HINT1 neuropathy: Expanding the genotype and phenotype spectrum

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Inherited peripheral neuropathy (IPN) comprises over 100 genetic causes.
• Neuromyotonia and axonal neuropathy (NMAN) linked to HINT1 variations was first described in 2012.
• HINT1 protein's role in transcription and cell-cycle control suggests potential neuropsychiatric involvement.

Purpose of the Study:

• To identify HINT1 pathogenic variations in French NMAN patients using Next Generation Sequencing.
• To compare genotypic and phenotypic data with existing literature.
• To expand the understanding of the HINT1-related neuropathy phenotype.

Main Methods:

• Next Generation Sequencing (NGS) for genetic analysis.
• Literature review for comparative analysis.
• Clinical phenotyping of seven French NMAN patients.

Main Results:

• Seven French patients with NMAN were identified, revealing a new HINT1 pathogenic variation (c.310G>C p.(Gly104Arg)).
• Phenotypic features, including age of onset, neuronal involvement (sensorimotor/motor), and skeletal abnormalities, align with previous findings.
• Six of seven patients exhibited neurodevelopmental or psychiatric features (GAD, OCD, ADHD, mood disorders), expanding the known HINT1-related neuropathy spectrum.

Conclusions:

• A new HINT1 variation associated with NMAN was identified.
• Neurodevelopmental and psychiatric disorders are potentially part of the HINT1-related disease spectrum.
• Further research is warranted to fully elucidate the clinical phenotype of HINT1-related neuropathy.