved; neurologic problems may not be evident.
In more severe forms, focal motor, sensory, visual, or cognitive problems may be present, depending on the location of the brain region affected.
In the most severe forms, polymicrogyria is bilateral and generalized, resulting in severe intellectual disability, cerebral palsy, and refractory epilepsy.
Individuals with the milder forms of polymicrogyria survive into adulthood, while those with the most severe forms, such as BFPP, may die at a young age as a result of such complications as seizures or pneumonia.[5] The prevalence of isolated polymicrogyria is unknown. Researchers believe that it may be relatively common overall, although BFPP is probably rare.[15]
* Radiological findings (MRI) demonstrated symmetric generalized polymicrogyria with decreasing anterior-posterior gradient, most prominent in frontoparietal cortex.[5]
* Numerous gyrus on the cortex
* Small gyri and sulci
* Thin cortex
### Methods/tests[edit]
This child presented with seizures. The coronal true inversion recovery sequence shows thickened and disordered cortex in superior frontal and cingulate gyri bilaterally (arrow). There are small convolutions visible at the corticomedullary junction. The appearance is that of cortical dysplasia, with polymicrogyria more likely than pachygyria due to the small convolutions visible. There are also small foci of grey matter signal in the corpus callosum, deep to the dysplastic cortex (double arrows). These probably represent areas of grey matter heterotopia.
There are different tests or methods used to determine GPR56 expression or visuals of the brain to analyze the specific sections that are affected. These tests for example, using animals such as mice, RNAi, Behavioral assay, Electron microscopy, CT scan, or MRI demonstrate different results that concludes an affected BFPP patient.[16] MRI's reveal either irregularity to the cortical surface suggestive of multiple small folds or an irregular, scalloped appearance of the gray matter-white matter junction.
Neuroimaging The diagnosis of polymicrogyria is typically made by magnetic resonance imaging (MRI) since computed tomography (CT) and other imaging methods generally do not have high enough resolution or adequate contrast to identify the small folds that define the condition. The cerebral cortex often appears abnormally thick as well because the multiple small gyri are fused, infolded, and superimposed in appearance.[5]
Neuropathology Gross neuropathologic examination reveals a pattern of complex convolutions to the cerebral cortex, with miniature gyri fused and superimposed together, often resulting in an irregular brain surface. The cortical ribbon can appear excessively thick as a result of the infolding and fusion of multiple small gyri.[5]
Microscopic examination demonstrates that the cerebral cortex is in fact abnormally thin and has abnormal lamination; typically the cortex is unlayered or has four layers, in contrast to the normal six layers. The most superficial layers between adjacent small gyri appear fused, with the pia (layer of the meninges) bridging across multiple gyri. Prenatal diagnosis for BFPP is also available for pregnancies at risk if the GPR56 mutations have been identified in an affected family member.[5]
## Treatment[edit]
Treatment plans will vary depending on the severity of the condition and its evidences in each patient. Areas that will probably need to be evaluated and assessed include speech, vision, hearing and EEG. Treatment measures may include physical therapy, occupational therapy, Speech therapy, anti-seizure drugs and orthotic devices. Surgery may be needed to assuage spastic motor problems. Various supportive measures such as joint contractures that could prevent complications. Genetic counseling may also be recommended[17]
## Prognosis[edit]
Once the diagnosis of polymicrogyria has been established in an individual, the following approach can be used for discussion of prognosis:
A pregnancy history should be sought, with particular regard to infections, trauma, multiple gestations, and other documented problems. Screening for the common congenital infections associated with polymicrogyria with standard TORCH testing may be appropriate. Other specific tests targeting individual neurometabolic disorders can be obtained if clinically suggested.
The following may help in determining a genetic etiology:
Family history
It is important to ask for the presence of neurologic problems in family members, including seizures, cognitive delay, motor impairment, pseudobulbar signs, and focal weakness because many affected family members, particularly those who are older, may not have had MRI performed, even if these problems came to medical attention. In addition, although most individuals with polymicrogyria do present with neurologic difficulties in infancy, childhood, or adulthood, those with mild forms may have no obvious deficit or only minor manifestations, such as a simple lisp or isolated learning disability. Therefore, if a familial polymicrogyria syndrome is suspected, it may be reasonable to perform MRI on relatives who are asymptomatic or have what appear to be minor findings. The presence of consanguinity in a child's parents may suggest an autosomal recessive familial polymicrogyria syndrome.
Physical examination
A general physical examination of the proband may identify associated craniofacial, musculoskeletal, or visceral malformations that could indicate a particular syndrome. Neurologic examination should assess cognitive and mental abilities, cranial nerve function, motor function, deep tendon reflexes, sensory function, coordination, and gait (if appropriate).[5]
Genetic testing
## See also[edit]
* Epilepsy Phenome/Genome Project
## References[edit]
1. ^ "Bilateral Frontoparietal Polymicrogyria (BFPP)." Welcome to the Research View. N.p., n.d. Web. 05 Nov. 2012. <http://www.neuroscienceandgenetics.it/syndrome/bilateral-frontoparietal-polymicrogyria-bfpp>.
2. ^ Bahi-Buisson, N., K. Poirier, N. Boddaert, C. Fallet-Bianco, N. Specchio, E. Bertini, O. Caglayan, K. Lascelles, C. Elie, J. Rambaud, M. Baulac, I. An, P. Dias, V. Des Portes, M. L. Moutard, C. Soufflet, M. El Maleh, C. Beldjord, L. Villard, and J. Chelly. "GPR56-related Bilateral Frontoparietal Polymicrogyria: Further Evidence for an Overlap with the Cobblestone Complex." Brain 133.11 (2010): 3194-209. Print
3. ^ Piao, Xianhua, and Christopher A. Walsh. "A Novel Signaling Mechanism in Brain Development." Pediatric Research 56.3 (2004): 309-10. Print.
4. ^ Lin, Dr. Hsi-Hsien. Personal Interview. 29 October 2012.
5. ^ a b c d e f g h i Chang B, Walsh CA, Apse K, et al. Polymicrogyria Overview. 2005 Apr 18 [Updated 2007 Aug 6]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1329/
6. ^ Parrini, Elena, Anna Rita Ferrari, Thomas Dorn, Christopher A. Walsh, and Renzo Guerrini. "Bilateral Frontoparietal Polymicrogyria, Lennox-Gastaut Syndrome, Andgene Mutations." Epilepsia 50.6 (2009): 1344-353. Print.
7. ^ Parriniy, E., Ferrariz A.R., Dorn T., Walsh C.A., Guerrini, R., Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations, Epilepsia, Volume 50 Issue 6, Pages 1344–1353, 2009.
8. ^ Piao, X., Chang, B. S., Bodell, A., Woods, K., BenZeev, B., Topcu, M., Guerrini, R., Goldberg-Stern, H., Sztriha, L., Dobyns, W. B., Barkovich, A. J. and Walsh, C. A. (2005), Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol., 58: 680–687. doi: 10.1002/ana.20616
9. ^ Luo, R., S.-J. Jeong, Z. Jin, N. Strokes, S. Li, and X. Piao. "G Protein-coupled Receptor 56 and Collagen III, a Receptor-ligand Pair, Regulates Cortical Development and Lamination." Proceedings of the National Academy of Sciences 108.31 (2011): 12925-2930. Print.
10. ^ Chiang NY, Hsiao CC, Huang YS, Chen HY, Hsieh IJ, et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J Biol Chem. 2011;286:14215–14225
11. ^ Borgatti, Renato, Susan Marelli, Laura Bernardini, Antonio Novelli, Anna Cavallini, Alessandra Tonelli, Maria Teresa Bassi, and Bruno Dallapiccola. "Bilateral Frontoparietal Polymicrogyria (BFPP) Syndrome Secondary to a 16q12.1-q21 Chromosome Deletion Involving GPR56 Gene." Clinical Genetics 79 (2009): 573-76. Print.
12. ^ Singer K, Luo R, Jeong S, Piao X. "GPR56 and the Developing Cerebral Cortex: Cells, Matrix, and Neuronal Migration." Molecular Neurobiology 2012. doi:10.1007/s12035-012-8343-0
13. ^ "Polymicrogyria." MedLink. N.p., 1 May 2011. Web. 28 Nov. 2012. <http://www.medlink.com/medlinkcontent.asp>
14. ^ Jeong, S.-J., Luo, R., Li, S., Strokes, N. and Piao, X. (2012), Characterization of G protein-coupled receptor 56 protein expression in the mouse developing neocortex. J. Comp. Neurol., 520: 2930–2940. doi: 10.1002/cne.23076
15. ^ "Polymicrogyria." Genetics Home Reference. N.p., 12 Nov. 2012. Web. 18 Nov. 2012. <http://ghr.nlm.nih.gov/condition/polymicrogyria>.
16. ^ Koirala, S., Z. Jin, X. Piao, and G. Corfas. "GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development." Journal of Neuroscience 29.23 (2009): 7439-449
17. ^ Guerrini, R., W. Dobyns, and A. Barkovich. "Abnormal Development of the Human Cerebral Cortex: Genetics, Functional Consequences and Treatment Options." Trends in Neurosciences 31.3 (2008): 154-62. Print.
## External links[edit]
Classification
D
* OMIM: 606854
* MeSH: C564652
* DiseasesDB: 33974
External resources
* Orphanet: 101070
* Bilateral Frontalparietal Polymicrogyria at NIH's Office of Rare Diseases
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
| Bilateral frontoparietal polymicrogyria | c1847352 | 3 | wikipedia | https://en.wikipedia.org/wiki/Bilateral_frontoparietal_polymicrogyria | "2021-01-18T19:10:33" | {"gard": ["10784"], "mesh": ["C564652"], "umls": ["C1847352"], "orphanet": ["268940", "101070"], "wikidata": ["Q4907578"]} |
Amaurosis fugax
The arteries of the choroid and iris. The greater part of the sclera has been removed.
