Molecular study of Pompe disease in Egyptian infants

Background Pompe disease (PD) is a serious genetic disorder caused by deficiency of acid α-glucosidase (GAA) and subsequent glycogen accumulation inside lysosomes. This study included a cohort of 5 Egyptian infants (1–8 months old) with far lower than average normal GAA activity and clinical signs of PD in 4 of the 5 cases. The fifth case was discovered by newborn screening (NBS). Molecular analysis of the GAA gene was performed to confirm the diagnosis and identify the underlying mutation. Results The study identified the causative mutations [c.1193T > C (p.Leu398Pro), c.1134C > G (p.Tyr378*) & c.1431del (p.Ile477Metfs*43)] in 4 cases. However, molecular analysis reversed the expected pathologic state in the fifth infant, where his reduced enzymatic activity was related to the presence of pseudodeficiency allele c.868A > G (p.Asn290Asp) in addition to heterozygous disease-causing mutation c.2238G > C (p.Trp746Cys). Conclusion This study presents the first molecular analysis of GAA gene in Egypt and has thrown some light on the importance of PD molecular diagnosis to provide precise diagnosis and enable therapeutic commencement in affected subjects.

Multicenter Targeted Population Screening of Late Onset Pompe Disease in Unspecified Myopathy Patients in Korea

Background: Pompe disease is a rare autosomal recessive disorder caused by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA). Early diagnosis and initiation of treatment with enzyme replacement therapy have remarkable effects on the prognosis of Pompe disease. We performed the expanded screening for late onset Pompe disease (LOPD) at eight centers in Korea.Methods: From September 1, 2015, GAA activity were measured from both dried blood spot (DBS) and mixed leukocyte for 188 available patients. For 12 patients with low GAA activity, we performed Sanger sequencing of <i>GAA</i> gene.Results: Among 188 patients, 115 were males. The mean of age of symptom onset and diagnosis were 34.3 years and 41.6 years. Among 12 patients with decreased GAA activity, two patients were confirmed to have LOPD with genetic test (c.1316T>A [p.M439K] + c.2015G>A [p.R672Q], c.1857C>G [p.S619R] + c.546G>C [leaky splicing]). Other two patients had homozygous G576S and E689K mutation, known as pseudodeficiency allele.Conclusions: This study is expanded study of LOPD screening for targeted Korean population. We found two patients with LOPD, and the detection rate of LOPD is 1.06%. With application of modified GAA cutoff value (0.4), which was previously reported, there were no false positive results of GAA activity test using DBS. Therefore, it could be an appropriate screening test for LOPD in especially East-Asian population, in which pseudodeficiency allele is frequent.