HINT1 Neuropathy in Norway: Clinical, Genetic and Functional Profiling

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2021 Mar 5

PMID 33663550

Citations 8

Authors

Silvia Amor-Barris

Helle Hoyer

Lin V Brauteset

Els De Vriendt

Linda Strand

Albena Jordanova

Geir J Braathen

Kristien Peeters

Affiliations

Soon will be listed here.

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.

Citing Articles

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Small Complex Rearrangement in -Related Axonal Neuropathy.

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Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

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The most common European HINT1 neuropathy variant phenotype and its case studies.

Rozevska M, Rots D, Gailite L, Linde R, Mironovs S, Timcenko M Front Neurol. 2023; 14:1084335.

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Jiang N, Vazquez Do Campo R, Kazamel M Front Neurol. 2023; 14:1007051.

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