Autosomal dominant hereditary sensory and autonomic neuropathy

Autosomal dominant hereditary sensory and autonomic neuropathy (AD-HSAN) encompasses a group of inherited peripheral neuropathies characterized by progressive degeneration of sensory and, to a variable extent, autonomic neurons. These conditions are also known as hereditary sensory neuropathy (HSN) or hereditary sensory and autonomic neuropathy (HSAN) with autosomal dominant inheritance. The most well-known subtype is HSAN type I, which is the most common hereditary sensory neuropathy and typically presents in adulthood. Multiple genetic subtypes exist, including HSAN1A (caused by mutations in the SPTLC1 gene), HSAN1B, HSAN1C (SPTLC2), and others. The disease primarily affects the peripheral nervous system, particularly the small sensory nerve fibers responsible for pain and temperature sensation, as well as autonomic nerve fibers. Key clinical features include progressive loss of pain and temperature sensation, predominantly in the distal lower extremities (feet and legs). This sensory loss leads to painless injuries, foot ulcerations, and secondary infections that can progress to osteomyelitis and may necessitate amputation. Lancinating (shooting) pains are common, particularly in HSAN type I. Autonomic dysfunction may manifest as reduced sweating, skin changes, and vasomotor instability. Motor involvement can occur in some subtypes, leading to distal muscle weakness and wasting. Sensorineural hearing loss is a feature in certain genetic subtypes. There is currently no cure for autosomal dominant HSAN. Management is primarily supportive and preventive, focusing on meticulous foot care to prevent ulceration and infection, appropriate wound management, pain management for neuropathic pain symptoms, and regular monitoring by a multidisciplinary team including neurologists, podiatrists, and orthopedic specialists. For HSAN1A specifically, dietary supplementation with L-serine has been investigated as a potential disease-modifying therapy, as the mutant SPTLC1 enzyme produces toxic deoxysphingolipids that may be reduced by increasing serine availability, though this approach remains under study.

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