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Heterozygous PNPT1 Variants Cause a Sensory Ataxic Neuropathy

Saif Haddad¹, Christopher J Record¹, Eleanor Self¹

¹Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.

European Journal of Neurology

|February 10, 2025

Abstract

Background:

Biallelic variants in polyribonucleotide-nucleotidyltransferase-1 (PNPT1) have been associated with a range of phenotypes from syndromic hearing loss to Leigh's syndrome. More recently, heterozygous variants in PNPT1, have been reported in three families with cerebellar ataxia and prominent sensory neuropathy.

Methods:

Whole genome sequencing was performed in two families with autosomal dominant sensory ataxic neuropathy (SAN).

Results:

Segregating heterozygous splice site (c.2014-3C>G) and nonsense (p.Arg715Ter) variants were detected in both families. All patients initially presented with an isolated SAN clinically and neurophysiologically with subsequent variable cerebellar involvement.

Conclusion:

We report two heterozygous PNPT1 variants in two families with a predominant SAN, including the novel p.Arg715Ter. This strengthens the argument of PNPT1 causing dominant disease and highlights a new cause for dominantly inherited SAN.

Keywords:

CMT ataxia neurogenetics sensory ataxic neuropathy spinocerebellar ataxia

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