bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson–Fabry disease: testing the effects with the Mainz Severity Score Index
Authors: Parini R , Rigoldi M , Santus F , Furlan F , De Lorenzo P , Valsecchi G , Concolino D , Strisciuglio P , Feriozzi S , Di Vito R , Ravaglia R , Ricci R , Morrone A
Published: January 2009

Anderson–Fabry disease (AFD) is a rare X‐linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0–6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 – males performing worse than females at baseline and 2 – severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres.
CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome
Authors: Wincent J , Holmberg E , Strömland K , Soller M , Mirzaei L , Djureinovic T , Robinson KL , Anderlid BM , Schoumans J
Published: January 2009

CHARGE syndrome is a disorder characterized by Coloboma, Heart defect, Atresia choanae, Retarded growth and/or development, Genital hypoplasia and Ear anomalies. Heterozygous mutations in the chromodomain helicase DNA‐binding protein 7 (CHD7) gene have been identified in about 60% of individuals diagnosed with CHARGE syndrome. We performed a CHD7 mutation screening by direct exon sequencing in 28 index patients (26 sporadic cases, 1 familial case consisting of a brother and sister and 1 case consisting of monozygotic twins) diagnosed with CHARGE syndrome in order to determine the mutations in a cohort of Swedish CHARGE syndrome patients. The patients without a detectable CHD7 mutation, or with a missense mutation, were further investigated by multiplex ligation‐dependent probe amplification (MLPA) in order to search for intragenic deletions or duplications. Thirteen novel mutations and five previously reported mutations were detected. The mutations were scattered throughout the gene and included nonsense, frameshift and missense mutations as well as intragenic deletions. In conclusion, CHD7 mutations were detected in a large proportion (64%) of cases diagnosed with CHARGE syndrome. Screening for intragenic deletions with MLPA is recommended in cases where mutations are not found by sequencing. In addition, a CDH7 mutation was found in an individual without temporal bone malformation.
Variable phenotypic expression of homozygous familial hypobetalipoproteinaemia due to novel APOB gene mutations
Authors: Di Leo E , Magnolo L , Bertolotti M , Bourbon M , Carmo Pereira S , Pirisi M , Calandra S , Tarugi P
Published: January 2009

Homozygous familial hypobetalipoproteinaemia (Ho‐FHBL) is a rare co‐dominant disorder characterized by extremely low levels of low‐density lipoprotein cholesterol (LDL‐C) and apolipoprotein B (apoB). Most patients with Ho‐FHBL have mutations in APOB gene resulting in truncated apoBs. Some patients are asymptomatic, while others have fatty liver, intestinal fat malabsorption and neurological dysfunctions. We investigated three adult subjects with severe hypobetalipoproteinaemia and a family history of FHBL. Proband FHBL‐47 had liver cirrhosis with hepatocarcinoma and a renal carcinoma but no clinical manifestations related to FHBL. He was a compound heterozygote for a 7‐bp deletion in exon 21 and a base insertion in exon 26 resulting in truncated apoBs (apoB‐22.46/apoB‐66.51). Proband FHBL‐53, with severe hepatic steatosis and fibrosis, had a nonsense mutation in exon 19 resulting in a truncated apoB (apoB‐20.61) and a rare nucleotide substitution in intron 14 (c.2068‐4T>A). The latter was also present in her daughter, found to have low plasma LDL‐C and apoB. Proband FHBL‐82 had chronic diarrhoea and steatorrhoea. She was found to be homozygous for a nonsense mutation in exon 24 resulting in a truncated apoB (apoB‐26.65). In adult subjects, the presence of chronic liver disease and chronic diarrhoea, when associated with severe hypobetalipoproteinaemia, may lead to the diagnosis of Ho‐FHBL.
A novel mutation in the FOXC1 gene in a family with Axenfeld–Rieger syndrome and Peters’ anomaly
Authors: Weisschuh N , Wolf C , Wissinger B , Gramer E
Published: January 2009

Peters anomaly and Axenfeld–Rieger syndrome (ARS) belong to the overlapping spectrum of disorders summarized as anterior segment dysgenesis (ASD). Five patients from a family with Peters’ anomaly and ARS were screened for mutations in the PITX2, CYP1B1 and FOXC1 genes by direct sequencing. All affected family members examined were heterozygous for a single nucleotide substitution, resulting in a nonsense mutation (Q120X) at a highly conserved residue of the FOXC1 gene that is essential for DNA binding. In this pedigree, all affected family members were diagnosed with ARS except for one who shows bilateral Peters’ anomaly. Our findings support the role of FOXC1 mutations in the spectrum of ASD.
Progress toward cell‐directed therapy for phenylketonuria
Authors: Harding CO
Published: January 2009

Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine‐free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non‐adherence to the diet is associated with learning disabilities, adult‐onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell‐directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU.
Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax
Authors: Ren H‐Z , Zhu C‐C , Yang C , Chen S‐L , Xie J , Hou Y‐Y , Xu Z‐F , Wang D‐J , Mu D‐K , Ma D‐H , Wang Y , Ye M‐H , Ye Z‐R , Chen B‐F , Wang C‐G , Lin J , Qiao D , Yi L
Published: January 2009

Primary spontaneous pneumothorax (PSP) is a common manifestation of Birt–Hogg–Dubé syndrome caused by folliculin gene (FLCN) mutation, which is also found in isolated familial PSP cases. A complete genetic analysis of FLCN was performed in 102 unrelated Chinese patients with isolated PSP and 21 of their family members. Three novel mutations (c.924_926del, c.1611_1631del and c.1740C>T) and a previously reported mutation (c.1733insC) were identified in five familial and five sporadic PSP patients. Of the 21 family members of patients with PSP including 3 previous considered as sporadic, 4 (19%) had history of at least one episode of PSP and 9 (43%) were FLCN mutant carriers without PSP. Seven of the nine (78%) mutant carriers had pulmonary cysts detected by high‐resolution computed tomography (HRCT). Although c.924_926del and c.1611_1631del were found in eight patients from the same geographic district, haplotype analysis demonstrated that they did not share the same affected haplotype, thus excluding common ancestry. This study first demonstrates that FLCN mutation contributes to not only familial but also ‘apparently sporadic’ patients with isolated PSP. It suggests that mutation analysis and HRCT scan may be recommended for first‐degree family members of PSP patients with FLCN mutations, irrespective of their family history status of PSP.
Molecular analyses of GCH‐1, TH and parkin genes in Chinese dopa‐responsive dystonia families
Authors: Wu Z‐Y , Lin Y , Chen W‐J , Zhao G‐X , Xie H , Murong S‐X , Wang N
Published: January 2009

The symptomatic treatment of dopa‐responsive dystonia (DRD) emphasizes the importance of molecular analyses of the GCH‐1, TH and parkin genes. However, these analyses have not been extensively studied in Chinese DRD patients. Ten DRD families from the Han ethnic group including 14 patients and 28 clinically unaffected relatives were screened for GCH‐1, TH and parkin mutations by direct sequencing, semiquantitative polymerase chain reaction (PCR), polymerase chain reaction–restriction fragment length polymorphism analysis and allele‐specific PCR. Variations were verified in 200 unrelated control subjects. We have identified six novel mutations and three known mutations. The novel mutations are Leu91Val, Pro95Leu, Val204Gly and 628delC in GCH‐1 gene; Gly216Ser in TH gene; and Cys253Phe in parkin gene. After molecular analyses of seven families with identified GCH‐1 mutations, nine asymptomatic cases were found among 23 relatives, which confirmed the low penetrance of DRD. Unlike previous publications, male patients with GCH‐1 mutations have early onset ages, while some female patients have very late onset ages in this medium‐size series. Our data show that it is difficult to establish an evident genotype–phenotype correlation for DRD. However, it is necessary to know the genetic defects of DRD patients in clinics, which will help elucidate the mode of inheritance, facilitate causal therapy with levodopa and evaluate the prognosis.
The role of evidence‐based medicine and clinical trials in rare genetic disorders
Authors: Kruer MC , Steiner RD
Published: January 2009

The drive to empirically evaluate and analyze tools for the screening, diagnosis, management and monitoring of disease captured by the phrase ‘evidence‐based medicine (EBM)’ has firmly entrenched itself as part of standard clinical care. However, rare genetic disorders, by their very nature, challenge the generation and application of EBM. This review presents many of the challenges encountered in applying EBM to rare genetic disorders, highlighting areas of recent emphasis in establishing multi‐institutional collaborative research networks and in the systematic evaluation of developing therapies. Resources for identifying EBM tools for the practitioner are discussed, and the features and limitations of such resources are presented. Although the application of EBM to rare genetic disorders has definite limitations, a foundation has been established, and ongoing efforts seeking to systematically summarize and critically evaluate available evidence will continue to help identify the most effective tools for screening, diagnosis, management, and monitoring.
Cathepsin S genotypes are associated with Apo‐A1 and HDL‐cholesterol in lean and obese French populations
Authors: Spielmann N , Mutch DM , Rousseau F , Tores F , Hager J , Bertrais S , Basdevant A , Tounian P , Dubern B , Galan P , Clément K
Published: January 2009

