Distal hereditary motor neuropathy type 5

Distal hereditary motor neuropathy type 5 (dHMN5), also known as distal spinal muscular atrophy type 5 or spinal muscular atrophy of the upper extremities (SMA-UE), is a rare inherited neuromuscular disorder characterized by progressive weakness and wasting (atrophy) of muscles in the hands and, to a lesser extent, the feet. It is caused by mutations in the GARS1 gene (glycyl-tRNA synthetase 1) or the BSCL2 gene (seipin), which lead to degeneration of the lower motor neurons in the spinal cord that control voluntary movement, particularly those supplying the distal limbs. The hallmark feature of dHMN5 is predominant upper limb involvement, with weakness and atrophy of the small muscles of the hands (especially the thenar eminence and first dorsal interosseous muscle), leading to difficulty with fine motor tasks such as writing, buttoning clothes, and gripping objects. Over time, lower limb involvement may also develop, with foot drop and gait difficulties. Importantly, sensory function is typically preserved or only minimally affected, distinguishing this condition from other peripheral neuropathies. Reflexes may be reduced in affected limbs. The disease is slowly progressive, and severity can vary considerably even within the same family. There is currently no cure or disease-modifying treatment for dHMN5. Management is supportive and symptomatic, including physical and occupational therapy to maintain function and prevent contractures, orthotic devices for foot drop, and assistive devices for hand weakness. Genetic counseling is recommended for affected individuals and their families. Research into the underlying molecular mechanisms, particularly aminoacyl-tRNA synthetase biology, is ongoing and may eventually lead to targeted therapies.

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