Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Department of Pediatric, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Mol Genet Genomic Med. 2021 Mar;9(3):e1606. doi: 10.1002/mgg3.1606. Epub 2021 Jan 29.
Congenital cervical spinal muscular atrophy (CCSMA) is a rare, nonprogressive, neurogenic disorder characterized by symmetric arthrogryposis and motor deficits mainly confined to upper extremities. Since its first proposal by Darwish et al. 39 years ago, only few cases have ever been reported. Vascular insult to the anterior horn of cervical spinal cord during fetal development was speculated to be the cause, however, the exact pathogenesis is still not well understood.
In this study, whole-exome sequencing (WES) and copy number variation (CNV) analysis were conducted on a definitive CCSMA patient, confirmed by the clinical manifestations and other supplementary examinations.
On physical examination, the patient was mainly characterized by symmetric, congenital, nonprogressive contractures, hypotonia, and muscle weakness mainly confined to the upper limbs, which were further supported by MRI and electromyography. Neuromuscular biopsy of the deltoid muscle demonstrated the type 1 myofiber predominance without any infiltration of inflammatory cells. The WES and CNV analysis unveiled a de novo Xp11.22-22.33 deletion. On further examination of the genes contained within this segment, we recognize UBA1 gene as the most likely pathogenic gene. Ubiquitin-like modifier activating enzyme 1 is encoded by UBA1 gene (MIM 314370) located in Xp11.3 and is a critical protein that plays a vital role in ubiquitin-proteasome system and autophagy. It is well documented that UBA1 gene mutation causes X-linked infantile spinal muscular atrophy (XL-SMA), which manifests phenotypes of arthrogryposis, hypotonia, and myopathic face. Type 2 XL-SMA, which follows a nonprogressive and nonlethal course is very similar to the presentations of CCSMA.
The phenotypic similarities between this CCSMA case and XL-SMA prompt us to hypothesize a possible connection between UBA1 gene deficit and the pathogenesis of CCSMA. Our study is the first to demonstrate that CCSMA might have a genetic etiology, thus, expanding our insights into the underlying cause of CCSMA.
先天性颈脊髓性肌萎缩症（CCSMA）是一种罕见的、非进行性的、神经源性疾病，其特征为对称性关节挛缩和运动功能障碍，主要局限于上肢。自 39 年前 Darwish 等人首次提出以来，仅有少数病例报告。推测在胎儿发育过程中，对颈脊髓前角的血管损伤是其病因，但确切的发病机制仍不清楚。
对一名经临床表现和其他辅助检查确诊的明确 CCSMA 患者进行全外显子组测序（WES）和拷贝数变异（CNV）分析。
体格检查主要表现为对称性、先天性、非进行性的挛缩、低张力和上肢为主的肌肉无力，进一步的 MRI 和肌电图检查也支持这一诊断。三角肌的神经肌肉活检显示 1 型肌纤维占优势，没有任何炎症细胞浸润。WES 和 CNV 分析揭示了一个新发的 Xp11.22-22.33 缺失。进一步检查该片段内包含的基因，我们认为 UBA1 基因是最有可能的致病基因。UBA1 基因（MIM 314370）编码的泛素样修饰酶激活酶 1 位于 Xp11.3，是泛素-蛋白酶体系统和自噬的关键蛋白。已有文献报道 UBA1 基因突变导致 X 连锁婴儿型脊髓性肌萎缩症（XL-SMA），其表现为关节挛缩、低张力和肌病面容。非进行性和非致死性病程的 2 型 XL-SMA 与 CCSMA 的表现非常相似。
本 CCSMA 病例与 XL-SMA 的表型相似，提示我们 UBA1 基因缺失与 CCSMA 发病机制之间可能存在联系。本研究首次证明 CCSMA 可能具有遗传病因，从而扩展了我们对 CCSMA 潜在病因的认识。