Cathepsin S (CTSS) is a cysteine protease that has a central role in remodeling the extracellular matrix and, as such, has been implicated in the etiology of cardiovascular disease. This study used five tag single nucleotide polymorphisms (tSNPs) to screen the CTSS gene in healthy lean (n = 1891) and obese French populations (n = 477) for their association with various phenotypes: body mass index, waist‐to‐hip ratio, glycemia, total cholesterol, triglycerides, high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A1 (Apo‐A1) and apolipoprotein B. Significant associations were identified between rs11576175 tSNP (A/G) and Apo‐A1 and HDL‐C plasma levels in a sex‐specific manner. Lean female subjects homozygous for the minor A‐allele had higher levels of circulating Apo‐A1 (p = 0.0003), while lean male A/A carriers had higher levels of HDL‐C (p = 0.007) compared with the other genotypes. In the obese cohort, associations were found between three tSNPs and Apo‐A1 levels in adult female subjects: rs10888390 (G/A), p = 0.01; rs10888394 (T/C), p = 0.03; and rs1136774 (C/T), p = 0.02; however, only rs10888390 remained significant in a combined model (p = 0.03). These results provide the first evidence that CTSS sequence variations are associated with two human metabolic risk factors for cardiovascular diseases: plasma Apo‐A1 and HDL‐C concentrations.
Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11
Authors: Hilgert N , Alasti F , Dieltjens N , Pawlik B , Wollnik B , Uyguner O , Delmaghani S , Weil D , Petit C , Danis E , Yang T , Pandelia E , Petersen MB , Goossens D , Favero JD , Sanati MH , Smith RJH , Van Camp G
Published: January 2009

Hearing loss is the most frequent sensorineural disorder affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait with about 100 gene localizations and 44 gene identifications for non‐syndromic hearing loss. Transmembrane channel‐like gene 1 (TMC1) has been identified as the disease‐causing gene for autosomal dominant and autosomal recessive non‐syndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, 2 dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non‐syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767delT and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene or alternatively at least one additional deafness‐causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.
Metachromatic leukodystrophy – mutation analysis provides further evidence of genotype–phenotype correlation
Authors: Biffi A , Cesani M , Fumagalli F , Carro U Del , Baldoli C , Canale S , Gerevini S , Amadio S , Falautano M , Rovelli A , Comi G , Roncarolo MG , Sessa M
Published: January 2009

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder resulting from the inherited deficiency of the arylsulfatase A (ARSA) enzyme. Currently, no valid therapeutic options are available for affected patients. A thorough knowledge of disease progression in its diverse clinical variants, together with the identification of reliable prognostic factors, could be instrumental in accurate patient selection for new upcoming therapeutic opportunities, such as enzyme replacement and gene therapy. The described correlation between genotype and clinical presentation proved helpful in predicting patient’s prognosis, only in the minority of MLD patients harboring common mutations. Molecular characterization of a cohort of 26 MLD patients allowed us to identify 18 mutations, excluding the common 0 and R alleles, 10 of which are rare and 8 are novel. By categorizing the rare mutations, we were able to confirm a correlation between ARSA gene mutations, age at onset and patterns of disease progression, not only in those patients bearing common mutations, but also in those carrying rare mutant alleles. Moreover, in the case of absent or delayed molecular diagnosis, or of newly identified mutations, the involvement of peripheral nervous system from disease onset proved to be a sensitive prognostic marker predicting a severe progression.
Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis
Authors: Boyd C , Smith MJ , Kluwe L , Balogh A , MacCollin M , Plotkin SR
Published: January 2009

Schwannomatosis is a third major form of neurofibromatosis that has recently been linked to mutations in the SMARCB1 (hSnf5/INI1) tumor suppressor gene. We analyzed the coding region of SMARCB1 by direct sequencing and multiplex ligation‐dependent probe amplification (MLPA) in genomic DNA from 19 schwannomatosis kindreds. Microsatellite markers in the SMARCB1 region were developed to determine loss of heterozygosity (LOH) in associated tumors. We detected four alterations in conserved splice acceptor or donor sequences of exons 3, 4 and 6. Two alterations that likely affect splicing were seen in introns 4 and 5. An additional four alterations of unclear pathogenicity were found to segregate on the affected allele in eight families including two non‐conservative missense alterations in three families. No constitutional deletions or duplications were detected by MLPA. Nine of 13 tumors examined showed partial LOH of the SMARCB1 region consistent with ‘second hits.’ Alterations were detected in tumors both with and without somatic NF2 gene changes. These findings support the hypothesis that SMARCB1 is a tumor suppressor for schwannomas in the context of familial disease. Further work is needed to determine its role in other multiple and single tumor syndromes.
Attitudes of couples identified through screening as carriers of Gaucher disease type 1
Authors: Zuckerman S , Lahad A , Zimran A , Levy‐Lahad E , Sagi M
Published: January 2009

