A number sign (#) is used with this entry because neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) is caused by heterozygous mutation in the MEF2C gene (600662) on chromosome 5q14.3.

Heterozygous deletion of the chromosome 5q14.3 region can result in a similar phenotype, sometimes with additional features.

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) is characterized by global developmental delay with hypotonia, poor motor development with limited walking, impaired intellectual development with poor or absent speech, and behavioral abnormalities. Almost all affected individuals demonstrate repetitive stereotypic hand movements that can be categorized as hyperkinetic and resembling those of Rett syndrome (RTT; 312750). About 80% of patients develop various types of seizures that may be refractory to treatment. Additional features may include dysmorphic facial features, particularly dysplastic ears, poor eye contact, episodic hyperventilation, tendency to infection, and abnormalities on brain imaging, such as enlarged ventricles, thin corpus callosum, and delayed myelination (summary by Vrecar et al., 2017, Paciorkowski et al., 2013).

Le Meur et al. (2010) reported a 7-year-old girl (patient 7) with global developmental delay, impaired intellectual development, poor eye contact, absent speech, stereotypic movements, and seizures. Brain MRI showed enlarged ventricles and periventricular white matter hyperintensities.

Zweier et al. (2010) reported 4 unrelated patients with severe developmental delay with absent speech, limited ability to walk, infantile-onset seizures, hypotonia, and variable subtle brain anomalies on imaging, such as enlarged ventricles and decreased myelination. Dysmorphic features included broad forehead, large ears with prominent ear lobes, mild upslanting palpebral fissures, and bowed or tented upper lip. Two additional patients with an overlapping phenotype had deletions involving the MEF2C gene.

Bienvenu et al. (2013) reported an 8-year-old girl who in infancy had poor feeding due to marked hypotonia, and poor eye contact due to strabismus. Motor milestones were delayed, and she walked at age 4 years. At age 18 months, she had a single episode of myoclonic febrile seizures that were easily controlled. At age 7 years, she had poor growth, microcephaly (-2.5 SD), lack of speech, stereotypic movements, unstable wide-based gait, and happy demeanor. There were mild dysmorphic features, including large eyebrows, open mouth with thick everted lower lip, and anteverted nares. Brain MRI was normal.

Carvill et al. (2013) reported 2 unrelated patients with epileptic encephalopathy. The patients had onset at 4 and 13 months, respectively, of multiple seizure types, including febrile seizures, hemiclonic seizures, absence seizures, tonic-clonic seizures, absence seizures, and myoclonic jerks. Both had EEG abnormalities, and 1 showed cognitive regression and autism spectrum disorder. The patients were ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes.

Paciorkowski et al. (2013) reported a 22-month-old girl (LR11-310) with NEDHSIL. She presented with developmental delay at age 11 months, had a febrile seizure at 12 months, and developed myoclonic seizures and atonic seizures at 18 months. The seizures were mostly refractory. She also had repetitive rocking movements and stereotypic hand movements. Brain imaging showed mildly thin white matter.

Vrecar et al. (2017) reported 5 unrelated children, ranging from 2 to 9 years of age, with a severe neurodevelopmental disorder. All had global developmental delay with poor or absent speech, delayed walking (up to 3 years), poor eye contact, and behavioral abnormalities, including autistic traits, happy or excitable demeanor, and preference for playing alone. One was noted to like water, and another to like water, light, and music. Four patients developed febrile seizures followed by afebrile generalized tonic-clonic or absence seizures in the first years of life. All had stereotypic hand movements, particularly of the hands; some patients had bruxism, hand mouthing, or tongue thrusting. Vrecar et al. (2017) noted the phenotypic overlap with other syndromic disorders, including Rett syndrome (RTT; 312750), Angelman syndrome (AS; 105830), and Pitt-Hopkins syndrome (PTHS; 610954).

Gordon et al. (2018) reported a boy who presented in infancy with hypotonia, little spontaneous movement, and severely delayed motor development. At age 2.5 years, he could not stand or walk independently, had poor eye contact, lack of speech, and stereotypic hand movements. Dysplastic ears, including a question mark ear, were noted. He did not have seizures, and brain imaging was normal. The authors suggested disruption of pathways involving development of the second pharyngeal arch.

