-Related Neurodevelopmental Disorder

CLINICAL CHARACTERISTICS

-related neurodevelopmental disorder (-NDD) is typically a progressive condition in which individuals have significant developmental and respiratory issues. A majority of affected individuals do not achieve independent ambulation or spoken language. Most affected individuals also have congenital and severe hypotonia, which can also lead to feeding issues and dysphagia, with many affected individuals requiring gastrostomy tube placement. Neuromuscular weakness usually affects the distal muscles first, leading to distal muscle wasting, and then the proximal muscles become involved. Electrophysiologic studies suggest that weakness is secondary to a motor neuronopathy. Respiratory issues are also progressive, with most affected individuals requiring noninvasive nocturnal respiratory support by age five years and about 75% of teenagers requiring a tracheostomy. Seizures are also common, and brain MRI imaging may show white matter lesions and progressive cortical atrophy over time. Most affected individuals exhibit some degree of developmental regression and/or neurologic decompensation in the setting of illness, which often raises clinical concerns for mitochondrial disorders. Other features include vision issues (including optic atrophy), the development of contractures and neuromuscular scoliosis, coarsening of facial features over time, recurrent nephrolithiasis and/or urinary tract infections, dyslipidemia without clear adverse cardiovascular events, and the development of left ventricular hypertrophy.

DIAGNOSIS/TESTING: The diagnosis of -NDD is established in a proband with suggestive findings and biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

Gastrostomy tube placement may be required for ongoing feeding issues and/or dysphagia. Nocturnal ventilatory support and/or tracheostomy may be required for those who have apnea and/or progressive neuromuscular weakness. Standard treatment for developmental delay / intellectual disability / neurobehavioral issues, epilepsy, neuromuscular weakness, spasticity/contractures, growth deficiency, bowel dysfunction, pancreatitis, osteopenia / frequent fractures, eye/vision issues, left ventricular hypertrophy, recurrent urinary tract infections, nephrolithiasis, and neurogenic bladder. No treatment is typically necessary for macroglossia. It remains unclear if treatment of dyslipidemia has a clinically meaningful impact. At each visit: measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for constipation and signs/symptoms of pancreatitis; monitor for signs/symptoms of chronic respiratory insufficiency, nocturnal hypoventilation, and apnea; assess for new manifestations, such as seizures, changes in tone, and weakness; monitor those with seizures as clinically indicated; assess for developmental progress and educational needs; assess for neurobehavioral concerns; and assess for progressive contractures and bony fractures. Annually or as clinically indicated: ophthalmology evaluation. Every one to two years: complete lipid panel; echocardiogram to assess for left ventricular hypertrophy (if symptomatic; or starting in adolescence). Every two to three years: DXA scan to evaluate for osteopenia. Based on clinical concern: sleep study; evaluation for urinary tract infections, neurogenic bladder, and nephrolithiasis. Some affected individuals have been reported to have adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the -NDD population remain unclear, so close monitoring is advised if bisphosphonates are clinically indicated.

GENETIC COUNSELING

-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception 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 and prenatal/preimplantation genetic testing are possible.