TaoMedAI/RareMedData huggingface dataset:
Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (ORPHA:314404)
A rare polymorphic disorder, subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by ataxia, sensorineural deafness and narcolepsy with cataplexy and dementia.
Epidemiology
Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (ADCA-DN) has been reported in more than 80 patients to date from Sweden, the United States, Italy, Brazil, Belgium, China, New Zealand, UK, Taiwan, Germany, and Canada.
Clinical description
Disease onset usually occurs in adulthood (from the ages of 30-40). Cases have been reported in adolescents. The clinical features include cerebellar ataxia, narcolepsy with cataplexy, sensorineural deafness and dementia including executive dysfunction and global cognitive impairement. Optic atrophy, cataracts, psychosis, depression, sensory neuropathy, pseudobulbar signs, incontinence and limb lymphedema have also been reported but present later in the disease course. Mild brain atrophy with cerebellum involvement is visible with magnetic resonance imaging (MRI).
Etiology
ADCA-DN is caused by a mutation in the DNA methyltransferase (DNMT1) gene located on chromosome 19p13.2. It encodes an enzyme essential for the repression of transcriptional activity in numerous postmitotic cells.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing, the finding of a mutation in the DNMT1 gene.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia (ADCA), and hereditary.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
ADCA-DN is inherited autosomal dominantly and genetic counseling is possible. Sporadic cases have also been reported. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for ADCA-DN and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity as well as to avoid falls. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease duration from disease onset to death is estimated to be between 10 to 30 years. Almost all affected individuals survive at least until late 40's.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK
Autosomal dominant cerebellar ataxia (ORPHA:99)
A clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1). In ACDA type 4, a cerebellar syndrome is associated with epilepsy.
Autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation (ORPHA:487814)
A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by childhood onset of slowly progressive distal muscle weakness and atrophy primarily affecting the lower limbs, associated with sensory impairment and ataxia presenting with an unsteady, broad-based gait and frequent falls. Additional signs include decreased deep tendon reflexes and hand tremor.
Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation (ORPHA:324611)
A rare form of axonal peripheral sensorimotor neuropathy characterized by classical CMT2 signs and symptoms (progressive weakness and atrophy of distal limb muscles, mild sensory deficits of position, vibration and pain/temperature, pes cavus, and symmetrically absent or reduced muscle and sensory action potentials with relatively preserved nerve conduction velocities in neurophysiological studies) as well as pyramidal tract involvement (spasticity, hyperreflexia). Spasticity and pain may be the presenting symptoms.
Autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation (ORPHA:435819)
A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, decreased deep tendon reflexes of lower limbs, and mild distal sensory loss leading to gait difficulties in most patients.
Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons (ORPHA:401964)
A rare subtype of axonal hereditary motor and sensory neuropathy characterized by distal muscle weakness and atrophy (principally of peroneal muscles) associated with distal sensory loss (tactile, vibration), pes cavus present since infancy or childhood, and axonal swelling with neurofilament accumulation on nerve biopsy. Other features may include hand muscle involvement, hypo/arreflexia, gait disturbances, muscle cramps, toe abnormalities and mild cardiomyopathy.
Autosomal dominant Charcot-Marie-Tooth disease type 2A1 (ORPHA:99946)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, presenting with a more prominent muscle weakness in lower than upper limbs and frequent postural tremor.
Autosomal dominant Charcot-Marie-Tooth disease type 2A2 (ORPHA:99947)
A subtype of Autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by the childhood onset of distal weakness and areflexia (with earlier and more severe involvement of the lower extremities), reduced sensory modalities (primarily pain and temperature sensation), foot deformities, postural tremor, scoliosis and contractures. Optic atrophy, vocal cord palsy with dysphonia, sensorineural hearing loss, spinal cord abnormalities and hydrocephalus have also been reported.
Autosomal dominant Charcot-Marie-Tooth disease type 2B (ORPHA:99936)
A severe form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the 2nd or 3rd decade, characterized by ulcerations and infections of feet. Symmetric and distal weakness develops mostly in the legs together with a severe symmetric distal sensory loss, tendon reflexes are only reduced at ankles and foot deformities, including pes cavus or planus and hammer toes, appear in childhood.
Autosomal dominant Charcot-Marie-Tooth disease type 2C (ORPHA:99937)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by the association of vocal cord anomalies, impairment of respiratory muscles and sensorineural hearing loss with the distal hands and feet weakness. Onset is between infancy and the 6th decade.
Autosomal dominant Charcot-Marie-Tooth disease type 2D (ORPHA:99938)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal weakness primarily and predominantly occurring in the upper limbs and tendon reflexes absent or reduced in the arms and decreased in the legs. Progression is slow.
