HINT1 neuropathy in Norway: clinical, genetic and functional profiling

Abstract

Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

“…Autosomal recessive variants of this gene have been previously reported, in particular from Central and South-East Europe, Russia, and Turkey. Four proven founder variants have been identified: p.Arg37Pro, the most common, p.Cys84Arg, p.His112Asn, and Cys38Arg [ 30 , 31 ]. Disease onset is frequently in the first or second decade, with a prevalent motor polyneuropathy that causes weakness in lower limbs’ muscles and gait impairment [ 32 ].…”

“…Disease onset is frequently in the first or second decade, with a prevalent motor polyneuropathy that causes weakness in lower limbs’ muscles and gait impairment [ 32 ]. In most of the patients, neuromyotonia is also present [ 31 , 32 ] ( Table 1 ). Recently, even neuro-psychiatric symptoms (late language development, social behavioral alterations) have been described [ 31 , 33 ] ( Table 1 ).…”

“…In most of the patients, neuromyotonia is also present [ 31 , 32 ] ( Table 1 ). Recently, even neuro-psychiatric symptoms (late language development, social behavioral alterations) have been described [ 31 , 33 ] ( Table 1 ).…”

Myasthenia gravis coexisting with HINT1-related motor axonal neuropathy without neuromyotonia: a case report

“…In some patients with HINT1 -related neuropathy, subtle sensory involvement may develop later [ 12 ]. Some rare symptoms have been reported, such as pain in hands and lower extremities, speech difficulties and social behavioral alterations [ 13 , 14 ]. The progression of the disease is very slow, and most of the reported patients remain ambulant until the sixth decade of life [ 4 ].…”

HINT1 neuropathy: Expanding the genotype and phenotype spectrum

“…10 To date, 128 patients with ARAN-NM have been described (108 families) worldwide. [11][12][13][14][15] Most of them are from eastern Europe, where the founder variant (c.110G>C, p.Arg37Pro) is mainly represented allele frequency 0.00043 in the European (Non-finish) population (gnomAD V3.1.2), 0.002 in Russia. 15 In addition, another founder variant (c.112T>C, p.Cys38Arg) has been identified in the Chinese population.…”