SpecialtyNeurology, ophthalmology
SymptomsTemporary fleeting of vision in one or both eyes
ComplicationsStroke[1][2]
DurationSeconds to hours
Amaurosis fugax (Greek amaurosis meaning darkening, dark, or obscure, Latin fugax meaning fleeting) is a painless temporary loss of vision in one or both eyes.[3]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Embolic and hemodynamic origin
* 2.2 Ocular origin
* 2.3 Neurologic origin
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 External links
## Signs and symptoms[edit]
The experience of amaurosis fugax is classically described as a temporary loss of vision in one or both eyes that appears as a "black curtain coming down vertically into the field of vision in one eye;" however, this altitudinal visual loss is relatively uncommon. In one study, only 23.8 percent of patients with transient monocular vision loss experienced the classic "curtain" or "shade" descending over their vision.[4] Other descriptions of this experience include a monocular blindness, dimming, fogging, or blurring.[5] Total or sectorial vision loss typically lasts only a few seconds, but may last minutes or even hours. Duration depends on the cause of the vision loss. Obscured vision due to papilledema may last only seconds, while a severely atherosclerotic carotid artery may be associated with a duration of one to ten minutes.[6] Certainly, additional symptoms may be present with the amaurosis fugax, and those findings will depend on the cause of the transient monocular vision loss.[citation needed]
## Cause[edit]
Prior to 1990, amaurosis fugax could, "clinically, be divided into four identifiable symptom complexes, each with its underlying pathoetiology: embolic, hypoperfusion, angiospasm, and unknown".[7] In 1990, the causes of amaurosis fugax were better refined by the Amaurosis Fugax Study Group, which has defined five distinct classes of transient monocular blindness based on their supposed cause: embolic, hemodynamic, ocular, neurologic, and idiopathic (or "no cause identified").[8] Concerning the pathology underlying these causes (except idiopathic), "some of the more frequent causes include atheromatous disease of the internal carotid or ophthalmic artery, vasospasm, optic neuropathies, giant cell arteritis, angle-closure glaucoma, increased intracranial pressure, orbital compressive disease, a steal phenomenon, and blood hyperviscosity or hypercoagulability."[9]
### Embolic and hemodynamic origin[edit]
With respect to embolic and hemodynamic causes, this transient monocular visual loss ultimately occurs due to a temporary reduction in retinal artery, ophthalmic artery, or ciliary artery blood flow, leading to a decrease in retinal circulation which, in turn, causes retinal hypoxia.[10] While, most commonly, emboli causing amaurosis fugax are described as coming from an atherosclerotic carotid artery, any emboli arising from vasculature preceding the retinal artery, ophthalmic artery, or ciliary arteries may cause this transient monocular blindness.
* Atherosclerotic carotid artery: Amaurosis fugax may present as a type of transient ischemic attack (TIA), during which an embolus unilaterally obstructs the lumen of the retinal artery or ophthalmic artery, causing a decrease in blood flow to the ipsilateral retina. The most common source of these athero-emboli is an atherosclerotic carotid artery.[11]
However, a severely atherosclerotic carotid artery may also cause amaurosis fugax due to its stenosis of blood flow, leading to ischemia when the retina is exposed to bright light.[12] "Unilateral visual loss in bright light may indicate ipsilateral carotid artery occlusive disease and may reflect the inability of borderline circulation to sustain the increased retinal metabolic activity associated with exposure to bright light."[13]
* Atherosclerotic ophthalmic artery: Will present similarly to an atherosclerotic internal carotid artery.
* Cardiac emboli: Thrombotic emboli arising from the heart may also cause luminal obstruction of the retinal, ophthalmic, and/or ciliary arteries, causing decreased blood flow to the ipsilateral retina; examples being those arising due to (1) atrial fibrillation, (2) valvular abnormalities including post-rheumatic valvular disease, mitral valve prolapse, and a bicuspid aortic valve, and (3) atrial myxomas.
* Temporary vasospasm leading to decreased blood flow can be a cause of amaurosis fugax.[14][15] Generally, these episodes are brief, lasting no longer than five minutes,[16] and have been associated with exercise.[10][17] These vasospastic episodes are not restricted to young and healthy individuals. "Observations suggest that a systemic hemodynamic challenge provoke[s] the release of vasospastic substance in the retinal vasculature of one eye."[16]
* Giant cell arteritis: Giant cell arteritis can result in granulomatous inflammation within the central retinal artery and posterior ciliary arteries of eye, resulting in partial or complete occlusion, leading to decreased blood flow manifesting as amaurosis fugax. Commonly, amaurosis fugax caused by giant cell arteritis may be associated with jaw claudication and headache. However, it is also not uncommon for these patients to have no other symptoms.[18] One comprehensive review found a two to nineteen percent incidence of amaurosis fugax among these patients.[19]
* Systemic lupus erythematosus[20][21]
* Periarteritis nodosa[22]
* Eosinophilic vasculitis[23]
* Hyperviscosity syndrome[24]
* Polycythemia[25]
* Hypercoagulability[26]
* Protein C deficiency[27]
* Antiphospholipid antibodies[28]
* Anticardiolipin antibodies[29]
* Lupus anticoagulant[30][31]
* Thrombocytosis[29]
* Subclavian steal syndrome
* Malignant hypertension can cause ischemia of the optic nerve head leading to transient monocular visual loss.[32]
* Drug abuse-related intravascular emboli[8]
* Iatrogenic: Amaurosis fugax can present as a complication following carotid endarterectomy, carotid angiography, cardiac catheterization, and cardiac bypass.[29]
### Ocular origin[edit]
Ocular causes include:
* Iritis[33]
* Keratitis[24]
* Blepharitis[24]
* Optic disc drusen[29]
* Posterior vitreous detachment[24]
* Closed-angle glaucoma[34]
* Transient elevation of intraocular pressure[8][33]
* Intraocular hemorrhage[8]
* Coloboma[29]
* Myopia[29]
* Orbital hemangioma[35]
* Orbital osteoma[36]
* Keratoconjunctivitis sicca[29] testing
### Neurologic origin[edit]
Neurological causes include:
* Optic neuritis[8]
* Compressive optic neuropathies[8][29]
* Papilledema: "The underlying mechanism for visual obscurations in all of these patients appear to be transient ischemia of the optic nerve head consequent to increased tissue pressure. Axonal swelling, intraneural masses, and increased influx of interstitial fluid may all contribute to increases in tissue pressure in the optic nerve head. The consequent reduction in perfusion pressure renders the small, low-pressure vessels that supply the optic nerve head vulnerable to compromise. Brief fluctuations in intracranial or systemic blood pressure may then result in transient loss of function in the eyes."[37] Generally, this transient visual loss is also associated with a headache and optic disk swelling.
* Multiple sclerosis can cause amaurosis fugax due to a unilateral conduction block, which is a result of demyelination and inflammation of the optic nerve, and "...possibly by defects in synaptic transmission and putative circulating blocking factors."[38]
* Migraine[39][40][41][42][43][44][45][46] (auras often involve temporary scotomas, and a spectrum up to transient full vision loss exists)
* Idiopathic Intracranial Hypertension[47]
* Intracranial tumor[47]
* Psychogenic[24]
## Diagnosis[edit]
Despite the temporary nature of the vision loss, those experiencing amaurosis fugax are usually advised to consult a physician immediately as it is a symptom that may herald serious vascular events, including stroke.[1][2] Restated, “because of the brief interval between the transient event and a stroke or blindness from temporal arteritis, the workup for transient monocular blindness should be undertaken without delay.” If the patient has no history of giant cell arteritis, the probability of vision preservation is high; however, the chance of a stroke reaches that for a hemispheric TIA. Therefore, investigation of cardiac disease is justified.[8]
A diagnostic evaluation should begin with the patient's history, followed by a physical exam, with particular importance being paid to the ophthalmic examination with regards to signs of ocular ischemia. When investigating amaurosis fugax, an ophthalmologic consult is absolutely warranted if available. Several concomitant laboratory tests should also be ordered to investigate some of the more common, systemic causes listed above, including a complete blood count, erythrocyte sedimentation rate, lipid panel, and blood glucose level. If a particular cause is suspected based on the history and physical, additional relevant labs should be ordered.[8]
If laboratory tests are abnormal, a systemic disease process is likely, and, if the ophthalmologic examination is abnormal, ocular disease is likely. However, in the event that both of these routes of investigation yield normal findings or an inadequate explanation, noninvasive duplex ultrasound studies are recommended to identify carotid artery disease. Most episodes of amaurosis fugax are the result of stenosis of the ipsilateral carotid artery.[48] With that being the case, researchers investigated how best to evaluate these episodes of vision loss, and concluded that for patients ranging from 36–74 years old, "...carotid artery duplex scanning should be performed...as this investigation is more likely to provide useful information than an extensive cardiac screening (ECG, Holter 24-hour monitoring, and precordial echocardiography)."[48] Additionally, concomitant head CT or MRI imaging is also recommended to investigate the presence of a “clinically silent cerebral embolism.”[8]
If the results of the ultrasound and intracranial imaging are normal, “renewed diagnostic efforts may be made,” during which fluorescein angiography is an appropriate consideration. However, carotid angiography is not advisable in the presence of a normal ultrasound and CT.[49]
## Treatment[edit]
If the diagnostic workup reveals a systemic disease process, directed therapies to treat that underlying cause should be initiated. If the amaurosis fugax is caused by an atherosclerotic lesion, aspirin is indicated, and a carotid endarterectomy considered based on the location and grade of the stenosis. Generally, if the carotid artery is still patent, the greater the stenosis, the greater the indication for endarterectomy. "Amaurosis fugax appears to be a particularly favorable indication for carotid endarterectomy. Left untreated, this event carries a high risk of stroke; after carotid endarterectomy, which has a low operative risk, there is a very low postoperative stroke rate."[50] However, the rate of subsequent stroke after amaurosis is significantly less than after a hemispheric TIA, therefore there remains debate as to the precise indications for which a carotid endarterectomy should be performed. If the full diagnostic workup is completely normal, patient observation is recommended.[8]
## See also[edit]
* Ocular ischemic syndrome
* Amaurosis
* Hemianopsia
## References[edit]
1. ^ a b Benavente O, Eliasziw M, Streifler JY, Fox AJ, Barnett HJ, Meldrum H (October 2001). "Prognosis after transient monocular blindness associated with carotid-artery stenosis". N. Engl. J. Med. 345 (15): 1084–90. doi:10.1056/NEJMoa002994. PMID 11596587.
2. ^ a b Rothwell PM, Warlow CP (March 2005). "Timing of TIAs preceding stroke: time window for prevention is very short". Neurology. 64 (5): 817–20. doi:10.1212/01.WNL.0000152985.32732.EE. PMID 15753415. S2CID 19550244.