Borlot et al. (2019) reported a 2-year-old boy with global developmental delay who presented at 7 months with atypical febrile seizures, focal seizures, and myoclonus. EEG showed generalized spike-wave discharges, polyspikes, and multifocal spike and slow waves. He had axial hypotonia, was unable to sit or roll over, and had impaired intellectual development with no speech. Brain imaging showed nonspecific T2-weighted white matter abnormalities in the parietal lobes. The authors retrospectively reviewed the epileptic phenotype of 22 additional patients with MEF2C-related epilepsy. Overall, 19 (82%) of 23 patients had seizures. Febrile seizures were the most common type (43%), with a mean age at onset of 13.5 months (range 3 to 36 months), followed in frequency by myoclonic, focal, generalized, and atonic. Most patients had accompanying EEG abnormalities, with epileptiform discharges as well as background slowing. The report indicated that there is a broad spectrum of seizure types associated with this disorder. Brain imaging tended to show nonspecific T2-weighted white matter abnormalities, cortical atrophy, enlarged ventricles, thin corpus callosum, thin cortical white matter, and delayed myelination.

Wright et al. (2021) reported 10 unrelated patients with NEDHSIL. Clinical details were available for 9 patients. All had global developmental delay with poor or absent speech, 8 had seizures, 5 had hypotonia, and 2 had stereotypic movements. The patients had impaired intellectual development with learning difficulties, sometimes with autistic features. Those with epilepsy had onset of febrile seizures in the first year of life followed by various types of afebrile seizures, including generalized tonic-clonic, myoclonic, absence, and atonic. Additional common features included hypotonia with delayed gross motor skills, broad-based gait, feeding difficulties, dystonic hand movements or stereotypies, bruxism, arachnodactyly, clinodactyly, and joint laxity. Many patients had dysmorphic features, including plagiocephaly, scaphocephaly, strabismus, flat nasal bridge, deep-set eyes, downslanting palpebral fissures, hypertelorism, prominent, low-set, or dysplastic ears, and high-arched palate. A few were noted to have visual impairment, hypermetropia, or myopia; 1 had hearing impairment. One patient had hypoplasia of the corpus callosum on brain imaging.

Chromosome 5q14 Deletion Syndrome

Sobreira et al. (2009) reported an 11-year-old boy with moderate intellectual disability, attention deficit-hyperactivity disorder, bilateral iris coloboma, hearing loss, dental anomaly, and dysmorphic facial features associated with a 7.4-Mb deletion on chromosome 5q14.3-q21.1 (see CYTOGENETICS below). Additional features included short stature, downslanting palpebral fissures, small optic nerves, cup-shaped ears, brachydactyly of the hands, and small feet. The dental anomaly was a misplacement of frontal and lateral incisors. Brain MRI showed a mild delay in myelination, but no structural brain defects.

Le Meur et al. (2010) reported 5 unrelated children, ranging in age from 9 months to 8 years, with severe intellectual disability, absent speech, hypotonia, poor eye contact, and stereotypic movements associated with a deletion of chromosome 5q14. Dysmorphic features included high broad forehead with variable small chin, short nose with anteverted nares, large open mouth, upslanted palpebral fissures, prominent eyebrows, and dysplastic ears, including a 'question mark' ear. Three patients had seizures, including myoclonic, tonic-clonic, and febrile. Brain MRI showed variable changes, including enlarged ventricles, abnormal corpus callosum, and frontoparietal atrophy, but none had periventricular heterotopia.

Novara et al. (2010) reported 2 unrelated boys with severely impaired intellectual development, seizures, hypotonia, lack of speech development, and variable dysmorphic features who carried different heterozygous deletions of chromosome 5q14 involving the MEF2C gene. Both presented in infancy with global psychomotor delay, poor visual contact, and hypotonia. Both had refractory myoclonic seizures, which progressed to refractory infantile spasms in 1. Brain MRI of 1 showed periventricular leukomalacia and frontal lobe atrophy, whereas imaging of the other patient showed ventricular dilatation and hypoplasia of the corpus callosum. Speech was absent in both patients, and 1 showed behavioral stereotypies. One patient had more significant dysmorphic features than the other, including plagiocephaly, hypertelorism, flattened nasal bridge, small and hooked nose, and low-set, dysmorphic ears.

