Syndromic microphthalmia-9 (MCOPS9), also referred to as pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect, is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The phenotype is variable, ranging from isolated clinical anophthalmia or microphthalmia to complex presentations involving the cardiac, pulmonary, diaphragmatic, and renal systems. At its most severe, infants are born without pulmonary structures and die soon after birth (Marcadier et al., 2015).

X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (Bonneau et al., 2002). LISX2 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 to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

A rare genetic neurological disease characterized by progressive encephalopathy, early-onset seizures with a hypsarrhythmic pattern, facial and limb edema, severe hypotonia, early arrest of psychomotor development and craniofacial dysmorphism (evolving microcephaly, narrow forehead, short nose, prominent auricles, open mouth, micrognathia), in the absence of neuro-ophthalmic or neuroradiologic findings. Poor visual responsiveness, growth failure and tapering fingers are also associated. There is evidence the disease is caused by homozygous mutation in the CCDC88A gene on chromosome 2p16.

Microhydranencephaly (MHAC) is a severe neurodevelopmental defect characterized by extreme microcephaly, profound motor and mental retardation, spasticity, and incomplete cerebral formation. Radiologic studies show gross dilation of the ventricles resulting from the absence of cerebral hemispheres or severe delay in their development, as well as hypoplasia of the corpus callosum, cerebellum, and brainstem (summary by Guven et al., 2012).

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Christianson syndrome (referred to as CS in this GeneReview), an X-linked disorder, is characterized in males by cognitive dysfunction, behavioral disorder, and neurologic findings (e.g., seizures, ataxia, postnatal microcephaly, and eye movement abnormalities). Males with CS typically present with developmental delay, later meeting criteria for severe intellectual disability (ID). Behaviorally, autism spectrum disorder and hyperactivity are common, and may resemble the behaviors observed in Angelman syndrome. Hypotonia and oropharyngeal dysphagia in infancy may result in failure to thrive. Seizures, typically beginning before age three years, can include infantile spasms and tonic, tonic-clonic, myoclonic, and atonic seizures. Subsequently, regression (e.g., loss of ambulation and ability to feed independently) may occur. Manifestations in heterozygous females range from asymptomatic to mild ID and/or behavioral issues.

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. For a general discussion of CDGs, see CDG1A (212065).

ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by Aldahmesh et al., 2011).

Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with KCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE resulting from other causes. Less common seizure phenotypes in individuals with KCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.

Developmental and epileptic encephalopathy-18 (DEE18) is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, and early onset of refractory seizures. Brain imaging shows a thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by Basel-Vanagaite et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.

Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by Zhang et al., 2014).

Rothmund-Thomson syndrome type 3 (RTS3) is characterized by poikiloderma, sparse hair, short stature, and skeletal defects. Patients also exhibit microcephaly, with moderate to severe neurodevelopmental delay and seizures (Averdunk et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of Rothmund-Thomson syndrome, see RTS2 (268400).

Autosomal recessive intellectual developmental disorder-43 (MRT43) is characterized by impaired intellectual development, poor language skills, short stature, and dysmorphic features. Some patients may have significant motor delays (summary by Gangfuss et al., 2022).

Developmental and epileptic encephalopathy-21 (DEE21) is an autosomal recessive neurologic disorder characterized by the onset of intractable seizures in the first months of life. Affected individuals have severely impaired psychomotor development with poor head control and inability to fix and follow visually. Other features may include axial hypotonia, peripheral hypertonia, and cerebral atrophy or delayed myelination on brain imaging (summary by Alazami et al., 2014 and Alsahli et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

GPIBD11 is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, and variable seizures. Some patients may have dysmorphic features or increased serum alkaline phosphatase. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Hogrebe et al., 2016). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the OPA1 gene.

UNC80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. The majority of individuals do not learn to walk. All individuals lack expressive language; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional features can include nystagmus, extremity hypertonia, a high-pitched cry, repetitive and self-stimulatory behaviors, constipation, clubfeet, joint contractures, and scoliosis. For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have a loss of skills suggestive of neurodegeneration.

Infants with ISCA2-related mitochondrial disorder (IRMD) typically attain normal development in the first months of life. At age three to seven months, affected individuals usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. As the disease progresses, global psychomotor regression continues at a variable pace and seizures may develop. Affected children become vegetative within one to two years. During their vegetative state, which may persist for years, affected individuals are prone to recurrent chest infections that may require ventilator support. Most affected individuals die during early childhood.

