Malekkou Anna, Theodosiou Athina, Alexandrou Angelos, Papaevripidou Ioannis, Sismani Carolina, Jacobs Edwin H, Ruijter George J G, Anastasiadou Violetta, Ourani Sofia, Athanasiou Emilia, Drousiotou Anthi, Grafakou Olga, Petrou Petros P
Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P. O. Box 23462, 1683 Nicosia, Cyprus.
Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, P. O. Box 23462, 1683 Nicosia, Cyprus.
Mol Genet Metab Rep. 2023 Aug 7;36:100997. doi: 10.1016/j.ymgmr.2023.100997. eCollection 2023 Sep.
Pompe disease is a rare metabolic myopathy caused by pathogenic variants affecting the activity of the lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Impaired GAA function results in the accumulation of undegraded glycogen within lysosomes in multiple tissues but predominantly affects the skeletal, smooth and cardiac muscle. The degree of residual enzymatic activity appears to roughly correlate with the age of onset and the severity of the clinical symptoms. Here, we report four siblings in which the variants NM_000152.5:c.2237G > C p.(Trp746Ser) and NM_000152.5:c.266G > A p.(Arg89His) were identified as an incidental finding of clinical exome sequencing. These variants are listed in the ClinVar and the Pompe disease variant databases but are reported here for the first time in compound heterozygosity. All four siblings displayed normal urine tetrasaccharide levels and no clinical manifestations related to Pompe disease. Nevertheless, GAA enzymatic activity was within the range for late onset Pompe patients. Our report shows an association between a novel genotype and attenuated GAA enzymatic activity. The clinical significance can only be established by the regular monitoring of these individuals. The study highlights the major challenges for clinical care arising from incidental findings of next generation sequencing.
庞贝病是一种罕见的代谢性肌病，由影响溶酶体糖原降解酶酸性α-葡萄糖苷酶（GAA）活性的致病性变异引起。GAA功能受损导致未降解的糖原在多个组织的溶酶体内蓄积，但主要影响骨骼肌、平滑肌和心肌。残余酶活性的程度似乎与发病年龄和临床症状的严重程度大致相关。在此，我们报告了4名兄弟姐妹，在临床外显子组测序中意外发现了变异NM_000152.5:c.2237G＞C p.(Trp746Ser)和NM_000152.5:c.266G＞A p.(Arg89His)。这些变异列于ClinVar和庞贝病变异数据库中，但首次以复合杂合性在此报告。所有4名兄弟姐妹的尿四糖水平均正常，且无与庞贝病相关的临床表现。然而，GAA酶活性处于晚发型庞贝病患者的范围内。我们的报告显示了一种新的基因型与GAA酶活性减弱之间的关联。其临床意义只能通过对这些个体的定期监测来确定。该研究突出了下一代测序意外发现给临床护理带来的重大挑战。
