Supplementary file 1_Case Report: Incidental late-onset Pompe disease diagnosis in a man with no clinical and instrumental evidence of neuromuscular dysfunction.pdf

Glycogen storage disease II or Pompe disease (PD), is a rare autosomal recessive disorder due to biallelic pathogenic variants in GAA, resulting in the enzymatic deficiency of alpha-1,4-glucosidase. Two clinical forms are recognized, namely, early onset (EOPD) and late-onset (LOPD). We present the case of an asymptomatic 33-year-old man who underwent a genetic screening for autosomal recessive disorders (parental prenatal counselling) and was found to carry the homozygous pathogenic GAA substitution NM_000152.5(GAA):c.-32-13T>G (IVS1). Neurological examination, serum CK levels, electromyography, muscle MRI, respiratory and cardiac screening were reported normal. We investigated the effects of the variant at transcript and protein levels in available tissues from the proband and his parents. The IVS1-32-13T>G variant (dbSNP: rs386834236, Clin Var ID: 4,027) occurs in 90% of Caucasian LOPD patients and is associated with a broad range of symptom onset. About 50 subjects have been reported harboring this variant in homozygosis and most of them are asymptomatic, although a subset develops symptoms with time. Residual levels of alpha-1,4-glucosidase activity and protein content do not seem to reflect clinical severity in homozygous IVS1 LOPD patients.

糖原贮积病II型（Glycogen Storage Disease II）又称庞贝病（Pompe Disease, PD），是一种罕见的常染色体隐性遗传病，由GAA基因双等位致病变异导致α-1,4-葡萄糖苷酶（alpha-1,4-glucosidase）的酶活性缺乏。目前公认存在两种临床表型：早发型庞贝病（EOPD）与晚发型庞贝病（LOPD）。本研究报告1例无症状33岁男性患者，该患者因需为其父母提供产前咨询而接受了常染色体隐性遗传病基因筛查，结果检出携带纯合致病GAA基因变异：NM_000152.5(GAA):c.-32-13T>G（IVS1）。对该患者进行的神经系统检查、血清肌酸激酶（CK）水平检测、肌电图（electromyography）、肌肉磁共振成像（muscle MRI）以及呼吸与心脏筛查结果均正常。我们在该先证者（proband）及其父母的可用组织样本中，对该变异在转录本（transcript）与蛋白水平的影响开展了研究。该IVS1-32-13T>G变异（单核苷酸多态性数据库（dbSNP）编号：rs386834236，临床变异数据库（ClinVar）ID：4027）在90%的高加索人群晚发型庞贝病患者中被检出，且与广泛的症状起病时间范围相关。目前已有约50例纯合携带该变异的病例被报道，其中多数患者无临床症状，但有部分患者随病程进展逐渐出现症状。在纯合IVS1型晚发型庞贝病患者中，α-1,4-葡萄糖苷酶的残留活性与蛋白含量似乎无法反映其临床严重程度。