KMT2E-Related Neurodevelopmental Disorder

Excerpt

Clinical characteristics: KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition characterized by global developmental delay, variable intellectual disability (typically in the mild-to-moderate range), and hypotonia. The majority of affected individuals are verbal but experience speech delays with or without articulation problems. All reported individuals who are older than infants have been able to obtain independent ambulation. About one third of affected individuals develop seizures, with no consistent seizure semiology or epilepsy syndrome. However, females may be more likely to develop seizures compared to males. Similarly, about one third of affected individuals have an autism spectrum disorder diagnosis, of which most to date are male. Growth parameters are typically in the normal range for length/height and weight, although about half of affected individuals have macrocephaly or relative macrocephaly. Constipation is the most frequent gastrointestinal issue, although gastroesophageal reflux, vomiting, and/or reduced bowel motility have been reported in almost half of affected individuals. About half of affected individuals experience some type of sleep disturbance, including frequent awakening and difficulties falling asleep.

Diagnosis/testing: The diagnosis of KMT2E-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2E identified by molecular genetic testing.

Management: Treatment of manifestations: Standard treatment for developmental delay / intellectual disability, neuropsychiatric issues, seizures, constipation, gastroesophageal reflux/dysmotility, vomiting, and sleep disturbance.

Surveillance: At each visit, measure growth parameters (including head circumference); assess for new neurologic manifestations and monitor those with seizures as clinically indicated; monitor developmental progress and educational need; assess for behavioral issues, including anxiety, ADHD, aggression, and self-injury; and assess for chronic vomiting, constipation, and signs/symptoms of sleep disturbance.

Genetic counseling: KMT2E-NDD is an autosomal dominant disorder. Most probands reported to date with KMT2E-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with KMT2E-NDD inherited a pathogenic variant from an affected parent who typically has mild intellectual disability. Each child of an individual with KMT2E-NDD has a 50% chance of inheriting the pathogenic variant. Once the KMT2E pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.