3. ^ Fisher CM (December 1989). "'Transient monocular blindness' versus 'amaurosis fugax'". Neurology. 39 (12): 1622–4. doi:10.1212/wnl.39.12.1622. PMID 2685658. S2CID 13315378.
4. ^ North American Symptomatic Carotid Endarterectomy Trial Collaborators; Barnett HJM; Taylor, D. W.; Haynes, R. B.; Sackett, D. L.; Peerless, S. J.; Ferguson, G. G.; Fox, A. J.; Rankin, R. N.; Hachinski, V. C.; Wiebers, D. O.; Eliasziw, M. (August 1991). "Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators". N. Engl. J. Med. 325 (7): 445–53. doi:10.1056/NEJM199108153250701. PMID 1852179.
5. ^ Lord RS (August 1990). "Transient monocular blindness". Aust N Z J Ophthalmol. 18 (3): 299–305. doi:10.1111/j.1442-9071.1990.tb00624.x. PMID 2261177.
6. ^ Donders RC; Dutch Tmb Study Group (August 2001). "Clinical features of transient monocular blindness and the likelihood of atherosclerotic lesions of the internal carotid artery". J. Neurol. Neurosurg. Psychiatry. 71 (2): 247–9. doi:10.1136/jnnp.71.2.247. PMC 1737502. PMID 11459904.
7. ^ Burde RM (September 1989). "Amaurosis fugax. An overview". J Clin Neuroophthalmol. 9 (3): 185–9. PMID 2529279.
8. ^ a b c d e f g h i j "Current management of amaurosis fugax. The Amaurosis Fugax Study Group". Stroke. 21 (2): 201–8. February 1990. doi:10.1161/01.STR.21.2.201. PMID 2406992.[permanent dead link]
9. ^ Newman NJ. (1998). "Cerebrovascular disease". In Hoyt, William Graves; Miller, Neil; Newman, Nancy J.; Walsh, Frank (eds.). Walsh and Hoyt's Clinical Neuro-Ophthalmology. 3 (5th ed.). Baltimore: Williams & Wilkins. pp. 3420–6. ISBN 0-683-30232-9.
10. ^ a b Jehn A, Frank Dettwiler B, Fleischhauer J, Sturzenegger M, Mojon DS (February 2002). "Exercise-induced vasospastic amaurosis fugax". Arch. Ophthalmol. 120 (2): 220–2. doi:10.1001/archopht.120.2.220 (inactive 2021-01-17). PMID 11831932. Archived from the original on 2007-09-29. Retrieved 2007-03-26.CS1 maint: DOI inactive as of January 2021 (link)
11. ^ Braat A, Hoogland PH, DeVries AC, de Mol VanOtterloo JC (2001). "Amaurosis Fugax and Stenosis of the Ophthalmic Artery". Vasc Endovascular Surg. 35 (2): 141–2. doi:10.1177/153857440103500210. PMID 11668383. S2CID 38943888.
12. ^ Kaiboriboon K, Piriyawat P, Selhorst JB (May 2001). "Light-induced amaurosis fugax". Am. J. Ophthalmol. 131 (5): 674–6. doi:10.1016/S0002-9394(00)00874-6. PMID 11336956.
13. ^ Furlan AJ, Whisnant JP, Kearns TP (November 1979). "Unilateral visual loss in bright light. An unusual symptom of carotid artery occlusive disease". Arch. Neurol. 36 (11): 675–6. doi:10.1001/archneur.1979.00500470045007. PMID 508123.
14. ^ Fisher M (1952). "Transient monocular blindness associated with hemiplegia". Arch. Ophthalmol. 47 (2): 167–203. doi:10.1001/archopht.1952.01700030174005. PMID 14894017.
15. ^ Ellenberger C, Epstein AD (June 1986). "Ocular complications of atherosclerosis: what do they mean?". Semin Neurol. 6 (2): 185–93. doi:10.1055/s-2008-1041462. PMID 3332423.
16. ^ a b Burger SK, Saul RF, Selhorst JB, Thurston SE (September 1991). "Transient monocular blindness caused by vasospasm". N. Engl. J. Med. 325 (12): 870–3. doi:10.1056/NEJM199109193251207. PMID 1875972.
17. ^ Imes RK, Hoyt WF (1989). "Exercise-induced transient visual events in young healthy adults". J Clin Neuroophthalmol. 9 (3): 178–80. PMID 2529277.
18. ^ Hayreh SS, Podhajsky PA, Zimmerman B (April 1998). "Occult giant cell arteritis: ocular manifestations". Am. J. Ophthalmol. 125 (4): 521–6. doi:10.1016/S0002-9394(99)80193-7. PMID 9559738.
19. ^ Goodman BW (November 1979). "Temporal arteritis". Am. J. Med. 67 (5): 839–52. doi:10.1016/0002-9343(79)90744-7. PMID 389046.
20. ^ Giorgi D, David V, Afeltra A, Gabrieli CB (March 2001). "Transient visual symptoms in systemic lupus erythematosus and antiphospholipid syndrome". Ocul. Immunol. Inflamm. 9 (1): 49–57. doi:10.1076/ocii.9.1.49.3980. PMID 11262668. S2CID 35161683.
21. ^ Gold D, Feiner L, Henkind P (September 1977). "Retinal arterial occlusive disease in systemic lupus erythematosus". Arch. Ophthalmol. 95 (9): 1580–5. doi:10.1001/archopht.1977.04450090102008. PMID 901267.
22. ^ Newman NM, Hoyt WF, Spencer WH (May 1974). "Macula-sparing monocular blackouts. Clinical and pathologic investigations of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa". Arch. Ophthalmol. 91 (5): 367–70. doi:10.1001/archopht.1974.03900060379006. PMID 4150748.[permanent dead link]
23. ^ Schwartz ND, So YT, Hollander H, Allen S, Fye KH (1986). "Eosinophilic vasculitis leading to amaurosis fugax in a patient with acquired immunodeficiency syndrome". Arch. Intern. Med. 146 (10): 2059–60. doi:10.1001/archinte.146.10.2059. PMID 3767551.
24. ^ a b c d e Bacigalupi M (April 2006). "Amaurosis Fugax-A Clinical Review" (PDF). The Internet Journal of Allied Health Sciences and Practice. 4 (2): 1–6.
25. ^ Berdel WE, Theiss W, Fink U, Rastetter J (March 1984). "Peripheral arterial occlusion and amaurosis fugax as the first manifestation of polycythemia vera. A case report". Blut. 48 (3): 177–80. doi:10.1007/BF00320341. PMID 6697006. S2CID 13588599.
26. ^ Mundall J, Quintero P, Von Kaulla KN, Harmon R, Austin J (March 1972). "Transient monocular blindness and increased platelet aggregability treated with aspirin. A case report". Neurology. 22 (3): 280–5. doi:10.1212/wnl.22.3.280. PMID 5062262. S2CID 552116.
27. ^ Smith DB, Ens GE (March 1987). "Protein C deficiency: a cause of amaurosis fugax?". J. Neurol. Neurosurg. Psychiatry. 50 (3): 361–2. doi:10.1136/jnnp.50.3.361. PMC 1031809. PMID 3559620.
28. ^ Digre KB, Durcan FJ, Branch DW, Jacobson DM, Varner MW, Baringer JR (March 1989). "Amaurosis fugax associated with antiphospholipid antibodies". Annals of Neurology. 25 (3): 228–32. doi:10.1002/ana.410250304. PMID 2729913. S2CID 28110036.
29. ^ a b c d e f g h Corbett, James W.; Digre, Kathleen B. (2003). "Amaurosis Fugax and Not So Fugax—Vascular Disorders of the Eye" (PDF). Practical viewing of the optic disc. Oxford: Butterworth-Heinemann. pp. 269–344. ISBN 0-7506-7289-7.
30. ^ Landi G, Calloni MV, Grazia Sabbadini M, Mannuccio Mannucci P, Candelise L (1983). "Recurrent ischemic attacks in two young adults with lupus anticoagulant". Stroke. 14 (3): 377–9. doi:10.1161/01.STR.14.3.377. PMID 6419415.[permanent dead link]
31. ^ Elias M, Eldor A (March 1984). "Thromboembolism in patients with the 'lupus'-type circulating anticoagulant". Arch. Intern. Med. 144 (3): 510–5. doi:10.1001/archinte.144.3.510. PMID 6367679.[permanent dead link]
32. ^ Hayreh SS, Servais GE, Virdi PS (January 1986). "Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy". Ophthalmology. 93 (1): 74–87. doi:10.1016/s0161-6420(86)33773-4. PMID 3951818.
33. ^ a b Sørensen PN (August 1983). "Amaurosis fugax. A unselected material". Acta Ophthalmol (Copenh). 61 (4): 583–8. doi:10.1111/j.1755-3768.1983.tb04348.x. PMID 6637419. S2CID 221395995.
34. ^ Ravits J, Seybold ME (September 1984). "Transient monocular visual loss from narrow-angle glaucoma". Arch. Neurol. 41 (9): 991–3. doi:10.1001/archneur.1984.04050200097026. PMID 6477235.[permanent dead link]
35. ^ Brown GC, Shields JA (October 1981). "Amaurosis fugax secondary to presumed cavernous hemangioma of the orbit". Ann Ophthalmol. 13 (10): 1205–9. PMID 7316347.
36. ^ Wilkes SR, Trautmann JC, DeSanto LW, Campbell RJ (April 1979). "Osteoma: an unusual cause of amaurosis fugax". Mayo Clin. Proc. 54 (4): 258–60. PMID 423606.
37. ^ Sadun AA, Currie JN, Lessell S (October 1984). "Transient visual obscurations with elevated optic discs". Annals of Neurology. 16 (4): 489–94. doi:10.1002/ana.410160410. PMID 6497356. S2CID 2245543.
38. ^ Smith KJ, McDonald WI (October 1999). "The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease". Philosophical Transactions of the Royal Society B. 354 (1390): 1649–73. doi:10.1098/rstb.1999.0510. PMC 1692682. PMID 10603618.
39. ^ Mattsson, Lundberg; Lundberg, PO (June 1999). "Characteristics and prevalence of transient visual disturbances indicative of migraine visual aura". Cephalalgia. 19 (5): 479–84. doi:10.1046/j.1468-2982.1999.019005479.x. PMID 10403062. S2CID 5961275.
40. ^ Cologno D, Torelli P, Manzoni GC (October 2002). "Transient visual disturbances during migraine without aura attacks". Headache. 42 (9): 930–3. doi:10.1046/j.1526-4610.2002.02216.x. PMID 12390623. S2CID 32304894.
