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Background <p>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).</p> Methods <p>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.</p> Results <p>We identified seven biallelic <i>GAN</i> variants in five patients from four unrelated families, including one homozygous and three compound heterozygous genotypes. Two novel pathogenic variants were identified: c.922G &gt; 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&#xa0;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&#xa0;years and was still alive at 72, representing the longest documented survival in GAN.</p> Conclusion <p>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 <i>GAN</i> in pediatric-onset CMT, even in the absence of classical features.</p>

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

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  • 发表日期：

    2025年7月16日

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  • Takahiro Hobara,
  • Masahiro Ando,
  • Yujiro Higuchi,
  • Jun-Hui Yuan,
  • Akiko Yoshimura,
  • Takashi Saito,
  • Takashi Shiihara,
  • Shiho Okuda,
  • Naoki Fukushima,
  • Hiroyuki Awano,
  • Takahito Inoue,
  • Chikashi Yano,
  • Fumikazu Kojima,
  • Kento Kodama,
  • Yu Hiramatsu,
  • Satoshi Nozuma,
  • Tomonori Nakamura,
  • Yusuke Sakiyama,
  • Akihiro Hashiguchi,
  • Jun Mitsui,
  • Shoji Tsuji,
  • Hiroshi Takashima

摘要

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.