MedGen

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years. [from GeneReviews]

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002). Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II Multiple forms of CDG type II have been identified; see CDG2B (606056) through CDG2Z (620201), and CDG2AA (620454) to CDG2BB (620546). [from OMIM]

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported. [from GeneReviews]

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. A subset of individuals show a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. To date, 72 individuals with GRIN1-NDD have been reported. [from GeneReviews]

X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (XDIBS), or Pettigrew syndrome is a central nervous system malformation characterized by severe intellectual deficit, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, dysmorphic face (long face with prominent forehead), and brain imaging abnormalities such as Dandy-Walker malformation, and iron deposition. (From Mondo:0010574) [from NCBI]

Patients with chromosome 2q37 deletion syndrome show highly variable clinical manifestations likely resulting from different deletion sizes and deletions of different genes. Variable clinical features included brachydactyly type E (BDE), affecting the metacarpals and metatarsals (in about 50% of patients), short stature, mild to moderate intellectual disability, behavioral abnormalities, and dysmorphic facial features. However, many individuals with deletions do not show cognitive deficits (summary by Villavicencio-Lorini et al., 2013, Wheeler et al., 2014, Jean-Marcais et al., 2015). [from OMIM]

X-linked intellectual developmental disorder-98 (XLID98) is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by de Lange et al., 2016). [from OMIM]

Developmental and epileptic encephalopathy-26 (DEE26) is a neurologic disorder characterized by onset of variable types of seizures late in infancy or in the first years of life. Affected children show developmental delay with intellectual disability, poor speech, and behavioral abnormalities. EEG shows multifocal epileptic discharges, and may show hypsarrhythmia (summary by Torkamani et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB) is characterized by impaired intellectual development or developmental delay, behavioral abnormalities including autistic features, and language impairment. Other features include seizures and developmental regression (Salpietro et al., 2019). [from OMIM]

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB) is characterized by global developmental delay apparent since infancy or early childhood, hypotonia with delayed motor development, impaired intellectual development with significant speech delay or absent speech, and variable behavioral abnormalities, such as autism, repetitive actions, or aggression. About two-thirds of patients have early-onset seizures that range from intractable to self-limiting. More variable features include nonspecific dysmorphic facial features, distal skeletal anomalies, and brain imaging abnormalities. The phenotypic manifestations and severity are highly variable (Muir et al., 2021). [from OMIM]

Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200). [from OMIM]

NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021). [from OMIM]

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements (NEDNEH) is an autosomal recessive severe neurologic disorder characterized by delayed psychomotor development with inability to walk or speak, early-onset refractory seizures, and nonepileptic hyperkinetic movement disorders, including myoclonus dystonia and dyskinesias. Patients require tube feeding and may die of respiratory failure in childhood or in the second decade (summary by Gorman et al., 2019). [from OMIM]

Den Hoed-de Boer-Voisin syndrome (DHDBV) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of DHDBV include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021). [from OMIM]

Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (NEDHAHM) is characterized by axial hypotonia apparent from birth, global developmental delay with impaired intellectual development and poor or absent language acquisition, and behavioral abnormalities, including autistic features, poor social interaction, and hang-wringing. Most patients have childhood-onset seizures that are usually responsive to medication, and a subset of patients develop cortical visual impairment and involuntary hyperkinetic movements, including chorea and dystonia. Some of the features are reminiscent of Rett syndrome (RTT; 312750) (summary by Salpietro et al., 2019). [from OMIM]

Developmental and epileptic encephalopathy-97 (DEE97) is characterized by developmental delay, epileptic encephalopathy, and impaired intellectual development. Other clinical features may include autistic features and hypotonia. For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758). [from OMIM]

Habitual clasping and wringing of the hands in the middle of the body, similar to a hand-washing movement. [from HPO]