OBJECTIVE GM2-gangliosidosis are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease: TS) or HEXB (Sandhoff disease: SD) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2-gangliosidosis. METHODS We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS We observed four typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above three manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging (MRI) feature was cerebellar atrophy, even in patients without cerebellar symptoms or leukodystrophy. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION Improved knowledge of GM2-gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. This article is protected by copyright. All rights reserved.

中文翻译：

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GM2神经节苷脂沉积症成年患者的自然病程

目的 GM2-神经节苷脂沉积症是由 HEXA（泰萨克斯病：TS）或 HEXB（Sandhoff 病：SD）基因中的双等位基因突变引起的溶酶体疾病，随后具有低氨基己糖苷酶活性。大多数患者在儿童时期发病，但有些患者在青春期/成年期会出现最初的症状。本研究旨在阐明 GM2-神经节苷脂贮积症成年患者的自然病程。方法 我们回顾性地描述了来自法国队列的 12 名患者和来自文献的 45 名患者。结果 我们观察到四种典型表现：（1）导致下肢近端无力并随后扩展到上肢的下运动神经元障碍，（2）小脑性共济失调，（3）精神病和/或严重情绪障碍（仅在 TS 患者中） , (4) 混合上述三种表现的复杂表型。腰大肌是下肢第一个也是最受影响的肌肉，而肱三头肌和骨间肌主要受累于上肢。复合运动动作电位的纵向研究表明，所有神经都逐渐减少，具有不同的动力学。感觉电位有时异常低，主要是在 SD 患者中。主要的脑磁共振成像 (MRI) 特征是小脑萎缩，即使在没有小脑症状或脑白质营养不良的患者中也是如此。预后主要与步态障碍有关，因为我们发现超过 20 年的疾病演变，一半的患者是轮椅使用者。解释 对成人 GM2-神经节苷脂贮积症的认识的提高将帮助临床医生获得正确的诊断并更好地告知患者的演变和预后。在测试新兴疗法时，它还可能有助于定义适当的结果测量。本文受版权保护。版权所有。