HINT1 – Autosomal Recessive Axonal Neuropathy with Neuromyotonia (Gamstorp-Wohlfart syndrome)

Background

The HINT1 gene encodes histidine triad nucleotide-binding protein 1, a ubiquitously expressed enzyme involved in SUMO protease activity and DNA damage response. Loss‐of‐function variants in HINT1 underlie autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), also termed Gamstorp-Wohlfart syndrome (Gamstorp-Wohlfart syndrome). Affected individuals present with early-onset distal muscle weakness, neuromyotonic discharges, and foot dorsiflexor weakness, often accompanied by cramps and sensory disturbances.

Genetic Evidence

Initial discovery in 33 families identified eight pathogenic HINT1 mutations by linkage and next-generation sequencing, establishing AR inheritance and loss-of-function as the mechanism ([PMID:22961002]). Subsequent cohort studies found biallelic HINT1 variants in 21 patients from 19 Czech families ([PMID:25342199]), 4 Greek index cases ([PMID:34694653]), 3 Chinese patients ([PMID:30001929]), 8 Lithuanian families including a p.Glu100Gly founder ([PMID:36242072]), and 2 Norwegian patients compound heterozygous for p.Arg37Pro and p.Arg95Gln ([PMID:33663550]). These >70 probands across >50 families demonstrate consistent segregation of homozygous or compound heterozygous variants with disease.

Variant Spectrum

The recurrent Slavic founder missense variant c.110G>C (p.Arg37Pro) predominates, alongside >20 distinct missense alleles, multiple frameshift and nonsense variants (e.g., c.283C>T (p.Arg95Ter)), splice-site disruptions, and deep intronic defects. Variants are uniformly inactivating, consistent with haploinsufficiency. No dominant-negative effects have been reported.

Functional Evidence

Biochemical assays show that HINT1 possesses zinc- and calmodulin-regulated SUMO protease activity, with disease-associated mutants (e.g., p.His112Asn, p.Val111fs) exhibiting impaired desumoylation of neural substrates ([PMID:31088288]). Patient-derived cells carrying p.Glu100Gly demonstrate reduced protein stability and catalytic activity, supporting a loss-of-function mechanism.

Integration and Clinical Utility

Collectively, robust genetic segregation in >50 families, consistent autosomal recessive inheritance, and concordant functional assays support a Strong gene–disease association. HINT1 genetic testing is clinically indicated for patients with early distal motor neuropathy and neuromyotonia. Identification of biallelic HINT1 variants enables accurate diagnosis, carrier screening, and genetic counselling.

Key Take-home: HINT1 loss-of-function variants cause a clinically distinct autosomal recessive axonal neuropathy with neuromyotonia, warranting targeted genetic testing for timely diagnosis and management.

References

• Nature Genetics • 2012 • Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. PMID:22961002
• Neurogenetics • 2015 • Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. PMID:25342199
• Journal of the Peripheral Nervous System • 2021 • HINT1-related neuropathy in Greek patients with Charcot-Marie-Tooth disease. PMID:34694653
• Neuromuscular Disorders • 2018 • Novel mutations in HINT1 gene cause autosomal recessive axonal neuropathy with neuromyotonia in two cases of sensorimotor neuropathy and one case of motor neuropathy. PMID:30001929
• Orphanet Journal of Rare Diseases • 2021 • HINT1 neuropathy in Norway: clinical, genetic and functional profiling. PMID:33663550
• Orphanet Journal of Rare Diseases • 2022 • HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling. PMID:36242072
• Antioxidants & Redox Signaling • 2019 • The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease. PMID:31088288

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