-Related Disorder

CLINICAL CHARACTERISTICS

-related disorder encompasses a broad phenotypic continuum that includes hyperkinetic movement disorders and/or epilepsy and is typically associated with developmental delay and intellectual disability. Viewed by age of onset, three clusters in this continuum can be observed: (1) infantile-onset developmental and epileptic encephalopathy (DEE) with or without prominent movement disorder; (2) infantile- or early childhood-onset prominent movement disorder and neurodevelopmental disorder with or without childhood-onset epilepsy with varying seizure types; (3) later childhood- or adult-onset movement disorder with variable developmental delay and intellectual disability. Epilepsy can be either DEE (onset typically within the first year of life of drug-resistant epilepsy in which developmental delays are attributed to the underlying diagnosis as well as the impact of uncontrolled seizures) or varying seizure types (onset typically between ages three and ten years of focal or generalized tonic-clonic seizures that may be infrequent or well controlled with anti-seizure medications). Movement disorders are characterized by dystonia and choreoathetosis, most commonly a mixed pattern of persistent or paroxysmal dyskinesia that affects the whole body. Exacerbations of the hyperkinetic movement disorder, which can be spontaneous or triggered (e.g., by intercurrent illness, emotional stress, voluntary movements), can last minutes to weeks. Hyperkinetic crises (including status dystonicus) are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing that can be life-threatening. Deaths in early childhood have been reported due to medically refractory epilepsy or hyperkinetic crises, but the phenotypic spectrum includes milder presentations, including in adults. As many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with -related disorder are underrecognized and underreported.

DIAGNOSIS/TESTING: The diagnosis of -related disorder in a proband with suggestive findings and a heterozygous pathogenic variant in identified by molecular genetic testing.

MANAGEMENT

There is no cure for -related disorder. Supportive care to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in child neurology, adult neurology, neurosurgery, physical medicine and rehabilitation, physical therapy, occupational therapy, orthopedic surgery, speech-language therapy, and psychology. Frequent evaluations by treating specialists are necessary to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

GENETIC COUNSELING

-related disorder is an autosomal dominant disorder most often caused by a pathogenic variant. Individuals with severe -related disorder phenotypes (i.e., DEE, severe developmental delay and/or intellectual disability, and/or an early-onset movement disorder) typically represent simplex cases (i.e., the only family member known to be affected) and have the disorder as the result of a pathogenic variant; however, recurrence of severe -related disorder phenotypes in affected sibs due to presumed parental germline mosaicism has been reported. Vertical transmission from an affected parent to an affected child has been reported in several families with the milder phenotype (i.e., later childhood- or adult-onset movement disorder with variable developmental delay and intellectual disability). Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.