背景:先天性糖基化疾病(CDG)是一组不断扩展的单基因疾病,会破坏糖蛋白和糖脂的生物合成,导致多系统表现。根据糖基化过程的哪个部分受损,将这些病症分为不同的组。CDG的心脏表现可以显着不同,不仅在不同类型之间,而且在具有相同CDG遗传原因的个体之间。心肌病是CDG的重要表型。CDG患者心肌病的临床表现和进展尚未得到很好的表征。这项研究旨在描述各种CDG遗传原因中心肌病的常见模式,并为该患者人群提出基线筛查和随访评估。
方法:根据对其病历的回顾性回顾,确定了CDG分子确认的患者,这些患者被纳入了先天性糖基化障碍联盟(FCDGC)自然史研究的前瞻性或纪念性研究。所有患者均由FCDGC成员的临床遗传学家在各自的学术中心进行评估。患者接受了心肌病筛查,并回顾性收集了详细的数据。我们分析了他们的临床和分子病史,心脏受累的影像学特征,心肌病的类型,最初出现心肌病的年龄,额外的心脏特征,给予的治疗,和他们的临床结果。
结果:在截至2023年6月参与FCDGC自然史研究的305名分子确认CDG患者中,有17名个体,九位女性八位男性,同时诊断为心肌病。这些患者大多数被诊断为PMM2-CDG(n=10)。然而,在其他诊断中也观察到心肌病,包括PGM1-CDG(n=3),ALG3-CDG(n=1),DPM1-CDG(n=1),DPAGT1-CDG(n=1),和SSR4-CDG(n=1)。所有PMM2-CDG患者均报告患有肥厚型心肌病。在三名患者中观察到扩张型心肌病,2例PGM1-CDG和1例ALG3-CDG;2例诊断为左心室致密化不全心肌病,1例PGM1-CDG,1例DPAGT1-CDG;2例,一个带有DPM1-CDG,一个带有SSR4-CDG,被诊断为非缺血性心肌病。估计诊断为心肌病的中位年龄为5个月(范围:产前-27岁)。在3例PMM2-CDG患者中观察到心脏改善。五名患者表现出心肌病的进行性过程,而8个人的情况保持不变。6例患者出现心包积液,三名患者表现出心脏压塞。一名SSR4-CDG患者最近被诊断为心肌病;因此,疾病的进展尚未确定。1例PGM1-CDG患者行心脏移植。七名病人死亡,包括五个PMM2-CDG,一个带有DPAGT1-CDG,和一个ALG3-CDG。两名患者死于心包积液引起的心包填塞;其余患者,心肌病不一定是死亡的主要原因.
结论:在这项回顾性研究中,在~6%的CDG患者中发现了心肌病。值得注意的是,大多数,包括所有带有PMM2-CDG的,表现为肥厚型心肌病。有些病例没有进展,然而,通常观察到心包积液,尤其是在PMM2-CDG患者中,偶尔会升级到危及生命的心包填塞。建议临床医生管理CDG患者,特别是那些带有PMM2-CDG和PGM1-CDG的,警惕心肌病风险和潜在危及生命的心包积液风险。心脏监测,包括超声心动图和心电图,应该在诊断时进行,在最初的五年中,每年,随后每2-3年检查一次,如果直到成年后才出现担忧。随后,建议每五年进行一次心脏常规检查。此外,诊断为心肌病的患者应接受持续的心脏护理,以确保对其病情进行有效的管理和监测。需要进行前瞻性研究以确定CDG中心肌病的真实患病率。
BACKGROUND: Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of genetic causes of CDG and to propose baseline screening and follow-up evaluation for this patient population.
METHODS: Patients with molecular confirmation of CDG who were enrolled in the prospective or memorial arms of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study were ascertained for the presence of cardiomyopathy based on a retrospective review of their medical records. All patients were evaluated by clinical geneticists who are members of FCDGC at their respective academic centers. Patients were screened for cardiomyopathy, and detailed data were retrospectively collected. We analyzed their clinical and molecular history, imaging characteristics of cardiac involvement, type of cardiomyopathy, age at initial presentation of cardiomyopathy, additional cardiac features, the treatments administered, and their clinical outcomes.
RESULTS: Of the 305 patients with molecularly confirmed CDG participating in the FCDGC natural history study as of June 2023, 17 individuals, nine females and eight males, were identified with concurrent diagnoses of cardiomyopathy. Most of these patients were diagnosed with PMM2-CDG (n = 10). However, cardiomyopathy was also observed in other diagnoses, including PGM1-CDG (n = 3), ALG3-CDG (n = 1), DPM1-CDG (n = 1), DPAGT1-CDG (n = 1), and SSR4-CDG (n = 1). All PMM2-CDG patients were reported to have hypertrophic cardiomyopathy. Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG; left ventricular non-compaction cardiomyopathy was diagnosed in two patients, one with PGM1-CDG and one with DPAGT1-CDG; two patients, one with DPM1-CDG and one with SSR4-CDG, were diagnosed with non-ischemic cardiomyopathy. The estimated median age of diagnosis for cardiomyopathy was 5 months (range: prenatal-27 years). Cardiac improvement was observed in three patients with PMM2-CDG. Five patients showed a progressive course of cardiomyopathy, while the condition remained unchanged in eight individuals. Six patients demonstrated pericardial effusion, with three patients exhibiting cardiac tamponade. One patient with SSR4-CDG has been recently diagnosed with cardiomyopathy; thus, the progression of the disease is yet to be determined. One patient with PGM1-CDG underwent cardiac transplantation. Seven patients were deceased, including five with PMM2-CDG, one with DPAGT1-CDG, and one with ALG3-CDG. Two patients died of cardiac tamponade from pericardial effusion; for the remaining patients, cardiomyopathy was not necessarily the primary cause of death.
CONCLUSIONS: In this retrospective study, cardiomyopathy was identified in ∼6% of patients with CDG. Notably, the majority, including all those with PMM2-CDG, exhibited hypertrophic cardiomyopathy. Some cases did not show progression, yet pericardial effusions were commonly observed, especially in PMM2-CDG patients, occasionally escalating to life-threatening cardiac tamponade. It is recommended that clinicians managing CDG patients, particularly those with PMM2-CDG and PGM1-CDG, be vigilant of the cardiomyopathy risk and risk for potentially life-threatening pericardial effusions. Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood. Subsequently, routine cardiac examinations every five years are advisable. Additionally, patients with diagnosed cardiomyopathy should receive ongoing cardiac care to ensure the effective management and monitoring of their condition. A prospective study will be required to determine the true prevalence of cardiomyopathy in CDG.