Hereditary Sensory and Autonomic Neuropathy (HSAN)
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stethoscope Medicine
A 35-year-old Indian man presents with progressive distal sensory loss, recurrent painless foot ulcers, and neuropathic pain in his lower limbs. Examination reveals insensitivity to pain and temperature in a stocking distribution, preserved motor strength, and normal deep tendon reflexes. His father and paternal grandfather had similar symptoms with adult-onset presentation. The inheritance pattern marked **A** in the diagram is most consistent with this clinical presentation. Which of the following genetic subtypes and inheritance patterns best explains this pedigree?
A. HSAN4 (CIPA) — autosomal recessive with NTRK1 mutation and anhidrotic hyperthermia
B. HSAN1 (Type I) — autosomal dominant inheritance with SPTLC1 or ATL1 mutations
C. HSAN2 — autosomal recessive with WNK1/HSN2 mutation and childhood-onset presentation
D. HSAN3 (Riley-Day syndrome) — autosomal recessive with IKBKAP/ELP1 mutation and consanguinity
Explanation
Why HSAN1 (Type I) — autosomal dominant inheritance with SPTLC1 or ATL1 mutations is right
The clinical presentation of adult-onset distal sensory loss, insensitivity to pain and temperature, recurrent painless ulcers, and neuropathic pain in a patient with vertical transmission across three generations (patient, father, paternal grandfather) is pathognomonic for HSAN1. The inheritance pattern marked A in the diagram explicitly describes HSAN1 as autosomal dominant, which explains the male-to-male transmission and vertical pedigree pattern observed here. SPTLC1 and ATL1 are the most common causative genes in HSAN1. The preserved motor strength and normal reflexes are consistent with the selective small-fiber sensory and autonomic involvement characteristic of HSAN1 (Auer-Grumbach M., Handbook Clin Neurol).
Why each distractor is wrong
HSAN3 (Riley-Day syndrome) — autosomal recessive with IKBKAP/ELP1 mutation and consanguinity: HSAN3 is autosomal recessive and almost exclusively occurs in Ashkenazi Jewish populations. It presents in infancy/childhood with absent fungiform papillae, alacrima, and labile blood pressure. This patient has adult-onset disease with no family history of consanguinity and lacks the characteristic features of Riley-Day syndrome.
HSAN4 (CIPA) — autosomal recessive with NTRK1 mutation and anhidrotic hyperthermia: HSAN4 is autosomal recessive and presents in infancy with anhidrotic hyperthermia, self-mutilation of tongue and fingers, and intellectual disability. This patient has adult-onset disease with no mention of anhidrosis or intellectual disability, ruling out HSAN4.
HSAN2 — autosomal recessive with WNK1/HSN2 mutation and childhood-onset presentation: HSAN2 is autosomal recessive with childhood-onset predominantly sensory loss and mutilation. The vertical three-generation pedigree with adult-onset disease in this case is incompatible with autosomal recessive inheritance and childhood presentation.
High-YieldNEET PG
HSAN1 is the only autosomal dominant subtype—remember vertical transmission and adult-onset distal sensory loss; all other major subtypes (HSAN2, 3, 4, 5) are autosomal recessive and often present in childhood or with consanguinity.
Auer-Grumbach M., Handbook Clin Neurol; Rotthier A et al., Nat Rev Neurol 2012
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