Axonal neuropathy - neuromyotonia - HINT1 mutations

What is Axonal neuropathy - neuromyotonia - HINT1 mutations?

Axonal neuropathy - neuromyotonia - HINT1 mutations is a rare disease. It is also known as ARAN-NM ARANNM.

The hallmark of this condition is the presence of continuous, spontaneous firing of motor unit potentials with variable intervals (1-20 sec) of electrical silence. Neuromyotonic discharges differ from myokymia in that they fire at higher frequencies (150-300Hz vrs 5-150Hz) and the amplitude typically wanes. Myotonic discharges occur on percussion and the sensory action potentials at the wrist are decreased in amplitude to 1/2 normal confirming other evidence of underlying HMSN type II (neuronal). Two sibs with underlying HMSN type II, were reported by Maurelli et al., (1998). The onset of the condition is usually towards the end of the first decade of life with distal weakness and wasting and increasing muscle stiffness, hence the `stiffman' designation. Tendon reflexes are usually absent and true muscle hypertrophy can occur. Myokymia and muscle cramps can be part of the clinical picture. Voluntary contractions are often followed by impaired muscle relaxation. See elsewhere for a possibly different `stiffman' syndrome and also `congenital stiffman syndrome'.
Note that this is probably not a single condition. Some are autosomal dominant, and this includes those with an underlying neuropathy (Hahn et al., 1991). Some cases are found to have an underlying chronic inflammatory demyelinating neuropathy (Odabasi et al., 1996) and some with a neuropathy, myasthenia and a thymoma (Perini et al., 1994, Martinelli et al., 1996). The case reported by Van Parijs et al., (2002) had anti-voltage-gated potassium and AChr antibodies and had myasthenia but not a thymoma. Sporadic, and possibly acquired cases have been reported (Newsome-Davis, 1993) and one case had antibodies to neuronal nucleoproteins, so-called anti-Hu-antibodies (Toepfer et al., 1999). Brothers were reported by Jamieson and Katirji (1994), and the condition called the Gamstorp-Wohlfart syndrome (MIM 137200) is probably the same as this. The condition is thought to be autoimmune (Sinha et al., 1991). A series of 20 patients were reported from India (Panagariya et al., 2006). Four had a Bell's palsy.
The condition has been mapped to 5q11 and homozygous mutations were found in HINT1 (Zimon et al., 2012). This encodes a histidine triad nucleotide- binding protein 1. Members of the Hahn et al., (1991) family had the same mutation.
This condition is characterized by delayed muscle relaxation after voluntary contraction resulting from hyperexitability (Zimon et al., (2012). Biallelic mutations were found in 21 patients from 19 families (Lassutkova et al., (2015). The myotonia can be subtle and needs to be actively looked for. Most were initially thought to have an axonal neuropathy (CMT2). Onset was towards the end of the first decade.
Peeters et al. (2016) summarized the current knowledge on HINT1-related axonal neuropathy with neuromyotonia. Characteristic clinical features included the onset of the disease in the first or second decade of life, distal (predominantly motor or pure motor) neuropathy with gait impairment and slow progression, early occurring hypotrophy of intrinsic hand muscles, finger flexion contractures and neuromyotomia (in 80%). Nerve conduction studies show neuromyotomia or myokymic discharges (in some individuals), axonal motor and sensory or pure motor polyneuropathy. CK levels ranged from normal to elevated. The most frequent mutations in individuals of European origin were R37P, C84R, H112N.
Rauchenzauner et al. (2016) described a girl with autosomal recessive axonal neuropathy with neuromyotonia due to a homozygous missense mutation in the HINT1 gene. Clinical characteristics included asymmetric gait impairment, foot drop, and action myotonia. Mild elevation of creatine kinase was present.
Two unrelated patients from consanguineous families with homozygous missense mutations in the HINT1 gene were reported by Wang et. al. (2018). Age of onset of the symptoms was between 13 and 15 years. Clinical characteristics included gait impairment, progressive distal muscle weakness and atrophy, neuromyotonia, foot deformities and slightly elevated serum CK. Electrophysiological studies showed axonal motor neuropathy and neuromyotonic discharges. Additional features observed in patient 1 were brachymetatarsia of the third metatarsals; patient 2 had atrioventricular reentrant tachycardia.

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* This information is courtesy of the L M D.

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What gene changes cause Axonal neuropathy - neuromyotonia - HINT1 mutations?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

The syndrome can be caused by mutations in the following gene/s location/s:

What are the main symptoms of Axonal neuropathy - neuromyotonia - HINT1 mutations?

The typical symptoms of the syndrome are:

How does someone get tested for Axonal neuropathy - neuromyotonia - HINT1 mutations?

The initial testing for Axonal neuropathy - neuromyotonia - HINT1 mutations can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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