Autosomal dominant Charcot-Marie-Tooth disease type 2DD (ORPHA:521414)
A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by predominantly distal weakness and muscle atrophy, decreased or absent tendon reflexes, and reduced vibratory sensation in the lower and upper extremities. Pes cavus develops in many patients. Additional symptoms like ataxia, tremor, or swallowing difficulties have been reported. Patients usually remain ambulatory even late in the disease. Age of onset ranges from childhood to adulthood, with earlier onset tending to be associated with a more severe disease phenotype.
Autosomal dominant Charcot-Marie-Tooth disease type 2E (ORPHA:99939)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the first to 6th decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and, after years, all patients have a pes cavus. Other signs may be present, including hearing loss and postural tremor.
Autosomal dominant Charcot-Marie-Tooth disease type 2F (ORPHA:99940)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by symmetric weakness primarily occurring in the lower limbs (distal muscles in a majority of cases) and reaching the arms only after 5 to 10 years, occasional and predominantly distal sensory loss and reduced tendon reflexes. It presents with gait anomaly between the 1st and 6th decade and early onset is generally associated to a more severe phenotype which may include foot drop.
Autosomal dominant Charcot-Marie-Tooth disease type 2G (ORPHA:99941)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy with onset associated to development of foot deformity and walking difficulties between the 1st and the 8th decades, with a median range in the 2nd one. Weakness and sensory loss involve primarily the legs and ankles tendon reflexes are reduced. This disorder has a slowly progressive course.
Autosomal dominant Charcot-Marie-Tooth disease type 2I (ORPHA:99942)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a late onset with severe sensory loss (paresthesia and hypoesthesia) associated with distal weakness, mainly of the legs, and absent or reduced deep tendon reflexes.
Autosomal dominant Charcot-Marie-Tooth disease type 2J (ORPHA:99943)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a relatively late onset, pupillary abnormalities and deafness, in most patients, associated with distal weakness and muscle atrophy.
Autosomal dominant Charcot-Marie-Tooth disease type 2K (ORPHA:99944)
An axonal Charcot-Marie-Tooth (CMT) peripheral sensorimotor polyneuropathy.
Epidemiology
CMT2K is a rare form of CMT with only three families reported in the literature so far.
Clinical description
It is characterized by a mild phenotype with onset during the second decade of life and very slow progression. Walking ability is retained (one of the reported patients was still able to walk at 70 years of age).
Etiology
CMT2K is caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission. Mutations in the same gene are associated with severe early-onset forms of CMT: CMT4A (an autosomal recessive demyelinating form of CMT4) and CMT4C4 (another autosomal recessive form of CMT4 with an axonal phenotype and an association with vocal cord paralysis; see this term).

                            Last update: 
                            January 2009


                            - Expert reviewer(s): 
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU
Autosomal dominant Charcot-Marie-Tooth disease type 2L (ORPHA:99945)
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. In the single family reported to date, CMT2L onset is between 15 and 33 years. Patients present with a symmetric distal weakness of legs and occasionally of the hands, absent or reduced tendon reflexes, distal legs sensory loss and frequently a pes cavus. Progression is slow.
Autosomal dominant Charcot-Marie-Tooth disease type 2M (ORPHA:228179)
A form of axonal Charcot-Marie-Tooth disease, a peripheral motor and sensory neuropathy, characterized by congenital pstosis and early cataract associated to a mildly progressive peripheral neuropathy of variable onset from birth to the 6th decade, pes cavus, reduced to absent ankles tendon reflexes and sometimes neutropenia.
Autosomal dominant Charcot-Marie-Tooth disease type 2N (ORPHA:228174)
A mild form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal legs sensory loss and weakness that can be asymmetric. Tendon reflexes are reduced in the knees and absent in ankles. Progression is slow.
Autosomal dominant Charcot-Marie-Tooth disease type 2O (ORPHA:284232)
A rare, genetic, subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by early childhood-onset of slowly progressive, predominantly distal, lower limb muscle weakness and atrophy, delayed motor development, variable sensory loss, and pes cavus in the presence of normal or near-normal nerve conduction velocities. Additional variable features may include proximal muscle weakness, abnormal gait, arthrogryposis, scoliosis, cognitive impairment, and spasticity.
Autosomal dominant Charcot-Marie-Tooth disease type 2Q (ORPHA:329258)
A rare subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by adolescent to adulthood-onset of symmetrical, slowly progressive distal muscle weakness and atrophy (with a predominant weakness of the distal lower limbs) associated with reduced or absent deep tendon reflexes, pes cavus and mild to moderated deep sensory impairment.