Gaucher disease (GD) type 1 is the most frequent autosomal recessive disorder among Ashkenazi Jews, but because the phenotype is tremendously variable, including it in the ‘Ashkenazi Panel’ of carrier screening is controversial. As part of a nationwide study conducted in Israel to evaluate the outcomes of carrier screening for GD, we studied the experience of 65/82 (79%) of the couples identified as being at risk for an affected child. We found that pre‐test information was regarded as insufficient and improved in post‐result counseling. About 70% of the subjects interpreted the genetic counseling as directive, mostly toward prenatal diagnosis (PND) but against pregnancy termination of affected fetuses. We evaluated the various motivations that had led couples to utilize PND. Subjects’ attitudes toward pregnancy termination correlated with their specific genotypes, with their perception of the severity of GD and with attending additional medical consultation. Of the 30 interviewed participants who were faced with having an affected fetus, 80% came to terms with their decision to utilize PND, but about half of the few who terminated the pregnancy regret their decision. Despite questionable benefits of screening, most of the participants did not regret having been tested and supported the continuation of this program. We offer explanations for these findings and suggest extensive genetic and medical counseling for any future carrier screening for low penetrance, treatable disease.
Drayer’s syndrome of mental retardation, microcephaly, short stature and absent phalanges is caused by a recurrent deletion of chromosome 15(q26.2→qter)
Authors: Rump P , Dijkhuizen T , Sikkema‐Raddatz B , Lemmink HH , Vos YJ , Verheij JBGM , Van Ravenswaaij CMA
Published: January 2009

We reevaluated a unique family with two sibs who had a presumed autosomal recessively inherited syndrome characterized by mental retardation, microcephaly, short stature and absent phalanges. This family was originally described by Drayer et al. in 1977. Using modern molecular techniques, we demonstrated that the syndrome is caused by the recurrence of an apparently de novo 15qter deletion of 5.8 Mb. Analysis of polymorphic markers revealed that the deletion was of maternal origin in both cases, indicating germline mosaicism in the clinically unaffected mother. This study demonstrates the possibility of parental mosaicism and the risk of recurrence in sibs for terminal subtelomeric deletions.
A new STAR on the horizon
Authors: Visscher H
Published: January 2009

Mutations in the cyclin family member FAM58A cause an X‐linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations Unger et al. (2008) Nature Genetics 40: 287–289
Seckel syndrome: when developmental pathways determining brain and body size go wrong
Authors: Visscher H
Published: January 2009

Mutations in pericentrin cause Seckel syndrome with defective ATR‐dependent DNA damage signaling Griffith et al. (2008) Nature Genetics 40: 232–236
Carrier screening for cystic fibrosis in US genetic testing laboratories: a survey of laboratory directors
Authors: Kaufman DJ , Katsanis SH , Javitt GH , Murphy JA , Scott JA , Hudson KL
Published: January 2009

Initial guidelines for cystic fibrosis (CF) carrier screening were issued in 2001 by the American College of Medical Genetics and the American College of Obstetricians and Gynecologists and updated in 2004. It is unknown how these guidelines have influenced laboratory practice. This study examined the uptake of two components of these guidelines for CF screening in genetic testing laboratories. A survey of directors of US genetic testing laboratories was conducted. Of 190 respondents, 178 answered questions about CF testing. Nearly half (49%) performed some type of DNA testing for CF; most of these (92%) performed CF carrier screening. Ten percent used a 23‐mutation panel for CF screening. The results of 5T tests were reported as a reflex test by 79% of laboratories, while 8% always returned 5T results and 7% never returned them. Seven percent of laboratories adopted both guidelines, 80% adopted one of the two guidelines, and 13% had not adopted either recommendation, suggesting that factors other than clinical guidelines may influence laboratories’ CF screening practices. Further studies are needed to determine whether the adoption of CF screening guidelines has significant clinical or economic effects on population‐based CF screening programs.
Multiplex MassARRAY spectrometry (iPLEX) produces a fast and economical test for 56 familial hypercholesterolaemia‐causing mutations
Authors: Wright WT , Heggarty SV , Young IS , Nicholls DP , Whittall R , Humphries SE , Graham CA
Published: January 2009

Familial hypercholesterolaemia (FH) is a common single gene disorder, pre‐disposing to cardiovascular disease, which is most commonly caused by mutations in the LDL‐receptor (LDLR) gene. About 5% of patients carry the p.R3527Q (previously R3500Q) mutation in the apolipoprotein B (APOB) gene and 2% carry the p.D374Y mutation in the PCSK9 gene, but the lack of high‐throughput methods make routine genetic diagnosis difficult. In this study, we developed an iPLEX MassARRAY Spectrometry mutation test to identify 56 mutations (54 in the LDLR gene, 1 in the APOB gene and 1 in the PCSK9 gene). The iPLEX test was verified by analysing 150 DNA samples from FH patients with a previously characterized mutation and 96 no‐mutation control samples. Mutations were identified in all 150 FH mutation‐positive samples using the iPLEX assay, with 96% directly called by the software. The false‐positive rate in no‐mutation control samples was 0.015%. The overall specific mutation assay failure rate was 2.1%. In the UK, this gives an average detection rate of 75%.The FH iPLEX test is not only designed for large‐scale targeted population screening for FH mutations, such as lipid clinic patients, but can also be used for population screening. The assay can easily be developed further to include additional FH‐causing mutations, thus increasing the sensitivity of the diagnostic assay.
A 2.1 Mb deletion adjacent but distal to a 14q21q23 paracentric inversion in a family with spherocytosis and severe learning difficulties
Authors: Lybæk H , Øyen N , Fauske L , Houge G
Published: January 2009