Band heterotopia (BH) is a neuronal migration disorder in which aberrantly located neurons, in the form of a band in the brain white matter, are present below a cortex that appears relatively normal by magnetic resonance imaging (MRI). Clinically, patients show severe developmental delay with intellectual disability, seizures, hypotonia, and hydrocephalus (Kielar et al., 2014, Shaheen et al., 2017).

Developmental and epileptic encephalopathy-49 (DEE49) is a severe autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period, global developmental delay with intellectual disability and lack of speech, hypotonia, spasticity, and coarse facial features. Some patients may have brain calcifications on imaging (summary by Han et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Developmental and epileptic encephalopathy-40 (DEE40) is an autosomal recessive neurologic disorder characterized by the onset of refractory infantile spasms within the first 6 months of life. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show developmental stagnation and severe neurologic impairment. EEG typically shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Additional features include poor feeding, axial hypotonia with peripheral spasticity, limited eye contact, profoundly impaired intellectual development with absent language, and poor fine motor skills (summary by Alfaiz et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Developmental and epileptic encephalopathy-38 (DEE38) is an autosomal recessive neurologic and neurodegenerative disorder characterized by the onset of various type of seizures usually between about 4 and 7 months of age. Prior to the onset of seizures, most infants show severely impaired global development, hypotonia with poor head control, and visual inattention with roving eye movements and nystagmus. Seizures are usually refractory to treatment and associated with status epilepticus. Patients have little or no development with inability to walk or speak, spasticity or abnormal movements, and often cortical blindness. There is failure to thrive, and many require tube-feeding. Death in early childhood due to aspiration or intractable epilepsy may occur. The disorder is associated with a defect in GPI-anchoring of membrane-bound proteins (summary by Palmer et al., 2016; Davids et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

NMIHBA is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay apparent from infancy and profoundly impaired intellectual development. Affected individuals have microcephaly with accompanying dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows variable abnormalities, including cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination (summary by Zollo et al., 2017).

NELABA is a severe autosomal recessive metabolic disorder characterized by onset at birth of progressive encephalopathy associated with increased serum lactate. Affected individuals have little or no psychomotor development and show brain abnormalities, including cerebral atrophy, cysts, and white matter abnormalities. Some patients die in infancy (summary by Habarou et al., 2017).

Developmental and epileptic encephalopathy-57 (DEE57) is a neurologic disorder characterized by global developmental delay with hypotonia, variably impaired intellectual development, and poor or absent language. Affected individuals have onset of refractory multifocal seizures in the first days or months of life, and may show developmental regression. EEG patterns include hypsarrhythmia, suggesting a clinical diagnosis of West syndrome, background slowing, and epilepsy of infancy with migrating focal seizures (EIMFS). Some patients may have mild dysmorphic features (summary by Ambrosino et al., 2018 and Mao et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Hypomyelinating leukodystrophy-17 is an autosomal recessive neurodevelopmental disorder characterized by poor, if any, development apparent from infancy. Affected individuals never learn to walk or speak, and have early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging shows multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination. Some patients may die in childhood (summary by Shukla et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.

Hypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (summary by Bjursell et al., 2011).

Squalene synthase deficiency (SQSD) is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to Smith-Lemli-Optiz syndrome. Key clinical features include facial dysmorphism, a generalized seizure disorder presenting in the neonatal period, nonspecific structural brain malformations, cortical visual impairment, optic nerve hypoplasia, profound developmental delay / intellectual disability, dry skin with photosensitivity, and genital malformations in males.

The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families. Infantile-onset phenotype. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus; some children have hypsarrhythmia on EEG. All have developmental delay; most are nonverbal and unable to walk. Feeding difficulties are common. More than half of affected children die in early childhood. Later-onset phenotype. All affected individuals have spastic paraplegia manifested by weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties; some have developmental delay/intellectual disability; some have brief seizures that resolve over time.

Microcephaly, growth deficiency, seizures, and brain malformations (MIGSB) is a severe autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency with severe microcephaly, and poor or absent psychomotor development. Additional features include optic atrophy, early-onset seizures, dysmorphic facial features, and brain malformations, such as partial agenesis of the corpus callosum and simplified gyration (summary by Shaheen et al., 2015).

Developmental and epileptic encephalopathy-75 (DEE75) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by onset of severe refractory seizures in the first months of life. Patients often have global developmental delay before the onset of seizures, and thereafter achieve few milestones. EEG usually shows multifocal spikes and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. They have severely impaired intellectual development with inability to walk, absent speech, and hypotonia with axial hyperreflexia. Brain imaging shows progressive cerebral atrophy, frontal lobe atrophy, white matter abnormalities, and delayed myelination. Since the disorder is due to mitochondrial dysfunction, some patients may develop other organ involvement, including cardiomyopathy or liver and renal dysfunction. Death may occur in childhood (summary by Yin et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

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).

