DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy

DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy (also known as spinal muscular atrophy, lower extremity-predominant, autosomal dominant, or SMA-LED) is a rare genetic neuromuscular disorder caused by heterozygous mutations in the DYNC1H1 gene, which encodes the cytoplasmic dynein 1 heavy chain 1 protein. This protein plays a critical role in intracellular transport along microtubules and is essential for normal neuronal development and function. The disease primarily affects the lower motor neurons of the spinal cord, leading to progressive or nonprogressive weakness and wasting of proximal muscles, predominantly in the lower extremities. The condition typically presents in early childhood with delayed motor milestones, difficulty walking, and proximal leg weakness that is often more prominent than upper limb involvement. Affected individuals may display a waddling gait, difficulty climbing stairs, and calf muscle pseudohypertrophy in some cases. The severity is variable, ranging from mild weakness allowing independent ambulation into adulthood to more significant disability requiring assistive devices. Some patients may also exhibit mild cognitive impairment or cortical malformations, as DYNC1H1 mutations can affect brain development in addition to spinal motor neurons. Deep tendon reflexes are often reduced or absent in the lower limbs. There is currently no cure or disease-specific treatment for DYNC1H1-related proximal spinal muscular atrophy. Management is supportive and multidisciplinary, including physical therapy to maintain mobility and prevent contractures, orthopedic interventions as needed, and occupational therapy. Regular monitoring by a neurologist and rehabilitation specialist is recommended. Genetic counseling is important for affected families, as the condition follows an autosomal dominant inheritance pattern, meaning each child of an affected individual has a 50% chance of inheriting the causative mutation. Many cases arise from de novo (new) mutations.

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