Sensory Autonomic Neuropathy with Analgesia and Gastroenterological Symptoms due to a Mutation in the SCN11A Gene

We report on a girl at the age of 12 years, which was admitted for first time to our hospital at the age of 8 months. At her first presentation, she showed gastrointestinal problems with failure to thrive, enhanced sweating, hyperkinetic movement disorder, and muscle hypotonia. The gastroenterological examinations were unremarkable—even electroencephalography, cranial magnetic resonance imaging, neurometabolic diagnostics, and muscle biopsy showed no pathological changes. In a follow-up examination at the age of 21 months, the mother reported that the patient had bitten off the tip of her tongue during a candida mycosis. Only at this time, it turned out that the patient has no pain perception. The sensory nerve conduction velocity was decreased. The histamine test was pathological. In the nerve biopsy, a slight decrease of myelinated fibers was observed. In the further clinical course, bone fractures occurred and chronic skin lesions have developed, which are associated with necrosis from recurrent tissue damage and severe mutilations. The motor development was clearly delayed, while the cognitive development was only slightly retarded. The gastroenterological symptoms disappeared, while the analgesia persisted.

All previously known genetic causes of hereditary sensory autonomic neuropathies were excluded. Using exome sequencing, a heterozygous de novo missense mutation in the SCN11A gene was detected (c.2432T> C; p.Leu811Pro). SCN11A encoded a sodium 1.9-voltage-controlled channel, which is predominantly expressed in nociceptors. In animal models, it has been shown that mice with the same mutation show a reduced sensitivity to pain. The detected gain-of-function mutation leads to persistent depolarization of the nociceptors and therefore to reduced formation of action potentials and an impaired synaptic transmission. In a worldwide search for patients with congenital analgesia of unknown origin, the identical mutation in SCN11A gene could be detected in a Swedish boy with autonomic neuropathy, analgesia, and gastroenterological symptoms.¹

Mutations in sodium channels cause a variety of neurological and cardiac disorders. The examinations of the presented patient have shown for the first time that a gain-of function mutation in the SCN11A gene leads to a sensory autonomic neuropathy with analgesia and gastroenterological symptoms (Leipold et al 2013). Meanwhile, SCN11A loss of function mutations has also been described in familial episodic pain syndromes.²

References

References

1 Leipold E, Liebmann L, Korenke GC, et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet 2013;45(11):1399–8211

2 Zhang XY, Wen J, Yang W, et al. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet 2013;93(5):957-966