# Charcot–Marie–Tooth-like presentation in giant axonal neuropathy: clinical variability and prevalence in a large Japanese case series

## TL;DR

This study shows that GAN can present like CMT and highlights the importance of genetic testing for accurate diagnosis in patients with inherited neuropathies.

## Contribution

Identifies novel GAN variants and reports the longest documented survival in GAN with a CMT-like phenotype.

## Key findings

- Seven biallelic GAN variants were identified in five Japanese patients with inherited peripheral neuropathies.
- Two novel pathogenic GAN variants, c.922G > T and c.456dup, were discovered.
- One patient with a mild CMT-like GAN phenotype survived until age 72, the longest documented survival in GAN.

## Abstract

Giant axonal neuropathy 1 (GAN) is a rare neurodegenerative disorder with autosomal recessive inheritance and significant phenotypic heterogeneity, ranging from milder presentations resembling Charcot–Marie–Tooth disease (CMT) to classical presentations involving central and peripheral nervous systems. We investigated the genetic and clinical spectrum of GAN in Japanese patients with inherited peripheral neuropathies (IPNs).

We conducted genetic screening of 3315 Japanese patients diagnosed with IPNs between 2007 and 2023 using targeted next-generation or whole-exome sequencing. Variant pathogenicity, clinical features, and neurophysiological and neuroimaging findings were reviewed.

We identified seven biallelic GAN variants in five patients from four unrelated families, including one homozygous and three compound heterozygous genotypes. Two novel pathogenic variants were identified: c.922G > T (p.Glu308*) and c.456dup (p.Ala153Cysfs*27). Two families exhibited the classical phenotype, whereas the other two exhibited a CMT-like phenotype. Mean onset age was 4.4 years (range 1.5–8), and gait disturbance was the initial symptom. The most common findings included distal weakness (n = 5), sensory impairment (n = 4), scoliosis (n = 3), autonomic dysfunction (n = 2). Neurophysiologically, all patients had sensorimotor axonal polyneuropathy. One patient with mild phenotype maintained a CMT-like state without systemic involvement until the age of 43 years and was still alive at 72, representing the longest documented survival in GAN.

This study expands the genetic and phenotypic spectrum of GAN by identifying novel variants and a long-term survivor. These findings underscore the importance of systematic genetic screening for GAN in pediatric-onset CMT, even in the absence of classical features.

The online version contains supplementary material available at 10.1007/s00415-025-13243-5.