Neuropathy, Hereditary Sensory And Autonomic, Type Vii

A number sign (#) is used with this entry because of evidence that hereditary sensory and autonomic neuropathy type VII (HSAN7) is caused by heterozygous mutation in the SCN11A gene (604385) on chromosome 3p22.

For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

Clinical Features

Leipold et al. (2013) reported 2 unrelated patients, a German girl and a Swedish boy, with hereditary sensory and autonomic neuropathy. The clinical history of both affected individuals was remarkably similar, involving a congenital inability to experience pain since birth resulting in self-mutilations, slow-healing wounds, and multiple painless fractures. Both patients also had mild muscle weakness and delayed motor development. Muscle biopsy and electromyography (EMG) were normal. Electroneurography showed slightly reduced motor and sensory nerve conduction velocities with normal amplitudes. Sural nerve biopsy of 1 patient did not show sensory axonal loss, and brain MRI and cognitive function were normal. Both patients also had hyperhidrosis and gastrointestinal dysfunction necessitating temporary parenteral nutrition, suggesting autonomic involvement. Intestinal biopsies from both patients were normal.

Woods et al. (2015) reported a third patient, of Scottish descent, with HSAN7 confirmed by genetic analysis. The phenotype was almost identical to the patients reported by Leipold et al. (2013). The patient reported by Woods et al. (2015) presented with failure to thrive secondary to intestinal dysmotility, and had ongoing abdominal and urinary discomfort with chronic constipation. Motor milestones were delayed, which was associated with mild hypotonia and muscle weakness, but intelligence was normal. The patient was unable to feel peripheral pain, which resulted in self-inflicted injuries, skin ulcers, particularly in the cervical region, slow healing wounds, and painless fractures. There was intolerance of moderate cold and moderate heat, but temperature changes could be sensed; hyperhidrosis was also present, which may have caused intense pruritis. There was no evidence of a peripheral neuropathy. The patient also adopted dystonia-like postures at the extremes of joint movement range both during sleep and while awake, similar to one of the patients reported by Leipold et al. (2013).

Salvatierra et al. (2018) reported a woman with severe pruritus and partial loss of pain sensation with remaining back, neck, and side pain, consistent with HSAN7. Her family history was negative. Her past medical history was significant for fractures in her lower extremities with minimal trauma, diurnal and nocturnal enuresis, constipation, intermittent diarrhea, developmental delay, heterotropic ossification with bilateral hip disease, scoliosis, hyperhidrosis, asthma, eczema, gastroesophageal reflux, hypoglycemia, vitamin D deficiency, headaches, and picking of the skin on her fingers. The patient reported that her pruritus was worse at night and often prevented her from falling asleep. On physical examination, she had a lack of position sense in the toes, distal movement sense in both ankles, and decreased sensation bilaterally. She was diagnosed with restless legs syndrome and a nonspecific anxiety disorder. She had improvement of her symptoms following treatment with cyproheptadine and gabapentin.

Molecular Genetics

In 2 unrelated patients with HSAN7, Leipold et al. (2013) identified the same de novo heterozygous missense mutation in the SCN11A gene (L811P; 604385.0001). The mutation in the first patient was found by whole-exome sequencing. The second mutation was found by sequencing of the SCN11A gene in 58 individuals with early-onset severe sensory loss. Transfection of the mutation into mice resulted in reduced pain sensitivity. Electrophysiologic studies in dorsal root ganglia from mutant mice and in isolated cells showed that the mutation resulted in a gain of function with a left-shift in resting membrane potential and channel activation and a decrease in the kinetics of channel deactivation. Leipold et al. (2013) hypothesized that this excess sodium influx and subsequent cell depolarization at rest may cause progressive conduction block in other ion channels that form the main constituents of the action potential in dorsal root ganglia neurons. Insufficient activation of calcium ion channels would result in impaired neurotransmitter release at presynaptic nerve terminals to transmit pain signals to the spinal cord.

In a Scottish patient with HSAN7, Woods et al. (2015) identified the same de novo heterozygous L811P mutation in the SCN11A gene that was originally reported by Leipold et al. (2013).

In a patient with debilitating pruritus and altered pain perception consistent with HSAN7, Salvatierra et al. (2018) identified de novo heterozygosity for the L811P mutation in the SCN11A gene. Using fluorescence tagging of the sodium channel in a mouse model, the authors showed that the channel is present in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia. Compared with control mice, mice with global knockout of the Scn11a gene showed reduced scratching behavior on application of pruritogens. Mice heterozygous for the L799P variant exhibited amplified scratching behavior in rest conditions, providing evidence for involvement of SCN11A in pruritus.