MedGen

Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by Ng et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of the classification of CDGs, see CDG1A (212065). [from OMIM]

Partington syndrome (PRTS) is an X-linked developmental disorder characterized by impaired intellectual development and variable movement disturbances. Partington syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (see 308350) to nonsyndromic intellectual disability (300419). Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). [from OMIM]

An autosomal dominant condition caused by mutations in the TMC1 gene, encoding transmembrane channel-like protein 1. It is characterized by bilateral progressive hearing loss. [from NCI]

Immunodeficiency-36 with lymphoproliferation (IMD36) is an autosomal dominant primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016). [from OMIM]

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRCD gene. [from MONDO]

The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. [from GeneReviews]

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the ESPN gene. [from MONDO]

The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. [from GeneReviews]

Spinocerebellar ataxia-36 (SCA36) is a slowly progressive neurodegenerative disorder characterized by adult-onset gait ataxia, eye movement abnormalities, tongue fasciculations, and variable upper motor neuron signs. Some affected individuals may develop hearing loss (summary by Garcia-Murias et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). [from OMIM]

Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment [65%]), and thumb malformations (89%; triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (42%), including end-stage renal disease (ESRD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%; flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation. [from GeneReviews]

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals. [from GeneReviews]

CILD36 is an X-linked recessive disorder characterized by chronic airway disease and recurrent sinopulmonary infections beginning in childhood and caused by defective ciliary function. Affected individuals also have infertility due to defective sperm flagella. About half of patients have laterality defects due to ciliary dysfunction at the embryonic node (summary by Paff et al., 2017). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400). [from OMIM]

PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp). [from GeneReviews]

Any cataract in which the cause of the disease is a mutation in the TDRD7 gene. [from MONDO]

Cone-rod dystrophy-15 (CORD15) is characterized by onset of reduced vision in the third to fifth decades of life. Visual acuity progressively worsens, and most patients exhibit reduced color vision and central scotomas (Cohen et al., 2012; Sobolewska et al., 2023). Retinitis pigmentosa-65 (RP65) is an adult-onset form of RP, with night blindness developing in the second to fourth decades of life. In addition to constriction of visual fields, patients may experience photophobia, reduced visual acuity, and difficulties with color vision (Henderson et al., 2010; Bessette et al., 2018; Dawood et al., 2021). Retinal macular dystrophy-5 (MCDR5) is a late-onset form of macular dystrophy, with most patients noting symptoms in the fourth to sixth decades of life. Symptoms include reduced visual acuity, glare, poor contrast vision, and metamorphopsia; night blindness is uncommon (Stingl et al., 2017; Charbel Issa et al., 2019; Ba-Abbad et al., 2021). Macular atrophy is a characteristic feature in all patients, and early involvement may be observed even in patients with RP who exhibit relatively preserved visual acuity (Malechka et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970; for retinitis pigmentosa, see 268000; for retinal macular dystrophy, see 136550. Reviews Bessette et al. (2018) reviewed published reports of patients with disease-causing mutations in the CDHR1 gene. The median age of patients was 36 years, and the majority retained visual acuity of 20/70 or better in at least one eye. Most patients developed symptoms between the first and third decades of life (range, infancy through fourth decade). Night blindness was the most common presenting symptom (54%), followed by photosensitivity (39%) and decreased vision (31%). Macular atrophy was the most common fundus feature reported (96%), followed by vascular attenuation (69%) and peripheral bone spicules (54%). The authors noted significant inter- and intrafamilial phenotypic variability among patients with CDHR1 mutations. [from OMIM]

CLCN4-related neurodevelopmental disorder (CLCN4-NDD), an X-linked disorder, is characterized in the 36 males reported to date by developmental delay or intellectual disability, behavioral/mental health issues (e.g., autism spectrum disorder, anxiety, hyperactivity, and bipolar disorder), epilepsy, and gastrointestinal dysfunction. The five heterozygous females with a de novo CLCN4 variant reported to date had findings very similar to those of affected males. Twenty-two of 25 heterozygous females identified in family studies following identification of an affected male were unaffected or had only mild specific learning difficulties and/or mental health concerns, whereas three were more severely affected. [from GeneReviews]

Adrenocorticotropic hormone (ACTH) hypersecretion by corticotroph adenomas of the pituitary result in excess cortisol secretion, or Cushing disease. The clinical features of Cushing disease include central obesity, moon facies, 'buffalo hump,' diabetes, hypertension, fatigue, easy bruising, depression, and reproductive disorders. Cushing disease is associated with increased morbidity and mortality, mainly due to cardiovascular or cerebrovascular disease and infections (summary by Perez-Rivas et al., 2015). Mutations in the USP8 gene, leading to an upregulated epidermal growth factor receptor (EGFR; 131550) pathway, have been identified in about 36 to 62% of corticotroph adenomas (summary by Mete and Lopes, 2017). [from OMIM]

Deutetrabenazine (brand name Austedo) is used to treat chorea associated with Huntington disease (HD) and tardive dyskinesia (TD). Both HD and TD are types of involuntary movement disorders. The recommended starting dose is 6 mg once daily for individuals with HD and 12 mg per day (6 mg twice daily) for individuals with TD. The maximum recommended daily dosage for both conditions is 48 mg (24 mg, twice daily). The active metabolites of deutetrabenazine are reversible inhibitors of vesicular monoamine transporter 2 (VMAT2). The VMAT2 protein transports the uptake of monoamines, such as dopamine, into the nerve terminal. The inhibition of VMAT2 leads to a depletion of pre-synaptic dopamine and reduces the amount of dopamine realized when that neuron fires. This is thought to lead to fewer abnormal, involuntary movements. The CYP2D6 enzyme converts the active metabolites of deutetrabenazine to minor, reduced activity metabolites. Individuals who have no CYP2D6 activity (“CYP2D6 poor metabolizers”) are likely to have a 3- to 4-fold increased exposure to active metabolites, compared with normal metabolizers, following the recommended standard doses of deutetrabenazine. The 2018 FDA-approved drug label for deutetrabenazine states that the daily dose of deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg) for individuals who are CYP2D6 poor metabolizers or concurrently taking a strong CYP2D6 inhibitor (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion). In addition, the drug label cautions that tetrabenazine, a closely related VMAT2 inhibitor, causes QT prolongation. Therefore, a clinically relevant QT prolongation may occur in some individuals treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor. [from Medical Genetics Summaries]

Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (Alahmad et al., 2020). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010. [from OMIM]