Paciorkowski et al. (2013) reported 15 unrelated patients with de novo heterozygous deletions of chromosome 5q14.3 containing part or all of the MEF2C gene. The patients were ascertained as a cohort and the phenotype was described retrospectively. All had global developmental delay with intellectual disability, absent speech, poor visual tracking, behavioral abnormalities, such as limited social engagement, happy demeanor and inappropriate laughter, high pain tolerance, and sleep disruption. All but 3 patients had seizures, usually with onset in infancy or soon after. The seizures were variable, including infantile spasms with hypsarrhythmia as well as myoclonic, generalized, and atonic seizures. The seizures were refractory in about 50% of cases. A few patients had febrile seizures but did not develop epilepsy. Partial deletion of the MEF2C gene was associated with lack of epilepsy compared to epilepsy among patients with full gene deletions. Almost all patients had hypotonia in infancy, but later developed abnormal constant rapid stereotypic hand movements consistent with a hyperkinetic movement disorder; dystonia and chorea were sometimes observed. The oldest patient was a 46-year-old man with hypokinetic movements with some midline hand wringing and dystonia. Some patients had subtle dysmorphic features, including hypertelorism, cupid-bow upper lip, and hypotonic facies. Gastrointestinal problems, such as gastroesophageal reflux, feeding difficulties, constipation, delayed gastric emptying, and dysphagia were also common. Brain imaging showed asymmetric ventricles, periventricular white matter signals, dysgenesis of the corpus callosum, and mild cerebellar vermis hypoplasia; however, imaging was normal in some patients. The deletions ranged from 0.05 to 11.6 Mb in size with no common breakpoints.

Sobreira et al. (2009) identified a 7.4-Mb deletion on chromosome 5q14.3-q21 (chr5:90,787,099-98,232,469, NCBI36) in an 11-year-old boy with intellectual disability, bilateral iris coloboma, hearing loss, dental anomaly, and dysmorphic facial features, but without periventricular heterotopia. Sobreira et al. (2009) referred to the report by Cardoso et al. (2009), who identified deletions of chromosome 5q14 in patients with periventricular heterotopia (PVNH5; 612881). One of those patients had a unilateral coloboma and shared part of the deletion with the patient reported by Sobreira et al. (2009). Comparison of the shared deleted regions between the 2 patients delineated a putative 2.6-Mb region for coloboma (95,538,699-98,232,465 bp) and a putative 1.84-Mb region for periventricular heterotopia (88,945,075-90,787,099 bp).

Engels et al. (2009) reported 3 unrelated patients with severe psychomotor retardation, seizures, and hypotonia associated with de novo interstitial deletions of chromosome 5q14.3-q15. The 3 deletions were different, measuring 5.7, 3.9, and 3.6 Mb, respectively, but were overlapping. The 1.6-Mb common region contained 5 genes, including CETN3 (602907) and GPR98 (602851); GPR98 is known to be involved in epilepsy. Two of the deletions contained the MEF2C gene, whereas the third did not. Two patients had myoclonic seizures and the third had absence-like seizures. Other features included dysmorphic facies and variable brain anomalies, such as enlarged ventricles, aplasia of the cerebellar vermis and posterior corpus callosum, or white matter abnormalities. One of the patients had concentric myocardial hypertrophy, and another had stereotypic hand movements.

In 5 unrelated children with severe developmental delay, stereotypic movements, epilepsy, and cerebral malformations, Le Meur et al. (2010) identified 5 different interstitial de novo deletions of chromosome 5q14 ranging in size from 216 kb to 8.8 Mb. The minimal common deleted region contained only the MEF2C gene. Le Meur et al. (2010) noted that the chromosome 5q14 region partially overlapped with that deleted in patients with periventricular heterotopia reported by Cardoso et al. (2009), but that only 1 of those patients had deletion of the MEF2C gene. Moreover, none of the patients reported by Le Meur et al. (2010) had periventricular heterotopia.

Array analysis of the 2 patients reported by Novara et al. (2010) showed 2 different deletions of 5q14. One had a 318-kb deletion involving only the MEF2C gene, whereas the other had a larger 1.1-Mb deletion encompassing the MEF2C and TMEM161B genes. None of the breakpoints was similar and none occurred in low copy repeat regions. One deletion was proven to be de novo.