41. ^ Connor RC (November 1962). "Complicated migraine. A study of permanent neurological and visual defects caused by migraine". Lancet. 2 (7265): 1072–5. doi:10.1016/s0140-6736(62)90782-1. PMID 14022628.
42. ^ Carroll D (April 1970). "Retinal migraine". Headache. 10 (1): 9–13. doi:10.1111/j.1526-4610.1970.hed1001009.x. PMID 5444866. S2CID 46246035.
43. ^ McDonald WI, Sanders MD (September 1971). "Migraine complicated by ischaemic papillopathy". Lancet. 2 (7723): 521–3. doi:10.1016/s0140-6736(71)90440-5. PMID 4105666.
44. ^ Wolter JR, Burchfield WJ (1971). "Ocular migraine in a young man resulting in unilateral transient blindness and retinal edema". Pediatr Ophthalmol. 8: 173–6.
45. ^ Kline LB, Kelly CL (September 1980). "Ocular migraine in a patient with cluster headaches". Headache. 20 (5): 253–7. doi:10.1111/j.1526-4610.1980.hed2005253.x. PMID 7451120. S2CID 29684052.
46. ^ Corbett JJ. (1983). "Neuro-ophthalmologic complications of migraine and cluster headaches". Neurol. Clin. 1 (4): 973–95. doi:10.1016/S0733-8619(18)31134-4. PMID 6390159.
47. ^ a b Hedges TR (1984). "The terminology of transient visual loss due to vascular insufficiency". Stroke. 15 (5): 907–8. doi:10.1161/01.STR.15.5.907. PMID 6474546. S2CID 8664120.[permanent dead link]
48. ^ a b Smit RL, Baarsma GS, Koudstaal PJ (1994). "The source of embolism in amaurosis fugax and retinal artery occlusion" (PDF). Int Ophthalmol. 18 (2): 83–6. doi:10.1007/BF00919244. PMID 7814205. S2CID 394747.
49. ^ Walsh J, Markowitz I, Kerstein MD (August 1986). "Carotid endarterectomy for amaurosis fugax without angiography". Am. J. Surg. 152 (2): 172–4. doi:10.1016/0002-9610(86)90236-9. PMID 3526933.
50. ^ Bernstein EF, Dilley RB (October 1987). "Late results after carotid endarterectomy for amaurosis fugax". J. Vasc. Surg. 6 (4): 333–40. doi:10.1067/mva.1987.avs0060333. PMID 3656582.
## External links[edit]
Classification
D
* ICD-10: G45.3
* ICD-9-CM: 362.34
* MeSH: D020757
* DiseasesDB: 501
External resources
* MedlinePlus: 000784
* eMedicine: neuro/480
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Extracranial arteries
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Other
* CADASIL
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Haemorrhagic stroke
Extra-axial
* Epidural
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Cerebral/Intra-axial
* Intraventricular
Brainstem
* Duret haemorrhages
General
* Intracranial hemorrhage
Aneurysm
* Intracranial aneurysm
* Charcot–Bouchard aneurysm
Other
* Cerebral vasculitis
* Cerebral venous sinus thrombosis
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| Amaurosis fugax | c0149793 | 4 | wikipedia | https://en.wikipedia.org/wiki/Amaurosis_fugax | "2021-01-18T18:33:28" | {"gard": ["9660"], "mesh": ["D020757"], "umls": ["C0149793"], "icd-9": ["362.34"], "icd-10": ["G45.3"], "wikidata": ["Q2146228"]} |
Drug-induced purpura
SpecialtyDermatology
Drug-induced purpura is a skin condition that may be related to platelet destruction, vessel fragility, interference with platelet function, or vasculitis.[1]:824
## See also[edit]
* Food-induced purpura
* Rumpel-Leede sign
* Skin lesion
## References[edit]
1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
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| Drug-induced purpura | c1264038 | 5 | wikipedia | https://en.wikipedia.org/wiki/Drug-induced_purpura | "2021-01-18T18:40:00" | {"umls": ["C1264038"], "wikidata": ["Q5308822"]} |
The prevalence of HIV/AIDS in Cambodia is among the highest in Asia. Although Cambodia is one of the poorest countries in the world, extensive HIV prevention and control efforts by the Royal Government of Cambodia and its partners have helped to reduce the spread of HIV. Between 2003 and 2005, the estimated HIV prevalence among Cambodian adults aged 15 to 49 declined from 2.0 percent to 1.6 percent.[1]
## Contents
* 1 Dynamics
* 2 History
* 3 See also
* 4 References
## Dynamics[edit]
Cambodia’s HIV/AIDS epidemic is spread primarily through heterosexual transmission and revolves largely around the sex trade. HIV transmission occurs mainly in sexual partnerships where one partner has engaged in high-risk behaviors. Women constitute a growing share of people living with HIV/AIDS, comprising an estimated 47 percent of people living with HIV/AIDS in 2003, compared with 37 percent in 1998.[1]
This increased proportion of infections among women may reflect declining prevalence rates among males, as well as deaths among males infected in the early years of Cambodia’s epidemic. Significantly, a low prevalence rate in the general population masks far higher prevalence rates in certain sub-populations, such as injecting drug users, people in prostitution, men who have sex with men, karaoke hostesses and beer girls, and mobile and migrant populations.[1]
By 2014, HIV prevalence was reduced to 0.4 percent through a successful prevention program. However, in 2015 a massive outbreak of HIV stemming mostly from Roka occurred. The cause is thought to be the reuse of syringes by an unlicensed doctor operating in the region who has since been jailed.[2]
## History[edit]
After the first case of HIV was detected in Cambodia in 1991, the prevalence of infection increased steadily to a high of 2 percent in 1998. In the general population, the prevalence declined to 0.5 percent in 2009, down from 1.2 percent in 2001. The prevalence of HIV infection among women visiting antenatal care (ANC) clinics also declined, from a high of 2.1 percent in 1999 to 1.1 percent in 2006.[1]
Among HIV-infected pregnant women, there was also a gradual increase in the percentage who received antiretroviral therapy (ART) to reduce the risk of mother-to-child transmission, from 1.2 percent in 2003 to 11.2 percent in 2007 to 32.3 percent in 2009.[1]
## See also[edit]
* National Centre for HIV/AIDS Dermatology and STDs, Cambodia
* Health in Cambodia
* HACC Cambodia
## References[edit]
1. ^ a b c d e "2008 Country Profile: Cambodia" Archived 2008-09-13 at the Wayback Machine. U.S. Department of State (2008). Accessed September 7, 2008. This article incorporates text from this source, which is in the public domain.
2. ^ https://news.vice.com/article/were-testing-about-20-people-a-day-inside-the-cambodian-village-devastated-by-an-hiv-outbreak
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HIV/AIDS - adult prevalence rate: 2.6% (2003 est.) HIV/AIDS - people living with HIV/AIDS: 170,000 (2003 est.) HIV/AIDS - deaths: 15,000 (2003 est.) Major infectious diseases: degree of risk: very high food or waterborne diseases: bacterial and protozoal diarrhea, hepatitis A, and typhoid fever vectorborne diseases: dengue fever, Japanese encephalitis, and malaria note: highly pathogenic H5N1 avian influenza has been identified in this country; it poses a negligible risk with extremely rare cases possible among US citizens who have close contact with birds (2008)
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A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-55 (EIEE55) is caused by compound heterozygous or homozygous mutation in the PIGP gene (605938) on chromosome 21q22.
For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Clinical Features
Johnstone et al. (2017) reported 2 sibs, born of unrelated parents of European ancestry, with early infantile epileptic encephalopathy. The patients presented in the first weeks of life with refractory seizures. EEG showed various abnormalities, including focal-spreading sharp waves, multifocal epileptiform discharges, slow background activity, and modified hypsarrhythmia. The older patient showed progressive growth impairment and small head circumference (less than 2nd percentile). Brain imaging showed thin corpus callosum and abnormal T2-weighted signals in the periventricular and subcortical white matter. At age 10 years, he had profound intellectual disability with little purposeful movements, no head control, no speech, central hypotonia, peripheral hypertonia, and feeding difficulties necessitating a G-tube. His younger sister had a similar disorder with refractory seizures, no eye contact or tracking, and hypotonia with fisted hands, clonus, and hyperreflexia. She died at age 26 months. Both patients had cortical visual impairment.
Krenn et al. (2019) reported a girl, born of unrelated Polish parents, with EIEE55. The neonatal period was complicated by lethargy and poor feeding. Her first seizure occurred at 7 months of age and was associated with status epilepticus and EEG sharp waves. She continued to have refractory seizures and showed global developmental delay and hypotonia. At age 2 years, she was unable to speak and had not achieved sitting or crawling. Brain imaging showed transient diffusion-weighted abnormalities and hippocampal asymmetry.
Inheritance
The transmission pattern of EIEE55 in the family reported by Johnstone et al. (2017) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 sibs with early infantile epileptic encephalopathy-55, Johnstone et al. (2017) identified compound heterozygous mutations in the PIGP gene isoform 1 (M25T, 605938.0001 and c.456delA, 605938.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased PIGP mRNA and presumably decreased protein levels, as well as decreased cell surface expression of GPI-anchored proteins; this defect could be rescued by overexpression of PIGP isoform 2. The findings implicated a role for PIGP and GPI-anchored proteins in neurodevelopment.
In a Polish girl with EIEE55, Krenn et al. (2019) identified a homozygous frameshift mutation in the PIGP gene (c.456delA; 605938.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Flow cytometric analysis of patient lymphocytes showed decreased expression of GPI-anchored proteins, suggesting a loss-of-function effect. The findings confirmed PIGP as a monogenic disease causing developmental and epileptic encephalopathy.
INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Small head circumference Eyes \- Cortical visual impairment \- No eye contact ABDOMEN Gastrointestinal \- Feeding difficulties \- Tube feeding SKELETAL \- Contractures \- Hyperlaxity MUSCLE, SOFT TISSUES \- Axial hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, refractory \- Delayed psychomotor development \- Intellectual disability, profound \- Absent speech \- Poor head control \- Inability to walk \- Multifocal epileptiform discharges seen on EEG \- Background slowing \- Hypsarrhythmia \- Limb hypertonia \- Hyperreflexia \- Clonus \- Thin corpus callosum \- Subcortical white matter abnormalities LABORATORY ABNORMALITIES \- Patient lymphocytes show decreased expression of GPI-anchored proteins MISCELLANEOUS \- Onset in infancy \- Three patients from 2 unrelated families have been reported (last curated June 2019) MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol glycan anchor biosynthesis class P protein (PIGP, 605938.0001 ) ▲ Close
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| EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 55 | c0393706 | 7 | omim | https://www.omim.org/entry/617599 | "2019-09-22T15:45:32" | {"doid": ["0080283"], "omim": ["617599"], "orphanet": ["1934"], "synonyms": ["Alternative titles", "GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 14"]} |
## Summary
### Clinical characteristics.
Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described.
### Diagnosis/testing.
The diagnosis of prolidase deficiency is established by detection of either biallelic PEPD pathogenic variants or reduced prolidase enzyme activity in a proband who has characteristic clinical findings and imidodipeptiduria.
### Management.
Treatment of manifestations: No curative treatment is available. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal. Developmental and educational interventions as needed to address motor and cognitive delays.
Prevention of secondary complications: Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting.
Surveillance: In the absence of formal surveillance guidelines, the authors recommend annual: skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers, complete blood count, liver function tests, and abdominal ultrasound examination to assess the size of the liver and spleen. Follow up as recommended by a pulmonologist and immunologist. Follow-up assessments of motor and cognitive development as recommended for educational planning.
Agents/circumstances to avoid: In those with splenomegaly: avoid contact sports given the increased risk for splenic rupture.
### Genetic counseling.
Prolidase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PEPD pathogenic variants in the family have been identified.
## Diagnosis
No formal diagnostic criteria or testing algorithms for prolidase deficiency have been published.
### Suggestive Findings
Prolidase deficiency should be suspected in individuals with the following clinical, laboratory, and biochemical findings.
Clinical
* Skin lesions, typically lower extremity ulcers. Other lesions such as telangiectasias of the face and hands are also common [Royce & Steinmann 2002, Dunn et al 2011].
* Recurrent infections, particularly of the skin and respiratory tract [Cleary et al 1994]
* Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype [Luder et al 2007]
* Dysmorphic facial features, including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline [Goodman et al 1968, Falik-Zaccai et al 2010, Dunn et al 2011]
* Developmental delay of variable degree [Hechtman 2001, Lupi et al 2008, Falik-Zaccai et al 2010, Besio et al 2015]
* Splenomegaly [Nasser et al 2015]
* Systemic lupus erythematosus-like phenotype [Falik-Zaccai et al 2010, Klar et al 2010, Butbul Aviel et al 2012]
Laboratory. Frequent, although not universal, laboratory findings include the following:
* Anemia, usually mild (hemoglobin >10 g/dL), but occasionally below that value [Powell et al 1974, Moulonguet et al 1989, Cleary et al 1994]
* Thrombocytopenia, usually mild (>100,000 platelets per μL), although rarely it can be lower [Ogata et al 1981]
* Elevated liver enzymes, with elevation of aspartate aminotransferase in the 100s [Sekiya et al 1985]
* Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM. Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG ~1600 mg/dL, IgA 350 mg/dL, and IgM 280 mg/dL.
* IgG levels >2,000 mg/dL have been reported numerous times [Ogata et al 1981, Gray et al 1983, Freij et al 1984, Cantatore et al 1993, Shrinath et al 1997, Lopes et al 2002, Kelly et al 2010] and as high as 3,680 mg/dL [Klar et al 2010].
* IgA levels >500 mg/dL have been reported on several occasions [Gray et al 1983, Freij et al 1984, Lopes et al 2002, Butbul Aviel et al 2012] and as high as 850 mg/dL [Ogata et al 1981].
* IgM concentrations as high as 568 mg/dL have been described [Shrinath et al 1997].
* Hypocomplementemia. Levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) have been published [Klar et al 2010], with C4 as low as 9 mg/dL (normal: 20-40 mg/dL) [Cleary et al 1994, Shrinath et al 1997].
Biochemical. Prolidase deficiency is characterized by massive imidodipeptiduria* (10-30 mmol/day) on urine amino acid analysis [Hechtman 2001].
* In individuals with prolidase deficiency imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease. (This finding has been used as the basis for urinary newborn screening in Quebec [Lemieux et al 1984].)
* Under normal circumstances the urinary excretion of glycylproline is negligible [Royce & Steinmann 2002]; thus, the absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency [Freij & Der Kaloustian 1986].
Click here (pdf) for information on laboratory methods used to detect imidodipeptiduria.
Other biochemical findings:
* The concentration of imidodipeptides is much lower in serum than urine [Royce & Steinmann 2002].
* Gly-Pro has been reported in the plasma by some investigators [Freij et al 1984], but not others [Hechtman 2001].
* CSF amino acid analysis was normal in the first report of probable prolidase deficiency [Goodman et al 1968].
*Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example glycylproline).
### Establishing the Diagnosis
The diagnosis of prolidase deficiency is established in a proband (who has the characteristic clinical findings and imidodipeptiduria) by detection of either biallelic PEPD pathogenic variants (see Table 2) or reduced prolidase enzyme activity.
Molecular genetic testing approaches include single gene testing and targeted analysis for pathogenic variants.
* Single-gene testing. For most individuals, sequence analysis of PEPD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
* Targeted analysis for pathogenic variants. For Amish from Geauga County, Ohio and Druze and Arab Muslims from northern Israel, testing for the founder variants p.Arg265Ter and p.Ser202Phe, respectively, may be performed first followed by sequence analysis and gene-targeted deletion/duplication analysis if one or no pathogenic variant is identified.
### Table 2.
Summary of Molecular Genetic Testing Used in Prolidase Deficiency
View in own window
Gene 1Test MethodPathogenic Variants DetectedProportion of Probands with Pathogenic Variants 2 Detectable by This Method
PEPDSequence analysis 3Sequence variants28/30 4
Gene-targeted deletion/duplication analysis 5Exon or whole-gene deletions2/30 4
Targeted analysis for pathogenic variantsp.Arg265Ter4/4 6
p.Ser202Phe17/20 7
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Lupi et al [2008]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
Amish from Geauga County, Ohio [Wang et al 2006]
7\.
Druze and Arab Muslims from northern Israel [Falik-Zaccai et al 2010]
Measurement of prolidase enzyme activity. In affected individuals, prolidase enzyme activity in erythrocytes, leukocytes, or cultured fibroblasts ranges from none to <10% [Lupi et al 2008].
Click here (pdf) for a short review of laboratory techniques used in the diagnosis of prolidase deficiency; see also Kurien et al [2006] and Viglio et al [2006].
## Clinical Characteristics
### Clinical Description
Skin. The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers. The ulcers are located mainly on the lower extremities, particularly the feet. However, individuals are reported with upper extremity involvement, including one with recurrent upper extremity ulceration beginning at age nine years [Sheffield et al 1977], one with active ulcers on the hands [Cantatore et al 1993], and one with a healed scar from prior ulcers in the dorsum of the hand [El-Darouti 2013]. One had scarring from healed ulcers over most of her body; however, at the time of publication active ulcers were mainly on the legs [Wysocki et al 1988].
Skin ulcers can begin as early as age six months [Mandel et al 2000] or as late as age 30 years [Dyne et al 2001].
Ulceration is recurrent, and individual ulcers can take months to heal.
Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor in at least two individuals [Gray et al 1983, Royce & Steinmann 2002]. See Figure 1.
#### Figure 1.
Typical skin ulcerations in individuals with prolidase deficiency.
A variety of skin findings can precede the appearance of ulcers by many years [Hechtman 2001]. In the first 20 patients reported [Freij et al 1984], eight had telangiectasias of the face, shoulders, and hands; five had scaly, erythematous, maculopapular lesions; and two had purpuric lesions in the absence of hematologic abnormalities. In addition, five had premature graying of the hair.
Occasional findings:
* Lymphedema [Sheffield et al 1977, Dunn et al 2011]
* Hyperkeratosis of the elbows and knees [Ogata et al 1981]
* Hirsutism [Ogata et al 1981]
* Perioral pitted scars [Dunn et al 2011] or radial scars [Tiller 1977]
As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [Fimiani et al 1999].
Dysmorphic facial features. Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [Royce & Steinmann 2002, Falik-Zaccai et al 2010, Besio et al 2015]. See Figure 2.
#### Figure 2.
Prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip can be appreciated.
Neurologic manifestations. Intellectual disability of variable degree has been described in approximately 75% of individuals with prolidase deficiency [Hechtman 2001]. Table 3 summarizes IQ scores reported in the medical literature to date.
* In a review 12 of 30 individuals with molecularly confirmed prolidase deficiency had intellectual disability [Lupi et al 2008].
* In a case series of 12 individuals with prolidase deficiency, one had speech delay, two had mild developmental delay, and six had intellectual disability; three had no delays [Besio et al 2015].
* In a case series of 20 Druze and Arab Muslims with prolidase deficiency living in northern Israel all had some degree of developmental delay, mainly moderate cognitive or speech delay [Falik-Zaccai et al 2010]. More specifically, two had speech delay, eight had mild developmental delay, five had moderate delay, and three had severe delay.
### Table 3.
IQ Scores Reported in Individuals with Prolidase Deficiency
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IQ ScoreTest UsedReference
30NRArata et al [1979]
48NROgata et al [1981]
52WISC-RFreij et al [1984]
52NRSekiya et al [1985]
55WISC-RMonafo et al [2000]
61WISC-RTiller [1977]
66NRCleary et al [1994]
74WISC-RDunn et al [2011]
85WISC-RPowell et al [1974]
87Peabody Picture Vocabulary Test, Form BPowell et al [1977]
80-90NRGoodman et al [1968]
NR = not reported; WISC-R = Wechsler Intelligence Scale for Children – Revised
Microcephaly was described in five of 11 individuals [Besio et al 2015].
Seizures have been described in rare cases [De Rijcke et al 1989, Wang et al 2006, Butbul Aviel et al 2012].
Brain MRI findings include:
* Multiple microthromboses bilaterally in the cerebral white matter [Arata et al 1991]
* Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [Butbul Aviel et al 2012]
* Findings compatible with vasculitis [Falik-Zaccai et al 2010]
* Normal (one affected individual) [Cantatore et al 1993]
On nerve conduction studies one affected individual had decreased amplitude of motor action potentials and sensory action potentials [Cantatore et al 1993].