Autosomal dominant Charcot-Marie-Tooth disease type 2U (ORPHA:397735)
A subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by late adult-onset (50-60 years of age) of slowly progressive, axonal, peripheral sensorimotor neuropathy resulting in distal upper limb and proximal and distal lower limb muscle weakness and atrophy, in conjunction with distal, panmodal sensory impairment in upper and lower limbs. Tendon reflexes are reduced and nerve conduction velocities range from reduced to absent. Neuropathic pain has also been associated.
Autosomal dominant Charcot-Marie-Tooth disease type 2V (ORPHA:447964)
A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of recurrent pain in legs with or without cramps, progressive loss of deep tendon reflexes and vibration sense, paresthesias in the feet and later in the hands. Patients often experience sleep disturbances and mild sensory ataxia.
Autosomal dominant Charcot-Marie-Tooth disease type 2W (ORPHA:488333)
A rare predominantly axonal hereditary motor and sensory neuropathy characterized by a broad phenotypic spectrum of slowly progressive signs and symptoms mainly affecting the lower limbs. Most patients present with gait difficulties and distal sensory impairment, while some may lack sensory symptoms altogether. Pes cavus is frequently reported. Age of onset is also highly variable, ranging from childhood to late adulthood.
Autosomal dominant Charcot-Marie-Tooth disease type 2Y (ORPHA:435387)
A rare, axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of variable onset and severity. Patients present with postural instability, gait and running difficulties, decreased deep tendon reflexes, foot deformities, fine motor impairment, and distal sensory impairment. Dysarthria, dysphagia, and mild cognitive and behavioral abnormalities have also been reported.
Autosomal dominant Charcot-Marie-Tooth disease type 2Z (ORPHA:466768)
A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by early onset of generalized hypotonia and weakness, or later onset of distal lower limb muscle weakness and atrophy, cramps, and sensory impairment. Weakness and atrophy progress in an asymmetric fashion to involve also the proximal and upper limbs in the course of the disease. Additional features are pyramidal signs like increased muscle tone and extensor plantar reflexes, as well as learning difficulties.
Autosomal dominant childhood-onset proximal spinal muscular atrophy (ORPHA:363447)
A rare genetic neuromuscular disease characterized by early onset muscular weakness with predominant proximal lower limb involvement. The disorder is static or only mildly progressive. The severity of manifestations ranges from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features.
Autosomal dominant congenital benign spinal muscular atrophy (ORPHA:1216)
A rare distal hereditary motor neuropathy, with a variable clinical phenotype, typically characterized by congenital, non-progressive, predominantly distal, lower limb muscle weakness and atrophy and congenital (or early-onset) flexion contractures of the hip, knee and ankle joints. Reduced or absent lower limb deep tendon reflexes, skeletal anomalies (bilateral talipes equinovarus, scoliosis, kyphoscoliosis, lumbar hyperlordisis), late ambulation, waddling gait, joint hyperlaxity and/or bladder and bowel dysfuntion are usually also associated.
Autosomal dominant cutis laxa (ORPHA:90348)
A rare connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated in some cases with internal organ involvement.
Epidemiology
The prevalence of ADCL is unknown but less than 50 cases have been reported in the literature so far.
Clinical description
Patients are usually diagnosed at birth or in early childhood due to the presence of excessive skin folds and loose, redundant skin. ADCL is considered to be a mild form of cutis laxa with limited systemic involvement although associated features may include hernias, cardiac valve anomalies (redundant mitral and tricuspid valves), cardiovascular manifestations (pulmonary stenosis and aortic and arterial dilatation and tortuosity), gastrointestinal diverticuli and emphysema.
Etiology
ADCL is genetically heterogeneous: mutations in the elastin gene (ELN; 7q11.1-q21.1) have been reported in some cases, whereas mutations in the gene encoding fibulin-5 (FBLN5; 14q31) have been identified in others. Homozygous mutations in the FBLN5 are associated with the more severe form of CL with extensive systemic involvement, autosomal recessive CL type 1 (ARCL1; see this term).
Diagnostic methods
Diagnosis is based on clinical examination, family history and pathognomonic histological findings (sparse, fragmented elastic fibers) on skin biopsies. Molecular testing may allow confirmation of the diagnosis.
Differential diagnosis
The differential diagnosis may include other forms of CL (ARC1 and ARCL2, and X-linked CL) and related syndromes (gerodermia osteodysplastica, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes, Cantu syndrome and Costello syndrome (see these terms).
