HINT1 Mutations Linked to CMT Spectrum in Greek Patients
Nerve damage caused by mutations in the HINT1 gene are as common among Greek patients with Charcot-Marie-Tooth disease (CMT) or a related condition as they are among patients in more central and eastern European countries, a study found.
Specifically, four reported cases of autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), a disease on the CMT spectrum, were found in a selected Greek population. Its frequency was comparable to that previously identified by studies in the Czech Republic and Russia.
ARAN-NM is a peripheral neuropathy (a disease causing nerve damage outside the brain and spinal cord) passed down in an autosomal recessive manner, meaning patients need two copies of the mutated gene to be affected. Typically with onset in childhood, it is characterized by slowly progressive neuropathy mainly affecting motor function, combined with spontaneous muscle activity at rest, impaired muscle relaxation, problems with gait, and contractures of the hands and feet.
The study “HINT1-related neuropathy in Greek patients with Charcot-Marie-Tooth disease” was published in the Journal of the Peripheral Nervous System.
Previous work has shown that mutations in HINT1 cause ARAN-NM. HINT1, the protein coded by this gene, is widely produced in the body, and interacts with a variety of cell signaling proteins throughout the nervous system. When HINT1 is no longer working appropriately, the peripheral nerves are affected, leading to a distinct form of CMT with neuromyotonia.
Neuromyotonia is a condition marked by spontaneous and continuous muscle twitching originating in the peripheral nerves.
Prior reports showed that neuropathy associated with the HINT1 gene has worldwide, but variable, distribution. It is especially prevalent among certain groups in central and southeastern Europe, but rare in western European countries. No studies to date have looked at its prevalence in the Greek population, its researchers noted.
A team in Athens investigated the prevalence of HINT1 mutations among patients with axonal hereditary neuropathy.
The researchers analyzed the DNA of 42 patients. A total of 36 had CMT type 2 (“axonal” disease characterized by damage to nerve fibers, or axons) while six had distal hereditary motor neuropathy, a progressive neuromuscular disorder resembling CMT but lacking its associated sensory deficits.
Participants also had a family history compatible with recessive inheritance or suggesting a sporadic mutation, and were selected from 520 cases referred to their institute’s hospital from 1993 to 2019.
Four patients had biallelic mutations, meaning mutations in both copies of the HINT1 gene (one from each biological parent). This represented 9.5% of all cases and 44.4% of cases with neuromyotonia. Overall, no patient had a disease-causing mutation in only one gene copy.
Among these people with biallelic mutations, all had gait impairment at symptom onset, which occurred between 8 and 15 years of age. The four patients were split evenly between males and females, and all had evidence of neuromyotonia at initial hospital examinations.
Two of them had homozygous mutations — the same mutation in each copy of the gene — and the other two had compound heterozygous mutations (meaning each gene copy had a different mutation). All four had the c.110G> C (p.Arg37Pro) mutation in HINT1; the c.250T> C (p.Cys84Arg) mutation was found in the two participants with compound heterozygous changes.
The scientists presented two of the four cases in more detail. One was a 19-year-old woman with walking difficulty that started when she was 8 years old. She gradually developed weakness when raising the foot towards the shin, as well as cramps. Further testing found damage to nerve fibers controlling movement with neuromyotonia.
At age 14, she started having episodes of myoclonus, which refers to involuntary muscle jerks. Generalized epilepsy was found at age 15, prompting a diagnosis of generalized myoclonic epilepsy.
After unsuccessful treatment with the antiepileptic therapy levetiracetam, she was switched to valproic acid, which resulted in substantial improvement.
The other case was that of a 49-year-old man with walking difficulties and hand stiffness that started at age 15. He gradually developed foot drop (difficulty lifting the front of the foot and toes) and fast, spontaneous muscle contractions. At an initial examination, the man had the characteristic clinical sign of “adducted thumbs.”
Notably, the two mutations observed in this study have been reported to be among the three most common mutations of the HINT1 gene in European populations.
Researchers then assessed the frequency of HINT1 mutations in patients presenting with hereditary neuropathy across multiple populations. The populations differed in regard to specific CMT form. However, the team found no significant difference when comparing between Greek patients and those in Czech, Russian, or other central and eastern European populations.
“In conclusion, biallelic HINT1 mutations are an important cause of … CMT/ dHMN in the Greek population, particularly in the presence of neuromyotonia,” the investigators wrote. “Screening for the most prevalent mutation, c.110G> C (p. Arg37Pro) should be recommended in all yet identified Greek patients with suspected hereditary neuropathy compatible with [autosomal recessive] inheritance.”