ENTPD1-Related Neurodevelopmental Disorder

Excerpt

Clinical characteristics: ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) is characterized by developmental delay / intellectual disability (ranging from borderline/mild to moderate/severe) and onset of progressive spastic paraplegia with progressive gait impairment beginning before age five years. Difficulty with balance and frequent falling are common and can result in loss of independent ambulation and wheelchair dependence in the teenage to young adult years.

Other neuromuscular findings can include abnormal deep tendon reflexes, weakness, neuropathy, epilepsy, dysarthria, and dysphagia. Behavior abnormalities and neurocognitive regression are common. Life span does not appear to be shortened.

Diagnosis/testing: The diagnosis of ENTPD1-NDD is established in a proband with suggestive clinical findings and biallelic pathogenic variants in ENTPD1 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for ENTPD1-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Multidisciplinary care is recommended by specialists in neurology (including treatment of seizures); developmental pediatrics and education (to address developmental delay / intellectual disability and need for individual education plan); physical medicine and rehabilitation / physical therapy and occupational therapy (including stretching to help avoid contractures and falls, facilitating activities of daily living, and use of positioning and mobility devices); speech-language pathology (to address dysarthria and dysphagia); orthopedics (to address scoliosis); and psychologists, behavioral therapists, and/or psychiatrists (to address behavioral issues with behavioral interventions and/or medications and to address issues associated with neurocognitive decline).

Surveillance: Regular clinic visits with the treating specialists are recommended to monitor existing or progressing manifestations and the individual's response to supportive care.

Genetic counseling: ENTPD1-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ENTPD1 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 inheriting neither of the familial pathogenic variants. Once the ENTPD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.