MedGen

The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported. [from GeneReviews]

GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy. [from GeneReviews]

Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (Herman et al., 2007). Some patients may have a primary immunodeficiency disorder with recurrent infections associated with variably abnormal T- and B-cell function (Tsujita et al., 2016). [from OMIM]

Autosomal recessive limb-girdle muscular dystrophy-18 (LGMD18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). [from OMIM]

Intellectual developmental disorder with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by Le Fevre et al., 2013). [from OMIM]

7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior problems including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilatation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies. [from GeneReviews]

PACS1 neurodevelopmental disorder (PACS1-NDD) is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Hypotonia is reported in about a third of individuals and is noted to improve over time. Approximately 60% of individuals are ambulatory. Feeding difficulty is common, with 25% requiring gastrostomy tube to maintain appropriate caloric intake. Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, short stature, and microcephaly. Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth. To date approximately 35 individuals with PACS1-NDD have been reported. [from GeneReviews]

EBF3 neurodevelopmental disorder (EBF3-NDD) is associated with developmental delay (DD) / intellectual disability (ID), speech delay, gait or truncal ataxia, hypotonia, behavioral problems, and facial dysmorphism. Variability between individuals with EBF3-NDD is significant. Although all affected children have DD noted in early infancy, intellect generally ranges from mild to severe ID, with two individuals functioning in the low normal range. Less common issues can include genitourinary abnormalities and gastrointestinal and/or musculoskeletal involvement. To date, 42 symptomatic individuals from 39 families have been reported. [from GeneReviews]

X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015). [from OMIM]

Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and delayed speech acquisition. Affected individuals tend to have expressive language deficits, with speech apraxia and dysarthria. Other features include macrocephaly and characteristic facial features, such as prominent forehead and hypertelorism, hypotonia, and joint laxity. The severity of the neurologic deficits and presence of nonneurologic features is variable (summary by Snijders Blok et al., 2018). [from OMIM]

Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging (summary by Fountain et al., 2019). [from OMIM]

Autosomal dominant intellectual developmental disorder-61 (MRD61) is characterized by global developmental delay apparent in infancy with mildly impaired intellectual development, expressive speech delay, and behavioral abnormalities, including autism spectrum disorder and attention deficit-hyperactivity disorder (ADHD). Most affected individuals learn to walk on time or with some mild delay. Additional features are highly variable and may include nonspecific dysmorphic features, obstipation, ocular anomalies, and poor overall growth (Snijders Blok et al., 2018). [from OMIM]

Stolerman neurodevelopmental syndrome (NEDSST) is a highly variable disorder characterized by developmental delay, often with motor and speech delay, mildly impaired intellectual development (in most patients), learning difficulties, and behavioral abnormalities, including autism spectrum disorder. Psychosis is observed in a small percentage of individuals over the age of 12 years. Most individuals have nonspecific and mild dysmorphic facial features without a common gestalt. A subset of patients may have involvement of other organ systems, including gastrointestinal with poor early feeding or gastroesophageal reflux, distal skeletal anomalies, and congenital heart defects. Most mutations occur de novo, but rare autosomal dominant inheritance with incomplete penetrance has been observed (Stolerman et al., 2019; Rots et al., 2023). [from OMIM]

Pilarowski-Bjornsson syndrome (PILBOS) is an autosomal dominant neurodevelopmental disorder characterized by delayed development, impaired intellectual development, often with autistic features, speech apraxia, and mild dysmorphic features. Some patients may have seizures. The phenotype is somewhat variable (summary by Pilarowski et al., 2018). [from OMIM]

Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) is a neurodevelopmental disorder characterized by delayed walking due to ataxia, intention tremor, and hypotonia apparent from early childhood. Affected individuals have global developmental delay with mildly impaired intellectual development and speech delay or learning disabilities. Eye movement abnormalities may also be present. Brain imaging shows cerebellar atrophy in some patients (summary by Webb et al., 2021). [from OMIM]

Marbach-Schaaf neurodevelopmental syndrom (MASNS) is characterized by global developmental delay with speech delay and behavioral abnormalities, including autism spectrum disorder and ADHD. Affected individuals also show movement disorders, such as dyspraxia and apraxia. More variable features include high pain tolerance, sleep disturbances, and variable nonspecific dysmorphic features (summary by Marbach et al., 2021). [from OMIM]

A type of apraxia that is characterized by difficulty or inability to execute speech movements because of problems with coordination and motor problems, leading to incorrect articulation. An increase of errors with increasing word and phrase length may occur. [from HPO]