DLG4-Related Synaptopathy

Excerpt

Clinical characteristics: DLG4-related synaptopathy is characterized by developmental delay, intellectual disability (most commonly in the mild-to-moderate range), and autism spectrum disorder. About half of affected individuals have epilepsy. Regression in motor development and/or language has been reported in about 40% of affected individuals. Other neurologic findings can include hypotonia, movement disorder (most commonly stereotypies and ataxia), dystonia, tremor, and migraine headaches. Sleep disturbance is common, with sleep onset and/or sleep maintenance difficulties being frequently reported. Strabismus is the most common ocular finding followed by hyperopia, nystagmus, and cortical blindness. Vomiting is observed in a number of individuals and can be triggered by seizures, motion sickness, or fatigue. Joint laxity is a relatively common finding (36.9%), and scoliosis is noted in 20% of individuals.

Diagnosis/testing: The diagnosis of DLG4-related synaptopathy is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in DLG4 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for DLG4-related synaptopathy. Supportive care includes standard treatment for developmental delay / intellectual disability, epilepsy, migraine, ataxia, dystonia, refractive errors, strabismus, and cerebral visual impairment. Behavioral therapy may aid those who have insomnia, while pharmacotherapy may be considered in those who have refractory sleep disturbance.

Surveillance: At each visit, monitor those with seizures; assess for new manifestations such as seizures, changes in tone, movement disorders, and migraine headaches; monitor developmental progress and educational needs; assess mobility and self-help skills; and assess for signs/symptoms of sleep disturbance. At each visit after infancy, assess for behavioral issues such as anxiety, autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, or self-injury. Annually or as clinically indicated, ophthalmology evaluation; and 24-hour EEG in those with significant cognitive/behavioral delay, developmental regression, or abnormal routine EEG.

Genetic counseling: DLG4-related synaptopathy is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with DLG4-related synaptopathy inherited a DLG4 pathogenic variant from a heterozygous or mosaic parent. In general, the risk to other family members is presumed to be low. However, once a DLG4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.