Neuromyotonia And Axonal Neuropathy, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive neuromyotonia and axonal neuropathy (NMAN) is caused by homozygous or compound heterozygous mutation in the HINT1 gene (601314) on chromosome 5q23.

Description

NMAN is an autosomal recessive neurologic disorder characterized by onset in the first or second decade of a peripheral axonal neuropathy predominantly affecting motor more than sensory nerves. The axonal neuropathy is reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A1, 118210) and distal hereditary motor neuropathy (see, e.g., HMN1, 182960). Individuals with NMAN also have delayed muscle relaxation and action myotonia associated with neuromyotonic discharges on needle EMG resulting from hyperexcitability of the peripheral nerves (summary by Zimon et al., 2012).

Clinical Features

Hahn et al. (1991) reported a Canadian brother and sister of Chinese origin with childhood-onset neuromyotonia and progressive motor neuropathy. The boy developed generalized muscle stiffening at age 10 years. He had difficulty in releasing his grip, his fingers tended to cramp on writing, and he had involuntary twitching of his fingers, forearm muscles, and thighs at rest. A few years later, he had gait difficulties due to foot drop and weakness of the hands. Physical examination showed distal wasting and weakness of the muscles of the upper and lower limbs with hyporeflexia and absent ankle jerks. Myokymia and fasciculations were observed at rest. He also showed action myotonia and percussion of the tongue resulting in tonic contractions, although percussion of the thenar eminence showed no abnormalities. There were no sensory abnormalities. His younger sister was less severely affected, with no spontaneous muscle activity at rest, but she showed weakness in the distal muscles of the upper and lower limbs. There was percussion myotonia of the tongue, but grip release was not delayed. Reflexes and sensory examination were normal. Electrophysiologic studies in both patients showed a chronic motor neuropathy with partial denervation of muscle and collateral reinnervation and evidence of abnormal spontaneous nerve activity due to hyperexcitability of peripheral nerve fibers. Muscle biopsy in the brother showed chronic partial denervation. The neuromyotonic symptoms improved with diphenylhydantoin, carbamazepine, and tocainide. In the sibs reported by Hahn et al. (1991), Zimon et al. (2012) identified compound heterozygous mutations in the HINT1 gene (601314.0006 and 601314.0007).

Zimon et al. (2012) reported 50 patients from 33 families with NMAN. Disease onset was typically in the first decade, and most patients presented with gait impairment due to distal leg weakness, although several presented with cramps in the hands and legs and muscle stiffness. The upper and lower limbs were affected. Some patients had foot deformities; most remained ambulatory in their thirties. Distal sensory impairment was present to a mild degree in about half of patients. Most patients showed delayed muscle relaxation of the hands after strong finger flexion, consistent with action myotonia. Nerve conduction studies showed an axonal neuropathy, which was pure motor in some and mixed motor and sensory in others. Sural nerve biopsy of some patients showed axonal neuropathy, even in the absence of clinical sensory abnormalities. Needle EMG showed spontaneous high-frequency motor unit action potentials consistent with neuromyotonic or myokymic discharges. Some patients had secondary increased serum creatine kinase. Skeletal muscle biopsie showed chronic denervation due to a peripheral neuropathy. The neuromyotonia was consistent with hyperexcitability of the peripheral nerve.

Inheritance

The transmission pattern of NMAN in the families reported by Zimon et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis of a Belgian family with autosomal recessive axonal neuropathy and neuromyotonia, Zimon et al. (2012) identified a disease-associated locus on chromosome 5q31.1.

Molecular Genetics

Zimon et al. (2012) identified 8 different HINT1 mutations (see, e.g., 601314.0001-601314.0007) in affected individuals from 33 families with autosomal recessive axonal neuropathy with neuromyotonia. All mutations were in homozygous or compound heterozygous state. The mutations were identified by linkage analysis combined with next-generation exome sequencing. The most common mutation, R37P (601314.0001), was identified as a polymorphism in heterozygous state in several control populations, but never occurred in homozygous state in controls. All mutations were located near the dimer interface, close to the enzyme's catalytic core, and complementation studies in Hint1-deficient yeast indicated that the mutant proteins had negligible enzyme activity, consistent with a loss of function. Heterozygous mutation carriers were unaffected.

History

Gamstorp and Wohlfart (1959) described a syndrome of myokymia (fine muscle twitches), myotonia, muscle wasting, and hyperhidrosis in 3 unrelated patients. Inheritance was probably dominant in 1 case, but the genetics was unclear in the others. The pattern of muscle wasting was similar to that observed in Charcot-Marie-Tooth disease. The myotonia was likely what was called neuromyotonia by Mertens and Zschocke (1965) because there was continuous nerve activity. Muscle stiffness was present, and anticonvulsants provided relief. Grund (1938) reported affected brothers.