Disorder

CLINICAL CHARACTERISTICS

disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.

DIAGNOSIS/TESTING: The diagnosis of disorder is established in a proband with congenital hypotonia and biallelic pathogenic (or likely pathogenic) variants in identified by molecular genetic testing.

MANAGEMENT

: Hearing aids may be helpful for those with hearing loss; ventilator support (e.g., BiPAP) for respiratory distress; consideration of Robinul or Botox injections for severe sialorrhea; feeding therapy and consideration of gastrostomy tube placement for persistent feeding difficulties and/or concern about aspiration; standard treatment for developmental delay / intellectual disability, epilepsy, cortical vision impairment, constipation, and spasticity / joint contractures. Assessment for new neurologic manifestations and/or adequacy of seizure control, developmental progress, growth and nutritional status, constipation, and joint mobility at each visit; ophthalmology evaluation every one to two years in those with optic atrophy; audiology evaluation as clinically indicated; sleep study every one to two years.

GENETIC COUNSELING

disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.