MedGen

3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by Baumgartner et al., 2001). Also see 3-methylcrotonylglycinuria I (MCC1D; 210200), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010). [from OMIM]

Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by Gerber et al., 2016 and McEntagart et al., 2016). [from OMIM]

Spinocerebellar ataxia type 15 (SCA15) is characterized by slowly progressive gait and limb ataxia, often in combination with ataxic dysarthria, titubation, upper limb postural tremor, mild hyperreflexia, gaze-evoked nystagmus, and impaired vestibuloocular reflex gain. Onset is between ages seven and 72 years, usually with gait ataxia but sometimes with tremor. Affected individuals remain ambulatory for ten to 54 years after symptom onset. Mild dysphagia usually after two or more decades of symptoms has been observed in members of multiple affected families and movement-induced oscillopsia has been described in one member of an affected family. [from GeneReviews]

Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000). [from OMIM]

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. [from GeneReviews]

Spinocerebellar ataxia-29 (SCA29) is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). [from OMIM]

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. [from GeneReviews]

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis. [from GeneReviews]

Cerebral palsy (CP) is defined as a nonprogressive but not unchanging disorder of posture or movement, caused by an abnormality of the brain and first evident at the stage of rapid brain development (Hughes and Newton, 1992). Cerebral palsy can be classified according to the type of movement disorder: spastic cerebral palsy accounts for approximately 60% of cases and can be subdivided into hemiplegic, diplegic, quadriplegic, and monoplegic types, whereas other forms include athetoid/dyskinetic, ataxic (605388), and mixed (Gustavson et al., 1969). Genetic Heterogeneity of Spastic Quadriplegic Cerebral Palsy See also CPSQ3 (617008), caused by mutation in the ADD3 gene (601568) on 10q24. Related phenotypes that were formerly classified in the CPSQ series include spastic paraplegia-47 (SPG47; 614066), spastic paraplegia-50 (SPG50; 612936), spastic paraplegia-51 (SPG51; 613744), spastic paraplegia-52 (SPG52; 614067), and neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026). [from OMIM]

A rare, genetic, neurologic disease characterized by primary hyperaldosteronism presenting with early-onset, severe hypertension, hypokalemia and neurological manifestations (including seizures, severe hypotonia, spasticity, cerebral palsy and profound developmental delay/intellectual disability). [from ORDO]

A rare genetic syndromic intellectual disability characterized by global developmental delay and borderline to severe intellectual disability, autism spectrum disorder with obsessive behavior, stereotypies, hyperactivity but frequently friendly and affable personality, feeding difficulties, short stature, muscular hypotonia, microcephaly, characteristic dysmorphic features (hypertelorism, high arched eyebrows, ptosis, deep and/or broad nasal bridge, broad/prominent nasal tip, short and/or upturned philtrum, narrow mouth, and micrognathia), and skeletal anomalies (kyphosis and/or scoliosis, arthrogryposis, slender habitus and extremities). Other clinical features may include hernias, congenital heart defects, cryptorchidism and seizures. [from ORDO]

MRT18 is an autosomal recessive disorder characterized by impaired intellectual development with or without epilepsy. Other features may include spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography (summary by Trehan et al., 2015). [from OMIM]

Tenorio syndrome (TNORS) is characterized by overgrowth, macrocephaly, and impaired intellectual development. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014). [from OMIM]

Developmental and epileptic encephalopathy-78 (DEE78) is a severe neurologic disorder characterized by onset of refractory seizures in the first days or months of life followed by severely impaired intellectual development. Additional features may include cortical visual impairment, hypotonia, and abnormal movements, such as spasticity (summary by Butler et al., 2018). One family with an attenuated disease course has been reported (Maljevic et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Developmental and epileptic encephalopathy-63 (DEE63) is an autosomal recessive neurologic disorder characterized by early-onset refractory infantile spasms and myoclonic seizures in the first months to years of life. Affected individuals have severe to profound developmental delay, often with hypotonia and inability to sit or speak (summary by Redler et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

A subtype of non-spastic cerebral palsy with loss of muscular coordination with abnormal force and rhythm, and impairment of accuracy; commonly presents with gait and trunk ataxia, poor balance, past pointing, terminal intention tremor, scanning speech, nystagmus and other abnormal eye movements, and hypotonia. Low tone is a prominent feature. [from SNOMEDCT_US]

Early-onset neurodegeneration with choreoathetoid movements and microcytic anemia (NDCAMA) is an autosomal recessive disorder characterized by severe psychomotor developmental abnormalities, abnormal movements, and functional iron deficiency (Costain et al., 2019). [from OMIM]

Sodium-dependent multivitamin transporter deficiency (SMVTD) is an autosomal recessive multisystemic metabolic disorder with highly variable manifestations. Affected individuals usually present at birth or in infancy with severe feeding problems, gastrointestinal reflux, cyclic vomiting, and diarrhea associated with failure to thrive. Gastrointestinal hemorrhage may occur; tube-feeding is often required for a short time. The course and severity of the disease varies: some patients have episodes of acute metabolic decompensation during infection that respond well to treatment, whereas others show more permanent neurologic regression with loss of early motor and cognitive milestones in the first year or so of life. Less severely affected patients have normal development or mild growth and motor delays, whereas more severely affected individuals may have seizures, ataxia, spasticity, peripheral neuropathy, immune defects, and osteopenia. In severely affected patients, brain imaging shows cerebral, cerebellar, and brainstem atrophy and thin corpus callosum. Treatment with biotin, pantothenic acid, and alpha-lipoic acid has been shown to result in significant clinical improvement (Byrne et al., 2019; Hauth et al., 2022). [from OMIM]

Neurodevelopmental, jaw, eye, and digital syndrome (NEDJED) is characterized by phenotypic diversity, with patients exhibiting a range of overlapping phenotypes. Most patients show developmental delay ranging from mild to severe, and often have behavioral disorders as well. Brain imaging shows hypoplasia of the corpus callosum, prominence of lateral ventricles, and/or white matter abnormalities. Many patients have retro- or micrognathia, but mild prognathism has also been observed. Ocular anomalies are variably present, and may be severe and complex; however, some patients show only mild myopia. Abnormalities of fingers and toes include brachydactyly, clinodactyly, syndactyly, and contractures; polydactyly is rarely seen (Holt et al., 2019). [from OMIM]