AUTOSOMAL RECESSIVE AXONAL NEUROPATHY WITH NEUROMYOTONIA CAUSED BY A MUTATION IN THE HINT1 GENE: A REPORT OF TWO CLINICAL CASES

Abstract

Hereditary sensorimotor neuropathies are characterized by high genetic heterogeneity, which complicates their diagnosis. Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), associated with mutations in the HINT1 gene, is a rare but clinically recognizable disease. Description of clinical cases is important for raising physician awareness and improving the diagnosis of this pathology. We present two patients, aged 13 and 15 years, with a homozygous p.Arg37Pro (c.110G>C) mutation in the HINT1 gene. Both had onset in the first decade of life, steppage gait, inability to walk on heels, difficulty in relaxing fingers after fist clenching (neuromyotonia), and hypo/areflexia in the lower limbs. Creatine phosphokinase (CPK) levels were elevated: in patient 1 — 1213 U/L, in patient 2 — 1790 U/L. Stimulation electroneuromyography revealed axonal neuropathy with reduced M-response amplitudes; sensory responses in the lower limbs were absent. Needle electromyography in patient 1 showed myokymic discharges. Magnetic resonance imaging of the lower extremities revealed moderate fatty degeneration of the calf muscles. Patient 1 presented with pain syndrome and sensory disturbances; patient 2 remained able to run. The 5-year-old brother of patient 1, carrying the same mutation, was diagnosed with autism spectrum disorder. Conclusion: When a child presents with distal muscle weakness, neuromyotonia, and elevated CPK, ARAN-NM should be considered. The same mutation can cause different disease courses in terms of severity and symptom spectrum. The p.Arg37Pro mutation in the HINT1 gene in a homozygous state may manifest as isolated neuropsychiatric disorders (e.g., autism spectrum disorder) without clinical signs of neuropathy, necessitating follow-up of asymptomatic relatives carrying the same mutation.