PHKA1-associated phosphorylase kinase deficiency: a monogenic disorder of exercise intolerance and myalgia.

IF 5.3 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2025-11-10 DOI:10.1038/s41525-025-00527-y

Rebecca L Koch, Angie H Fares, Benjamin T Cocanougher, Jamie Lim, Andrea B Haijer-Schreuder, Terry G J Derks, Sarah C Grünert, Reena Sharma, Karra A Jones, Priya S Kishnani

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Abstract

Muscle phosphorylase kinase deficiency results from X-linked pathogenic variants in PHKA1, leading to glycogen storage disease (GSD) type IXα1 (also known as GSD IXd). As part of an international collaboration, we describe 14 previously unreported cases (12 males, 2 females; ClinicalTrials.gov NCT04454216, registered 2020-07-01). We compared our cohort to 18 cases previously reported and to an additional 16 cases identified through the National Institutes of Health All of Us Research Program. The clinical presentations highlight the predominance of myopathic symptoms on exertion and emphasize the variability in age of onset. Examination of muscle biopsies revealed glycogen accumulation and an increase in lipid droplets indicative of mitochondrial dysfunction and mitophagy. We encourage clinicians to maintain a high level of suspicion even in the setting of normal blood creatine kinase levels. Comprehensive longitudinal natural history studies remain necessary to improve disease detection, inform management guidelines, and provide a foundation for therapeutic development.

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phka1相关磷酸化酶激酶缺乏症：运动不耐受和肌痛的单基因疾病。

肌肉磷酸化酶激酶缺乏是由PHKA1的x连锁致病性变异引起的，导致糖原储存病（GSD） IXα1型（也称为GSD IXd）。作为国际合作的一部分，我们描述了14例以前未报告的病例（12例男性，2例女性；ClinicalTrials.gov NCT04454216，注册日期2020-07-01）。我们将我们的队列与先前报道的18例病例和通过美国国立卫生研究院“我们所有人”研究计划确定的另外16例病例进行了比较。临床表现突出肌病症状的优势在运动，并强调在年龄的变化发病。肌肉活组织检查显示糖原积聚和脂滴增加表明线粒体功能障碍和线粒体自噬。我们鼓励临床医生保持高度的怀疑，即使在设定正常血肌酸激酶水平。全面的纵向自然病史研究仍然是必要的，以改善疾病检测，告知管理指南，并为治疗发展提供基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.