Organomegaly. Hepatomegaly and splenomegaly are common [Royce & Steinmann 2002] and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) has been reported [Nasser et al 2015].
Liver enzymes may be mildly elevated [Wang et al 2006, Butbul Aviel et al 2012].
Hematologic manifestations. Anemia can be either mild microcytic hypochromic anemia [Powell et al 1974, Powell et al 1977, Pedersen et al 1983, Milligan et al 1989] or normocytic normochromic anemia [Dunn et al 2011].
Hemolysis has been described [Lapiere & Nusgens 1969], with reticulocytosis varying from 5.9% [Powell et al 1977] to 8.6% [Powell et al 1974].
Thrombocytopenia is fairly common [Powell et al 1974, Ogata et al 1981, Kavala et al 2006, Wang et al 2006, Butbul Aviel et al 2012].
Immunologic manifestations. Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common [Royce & Steinmann 2002].
Elevated levels of IgG, IgA and IgM, and hypocomplementemia have been reported [Cleary et al 1994], as has decreased neutrophil chemotaxis [Cleary et al 1994, Shrinath et al 1997, Lopes et al 2002]. Serum levels of C1q have been normal [Gray et al 1983, Kurien et al 2013].
Increased serum IgE levels have been reported [Di Rocco et al 2007, Kelly et al 2010, Klar et al 2010]:
* Martins et al [2000] reported a patient with an IgE level of 20,000 IU/mL, which was as high as 77,600 IU/mL on follow up, with a Grimbacher score of 34 [Lopes et al 2002].
* Fukumura et al [2009] reported an individual with a level of 23,000 IU/mL.
* Hershkovitz et al [2006] reported a patient with levels of 1,000-2,000 IU/mL with a Grimbacher score of 41, suggestive of autosomal dominant hyper IgE syndrome.
Pulmonary manifestations. Asthma-like chronic reactive airway disease was described in three of four Amish individuals with prolidase deficiency [Wang et al 2006].
Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis phenotype including elevated sweat chloride and transepithelial potential difference has been described [Luder et al 2007].
One male developed severe progressive restrictive lung disease at age 45 years [Luder et al 2007].
A Druze woman age 24 years had progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity [Butbul Aviel et al 2012]. She experienced further deterioration in her pulmonary function and secondary pulmonary hypertension, and became oxygen dependent.
An Amish boy age six years with pulmonary hypertension required supplemental oxygen [Kelly et al 2010].
Systemic lupus erythematosus-like findings. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described in at least ten individuals, including three of 23 individuals from northern Israel [Butbul Aviel et al 2012].
This association, first described by Bissonnette et al [1993] in a female age 16 years, included Raynaud's phenomenon, photosensitivity, arthritis, nephritis (with segmental mesangial deposits of IgA, IgM, and C3), antinuclear antibodies 1:650, and a positive rheumatoid factor.
Shrinath et al [1997] reported two cousins with prolidase deficiency and SLE:
* One had a malar facial rash, joint swellings, thrombocytopenia, neutropenia, proteinuria, pericarditis, hypocomplementemia, positive antinuclear antibody test (ANA), and strongly positive anti-dsDNA;
* The other had recurrent mouth ulcers, a malar rash, thrombocytopenia, neutropenia, positive ANA, positive anti-dsDNA, and positive pANCA.
A boy age 11 years had photosensitivity, malar erythema, and a positive ANA of 1:40 [Cabrera et al 2004].
A boy age six years diagnosed with SLE was treated for two years with steroids and azathioprine, with amelioration of the immunologic abnormalities but worsening of the skin lesions [Lupi et al 2004].
A male age 25 years had bilateral and symmetric synovitis affecting hands, elbows, and knees, a positive rheumatoid factor (516 IU/mL) and homogeneous ANA (1:640), and low C4 and CH50 (0.07 g/L and 61%) [Marotte et al 2010]. He fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis and SLE (rhupus). Although he was diagnosed with prolidase deficiency based on increased imidodipeptiduria, prolidase enzymatic activity was not measured and PEPD sequencing was not performed. This patient did have increased bone turnover, a known cause of imidodipeptiduria in the absence of prolidase deficiency.
An Amish boy age 2.5 years with fever of unknown etiology had urinalysis with 2+ proteinuria and hypoalbuminemia, ANA of 1:1080 with speckled pattern, and a positive anti-dsDNA [D'Souza et al 2006].
Of two sibs reported by Klar et al [2010]:
* A girl age eight years had Raynaud's phenomenon, a positive ANA (1:1280; homogenous pattern), a positive anti ds-DNA >1:160, positive anti-ENA, anti-RNP and anti-Smith;
* Her brother, age 12 years, had Raynaud's phenomenon, a positive ANA (1:40; homogeneous) and anti ds-DNA (1.6 μg/mL), and low C3 (30-74 mg/dL).
An individual with positive ANA and anti-dsDNA titers, as well as low complement levels had no hematologic, renal, or articular problems; although he was given a diagnosis of SLE, he did not fulfill ACR diagnostic criteria [Di Rocco et al 2007].
Falik-Zaccai et al [2010] reported two individuals:
* One with Coombs-positive hemolytic anemia, severe medication-resistant thrombocytopenia which required splenectomy, high levels of ANA and anti-cardiolipin antibodies, and a strongly positive anti-dsDNA;
* One with aphthous stomatitis, macroscopic hematuria and proteinuria eventually leading to renal failure (with a renal biopsy compatible with lupus nephritis), seizures, pancytopenia, Coombs-positive hemolytic anemia, hypocomplementemia, and elevated ANA and anti-dsDNA antibodies).
Butbul Aviel et al [2012] reported three individuals with the SLE/prolidase deficiency association:
* A boy age 4.5 years with a rash consistent with hypertrophic discoid lupus on biopsy, proteinuria and mild hematuria with a renal biopsy consistent with WHO Class IV lupus nephritis, low C3 and C4 levels, positive ANA (1:640; homogeneous pattern), anti ds-DNA, anti-RNP, anti-SM, anti Ro (SS-A) and anti La (SS-B)
* A girl age 16 years with macroscopic hematuria and proteinuria, with a renal biopsy demonstrating WHO Class IV lupus nephritis; she had low C3 and C4, as well as a highly positive ANA and positive anti ds-DNA titer
* A woman age 24 years with thrombocytopenia, a positive Coombs test, low C3 and C3 levels, and positive ANA and anti ds-DNA titers
Positive ANA, anti-dsDNA, anti-ENA (anti-Ro), anti-Sm and anti-chromatin have been found in individuals with prolidase deficiency even in the absence of clinical findings of SLE [Kurien et al 2013].
Bone manifestations. Among 12 affected individuals reported by Besio et al [2015], short stature was described in seven, osteopenia in six, and genu valgum in four.
Other bone findings include spina bifida of C3 and 13 thoracic vertebrae [Freij et al 1984]; fusion of C2 and C3 [Lacarbonara et al 2014]; and delayed bone age [Pedersen at al 1983, Lacarbonara et al 2014].
Digital clubbing, in the presence and in the absence of pulmonary abnormalities, has also been reported [Luder et al 2007, Kelly et al 2010].
Other manifestations
* Joint laxity [Pasquali Ronchetti et al 1991, Lombeck et al 1986, Kavala et al 2006], including hip dislocation [Arata et al 1979, Ogata et al 1981]
* Protuberant abdomen in five of the first 17 cases reported [Freij et al 1984]
* Obesity [Andry et al 1992]
* Optic and chorioretinal atrophy [Ogata et al 1981], keratitis [Ogata et al 1981, Freij et al 1984] and pathologic myopia [Kiratli & Satilmiş 1998]
* Erosive cystitis (one individual) [Milligan et al 1989]
* Dental dysplasia [Moulonguet et al 1989]
* Autoimmune adrenal failure (one individual) [Luder et al 2007]
Prognosis. The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one [Lupi et al 2006] or all toes [Sekiya et al 1985], whereas others remain entirely asymptomatic.
Two individuals diagnosed through systematic urinary newborn screening in Quebec [Lemieux et al 1984] remained asymptomatic 14 years later [Hechtman 2001].
A man age 26 years, whose younger sister was affected, had imidodipeptiduria and prolidase deficiency in erythrocytes but no clinical manifestations [Isemura et al 1979].
A woman age 29 years, the sister of an affected individual, had absence of prolidase activity in serum or erythrocytes, but no skin ulcers or other clinical manifestations of prolidase deficiency [Lupi et al 2006].
In most instances, individuals with prolidase deficiency experience severe morbidity and early death, usually due to infection.
The individual with probable prolidase deficiency reported by Goodman et al [1968] had died of influenza by the time of a follow-up biochemical report four years later [Buist et al 1972]. He was about age 50 years at the time of death [Royce & Steinmann 2002].
The female reported by Lapiere & Nusgens [1969] died at age 36 years [Endo et al 1990]; she had superinfection of skin ulcers with Pseudomonas aeruginosa, which lead to septic shock and disseminated intravascular coagulation [Royce & Steinmann 2002].
A female died of a fungal infection and disseminated intravascular coagulation [Sekiya et al 1985].
A girl age 16 years with prolidase deficiency and SLE developed cellulitis of the leg, followed by adult respiratory distress syndrome and death [Bissonnette et al 1993].
A male died at 15 years of age of unknown reasons [Endo et al 1990].
A patient age 15 years died of terminal liver failure and cardiac failure [Royce & Steinmann 2002].
A patent age 11 years died of unknown causes [Besio et al [2015].
A boy age eight years with prolidase deficiency and SLE died after developing a facial abscess and septicemia [Shrinath et al 1997].
The youngest reported death was at age four years [Mandel et al 2000].
### Genotype-Phenotype Correlations
There are no known genotype-phenotype correlations. Marked phenotypic variability has been found among affected individuals from the same family (who have the same pathogenic variants) [Falik-Zaccai et al 2010].
### Nomenclature
Prolidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.
### Prevalence
Approximately 90 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of under-recognition by physicians.
The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal Urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 [Renaud & Dagenais 2009]. Thus, a few thousand cases would be predicted to exist worldwide, as opposed to only 90 cases reported to date.
Prolidase deficiency has been diagnosed throughout the world [Lupi et al 2008].
A founder variant has been described in the Geauga County settlement in Ohio [Wang et al 2006], as well as in the Druze population in northern Israel, the latter with a carrier frequency of 1:21 [Falik-Zaccai et al 2008].