The heterozygous mutations in the MEF2C gene gene that were identified in patients with NEDHSIL by Le Meur et al. (2010) and Wright et al. (2021) occurred de novo.

In a child with NEDHSIL, Le Meur et al. (2010) identified a de novo heterozygous nonsense mutation in the MEF2C gene (S228X; 600662.0001).

Zweier et al. (2010) identified 4 different de novo heterozygous point mutations in the MEF2C gene (see, e.g., 600662.0002-600662.0004) in 4 (1.1%) of 362 probands with intellectual disability who were screened for mutations in this gene. Two of the mutations were missense and 2 were truncating. Two additional patients with a similar disorder had heterozygous deletions (2.4- and 1.5-Mb, respectively) involving the MEF2C gene. Analysis of blood-derived RNA showed significantly decreased levels of MEF2C isoform-2 mRNA in all patients with deletions in the MEF2C region, including the patients reported by Engels et al. (2009), Cardoso et al. (2009), and Le Meur et al. (2010), suggesting haploinsufficiency as the disease mechanism. Decreased MEF2C levels were also found in the patient reported by Engels et al. (2009) whose deletion did not directly affect the MEF2C gene, consistent with a regulatory positional effect. The 2 patients with missense mutations did not show decreased MEF2C mRNA levels. All deletions and mutations caused significantly decreased MEF2C transcriptional activity, which could be rescued by wildtype MEF2C. The MEF2C gene was demonstrated to activate promoters of the MECP2 (300005) and CDKL5 (300203) genes. Finally, all patients, including the 2 with missense mutations, showed decreased levels of MECP2 mRNA, and all except 2 patients had decreased levels of CDKL5 mRNA. These 2 genes are involved in Rett or Rett syndrome-like phenotypes (312750 and 300672, respectively), which share some features with MRD20. Zweier et al. (2010) concluded that the phenotype results from involvement of a common pathway involving these 3 genes.

In an 8-year-old girl with severe NEDHSIL, Bienvenu et al. (2013) identified a de novo heterozygous frameshift in the MEF2C gene (600662.0005). Functional studies were not performed.

In a 22-month-old girl with NEDHSIL, Paciorkowski et al. (2013) identified a heterozygous frameshift mutation in the MEF2C gene (600662.0006). Functional studies of the variant, studies of patient cells, and segregation were not reported.

In 5 unrelated children with NEDHSIL, Vrecar et al. (2017) identified de novo heterozygous mutations in the MEF2C gene. Four patients carried small intragenic deletions affecting the N-terminal region, and 1 carried a nonsense mutation (E74X; 600662.0007). Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in haploinsufficiency.

In 10 unrelated patients with NEDHSIL, Wright et al. (2021) identified 10 de novo heterozygous point mutations or small intragenic deletions affecting the 5-prime untranslated region (UTR) of the MEF2C gene (see, e.g., 600662.0008-600662.0010). The mutations in the first patients were found by specific analysis of the 5-prime UTR regions in a select group of candidate genes. Additional patients with similar point mutations or small copy number variants (CNVs) affecting only the 5-prime UTR of MEF2C were subsequently identified from different patient cohorts through international collaboration. Two patients carried mutations that created upstream start codons (uAUGs) that were out-of-frame with the coding sequencing, predicted to result in premature termination. Six patients carried mutations that created uAUGs that were in-frame with the coding sequencing, predicted to result in N-terminal extensions. The CNVs identified in 2 patients were predicted to remove the promoter and part of the 5-prime UTR, which would abolish normal transcription. Wright et al. (2021) noted that the N terminus of the protein is in direct contact with DNA, indicating that this is a functional domain. In vitro functional expression studies using a luciferase reporter showed that the point mutations decreased MEF2C translational efficiency and had reduced activation of target gene transcription to varying degrees compared to wildtype. The findings were most consistent with haploinsufficiency as the disease mechanism. Wright et al. (2021) concluded that disease-causing 5-prime UTR variants can be detected in exome sequencing datasets that were designed to capture coding sequencing, and may be an important tool to increase diagnostic yield.