A familial q21.1q23.2‐inversion on chromosome 14 that co‐segregated with spherocytosis and learning difficulties or mild mental retardation was extensively investigated by bacterial artificial chromosome fluorescence in situ hybridization and array‐comparative genomic hybridization. As expected, a deletion of the beta‐spectrin gene SPTB, a known cause of spherocytosis, was found. More unexpectedly, this deletion was ∼1.6 Mb distal to the 14q23.2‐inversion breakpoint. The deletion spanned ∼2.1 Mb and contained 15 annotated genes in addition to SPTB, among them PLEKHG3, a guanide nucleotide exchange factor for Rho GTPases. This gene is highly expressed in the brain and our best candidate for causing the mild mental retardation. The case illustrates that inversions can be associated with microdeletions close to but not including one of the inversion breakpoints.
Finding genes underlying human disease
Authors: Stein CM , Elston RC
Published: January 2009

With the surge in genome‐wide association studies (GWAS), many have asked the question ‘Are linkage studies dead?’ In this article, we survey the approaches used in mapping human disease genes, reviewing the analysis strategies that preceded and laid the groundwork for GWAS. We note that earlier approaches are still useful and the development of new methodology is warranted.
A clinical and genetic study of the Say/Barber/Biesecker/Young‐Simpson type of Ohdo syndrome
Authors: Day R , Beckett B , Donnai D , Fryer A , Heidenblad M , Howard P , Kerr B , Mansour S , Maye U , McKee S , Mohammed S , Sweeney E , Tassabehji M , De Vries BBA , Clayton‐Smith J
Published: January 2009

We report a series of eight patients with the Say/Barber/Biesecker/Young‐Simpson (SBBYS) type of Ohdo syndrome, which is the largest cohort described to date. We expand on the type, frequency and severity of the clinical characteristics in this condition; comment on the natural history of Ohdo syndrome and further refine previously published diagnostic criteria. Cytogenetic investigations and microarray CGH analysis undertaken in this cohort of patients failed to identify a chromosomal aetiology. It remains possible that this rare condition is heterogeneous and therefore caution must be undertaken during counselling until the underlying genetic mechanism(s) is (are) identified.
Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2
Authors: Ballif BC , Theisen A , McDonald‐McGinn DM , Zackai EH , Hersh JH , Bejjani BA , Shaffer LG
Published: January 2009

We report the identification of microdeletions of 16q11.2q12.2 by microarray‐based comparative genomic hybridization (aCGH) in two individuals. The clinical features of these two individuals include hypotonia, gastroesophageal reflux, ear anomalies, and toe deformities. Other features include developmental delay, mental retardation, hypothyroidism, and seizures. The identification of common clinical features in these two individuals and those of one other report suggests microdeletion of 16q12.1q12.2 is a rare, emerging syndrome. These results illustrate that aCGH is particularly suited to identify rare chromosome abnormalities in patients with apparently non‐syndromic idiopathic mental retardation and birth defects.
CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome
Authors: Jongmans MCJ , Van Ravenswaaij‐Arts CMA , Pitteloud N , Ogata T , Sato N , Claahsen‐van der Grinten HL , Van Der Donk K , Seminara S , Bergman JEH , Brunner HG , Crowley WF , Hoefsloot LH
Published: January 2009

Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7‐positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.
The Genetics of Birth Timing: Insights into a Fundamental Component of Human Development
Authors: Chaudhari BP , Plunkett J , Ratajczak CK , Shen TT , DeFranco EA , Muglia LJ
Published: January 2009

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.
Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations
Authors: Barrow E , Robinson L , Alduaij W , Shenton A , Clancy T , Lalloo F , Hill J , Evans DG
Published: January 2009

Lynch syndrome or hereditary non‐polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first‐degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty‐four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high‐risk clinic.
ALAS, our frailty is the cause … of a new for form of protoporphyria
Authors: Brunham LR
Published: January 2009

C‐terminal deletions in the ALAS2 gene lead to gain of function and cause X‐linked dominant protoporphyria without anemia or iron overload Whatley et al. (2008) The American Journal of Human Genetics 83: 408–414
The genetics of brachyolmia: between cilia and cell volume regulation
Authors: Stein RA
Published: January 2009

