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Mayo Clin Proc. 2010 June; 85(6): 594–595.
PMCID: PMC2878264

A Potential Novel Variant of Hereditary Sensory Neuropathy in a 61-Year-Old Man With Cough-Induced Syncope and Vertebral Artery Dissection

Emil Lou, MD, PhD
Memorial Sloan-Kettering Cancer Center
New York, NY
Stephan Züchner, MD and Jeffery Vance, MD, PhD
Miami Institute for Human Genomics, University of Miami Miller School of Medicine
Miami, FL

To the Editor: A 61-year-old man with history of hereditary sensory neuropathy was admitted for severe coughing and sudden-onset worsening of chronic numbness in his extremities. He had a chronic cough of more than 30 years' duration, and his coughing occurred several times a day, often precipitated by fumes or eating. The cough was almost always accompanied by worsening of the chronic numbness and tingling in various extremities. After an episode of dizziness and syncope, he subsequently developed severe right neck pain and headache. Family history was notable for 2 sisters with hereditary sensory neuropathy with similar persistent lower extremity numbness and burning. The patient worked in road construction and thus was exposed to noxious fumes that exacerbated his cough.

Prior evaluation included nerve conduction studies that resulted in unobtainable sural and radial sensory responses, whereas median sensory responses had low amplitudes and normal distal latencies. Median and peroneal motor responses were normal. Findings on this study were consistent with a sensory neuropathy or axonal neuropathy. An extensive laboratory evaluation for acquired causes was negative; paraneo-plastic work-up was also negative.

On examination of the patient, there was no evidence of sensorineural hearing loss or nystagmus. He had a length-dependent decrease to vibration, pinprick, and temperature sensation with intact proprioception. Romberg sign was positive. Laboratory values were essentially normal, including creatine kinase. Cardiac work-up and chest radiographic results were normal. Computed tomogaphy of the head showed no acute intracranial process. However, subsequent computed tomogaphic angiography revealed a right vertebral artery dissection. It was thought this was precipitated by the severe coughing spell.

After extensively ruling out common causes of syncope and cough, consideration of a mutation in the serine palmitoyltransferase gene (SPTLC1, formerly known as HSN1) was warranted. Serine palmitoyltransferase is a key enzyme in the production of sphingomyelin.1 Deficiency or mutation of this important enzyme has been reported as a rare cause of autosomal dominant hereditary sensory neuropathy manifesting with peripheral sensory neuropathy, chronic cough, and syncope.1-3 Mutation of SPTLC1 leads to accumulation of ceramide, which precipitates neuronal cell degeneration and apoptosis, causing significant demyelination of axons of the ventral and dorsal roots of the spinal cord.1 Clinically, this manifests as progressive lower limb sensory axonal neuropathy and distal muscle weakening and ulcerations.1

Even more rarely, SPTLC1 in the form of distal sensory axonal deficits can present along with gastroesophageal reflux with adult onset of paroxysmal cough, which can lead to syncope. This constellation of symptoms constitutes a rare familial disorder characterized thus far in only a few case reports that include genetic analysis of a large Australian family.3-5 The cough is attributed to denervation hypersensitivity of the upper airways and esophagus. The chromosome linkage is on 3p22-p24, which is thought to be a distinctly unique and novel variant of SPTLC1.3 A study was also perfomed in 4 generations of a Japanese family that was discovered to have a motor neuropathy in addition to the sensory neuropathy with recurrent paroxysmal dry cough; other notable findings included fine postural tremors, muscle cramping with elevation of creatine kinase levels, and neurogenic bladder. Genetic testing in this family showed no evidence of linkage to 3p22-p24.5

We performed extensive genetic evaluation and testing of our patient and found no mutation of SPTLC1. Additional testing for MPZ, RAB7A (previously known as RAB7), TRKA, NGF (previously known as NGFB), HSN2, and Friedrich ataxia was also negative (Table). In the absence of mutations in any of these tested genes, it is likely that our patient had a novel, previously uncharacterized variant of hereditary sensory neuropathy that resulted in severe coughing, leading to syncope and vertebral artery dissection.

Review of Genetic Tests Evaluated in 61-Year-Old Man, All of Which Were Negative


1. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001;27:309-312 [PubMed]
2. Bejaoui K, Wu C, Scheffler MD, et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001;27:261-262 [PubMed]
3. Spring PJ, Kok C, Nicholson GA, et al. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24. Brain 2005;128:2797-2810 [PubMed]
4. Kok C, Kennerson ML, Spring PJ, Ing AJ, Pollard JD, Nicholson GA. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet. 2003;73:632-637 [PubMed]
5. Miura S, Shibata H, Kida H, et al. Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. J Neurol Sci. 2008;273:88-92 [PubMed]

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