Autosomal recessive axonal neuropathy with neuromyotonia

Autosomal recessive axonal neuropathy with neuromyotonia is a rare inherited condition. It involves a progressive poly-neuropathy along with neuromyotonia, myokymia, pseudo-myotonia, and contractures of the hands and feet. Needle EMG shows abnormal neuro-myotonic and myokymic activity. As of the latest OMIM data, about 52 cases had been documented in medical literature, with additional cases—mainly from Europe and North America—reported after 2014.

People with this disorder typically develop axonal neuropathy, muscle wasting in the hands, feet, and legs, chronic muscle weakness that becomes noticeable during exercise, an abnormal gait, a high risk of falls, and joint contractures. Neuromyotonia and myokymia are also present. In some individuals, the axonal neuropathy leads to reduced sensitivity to cold, heat, and touch in the distal parts of the arms and legs. Certain symptoms temporarily worsen when the person is exposed to cold.

The condition results from a homozygous mutation in the HINT1 gene on chromosome 5, most commonly the c.110 G > C (p.Arg37Pro) mutation.

The syndrome was first described in 1991 by Hahn and colleagues, who reported two Chinese-Canadian siblings of opposite sexes. The brother had difficulty releasing his grip, childhood-onset neuromyotonia and muscle stiffness, progressive motor neuropathy, finger cramping during and after writing, involuntary twitches in his fingers, thighs, and forearms, foot drop-related gait problems, hand weakness, hyporeflexia, and tongue percussion. His younger sister was less affected, sharing only some symptoms, including upper and lower distal muscle weakness. Both siblings showed chronic motor neuropathy, peripheral nerve fiber hyperexcitability, and multiple denervations. A muscle biopsy in the brother revealed chronic partial denervation. Through these siblings and 50 additional patients from 33 families worldwide, it was determined that the disorder is caused by HINT1 mutations.