Jaubert Pauline, Loret Camille, Stojkovic Tanya, Attarian Shahram, Bonello-Palot Nathalie, Bouhour Françoise, Camdessanche Jean-Philippe, Cassereau Julien, Chanson Jean-Baptiste, Cintas Pascal, Creange Alain, Esselin Florence, Genestet Steeve, Giordano Sophie, Gitiaux Cyril, Guillaud-Bataille Marine, Isapof Arnaud, Kumaran Deiva, Labeyrie Céline, Laugel Vincent, Leonard-Louis Sarah, Lozeron Pierre, Magy Laurent, Mercier Sandra, Merle Philippe, Michaud Maud, Nicolas Guillaume, Ollagnon Elisabeth, Pereon Yann, Puma Angela, Poinsignon Vianney, Roy Susana Quijano, Sole Guilhem, Tard Céline, Vidoni Léo, Lia Anne-Sophie, Echaniz-Laguna Andoni
Neurology Department, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, France.
French National Reference Centre for Rare Neuropathies (CERAMIC), Le Kremlin-Bicêtre, France.
Eur J Neurol. 2025 Aug;32(8):e70313. doi: 10.1111/ene.70313.
Autosomal recessive mutations in the SH3TC2 gene cause Charcot-Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy.
In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023.
Mean age was 42 years (2-80), and 49% of patients were female. Mean age at disease onset was 14 years (0-52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis-related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants.
This study shows CMT4C is a severe childhood- and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype-phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.
SH3TC2基因的常染色体隐性突变会导致4C型遗传性运动感觉神经病（CMT4C），这是一种脱髓鞘性周围神经病。
在这项涉及27家法国大学医院的全国性观察性回顾性研究中，我们分析了2003年至2023年间确定的89个家庭中103例携带纯合和复合杂合SH3TC2基因突变患者的临床、电生理和基因特征。
患者平均年龄为42岁（2至80岁），49%为女性。疾病发病的平均年龄为14岁（0至52岁），60%的患者在10岁之前发病，24%在20岁之后发病。患者表现为远端运动无力（93%的病例）、感觉丧失（86%）、足部畸形（83%）、脊柱侧弯（73%）、近端肢体无力（40%）、颅神经受累（48%）、听力丧失（37%）、脊柱侧弯相关的呼吸功能不全（14%）和泌尿生殖系统疾病（6%）。一半的患者（48%）在50岁之前能够独立行走，相比之下，50岁之后只有13%的患者能够独立行走。50岁之后，23%的患者需要依靠轮椅行动。神经传导研究显示，所有病例均存在脱髓鞘范围内的感觉运动异常。我们在SH3TC2基因中鉴定出56种不同的致病变异，其中22种是以前未描述过的。携带两个SH3TC2基因截短变异的患者比携带一个或零个截短变异的患者症状更严重。
本研究表明，CMT4C是一种严重的儿童期和成人期发病的脱髓鞘性周围神经病，在50岁以上的患者中，很大一部分患者常伴有脊柱侧弯、听力丧失和行走能力丧失。基因型与表型的相关性表明，两个SH3TC2基因截短变异会导致更严重的表型。
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