探讨CHKB基因突变致巨锥型先天性肌营养不良(CMD)患儿的遗传学病因、临床特征和治疗方案。

选择2014年6月与2021年8月于中山大学孙逸仙纪念医院儿童医学中心进行2次住院治疗的1例CHKB基因突变致巨锥型CMD患儿(先证者)为研究对象。采用回顾性分析方法，对其病史、临床表现，以及入院体格检查、实验室检查、肌组织病理学活检结果、治疗及随访结果进行分析。于本院第2次住院时，对先证者及其父母进行全外显子组测序(WES)，并采用Sanger测序进行验证。分别以"巨锥型先天性肌营养不良"和"CHKB gene mutation""myasthenic""megaconial congenital muscular dystrophy"等为中、英文关键词，在中国知网、万方数据知识服务平台及PubMed数据库中，对关于CHKB基因突变致巨锥型CMD患者研究相关文献进行检索。本次检索年限设定为各数据库建库至2024年12月31日。本研究遵循的程序通过中山大学孙逸仙纪念医院医学伦理委员会批准(审批文号：SYSKY-2024-728-01)。

①先证者为女性，于本院第1、2次住院治疗时，年龄分别为4岁9个月与11岁11个月，父母为近亲婚配，无围产期并发症，先证者于婴儿期起病，最初表现为肌张力低下，语言、运动发育迟缓，1岁8个月时能独走，但是四肢乏力，步态呈鸭步，易摔倒，5岁后出现双下肢肌萎缩。曾有2次癫痫发作，脑电图检查结果显示双侧多发性棘波。先证者体格发育较同龄儿落后，生后血清肌酸激酶(CK)一直异常增高，为1 118~1 884 U/L(正常参考值为40~200 U/L)，多次进行心脏彩色多普勒超声检查未见明显异常。先证者于本院第1次住院时，《Gesell发育量表》评估结果显示，适应性评分为53分，精细动作评分为51分，语言评分为51分，个人社交行为评分为54分，大运动评分为54分，提示为中度智能障碍；对其采取肌组织病理学活检(光学显微镜及免疫组织化学)，被诊断为"肌源性损害改变，肌营养不良"；肌组织病理学活检(电子显微镜)诊断：肌源性超微损害改变。先证者于本院第2次住院时，WES结果显示，22号染色体上CHKB基因c.598delC(p.Gln200Argfs*11)(NM_005198.5)纯合移码突变，遗传自父母(先证者父亲和母亲各携带1个该位点杂合突变)；根据先证者临床表现、辅助检查及基因检测结果，先证者最终被确诊为CHKB基因突变所致巨锥型CMD。对其采取左卡尼汀、果糖二磷酸钠、肌苷片与维生素B2、B6、B12治疗后，肌无力较治疗前好转。随访至2022年3月(年龄为12岁6个月)，先证者因"暴发性心肌炎、心源性休克"，于外院就诊，经抢救无效死亡。②文献检索结果显示，共计50例巨锥型CMD患者(未包含本研究先证者)被纳入文献报道。对其进行遗传学病因与临床特征综合分析的结果显示，巨维型CMD患者的发病年龄为2个月龄至40岁，45例于儿童期被诊断，均发生CHKB基因突变；主要临床表现中，肌无力为50例(100.0%)，运动发育迟缓为50例(100.0%)，智力障碍为48例(96.0%)，言语发育迟缓为45例(90.0%)。

CHKB基因突变所致巨锥型CMD患儿较为罕见，主要临床表现为肌无力、运动发育迟缓、智力障碍等，肌组织病理学活检及WES是诊断该病的有效方法。对先证者采取左卡尼汀、果糖二磷酸钠、肌苷片、多种维生素治疗，可改善肌无力症状，但是须防治心脏相关并发症。

To explore the genetic etiology, clinical characteristics and treatment options of children with megaconial congenital muscular dystrophy (CMD) caused by CHKB gene mutation.

A child (the proband) with megaconial CMD caused by CHKB gene mutation, who was hospitalized twice in June 2014 and August 2021 at the Children′s Medical Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University was selected as the study subject. A retrospective analysis was conducted on the medical history, clinical manifestations, physical examinations, laboratory tests, muscle biopsy pathology results, treatment, and follow-up outcomes of the proband. During the second hospitalization, whole-exome sequencing (WES) was performed on the proband and her parents, with Sanger sequencing used for validation. Literature on patients with megaconial CMD caused by CHKB gene mutation was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases using the Chinese keyword " megaconial congenital muscular dystrophy" and English keywords " CHKB gene mutation" " myasthenic" and " megaconial congenital muscular dystrophy". The retrieval time was set from the inception of each database to December 31, 2024. The study protocol was approved by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Approval No. SYSKY-2024-728-01).

①The proband was female, aged 4 years 9 months and 11 years 11 months during her first and second hospitalizations, respectively. Her parents were consanguineous and there were no perinatal complications. The disease began in infancy with initial manifestations of hypotonia, delayed language and motor development. She could walk independently at 1 year 8 months but had limb weakness, a waddling gait, was prone to falls, and developed lower limb muscle atrophy after age 5. She experienced two epileptic seizures, and electroencephalogram showed bilateral multiple spike waves. Her physical development lagged behind peers. Her serum creatine kinase (CK) remained abnormally elevated after birth, ranging from 1 118 to 1 884 U/L (normal reference value is 40 to 200 U/L). Multiple cardiac color Doppler ultrasounds showed no significant abnormalities. During the first hospitalized in our hospital, Gesell Developmental Scale assessments in our hospital indicated adaptive behavior 53 points, fine motor 51 points, language 51 points, personal-social 54 points, and gross motor 54 points, suggesting moderate intellectual disability. Muscle biopsy (light microscopy and immunohistochemistry) pathology indicated " myopathic damage consistent with muscular dystrophy" ; electron microscopy was consistent with myogenic ultrastructural damage. During the second hospitalized in our hospital, WES revealed a homozygous frameshift mutation in the CHKB gene on chromosome 22: c. 598delC(p.Gln200Argfs*11) (NM_005198.5), inherited from both parents (each carrying a heterozygous mutation). And based on clinical presentation, auxiliary examinations, and genetic testing, the proband was finally diagnosed with megaconial CMD caused by CHKB gene mutation. After treatment with levocarnitine, fructose sodium diphosphate, inosine tablets, and vitamins B2, B6, and B12, her muscle weakness improved compared with before treatment. Follow-up until March 2022 (age 12 years 6 months) showed that the proband died due to " fulminant myocarditis and cardiogenic shock" despite emergency treatment at another hospital. ② The results of the literature review showed that 50 patients with megaconial CMD (excluding the proband) were included in the study. The results of a comprehensive analysis of genetic etiology and clinical characteristics revealed that the age of onset for megaconial CMD ranged from 2 months to 40 years, and 45 cases were diagnosed in childhood, all with CHKB gene mutations. Main clinical manifestations: muscle weakness in 50 cases (100.0%), motor developmental delay in 50 cases (100.0%), intellectual disability in 48 cases (96.0%), and speech delay in 45 cases (90.0%).

Children with megaconial CMD caused by CHKB gene mutation are rare. The main clinical manifestations are muscle weakness, motor developmental delay, intellectual disability. Muscle tissue biopsy and WES sequencing are effective methods for the diagnosis of the disease. Treatment with levocarnitine fructose sodium diphosphate, inosine tablets, and multivitamins for the proband can improve the muscle weakness symptoms, but cardiac related complications must be prevented and treated.