Current Status of Newborn Screening for Pompe Disease in Japan

Abstract

Background: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (AαGlu). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease.Results: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years.Conclusions: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

The earliest enzyme replacement for infantile‐onset Pompe disease in Japan

“…A detailed review by Sawada et al 24 provides further detailed information about global PD NBS programs. Patient 1 in this report is the first Japanese IOPD case detected by an NBS program that screened 296 759 newborns from April 2013 to October 2020, 13 which indicates that the incidence of IOPD in Japan is comparable to that in the USA, but is much lower than in Taiwan and some European countries.…”

“…Fukuhara et al 15 reported 28 variants in 38 patients, among which four variants (R40X, Q57X, R608X, Y609X) are listed as possible CRIM-negative in the Pompe disease GAA variant database. 41 Next, Sawada et al 13 reported 29 disease-associated and 14 probably-damaging variants in 296 759 newborns screened for PD, among which only two variants (Y685X and R854X) are associated with CRIM-negative status. 41 All patients detected by NBS in their study had at least one CRIM-positive variant.…”

“…Enzymatic screening for PD is technically feasible, as indicated by Japanese 13,14 and international 25,26 studies. A common problem when screening for rare diseases is the false positive or recall rate, which in Japan is reported to be between 0.1% and 0.3% and is mainly related to the high prevalence of pseudodeficiency alleles, 13,14 an issue discussed in detail below. Using enzymatic or genetic second‐tier strategies could reduce false positives 14,26 .…”

“…A detailed description of the methodology was reported previously. 5,13 For patient 2, GAA activity measurements and gene sequencing were performed at the National Center for Child Health and Development, Tokyo, Japan. Enzymatic activity was determined by fluorometric assay as described elsewhere.…”

“…After referral, GAA gene analysis was performed on DNA extracted from total blood first by next‐generation sequencing followed by re‐sequencing using the Sanger method, at the Department of Pediatrics, Kumamoto University, Japan. A detailed description of the methodology was reported previously 5,13 . For patient 2, GAA activity measurements and gene sequencing were performed at the National Center for Child Health and Development, Tokyo, Japan.…”