Cerebellar atrophy with seizures and variable developmental delay (CASVDD) is an autosomal recessive neurologic disorder characterized by cerebellar ataxia associated with atrophy of the cerebellar vermis on brain imaging. Most patients also have onset of severe refractory seizures in the first year of life and show global developmental delay, compatible with epileptic encephalopathy (summary by Edvardson et al., 2013). However, at least 1 patient with normal cognitive development and only 1 febrile seizure has been reported (Valence et al., 2019), suggesting significant clinical variability of this disorder.

Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis (NEDBSS) is an autosomal recessive disorder characterized by severely impaired psychomotor development, hypotonia, seizures, and structural brain anomalies, including thin corpus callosum and cerebellar atrophy. Other features include scoliosis, dysmorphic facies, and visual impairment. Affected individuals are usually unable to walk or speak and may require tube feeding in severe cases. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Knaus et al., 2019). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (NEDBASS) is an autosomal recessive neurologic disorder characterized by global developmental delay apparent from early infancy, poor overall growth often with microcephaly, impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum. Early death may occur (summary by Bend et al., 2020).

Kilquist syndrome (KILQS) is an autosomal recessive multisystem disorder characterized by neurologic, gastrointestinal, and secretory dysfunction. Affected individuals present at birth with hypotonia, feeding difficulties, mild dysmorphic features, and sensorineural hearing loss. They show poor overall growth associated with gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, as well as profound global developmental delay with inability to sit or speak. Tear, sweat, and saliva production is also impaired, causing dry mouth and recurrent bronchial mucus plugging. Some of the clinical features are reminiscent of cystic fibrosis (CF; 219700) (summary by Stodberg et al., 2020).

Developmental and epileptic encephalopathy-90 (DEE90) is an X-linked neurologic disorder characterized by onset of refractory seizures in the first days or months of life. Although most patients have focal seizures associated with oromotor automatisms and apnea, various seizure types may occur, including epileptic spasms, generalized tonic-clonic, and absence. EEG shows multifocal discharges; hypsarrhythmia, intermittent burst suppression, and slow spike-wave background resembling Lennox-Gastaut syndrome may also be observed. Affected individuals have global developmental delay with variable severity, but it is usually profound or severe. Some are unable to walk or speak, whereas others may achieve some milestones and show autistic features (summary by Fry et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Infantile hypotonia with psychomotor retardation and characteristic facies-3 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently (summary by Bhoj et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-1 (TEBIVANED1) is characterized by poor overall growth with short stature, microcephaly, hypotonia, profound global developmental delay often with poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur (Tessadori et al., 2017). Genetic Heterogeneity of Tessadori-van Haaften Neurodevelopmental Syndrome See also TEBIVANED2 (619759), caused by mutation in the H4C11 gene (602826); TEBIVANED3 (619950), caused by mutation in the H4C5 gene (602830); and TEBIVANED4 (619951), caused by mutation in the H4C9 gene (602833).

Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Dentici-Novelli neurodevelopmental syndrome (DENNED) is an autosomal recessive disorder characterized by global developmental delay with impaired intellectual development apparent from infancy. The severity of the phenotype is highly variable: more severely affected individuals have axial hypotonia, peripheral spasticity, microcephaly, early-onset seizures, brain imaging abnormalities, and are unable to walk or speak. Those with a less severe phenotype may achieve some developmental goals and show less severe intellectual disability (Dentici et al., 2022).

Developmental and epileptic encephalopathy-110 (DEE110) is an autosomal recessive disorder characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life. Affected individuals achieve almost no developmental milestones and show impaired intellectual development, poor or absent speech, inability to walk or grasp objects, peripheral spasticity, and poor eye contact. Brain imaging shows hypoplastic corpus callosum and cortical atrophy (Dahimene et al., 2022). For a discussion of genetic heterogeneity of DEE, see 308350.

Congenital muscular dystrophy with or without seizures (MYOS) is an autosomal recessive disorder characterized by severe muscle hypotonia apparent from birth, as well as developmental delay. Laboratory studies show increased serum creatine kinase and muscle biopsy shows nonspecific dystrophic features. Most patients develop seizures or have abnormal epileptiform findings on EEG studies; other variable findings may include feeding difficulties, nystagmus, myopathic facies, areflexia, and brain atrophy on MRI (summary by Larson et al., 2018 and Henige et al., 2021).