Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2–18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1–5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8–14), and patients used a wheelchair at a mean age of 16 years (14–18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.

中文翻译：

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巨大的轴索神经病：具有基因型频谱扩展的多中心回顾性研究。

巨大轴突神经病（GAN）是一种常染色体隐性遗传疾病，由编码gigaxonin的GAN基因突变引起。患者发展出进行性感觉运动神经病，影响周围神经系统（PNS）和中枢神经系统（CNS）。方法：在这项多中心观察性回顾性研究中，我们记录了法国GAN患者突变，确定了10例患者。患者的平均年龄为9.7岁（2-18岁），其中8例为女性（80％），所有患者均达到婴儿发育里程碑并有近亲血统。发病的平均年龄为3.3岁（1-5岁），进行性小脑共济失调和远端运动无力是所有病例的最初症状。近端运动无力和延髓症状出现在平均年龄为12岁（8-14岁），患者使用轮椅的平均年龄为16岁（14-18岁）。一名患者在18岁时死于吸入性肺炎。在所有情况下，神经传导研究均显示混合性脱髓鞘和轴突感觉运动神经病变，而MRI则显示脑和小脑白质异常。多发性神经病和脑病在疾病过程中均加重。患者还表现出各种相关的发现，包括卷发（占病例的100％），大肠炎（占80％），眼科异常（占30％）和脊柱侧弯（占30％）。五新发现GAN突变，包括第一个同义突变和大量的基因内缺失。我们的发现扩大了GAN突变的基因型谱，并对该基因的分子分析产生了相关影响，并证实GAN是与年龄相关的进行性神经退行性疾病，涉及PNS和CNS。