## Differential Diagnosis
### Disorders with Imidodipeptiduria
Imidodipeptiduria has been described in bone disorders, presumably originating from collagen under conditions of high bone turnover.
Glycylproline has been found in the urine of:
* A child with severe bone disease and hyperphosphatasia [Seakins 1963];
* Two sisters with multiple fractures and striking bone deformities of unknown etiology [Alderman et al 1969];
* A woman age 28 years with osteomalacia and severe hyperparathyroidism who excreted large amounts of glycylproline, equivalent to ~1 g/day [Cahill et al 1970];
* Three individuals with rickets [Scriver 1964] who excreted decreasing amounts of glycylproline concomitant with clinical improvement, until the imidodipeptiduria disappeared with recovery from the disease.
### Disorders with Skin Ulcers
Werner syndrome is characterized by cancer predisposition and the premature appearance of features associated with normal aging. Findings shared by prolidase deficiency and Werner syndrome are chronic lower extremity ulcers [Sternberg et al 1982, Yeong & Yang 2004, Noda et al 2011], premature graying of the hair, and a "bird-like" facial appearance [Milligan et al 1989, Pasquali Ronchetti et al 1991, Zanaboni et al 1994]. Imidodipeptiduria has not been reported in Werner syndrome. Werner syndrome is caused by biallelic pathogenic variants in WRN and inherited in an autosomal recessive manner.
Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Leg ulcers which are relatively common in SCD were found in 2.5% of patients from the Cooperative Study of Sickle Cell Disease in the US [Koshy et al 1989], in 43% in the Jamaican Cohort Study [Clare et al 2002], and in 1.7% [Akinyanju & Akinsete 1979] to 13.2% [Knox-Macaulay 1983] of Africans.
Although urinary excretion of hydroxyproline has been shown to be significantly increased in persons with sickle cell disease compared to controls [Mohammed et al 1991] (presumably due to bone involvement), glycylprolinuria has not been reported in SCD. More importantly, although individuals with prolidase deficiency can have mild findings of hemolysis, they do not have veno-occlusive episodes. SCD is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.
Beta-thalassemia is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in reduced amounts of hemoglobin A, microcytic hypochromic anemia, and an abnormal peripheral blood smear with nucleated red blood cells. Affected individuals with other hemoglobinopathies such as β-thalassemia can also have chronic leg ulcers [Stevens et al 1977, Gimmon et al 1982, Levin & Koren 2011, Taher et al 2013], but again no imidopeptiduria is known to occur. Persons with prolidase deficiency should have a normal hemoglobin electrophoretic pattern. β-thalassemia is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.
Acquired causes of lower-extremity ulcers include arterial insufficiency, venous insufficiency, pressure ulcers, vasculitis, systemic lupus erythematosus, and infectious etiologies, among others. Although glycineprolinuria could be anticipated in cases of secondary skin ulcers given the high content of collagen in the dermis, a number of patients with extensive skin ulceration have been tested, and imidodipeptiduria was only found when accompanied by severe concurrent bone disease (e.g., multiple fractures) [Sheffield et al 1977].
### Disorders with Hyper IgE
Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency syndrome characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities like osteopenia, minimal trauma fractures, and scoliosis. AD-HIES is caused by mutation of STAT3. A Grimbacher score of >40 is suggestive of AD-HIES.
Autosomal recessive hyper IgE syndrome (AR-HIES) (OMIM 243700) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections [Renner et al 2004], all of which can also be seen in prolidase deficiency. Prolidase deficiency differs from AD-HIES by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts) and virus-driven malignancies, as well as absence of the non-immunologic findings of AD-HIES (e.g., connective tissue, skeletal and dental involvement) [Renner et al 2004]. AR-HIES is caused by biallelic pathogenic variants in DOCK8.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the following evaluations are recommended:
* Review of systems to assess for the possibility of pulmonary complications. In those with a history of pulmonary complications, consider chest imaging, pulmonary function tests, an echocardiogram to assess for pulmonary hypertension, and consultation with a pulmonologist.
* Physical examination to evaluate for splenomegaly. If present, perform an abdominal ultrasound examination to evaluate the extent of splenomegaly.
* Complete blood count to evaluate for anemia and thrombocytopenia
* Liver function tests to assess for the possibility of elevated liver enzymes
* Developmental assessment
* Consultation with a wound care specialist
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
No curative treatment is available.
Care is preferably provided by a multidisciplinary team. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal.
Click here (pdf) for further details, including treatments in which only partial or short-term benefit was reported.
### Prevention of Secondary Complications
Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.
Antibiotic prophylaxis should also be considered in the appropriate setting.
### Surveillance
In the absence of formal surveillance guidelines, the authors recommend:
* Annual:
* Skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers
* Complete blood count
* Liver function tests
* Abdominal ultrasound examination to assess liver and spleen size
* Follow up as recommended by a pulmonologist and immunologist;
* Follow-up assessments of motor and cognitive development as recommended for educational planning.
### Agents/Circumstances to Avoid
Individuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Adenovirus-mediated gene transfer. Ikeda et al [1997] performed transfer of the human prolidase cDNA into fibroblasts from patients with prolidase deficiency. This increased the fibroblast prolidase activity up to 75 times normal.
Intracellular delivery of liposome-encapsulated prolidase. Perugini et al [2005] showed that active prolidase encapsulated in liposomes was completely transported via endocytosis into fibroblasts six days after incubation.
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.
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| Prolidase Deficiency | c0268532 | 8 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | "2021-01-18T21:01:35" | {"mesh": ["D056732"], "synonyms": []} |
Polyneuropathy associated with IgM monoclonal gammapathy (MG) with anti-MAG (myelin-associated-glycoprotein) activity is a demyelinating polyneuropathy characterized clinically by sensory ataxia, tremor, paresthesia, and impaired gait.
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| Polyneuropathy associated with IgM monoclonal gammapathy with anti-MAG | c1736154 | 9 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=639 | "2021-01-23T18:02:28" | {"umls": ["C1736154"], "icd-10": ["G61.8"], "synonyms": ["Anti-MAG neuropathy", "Neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein"]} |
A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-20 (CMS20) is caused by homozygous or compound heterozygous mutation in the SLC5A7 gene (608761) on chromosome 2q12.
Description
Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Clinical Features
Bauche et al. (2016) reported 7 patients, including 2 brothers, with CMS20. The patients presented at birth with hypotonia and frequent episodic apneas often requiring ventilatory assistance. The 2 brothers had a more severe phenotype with antenatal hydramnios and arthrogryposis; these infants died at day 10 and day 15 of life. The 5 remaining patients, who ranged in age from 3 years and 9 months to 16 years, had delayed walking, proximal weakness of the lower limbs, axial weakness, fatigability, ptosis, ophthalmoparesis, chronic hypoventilation, and bulbar signs, such as poor sucking and swallowing, dysphonia, dysphagia, and stridor. There was daily or several-day fluctuations of the disease course. Four patients showed a decremental response on repetitive nerve stimulation, all of whom had a favorable response to treatment with AChE inhibitors. Three patients were noted to have cognitive deficits, whereas the other 2 had normal cognition. Muscle biopsies from the 16-year-old male and 1 of the deceased brothers with the antenatal form of the disorder showed abnormalities at the neuromuscular junction (NMJ). The older surviving boy had evidence of a denervation-renervation process with small nerve terminals and empty synaptic gutters, although the postsynaptic element looked normal. The deceased infant had immature NMJs with thin and unbranched terminal axons. Both biopsies showed abnormally strong immunostaining for butyrylcholinesterase (BChE), possibly suggesting synaptic remodeling or impaired maintenance.
Inheritance
The transmission pattern of CMS20 in the families reported by Bauche et al. (2016) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 7 patients, including 2 sibs, with CMS20, Bauche et al. (2016) identified biallelic mutations in the SLC5A7 gene (see, e.g., 608761.0002-608761.0006). The mutations in the first 2 families were found by whole-exome sequencing; mutations in the 4 subsequent families were found by Sanger sequencing of exons in the SLC5A7 gene in 95 individuals with a similar disorder. In vitro functional expression studies in HEK293 cells of 5 missense mutations showed that all were expressed at normal levels, but had significantly decreased choline uptake compared to controls, consistent with a recessive loss of function.
INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial weakness Eyes \- Ptosis \- Ophthalmoparesis Neck \- Neck muscle weakness RESPIRATORY \- Episodic apnea due to muscle weakness \- Chronic hypoventilation \- Stridor ABDOMEN Gastrointestinal \- Poor feeding \- Poor sucking \- Poor swallowing \- Dysphagia SKELETAL \- Arthrogryposis (in some patients) Spine \- Kyphosis \- Scoliosis MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness \- Muscle fatigability \- Proximal muscle weakness of the lower limbs \- Delayed walking \- Axial weakness \- Bulbar muscle weakness \- Decremental muscle response to repetitive nerve stimulation NEUROLOGIC Central Nervous System \- Cognitive impairment (in some patients) VOICE \- Dysphonia PRENATAL MANIFESTATIONS Amniotic Fluid \- Hydramnios (in some patients) MISCELLANEOUS \- Onset at birth or in utero \- Variable severity \- Death in infancy may occur \- Fluctuating disease course \- Favorable response to AChE inhibitors MOLECULAR BASIS \- Caused by mutation in the solute carrier family 5 (choline transporter), member 7 gene (SLC5A7, 608761.0002 ) ▲ Close
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| MYASTHENIC SYNDROME, CONGENITAL, 20, PRESYNAPTIC | c0751884 | 10 | omim | https://www.omim.org/entry/617143 | "2019-09-22T15:46:42" | {"doid": ["0110661"], "mesh": ["D020294"], "omim": ["617143"], "orphanet": ["98914", "590"]} |
For a phenotypic description and a discussion of genetic heterogeneity of progressive supranuclear palsy (PSP), see PSNP1 (601104).
Clinical Features
De Yebenes et al. (1995) studied a 5-generation Spanish family in which progressive supranuclear palsy was transmitted as an autosomal dominant trait. The proband had the classic presentation of this disorder beginning with axial rigidity, slowness of movement, and gait difficulty. Over the course of 2 years he progressed to complete vertical gaze palsy, axial dystonia, and retrocollis, as well as generalized severe akinesia. Postmortem examination demonstrated neuronal loss and atrophy of the brainstem, cerebellum, and diencephalon. There were also neurofibrillary tangles and gliosis without prominent senile plaques, the same pathology that was observed in the sporadic cases of progressive supranuclear palsy originally reported by Steele et al. (1964). Rojo et al. (1999) reported clinical findings on an additional 25 family members.
