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.