Gain‐of‐function mutations in TRPV4 cause autosomal dominant brachyolmia Rock et al. (2008) Nature Genetics 40 (8): 999–1003
Comparison of proactive and usual approaches to offering predictive testing for BRCA1/2 mutations in unaffected relatives
Authors: Evans DGR , Binchy A , Shenton A , Hopwood P , Craufurd D
Published: January 2009

There have been few studies addressing uptake of predictive testing for BRCA1/2, only one comparing a proactive with usual family networking approach to dissemination. We report uptake of predictive genetic testing after directly offering BRCA1 presymptomatic genetic testing to 100 individuals in two generations of 5 large BRCA1 families compared with service testing of 196 families since that time. Uptake was significantly higher in the first generation (group 1), who were directly offered testing, and much higher in females. Seventy‐four percent of unaffected women in the first generation proceeded to testing, 42% of men. This decreased to 44% of women in the second generation (group 2) and 9% males (p = 0.0003). Uptake in unaffected individuals in the final group (group 3) with no proactive approach was significantly lower than that in the first group. Overall uptake after 10 years was 56% (95% confidence interval, CI, 50–62%) for group 1 and 36% (95% CI 34.3–37.7%) for 1084 group 3 individuals (p = 0.0003). Among women, uptake was 74% (95% CI 67–81%) in group 1 at 10 years compared with 51.5% (95% CI 49–54%) in 552 group 3 women (p = 0.023). In men, uptake was 42% (95% CI 33–52%) in group 1 and 21.1% (95% CI 18.1–23.1%) among 532 men in group 3 (p = 0.0098). Although these results are not from a randomized trial, they show particularly among men a substantially higher uptake of genetic services with a direct approach. Importance should be given to more proactive approaches to ensure that men in BRCA1/2‐positive families receive the appropriate information.
We should work less at night
Authors: MERETOJA O. A.
Published: January 2009

There is growing amount of evidence that doctors' performance is poorer if they work for over‐prolonged duties or at night. These working patterns decrease the standard of care and increase the health care expenses. Furthermore, night workers have serious health risks due to their non‐physiological work shifts. Effective ways to reduce the overall consequences of fatigue and night work include minimising the amount of work carried out at nighttime and setting up rules for maximal hours for each work shift.
Pregnancy‐associated Glycoprotein Profile during the First Trimester of Pregnancy in Egyptian Buffalo Cows
Authors: El‐Battawy KA , Sousa NM , Szenci O , Beckers JF
Published: January 2009

Pregnancy‐associated glycoprotein (PAG) concentrations were measured in buffalo cows starting from day 28 after breeding. Oestrus was synchronized in 10 buffaloes using two injections of 25 mg prostraglandin (PG)F2α (Lutalyse®) at a 11‐day interval. Blood sampling was conducted nearly twice weekly. Results indicated that plasma PAG concentrations in non‐pregnant buffaloes were low (<0.20 ng/ml) during the whole experimental period (day 28 to 103), while in pregnant animals plasma PAG levels increased from day 28 (4.48 ± 0.92 ng/ml) until day 41 (27.27 ± 6.74 ng/ml), remaining high (20.71 ± 9.20 ng/ml) until day 103. Progesterone levels were significantly (p < 0.0001) higher in pregnant (3.51–4.80 ng/ml) than in non‐pregnant buffaloes (0.28–1.52 ng/ml). A significant difference (p < 0.0001) in plasma PAG concentrations between pregnant and non‐pregnant animals starting at day 28 after breeding suggests that PAG‐radioimmunoassay could be suitable for pregnancy diagnosis in buffaloes during this period. In conclusion, PAG test offers the advantages that it requires a single plasma sample for early pregnancy diagnosis as well as the accuracy of the test for the detection of pregnancy as early as day 28.
Survey of benzodiazepine and antidepressant use in outpatients with mood disorders in Japan
Authors: Uchida Hiroyuki , Suzuki Takefumi , Mamo David C. , Mulsant Benoit H. , Tsunoda Kenichi , Takeuchi Hiroyoshi , Kikuchi Toshiaki , Nakajima Shinichiro , Nomura Kensuke , Tomita Masayuki , Watanabe Koichiro , Kashima Haruo
Published: January 2009

Data on benzodiazepine use in mood disorders are still limited, especially among seniors. A cross‐sectional review of psychotropic prescriptions in 948 outpatients with mood disorders (405 male; mean ± SD age, 52 ± 17 years; age range, 16– 91 years) was conducted in Japan. The use of benzodiazepine‐derivative anxiolytics was approximately 60% in all decades, including older patients, without a group difference. The frequent use of benzodiazepines is a cause for concern because they are not preferred treatment, given their well‐known adverse effects especially in the elderly.
Families' acceptance of near death: A qualitative study of the process for introducing end‐of‐life care
Authors: Wakunami Mitsuru , Kawabata Hidenobu , Murakami Manabu , Maezawa Masaji
Published: January 2009

Aim:  Providing effective end‐of‐life (EOL) care for the elderly with severe brain damage is difficult because patients' families find it hard to accept the condition of their loved ones as “near death”. In Japan, this has become an urgent social problem. Although health‐care teams sometimes expect that the elderly with severe brain damage should be treated as terminal, many find that patients' families cannot accept the condition as near death. As a result, they are not able to appropriately introduce any EOL services. It was the aim of the present study to develop a comprehensive understanding of the process by which families accept the elderly with severe brain damage as near death.

