Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Eur J Neurol. 2024 Oct;31(10):e16416. doi: 10.1111/ene.16416. Epub 2024 Jul 25.
Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy.
This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed.
The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients.
GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.
甘氨酰-tRNA 合成酶 1（GARS1）基因的致病性变异已被描述为导致 2D 型腓骨肌萎缩症、以上肢为主的运动轴索性神经病（远端遗传性运动神经病 [dHMN] 型 V）和婴儿型脊髓性肌萎缩症的原因。
本横断面、回顾性、观察性研究纳入了 12 名携带 GARS1 中 c.794C>T（p.Ser265Phe）错义致病性变异的患者。回顾了患者的临床数据、神经传导研究、磁共振成像（MRI）以及皮肤活检中的表皮内神经纤维密度。
发病年龄的平均值为 9.5 岁；内在手部肌肉在远端腿部肌肉之前或同时受累。临床检查显示远端肌肉的无力更严重，手鱼际复合体和第一背侧骨间肌在上肢的受累更为明显。电生理研究与单纯运动轴索性神经病一致。6 例患者存在病理性分指指数。肌肉 MRI 显示腿部前外侧和浅层后间隔的脂肪浸润和萎缩更为明显。大多数患者报告存在远端刺痛感觉丧失。9 例患者的皮肤活检显示近端和远端部位的表皮内神经纤维密度降低。
GARS1 变异可导致出现“分指”和感觉障碍的 dHMN 表型，即使感觉神经传导研究正常也是如此。这可以通过背根神经节中感觉神经元的功能障碍来解释，这种功能障碍反映为皮肤活检中的真皮神经末梢减少，而没有远端梯度。
