Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital/Harvard Medical School, United States; Department of Genetics and Genome Sciences, Case Western Reserve University and University Hospitals, United States; Department of Urology, Case Western Reserve University and University Hospitals, United States.
Department of Pediatrics, SUNY Downstate Health Sciences University, United States.
Mol Genet Metab. 2023 Jul;139(3):107626. doi: 10.1016/j.ymgme.2023.107626. Epub 2023 Jun 10.
Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK-related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families.
辛格综合征（OMIM# 212350）是一种罕见的常染色体隐性遗传的线粒体疾病，由 AGK 基因的双等位致病性变异引起，该基因编码酰基甘油激酶酶。该综合征最初被定义为“三联征”，即肥厚型心肌病、白内障和乳酸性酸中毒，伴有或不伴有骨骼肌病。辛格综合征的临床表现表现出显著的异质性，包括轻度和重度/婴儿型。此外，在一个非综合征性孤立性白内障的家族病例中也发现了双等位 AGK 致病性变异（OMIM# 614691），这扩展了我们对该基因影响的理解，超出了最初定义的综合征范围。在这项研究中，我们提供了一个系统综述，其中包括双等位 AGK 致病性变异的分子确诊病例（补充表 1）。我们的分析表明，辛格综合征的中心特征具有可变的外显率和穿透性，如下所示：白内障（98%）、心肌病（88%）、乳酸性酸中毒（调整后 88%）和骨骼肌病（调整后 74%）（表 1）。此外，我们研究了基因型、生化特征和临床结局之间的关联，特别关注婴儿死亡率。我们的发现表明，携带纯合无义变异的患者婴儿死亡率较高，死亡中位年龄较低（p=0.005 和 p=0.02，表 2a）。然而，AGK 结构域内致病性变异的位置与婴儿死亡没有显著关联（p=0.62，表 2b）。此外，我们观察到无乳酸性酸中毒与更长的生存时间之间存在边缘关联（p=0.053，表 2c）。总的来说，我们的系统综述揭示了 AGK 相关疾病的多种临床表现，并强调了影响其预后的潜在因素。这些为受影响个体和家庭的诊断、治疗和咨询提供了重要启示。
