Neurodevelopmental Disorder With Epilepsy, Cataracts, Feeding Difficulties, And Delayed Brain Myelination

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM) is caused by heterozygous mutation in the NACC1 gene (610672) on chromosome 19p13.

Description

Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination is a syndromic form of severe to profound intellectual disability with onset of delayed psychomotor development and seizures in infancy. Affected children have hypotonia, feeding difficulties resulting in failure to thrive, and inability to speak or walk, and they tend to show repetitive stereotypic behaviors. Brain imaging shows cerebral atrophy and delayed myelination (summary by Schoch et al., 2017).

Clinical Features

Schoch et al. (2017) reported 7 unrelated patients, ranging in age from 13 months to 18 years, with a similar neurodevelopmental disorder with severe to profound intellectual disability and a recurrent mutation in the NACC1 gene. All patients had global developmental delay apparent from infancy as well as severe feeding difficulties resulting in failure to thrive and often necessitating a feeding tube. Six patients were more severely affected; these patients had hypotonia, onset of seizures in the first year of life, which were often associated with developmental regression, and they were unable to sit, walk, speak, or track visually. At least 3 patients had hypsarrhythmia on EEG, although seizures in the patients overall were variably controlled. Other features included early-onset bilateral cataracts, sleep disorders, stereotypic hand movements, irritability, and breath-holding spells. Five patients had microcephaly, and some had dysmorphic features, but the only common feature was a broad nasal tip. Brain imaging showed cerebral atrophy, reduced white matter, and delayed myelination. One of the older patients had spasticity, joint contractures, and scoliosis at age 18 years. One patient, a 12-year-old boy who was mosaic for the mutation, had severe speech delay but could walk with difficulty. This patient had a single febrile seizure at age 2 years, and later developed nocturnal seizures.

Inheritance

Schoch et al. (2017) demonstrated that the inheritance pattern of NECFM is autosomal dominant.

Molecular Genetics

In 7 unrelated patients with NECFM, Schoch et al. (2017) identified a recurrent de novo heterozygous missense mutation in the NACC1 gene (R298W; 610672.0001). One of the patients (patient 7) was mosaic for the mutation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not confirmed.