A lethal combination of manifestations including short stature, congenital cataracts, encephalopathy with epileptic fits and postmortem confirmation of nephropathy (renal tubular necrosis). The combination has been described in 2 female infant children of first cousin parents. The infants did not survive beyond 4 and 8 months respectively. There have been no further descriptions in the literature since 1963.

A rare genetic non-syndromic central nervous system malformation with characteristics of absence of the telencephalon and absent or abnormal diencephalic structures, combined with severe abnormalities of the mesencephalon and cerebellum. Further malformations, for example of the hands and feet, have been described in addition.

The category of 3-methylglutaconic aciduria type IV (MGCA4) represents a heterogeneous unclassified group of patients who share mild or intermittent urinary excretion of 3-methylglutaconic acid. MGCA excretion is a nonspecific finding observed in many other disorders caused by defects in mitochondrial energy metabolism (Gunay-Aygun, 2005). For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950)

Chudley-McCullough syndrome is an autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal (summary by Alrashdi et al., 2011).

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (van Reeuwijk et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Beltran-Valero de Bernabe et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

An autosomal recessive muscular dystrophy caused by mutations in the POMGNT1 gene. It is associated with characteristic brain and eye malformations, profound mental retardation, and death usually in the first years of life.

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The brain shows cobblestone lissencephaly, a cortical malformation. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Vuillaumier-Barrot et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Stevens et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

Myopathy with extrapyramidal signs is an autosomal recessive disorder characterized by early childhood onset of proximal muscle weakness and learning disabilities. While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling (summary by Logan et al., 2014). Brain MRI in 1 patient showed congenital malformations, including polymicrogyria and cerebellar dysplasia (Wilton et al., 2020).

Poretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (summary by Aldinger et al., 2014).

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320).

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.

ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures (summary by Gueneau et al., 2018).

Congenital muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) are characterized by early onset of muscle weakness, usually before ambulation is achieved; intellectual disability mild brain anomalies are variable (Balci et al., 2005; Godfrey et al., 2007). Congenital muscular dystrophy-dystroglycanopathies with or without impaired intellectual development (type B) represent the intermediate range of the spectrum of dystroglycanopathies. They are less severe than muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, 236670), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and more severe than limb-girdle muscular dystrophy-dystroglycanopathy (type C; see MDDGC1, 609308). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with or without Impaired Intellectual Development (Type B) Congenital muscular dystrophy with impaired intellectual development due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGB2 (613156), caused by mutation in the POMT2 gene (607439); MDDGB3 (613151), caused by mutation in the POMGNT1 gene (606822); MDDGB4 (613152), caused by mutation in the FKTN gene (607440); MDDGB5 (616612), caused by mutation in the FKRP gene (606596); MDDGB6 (608840), caused by mutation in the LARGE gene (603590); MDDGB14 (615351), caused by mutation in the GMPPB gene (615320); and MDDGB15 (618992), caused by mutation in the DPM3 gene (605951).