Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：甘氨酰-tRNA合成酶1（GARS1）基因的致病变体已被描述为Charcot-Marie-Tooth疾病2D型的原因，以上肢为主的运动轴索神经病（远端遗传性运动神经病[dHMN]V型），和婴儿脊髓性肌萎缩症.
方法：这个横截面，回顾性,对12例c.794C>T的患者进行了观察性研究（p。Ser265Phe)在GARS1中的错义致病变异。患者的临床数据，神经传导研究,磁共振成像（MRI），并对皮肤活检中的表皮内神经纤维密度进行了综述。
结果：发病的平均年龄为9.5岁；内在手部肌肉在腿部远端肌肉组织之前或同时受到影响。临床检查显示远端肌肉更加虚弱，与大际复合体和第一背侧骨间在上肢更明显的参与。电生理研究与仅运动性轴索神经病一致。在6例患者中发现了病理性分裂手指数。肌肉MRI显示腿部前外侧和浅后部主要脂肪浸润和萎缩。大多数患者报告远端针刺感觉丧失。在9例患者的近端和远端部位的皮肤活检中，表皮内神经纤维密度明显降低。
结论：GARS1变异可能会产生具有“分裂手”和感觉障碍的dHMN表型，即使感觉神经传导研究是正常的。这可以通过背神经节中感觉神经元的功能障碍来解释，这反映为皮肤活检中没有远端梯度的真皮神经末梢的减少。
方法：这个横截面，回顾性,对12例c.794C>T的患者进行了观察性研究（p。Ser265Phe)在GARS1中的错义致病变异。患者的临床数据，神经传导研究,磁共振成像（MRI），并对皮肤活检中的表皮内神经纤维密度进行了综述。
结果：发病的平均年龄为9.5岁；内在手部肌肉在腿部远端肌肉组织之前或同时受到影响。临床检查显示远端肌肉更加虚弱，与大际复合体和第一背侧骨间在上肢更明显的参与。电生理研究与仅运动性轴索神经病一致。在6例患者中发现了病理性分裂手指数。肌肉MRI显示腿部前外侧和浅后部主要脂肪浸润和萎缩。大多数患者报告远端针刺感觉丧失。在9例患者的近端和远端部位的皮肤活检中，表皮内神经纤维密度明显降低。
结论：GARS1变异可能会产生具有“分裂手”和感觉障碍的dHMN表型，即使感觉神经传导研究是正常的。这可以通过背神经节中感觉神经元的功能障碍来解释，这反映为皮肤活检中没有远端梯度的真皮神经末梢的减少。
