DYNC1H1-Related Disorders

Excerpt

Clinical characteristics: DYNC1H1-related disorders are primarily characterized by an axonal neuropathy with a wide phenotypic spectrum ranging from a neuromuscular-only phenotype (DYNC1H1-related neuromuscular disorder, or DYNC1H1-NMD) to phenotypes involving both the central nervous system and peripheral nervous system referred to collectively as DYNC1H1-related neurodevelopmental disorder (DYNC1H1-NDD).

DYNC1H1-NMD manifestations are limited to the peripheral nervous system and characterized predominantly by motor neuropathy initially most pronounced in the lower limbs; muscle weakness and atrophy variably associated with foot deformities, contractures, and other skeletal involvement; and/or delayed motor milestones.

DYNC1H1-NDD manifestations include motor axonal neuropathy and often global developmental delay / intellectual disability, epilepsy, neurobehavioral/psychiatric manifestations, and movement disorders with or without malformations of cortical development and/or microcephaly. In an individual with more significant central nervous system involvement, the motor axonal neuropathy may not be evident clinically and, thus, is only detected on further evaluation such as electrophysiologic testing.

Diagnosis/testing: The diagnosis of a DYNC1H1-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in DYNC1H1 identified by molecular genetic testing.

Management: Treatment of manifestations: For all individuals with a DYNC1H1-related disorder, supportive treatment typically includes multidisciplinary care by specialists in pediatric neurology, developmental pediatrics, orthopedics, physical medicine and rehabilitation, physical therapy, and medical genetics/genetic counseling. For individuals with DYNC1H1-NDD, supportive treatment often also includes care by specialists in mental health, pediatric gastroenterology, speech-language pathology, nutrition for feeding difficulties, and ophthalmology.

Surveillance: Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations should be performed routinely by members of the multidisciplinary care team.

Genetic counseling: DYNC1H1-related disorders are autosomal dominant disorders typically caused by a de novo pathogenic variant. Most individuals with DYNC1H1-NMD have the disorder as the result of a de novo pathogenic variant, although transmission of a DYNC1H1 pathogenic variant from an affected to parent to an affected child has been reported in several families. Almost all individuals diagnosed with DYNC1H1-NDD have the disorder as the result of a de novo pathogenic variant to date. Once the DYNC1H1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.