HSAN1

HSAN1, or hereditary sensory and autonomic neuropathy type 1, is a rare genetic disorder characterized by progressive loss of distal sensory function and autonomic symptoms. It is typically inherited in an autosomal dominant manner and is caused by mutations in the SPTLC1 gene, which encodes a subunit of the serine palmitoyltransferase enzyme involved in the first step of sphingolipid synthesis. Onset can occur in infancy or later in life, with symptoms often beginning in the feet and legs.

Pathophysiology of HSAN1 involves mutations in SPTLC1 that alter the substrate specificity of serine palmitoyltransferase. This leads to the accumulation of deoxysphingolipids, such as deoxysphinganine and deoxysphingosine, which are neurotoxic. The resulting toxicity predominantly affects small sensory fibers and autonomic neurons, contributing to sensory loss, pain abnormalities, and dysautonomia.

Clinical features commonly include distal symmetric loss of pain and temperature sensation, numbness, tingling, and progressive weakness in the lower limbs. Patients may develop foot ulcers or unnoticed injuries due to reduced pain perception. Autonomic symptoms can include abnormal sweating, blood pressure regulation issues, and other signs of dysautonomia. Deep tendon reflexes may be diminished or absent.

Diagnosis is based on clinical presentation and family history, supported by molecular genetic testing showing a pathogenic SPTLC1 variant. Elevated plasma deoxysphingolipid levels can serve as a biomarker, and nerve conduction studies typically reveal axonal neuropathy. Skin biopsy may show reduced intraepidermal nerve fiber density.

Management is supportive and multidisciplinary, focusing on injury prevention, wound care, infection prevention, and management of neuropathic pain. Genetic counseling is recommended. Experimental approaches, such as serine supplementation to reduce deoxysphingolipid levels, have shown promise in small studies, but larger trials are needed.