Ros et al. (2005) reported follow-up on the family originally reported by de Yebenes et al. (1995). Four members had typical PSP, characterized by supranuclear gaze palsy, dysarthria, dysphagia, akinesia, rigidity, postural tremor, and frontal lobe dysfunction. At least 5 ancestors were reportedly affected. Several asymptomatic or mildly symptomatic individuals showed abnormal neuroimaging results on PET scan, including decreased dopa uptake and/or reduced frontal lobe glucose metabolism; these individuals were considered to be presymptomatic and thus affected (Piccini et al., 2001).
Mapping
By genomewide linkage analysis of the large family with PSP, Ros et al. (2005) achieved a maximum multipoint lod score of 3.53 between markers D1S428 and D1S461 assuming autosomal dominant inheritance and 90% penetrance. Haplotype analysis identified a 3.4-cM candidate disease locus between markers D1S238 and D1S2823 on chromosome 1q31.1. Ros et al. (2005) noted that the power of the linkage analysis was increased by detecting presymptomatic individuals with PET scans and assuming that they were affected. No linkage was found to the MAPT gene (157140) on chromosome 17q21.
INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Blurred vision \- Diplopia \- Photophobia \- Eyelid apraxia \- Supranuclear gaze palsy ABDOMEN Gastrointestinal \- Dysphagia NEUROLOGIC Central Nervous System \- Parkinsonism \- Bradykinesia \- Akinesia \- Rigidity \- Axial dystonia \- Poor mobility \- Gait imbalance \- Falls \- Supranuclear gaze palsy \- Dysarthria \- Retrocollis \- Postural tremor \- Frontolimbic dementia \- Neuropathology shows neuronal loss in basal ganglia, brainstem, and cerebellum \- Granulovacuolar degeneration \- Gliosis \- Neurofibrillary tangles Behavioral Psychiatric Manifestations \- Forgetfulness \- Irritability \- Apathy \- Frontal release signs MISCELLANEOUS \- Genetic heterogeneity (see PSNP1 601104 ) ▲ Close
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| SUPRANUCLEAR PALSY, PROGRESSIVE, 2 | c0038868 | 11 | omim | https://www.omim.org/entry/609454 | "2019-09-22T16:06:02" | {"doid": ["678"], "mesh": ["D013494"], "omim": ["609454"], "orphanet": ["240071", "683"]} |
A rare, genetic, inborn error of metabolism disorder characterized by psychomotor delay and severe myopathy (hypotonia, absent tendon reflexes and delayed myelination) from birth, associated with hypermethioninemia and elevated serum creatine kinase levels.
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| S-adenosylhomocysteine hydrolase deficiency | c3151058 | 12 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88618 | "2021-01-23T17:34:25" | {"mesh": ["C564683"], "omim": ["613752"], "umls": ["C3151058"], "icd-10": ["E72.1"]} |
Keratoendotheliitis fugax hereditaria
Other namesKeratitis fugax hereditaria
SpecialtyOphthalmology
Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin[1] (also known as NALP3) that in humans is encoded by the NLRP3 gene [2] located on the long arm of chromosome 1.[3]
In keratoendotheliitis fugax hereditaria, patients suffer from periodical transient inflammation of the corneal endothelium and stroma, leading to short term obscuration of vision and, in some patients after repeated attacks, to central corneal stromal opacities.[4][5][6] Approximately 50 known cases have been reported in the literature. The disease so far has only been described from Finland, but exome databases suggest it may be more widely distributed in people of European ancestry.[1]
Keratoendotheliitis fugax hereditaria is thought to belong to cryopyrin-associated periodic syndromes.
## Contents
* 1 Presentation
* 2 Genetics
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 History
* 7 References
* 8 External links
## Presentation[edit]
Patients experience repeated unilateral attacks of keratitis 1 to 6 times per year, beginning at the age of 5 to 28 years. Men and women are equally affected. Attacks get less severe and less frequent in middle age. No seasonal variation has been reported. The symptoms are redness of the eye, pain, and photophobia. The attack may be associated with anterior chamber flare. These symptoms disappear in 1 to 2 days, but blurred vision may last for a few weeks.
During the acute symptoms, a slit lamp shows pseudoguttae, dark patches in the corneal endothelium, thought to represent patchy corneal endothelial swelling. The endothelium appears normal between attacks. The attack can be misdiagnosed and treated as an acute iridocyclitis. Visual acuity transiently deteriorates during the attack.
A typical corneal opacity of the patient with keratoendotheliitis fugax hereditaria.
Older patients may show faint to definite central, horizontally oval, bilateral stromal opacities. The opacities may be associated with decreased visual acuity, but they have not been severe enough to need corneal transplantation.
## Genetics[edit]
Keratoendotheliitis fugax hereditaria is inherited in an autosomal dominant manner, meaning an affected individual must inherit only one mutated allele from one parent. The protein, cryopyrin is coded for by the gene NLRP3, located at 1q44. The disease is frequent in Finland,[1] and this population has a common mutation D21H accounting for all reported cases in this population. It has not been described in any other populations. However, the mutation was found in exome databases at a minor allele frequency (MAF) of 0.023% and in the Finnish and at an MAF of 0.0090% in aggregated non-Finnish European populations.[1]
## Diagnosis[edit]
Upon clinical suspicion, diagnostic testing will consist of identifying cornea pseudoguttata by using a specular microscope or confocal microscope. Molecular genetic testing is also an option.[1]
## Treatment[edit]
Patients have reported benefit from immediate treatment of their attacks with a topical corticosteroid or non-steroidal anti-inflammatory drug (NSAID) applied a few times a day for up to one week. Some patients have found more benefit from an oral NSAID.
## Prognosis[edit]
The repeated corneal inflammation over time can lead to reduced visual acuity.
## History[edit]
Keratoendotheliitis fugax hereditaria was first described in 1964 by Olavi Valle (1934-2013),[4] a Finnish ophthalmologist with an interest in hereditary eye diseases. He reported this disease as keratitis fugax hereditaria in a family with 10 affected members over 4 generations.[5] Two decades later, a second Finnish family with 21 affected members in 5 generations was reported by other Finnish ophthalmologists who highlighted transient corneal endothelial changes, and proposed the term keratoendotheliitis fugax hereditaria.[6]
## References[edit]
1. ^ a b c d e Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184: 41–50. doi:10.1016/j.ajo.2018.01.017. PMID 29366613.
2. ^ Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human)], Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015.
3. ^ Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC 1378006. PMID 10741953.
4. ^ a b Valle O (1964). "Keratitis fugax hereditaria". Duodecim. 80: 659–664. PMID 14213210.
5. ^ a b Valle O (1964). "Keratitis fugax hereditaria - a new eye syndrome". Ophthalmologica. 151 (5): 537–547. doi:10.1159/000304912. PMID 4380911.
6. ^ a b Ruusuvaara P, Setälä K (1987). "Keratoendotheliitis fugax hereditaria. A clinical and specular microscopic study of a family with dominant inflammatory corneal disease". Acta Ophthalmol (Copenh). 65 (2): 159–169. doi:10.1111/j.1755-3768.1987.tb06995.x. PMID 3604606.
## External links[edit]
Classification
D
* ICD-10: H16.39
* OMIM: 148200
* MeSH: C11.204.564
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| Keratoendotheliitis fugax hereditaria | c1835697 | 13 | wikipedia | https://en.wikipedia.org/wiki/Keratoendotheliitis_fugax_hereditaria | "2021-01-18T18:32:25" | {"mesh": ["C563650"], "umls": ["C1835697"], "wikidata": ["Q55615849"]} |
For a general phenotypic description and a discussion of genetic heterogeneity of familial temporal lobe epilepsy, see 600512.
Clinical Features
Deprez et al. (2007) reported a 5-generation Belgian family with dominantly inherited occipitotemporal lobe epilepsy and migraine with visual aura. Age at onset ranged from childhood to adulthood. A total of 14 individuals were affected. Ten individuals had occipitotemporal lobe epilepsy, 5 of whom also had migraine with aura. Nine of the 10 patients had simple partial seizures with visual symptoms being most common (60%), followed by cognitive (50%), autonomic (50%), motor (50%), and somatosensory (20%) symptoms and olfactory (40%) and auditory (20%) hallucinations. None had deja vu. Three of the 10 patients had complex partial seizures, and 3 had secondary generalization. Four family members had a single isolated seizure; only 1 of the 4 also had migraine with aura. Median age at the onset of aura was 42 years (range 30 to 65). Seizures and migraine attacks were temporally independent in all patients except one. There was no history of febrile seizures. EEG and brain MRI were normal except in 2 patients with age-related white matter changes. Disease penetrance was about 75%.
Teive et al. (2008) commented that the possible relationship between epilepsy and migraine in the family reported by Deprez et al. (2007) was consistent with the hypothesis of cortical spreading depression in epilepsy and migraine put forth by Leao (1944).
Mapping
By genomewide linkage and haplotype analysis of an affected Belgian family, Deprez et al. (2007) identified a 9.95-cM candidate region on chromosome 9q21-q22 between markers GATA152H04 and D9S253 (maximum 2-point lod score of 3.3 at D9S257). The disease haplotype was present in all those with epilepsy and in all those with migraine with aura. The findings suggested a causal monogenic link between epilepsy and migraine with aura in this family.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, simple partial \- Seizures, complex partial \- Visual symptoms (in 60% of patients) \- Autonomic symptoms \- Olfactory or auditory hallucinations \- Secondary generalization (rare) \- Migraine with aura, usually visual (in 50% of patients) MISCELLANEOUS \- Variable age at onset of seizures \- Mean age at onset of migraines is 42 years \- Reduced penetrance (75%) ▲ Close
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| EPILEPSY, FAMILIAL TEMPORAL LOBE, 4 | c1842564 | 14 | omim | https://www.omim.org/entry/611631 | "2019-09-22T16:03:04" | {"doid": ["0060753"], "mesh": ["C536956"], "omim": ["611631"], "orphanet": ["98819"], "synonyms": ["Alternative titles", "EPILEPSY, OCCIPITOTEMPORAL LOBE, AND MIGRAINE WITH AURA"]} |
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