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

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Charcot–Marie–Tooth disease; Giant axonal neuropathy; Gigaxonin; Inherited peripheral neuropathy; Next-generation sequencing; Phenotypic heterogeneity.

Fig. 1

Analysis of GAN variants, pedigree analysis, and conservation analysis in four families. A Biallelic variants in the GAN gene were identified in five individuals across four families. Families 1, 3, and 4 exhibited compound heterozygous variants, whereas Family 2 had a homozygous variant. Arrows indicate probands. wt, wild type. B Sanger sequencing of the GAN gene in each family. Arrows indicate the locations of gene mutations. In Families 1, 3 and 4, the parents were heterozygous for the mutations, with affected individuals having biallelic mutations and unaffected individuals being either heterozygous or wild type, indicating segregation. In Family 2, the affected individual had a homozygous mutation, whereas the mother and unaffected sibling were heterozygous. Genetic analysis could not be conducted in the father. C The Schematic diagram of the GAN domains and the tolerance landscape of the GAN protein from MetaDome. Although the gene mutations identified in the four families in this study span various regions, they are predominantly located within intolerant regions

Fig. 2

Brain MRI and spinal imaging of Patients 4 and 5 with classical GAN. A–C Axial FLAIR images of Patient 4 at 8 years old revealing high-intensity lesions in the periventricular white matter and bilateral cerebellar hemispheres, along with brainstem atrophy. D–E Axial FLAIR images of Patient 5 at 9 (D) and 14 years old (E). At 9, only a mild hyperintense lesion was observed in the periaqueductal gray matter of the midbrain. By 14 years of age, hyperintense lesions had expanded to the bilateral cerebellar hemispheres. F Abdominal radiograph of Patient 5 at 9 years old revealing scoliosis and bowel gas accumulation. FLAIR, fluid-attenuated inversion recovery