Methods:  Qualitative methodology with focus groups and semi‐structured interviews were used. Twenty‐three participants in two sets of male and female focus groups were interviewed in a semi‐structured format. Ten participants (five men and five women) who made important medical decisions were then interviewed separately.

Results:  Eleven categories emerged: (i) family affection with wishes for continued survival; (ii) vacillation of desire for death with dignity; (iii) family members' hierarchy; (iv) awareness that others may make different decisions; (v) family members' discussion overcoming discordance; (vi) satisfaction with physicians' explanations; (vii) impressions of life‐sustaining measures; (viii) entrusting important decisions to hospital physicians; (ix) significance of family members' previous experiences; (x) patient's age; and (xi) duration of medical treatment.

Conclusion:  We developed a conceptual model that is useful for evaluating which stage of the process families are currently experiencing as well as introducing EOL care in a timely manner.
Risk factors for cesarean hysterectomy in tertiary center in Thailand: A case–control study
Authors: Yamasmit Waralak , Chaithongwongwatthana Surasith
Published: January 2009

Aim:  To identify the risk factors for cesarean hysterectomy in a tertiary center in Bangkok, Thailand.

Methods:  A case–control study was conducted by reviewing the medical records of pregnant women delivered at BMA Medical College and Vajira Hospital between 1 January 2001 and 28 February 2007. The case refers to pregnant women who underwent hysterectomy immediately or within 24 h following cesarean delivery. Controls included pregnant women who received cesarean section during the same study period by a ratio of 1:5 (case : control).

Results:  During the study period, cesarean hysterectomy complicated 30 deliveries out of 31 106 deliveries (0.96:1000). Independent risk factors for cesarean hysterectomy from a multivariate logistic regression analysis were placental adherence (odds ratio [OR] = 440, 95% confidence interval [CI] 28–7000), placenta previa (OR = 57, 95% CI 6.0–540) and uterine atony (OR = 37, 95% CI 7.5–190). Sixty‐three percent (5/8) of placental adherence were associated with placenta previa. Of these five patients, four had a uterine scar from a prior cesarean section. The following outcomes were significantly higher in the cesarean hysterectomy group as compared to the controls: operative time, blood loss, hypovolemia, coagulopathy, transfusions, febrile morbidity, secondary surgery, and duration of hospitalization.

Conclusion:  Placental adherence, placenta previa and uterine atony were identified as significant risk factors for cesarean hysterectomy. Cesarean section due to placenta previa should be electively scheduled with well‐prepared blood components. The obstetrician should provide counsel and obtain detailed informed consent with regard to the possibility of cesarean hysterectomy.
Should diagnostic laparoscopy be performed initially or not, during infertility management of primary and secondary infertile women? A cross‐sectional study
Authors: Kahyaoglu Serkan , Kahyaoglu Inci , Yılmaz Bulent , Var Turgut , Ertas Ibrahim Egemen , Mollamahmutoglu Leyla , Batioglu Sertac
Published: January 2009

Objective:  The debate about the timing of diagnostic laparoscopy in unexplained infertile women has been investigated in this prospective study.

Study design:  A total of 328 infertile women who underwent diagnostic laparoscopy for investigation of infertility at any stage of their infertility management from April 2001 to April 2003 were investigated. When the study group was resized according to the inclusion criteria 191 unexplained infertile patients were included. Preoperative and postoperative treatment strategies were compared. The correlation between hysterosalpingography and laparoscopy findings was identified. The results were evaluated using SPSS version 10.0 for Windows.

Results:  A total of 106 patients were primary and 85 were secondary infertile. The mean ages of primary and secondary infertile patients were 27 ± 5 and 29 ± 5, respectively. Sixty percent of primary and 69% of secondary infertile patients had pelvic pathologies. Treatment strategies of 29 (43%) primary infertile and 27 (49%) secondary infertile patients with infertility‐related risk factors changed after diagnostic laparoscopy.