Genetic counseling
Genetic counseling should be provided to affected families and prenatal diagnosis may be feasible for families in which the disease-causing mutation has been identified.
Management and treatment
There is no specific treatment for cutis laxa. Management should include symptomatic treatment of any associated manifestations. ADCL is generally a mild cutaneous disease and internal organ involvement is rare.
Prognosis
Most patients have a good prognosis and life expectancy is usually normal.

                            Last update: 
                            January 2011


                            - Expert reviewer(s): 
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS
Autosomal dominant deafness-onychodystrophy syndrome (ORPHA:79499)
A rare multiple congenital anomalies syndrome characterized by congenital hearing impairment, small or absent nails on the hands and feet, and small or absent terminal phalanges.
Epidemiology
The prevalence is unknown but it has been reported in 22 individuals from ten families to date.
Clinical description
The main clinical characteristics of dominant deafness-onychodystrophy (DDOD) syndrome are severe sensorineural hearing loss or deafness and onychodystrophy (small or absent fingernails and toenails, sometimes limited to the nails of the first and fifth digits). Brachydactyly, long, finger-like or tri-phalangeal thumbs as well as conical, hypoplastic teeth or oligodontia have also been reported in several patients. Syndactyly, minor facial dysmorphism (mild hypotelorism, deep set eyes and midface hypoplasia), and epilepsy have been seen in individual cases. Unlike DOORS syndrome, most patients with DDOD follow a normal development and have normal intelligence.
Etiology
DDOD syndrome is caused, in some cases, by heterozygous mutations in the ATP6V1B2 gene (8p21.3) encoding a vacuolar ATPase (V-ATPase) involved in protein translocation. It is at present unknown whether there can be genetic heterogeneity or not, as not all known families have been tested.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical findings. X-rays of the hands and feet and a brain stem auditory evoked response (BAER) test for hearing loss should be performed. Molecular genetic testing identifying a ATP6V1B2 mutation may confirm the diagnosis but as it is at present uncertain whether DDOD syndrome is genetically heterogeneous, the absence of a mutation will not mean that a diagnosis of DDOD syndrome is incorrect.
Differential diagnosis
The main differential diagnosis is DOORS syndrome and Coffin-Siris syndrome. The limb anomalies seen in DDOD syndrome can also be found in several other entities including Zimmermann-Laband syndrome, Adams-Oliver syndrome, Temple-Baraitser syndrome and Fontaine Progeroid Syndrome.
Antenatal diagnosis
Prenatal diagnosis of DDOD syndrome has not been performed to date.
Genetic counseling
DDOD syndrome is inherited autosomal dominantly so if the clinical diagnosis has been established reliably, genetic counseling is possible. In this case, affected families should be informed that risk of transmission from an affected parent to offspring is 50%.
Management and treatment
Treatment is supportive and involves special education for the hearing impaired as well as regular follow-up. Corrective surgery is in principle possible for those with syndactyly, although generally not necessary.
Prognosis
The disease is not life threatening. The main influence on quality of life is hearing loss.

                            Last update: 
                            March 2020


                            - Expert reviewer(s): 
                            Dr Philippe CAMPEAU
Autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome (ORPHA:476093)
A rare genetic neuromuscular disease characterized by length-dependent axonal motor neuropathy predominantly affecting the lower limbs, in combination with a myopathy with morphological features of myofibrillar myopathy with aggregates and rimmed vacuoles. Age of onset is typically in the second to third decade of life. Patients present with slowly progressive muscle weakness and atrophy initially affecting the distal lower limbs and later progressing to involve proximal limbs and also truncal muscles. There is no involvement of respiratory and cardiac muscles.
Autosomal dominant distal renal tubular acidosis (ORPHA:93608)
A rare autosomal dominant form of distal renal tubular acidosis characterized by hyperchloremic metabolic acidosis often but not always associated with hypokalemia. Disease onset is in adolescence or adulthood and initial manifestations can include polyuria, polydipsia, muscle weakness and fatigue. Osteomalacia or osteopenia, hypercalciuria, nephrolithiasis and nephrocalcinosis may also develop. Renal failure has not been described.
Autosomal dominant focal dystonia, DYT25 type (ORPHA:329466)
A form of focal dystonia characterized by cervical, laryngeal and hand-forearm dystonia.
Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering (ORPHA:402003)
A rare, genetic, isolated, focal palmoplantar keratoderma disease characterized by focal thickening of the skin of the soles, and often of the palms, associated with minimal or no nail involvement. Patients frequently present non-epidermolytic painful plantar blistering and, occasionally, subtle oral leukokeratosis or plantar hyperhidrosis.