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BCKDK基因突变作为一种导致合并神经发育迟缓、自闭症和癫痫的罕见病症:4例患者的病例系列

BCKDK gene mutations as a rare condition responsible for comorbid neurodevelopmental delay, autism, and epilepsy: a case series of four patients.

作者信息

Karimzadeh Parvaneh, Kachuei Maryam, Najmabadi Hossein, Keramatipour Mohammad, Rezazadeh Mohammad, Tasharrofi Behnoosh, KamaliTabar Fatemeh

机构信息

Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Department of Pediatric Neurology, Hazrat-e Ali Asghar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

出版信息

Ann Med Surg (Lond). 2025 Jun 16;87(7):4046-4052. doi: 10.1097/MS9.0000000000003460. eCollection 2025 Jul.

DOI:10.1097/MS9.0000000000003460
PMID:40851941
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12369739/
Abstract

INTRODUCTION

Mutations in the branched-chain keto-acid dehydrogenase kinase gene (BCKDK), leading to low plasma branched-chain amino acids (BCAAs) levels, have been reported as a contributor to comorbid intellectual disability, autism, epilepsy, and neurodevelopmental delay (NDD). Due to the rarity of knowledge about these mutations, the current case series aims to introduce four confirmed cases.

METHODS

This case series study analyzed children from a neurometabolic clinic. Social and adaptive functions were assessed using the vineland social maturity scale (VSMS). Whole exome sequencing (WES) identified genetic variants filtered using population databases. Candidate variants were confirmed through Sanger sequencing and interpreted based on ACMG guidelines.

RESULTS

Four children of unrelated consanguineous families suffering from global NDD and autism were referred to our center. Neuroimaging assessments revealed negligible findings; thus, metabolic tests were sent, in which BCAAs were lower than normal limits. Therefore, genetic testing was done, and genetic variants compatible with BCKDK deficiency were detected. By initiating a BCAAs-rich regimen, the patients had significant improvements in psychomotor and speech development.

CONCLUSION

The diagnosis of BCKDK deficiency should be suspected in patients with NDD and autism, and BCAA supplementation should be initiated as soon as diagnosis confirmation to prevent irreversible brain damage. The results emphasize that early diagnosis and dietary intervention by regulating plasma BCAA levels lead to the prevention of irreversible neurodevelopmental implications.

摘要

引言

据报道,支链酮酸脱氢酶激酶基因(BCKDK)突变会导致血浆支链氨基酸(BCAA)水平降低,这是导致合并智力残疾、自闭症、癫痫和神经发育迟缓(NDD)的一个因素。由于对这些突变的了解较少,本病例系列旨在介绍4例确诊病例。

方法

本病例系列研究分析了来自神经代谢门诊的儿童。使用文兰社会成熟量表(VSMS)评估社会和适应功能。全外显子组测序(WES)确定了使用人群数据库筛选的基因变异。候选变异通过桑格测序得到确认,并根据美国医学遗传学与基因组学学会(ACMG)指南进行解释。

结果

4名来自非近亲家庭的患有全面性NDD和自闭症的儿童被转诊至我们中心。神经影像学评估结果显示可忽略不计;因此,进行了代谢检查,其中BCAA低于正常范围。因此,进行了基因检测,并检测到与BCKDK缺乏症相符的基因变异。通过启动富含BCAA的治疗方案,患者在精神运动和语言发育方面有显著改善。

结论

对于患有NDD和自闭症的患者,应怀疑BCKDK缺乏症的诊断,一旦确诊应立即开始补充BCAA,以防止不可逆转的脑损伤。结果强调,通过调节血浆BCAA水平进行早期诊断和饮食干预可预防不可逆转的神经发育影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1c3/12369739/f6f5de486819/ms9-87-4046-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1c3/12369739/759fedbf5116/ms9-87-4046-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1c3/12369739/f6f5de486819/ms9-87-4046-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1c3/12369739/759fedbf5116/ms9-87-4046-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1c3/12369739/f6f5de486819/ms9-87-4046-g002.jpg

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