Conclusion:  Diagnostic laparoscopy in preparation for operative procedures (especially for secondary infertile women) should be performed initially in all unexplained infertile patients with or without risk factors related to pelvic pathologies.
Comparison of intramuscular magnesium sulfate with low dose intravenous magnesium sulfate regimen for treatment of eclampsia
Authors: Chowdhury Joydeb Roy , Chaudhuri Snehamay , Bhattacharyya Nabendu , Biswas Pranab Kumar , Panpalia Madhabi
Published: January 2009

Objectives:  Our objective was to compare intramuscular (i.m.) magnesium sulfate with a low dose intravenous (i.v.) magnesium sulfate regimen in prevention of convulsion recurrence and maternal deaths in women with eclampsia.

Methods:  This prospective trial was conducted in Nilratan Sircar Medical College, India from January 2001 to December 2005. All women with a clinical diagnosis of eclampsia were included in the trial. Magnesium sulfate (4 gm) was given as an i.v. loading dose, followed by either i.m. injections as recommended by Pritchard or low dose i.v. infusions (0.6 gm/h). Primary measures of outcome were recurrence of convulsions and maternal death. Secondary measures of outcome were potentially life threatening events, events related to labor and delivery as well as perinatal mortality and morbidity.

Results:  Of the 630 women participating in the trial, 480 women received i.m. magnesium sulphate according to the Pritchard regimen and 150 women were subjected to a low dose i.v. regimen of magnesium sulphate. There was no significant difference in recurrence of convulsion (3.3% in the i.m. and 2% in the i.v. groups P = 0.586). Maternal deaths were not significantly lower in the i.v. group than the i.m. group (5% in the i.m. and 3.3% in the i.v. groups, P = 0.506) There were no significant differences in other measures of serious maternal morbidity, in perinatal morbidity or mortality.

Conclusion:  Low dose i.v. magnesium sulfate regimen is equally effective in prevention of convulsion recurrence and maternal deaths in eclamptic women when compared with an i.m. magnesium sulfate regimen.
Numerical and experimental applications of the least‐squares method to determine mode‐II stress intensity factors for double fillet welded lap joints
Authors: CHUNG H. Y. , LIN Y. Z. , LIN R. S.
Published: January 2009

Due to its simplicity, the least‐squares method provides an efficient means to evaluate the stress intensity factors (SIFs) of cracks in complicated structures. This paper demonstrates numerical and experimental applications of the least‐squares method to study mode‐II SIFs of double fillet welded lap joints. In the numerical application, double fillet welded lap joints with different geometric parameters, including overlap length, weld leg size, plate thickness and plate length, were systematically analysed by the finite‐element method combined with the least‐squares method. The computed SIF results were then employed to develop the general formulae of the shearing fracture mode (mode‐II) stress intensity factors. To validate the numerical results, three double fillet welded lap joint specimens were tested by a non‐contact optical experiment using a common digital camera and a proposed image processing scheme. The measured crack shearing displacements near the crack tip were substituted into the least‐squares procedure to obtain the SIFs of the specimens. The numerical and experimental results were in good agreement with the existing numerical results for double fillet welded lap joints provided in the handbook (Murakami, 1987). The non‐contact optical experiment makes the field measurement of SIFs possible, which is very useful for fracture analysis or fatigue evaluation of structures like steel bridges, naval structures and offshore structures.
The distribution and molecular diversity of the Eastern Atlantic and Mediterranean chthamalids (Crustacea, Cirripedia)
Authors: Shemesh Eli , Huchon Dorothée , Simon‐Blecher Noa , Achituv Yair
Published: January 2009

The three chthamalids Chthamalus stellatus, C. montagui and Euraphia depressa are common inhabitants of the intertidal zone in the Eastern Atlantic, Mediterranean Sea and Black Sea. In this study, we investigated the occurrence of these barnacles in a wide range of their distribution. Population divergences of these two species have been inferred using three molecular markers — internal transcribed spacer (ITS), elongation factor 1α (EF‐1α) and cytochrome oxidase subunit I (COI). ITS sequences of C. stellatus were identical throughout the species range, whereas ITS sequences of C. montagui indicated that the Black Sea and Mediterranean populations are isolated from the Atlantic population. The COI and EF‐1α sequences were the most variable and informative. They indicated a high genetic divergence between Atlantic, Mediterranean and Black Sea populations for C. montagui. In addition significant genetic structure was found among the populations of C. stellatus based on EF‐1α but not COI. Interestingly, our molecular dating analysis correlated the pattern of diversification in C. montagui to major geological changes that occurred in the Mediterranean during the end of the Messinian and Pleiocene periods. We suggest that palaeohistory shaped the divergences between Chthamalus populations that have probably been maintained by current hydrographic conditions. Finally, COI phylogenetic analysis placed the genus Euraphia within the Chthamalus clade, suggesting the need for a taxonomic revision of Euraphia. This study represents the most detailed phylogeographical analysis of intertidal Mediterranean species to date, and shows that geological events have strongly shaped the current diversity pattern of this fauna.