Murphy Ross T, Mogensen Jens, McGarry Kate, Bahl Ajay, Evans Alison, Osman Eyman, Syrris Petros, Gorman Grainne, Farrell Michael, Holton Janice L, Hanna Michael G, Hughes Sian, Elliott Perry M, Macrae Calum A, McKenna William J
The Heart Hospital, University College London, London, United Kingdom.
J Am Coll Cardiol. 2005 Mar 15;45(6):922-30. doi: 10.1016/j.jacc.2004.11.053.
The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM).
Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease.
Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM.
Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years.
The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.
本研究旨在基于对已知突变携带者12年的随访，调查单磷酸腺苷激活蛋白激酶（AMPK）基因突变（PRKAG2）在单磷酸腺苷（AMP）激酶疾病中的临床表型，并确定肥厚型心肌病（HCM）中PRKAG2突变的患病率。
单磷酸腺苷激活蛋白激酶基因突变会导致伴有 Wolff-Parkinson-White 综合征和传导疾病的肥厚型心肌病。
对44例已知AMP激酶疾病患者进行临床评估分析。通过荧光单链构象多态性分析和对200例肥厚型心肌病患者异常构象体进行直接测序，对PRKAG2进行突变分析。
仅发现另外1个突变。45名基因携带者临床诊断时的平均年龄为24岁（中位数20岁，范围9至55岁）。31名（69%）基因携带者有心悸、呼吸困难、胸痛或晕厥症状；7名（15%）主诉肌痛并有近端肌病的临床证据。骨骼肌活检显示线粒体增多和破碎红纤维，糖原积累极少。由典型心电图异常定义的疾病外显率在18岁时为100%。41名成年人中有32名（78%）超声心动图显示左心室肥厚（LVH），随访期间记录到进行性LVH。平均随访12.2年时生存率为91%。45名患者中有17名（38%）在平均年龄38岁时因进行性传导疾病需要植入起搏器。
AMP激酶疾病在肥厚型心肌病中不常见，其特征为进行性传导疾病和心脏肥大，包括骨骼肌病等心外表现，与全身性代谢性贮积病一致。三磷酸腺苷利用缺陷或特定细胞底物缺陷，而非仅仅是支链淀粉的被动沉积，可能是这些临床特征的原因。
