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Infantile-onset Pompe disease (IOPD) is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). It is characterized by severe and progressive hypertrophic cardiomyopathy and muscle weakness with death in the first 2 years of life if left untreated. Enzyme replacement therapy (ERT) with alglucosidase-alfa is lifesaving, but its effectiveness is influenced by the patient's cross-reactive immunologic material (CRIM) status, dose of ERT, and the development of high antibody titers, which can reduce the therapy's efficacy. The inability of CRIM-negative IOPD patients to produce native GAA exposes them to a high risk of development of anti-rhGAA IgG antibody titers, leading to treatment failure. We present the case of CRIM-negative dizygotic twins treated with high-dose alglucosidase-alfa (40 mg/kg/week), initiated at 28 days (Twin A) and 44 days (Twin B). Both twins received immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG to mitigate antibody response. Initial evaluations revealed elevated left ventricular mass index (LVMI) and elevated biomarkers (urine glucose tetrasaccharide (Glc4), creatine kinase (CK), and aspartate aminotransferase (AST)) in both twins. Following treatment, cardiac function and biomarkers normalized within several months, with a slight delay in Twin B compared to Twin A, likely attributed to the later initiation of ERT. Both twins safely tolerated ITI, achieving immune tolerance with low antibody titers. At 28 months, the twins transitioned to avalglucosidase-alfa (40 mg/kg every other week (EOW)), which was well tolerated without an increase in antibody titers. At 39 months, both twins exhibited normal cardiac function, LVMI, and biomarkers. Motor skills continued to improve, though some kinematic concerns persisted. These cases underscore the importance of early, high-dose ERT combined with ITI in managing CRIM-negative IOPD. While transitioning to avalglucosidase-alfa at 40 mg/kg/EOW was beneficial and well-tolerated in our patients, further studies are needed to confirm its long-term efficacy compared to the high-dose weekly 40 mg/kg alglucosidase-alfa.

Background: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. Methods: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. Results: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. Conclusions: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction. [ABSTRACT FROM AUTHOR]

The addition of Pompe disease (PD) and other conditions with later-onset forms to newborn screening (NBS) in the United States (US) has been controversial. NBS technology cannot discern infantile-onset PD (IOPD) from later-onset PD (LOPD) without clinical follow-up. This study explores genetic health care practitioners' (HCPs) experiences and challenges providing NBS patient care throughout the US and their resultant opinions on NBS for PD. An online survey was distributed to genetic counselors, geneticists, NBS follow-up care coordinators, and nurse practitioners caring for patients with positive NBS results for PD. Analysis of 78 surveys revealed the majority of participating HCPs support inclusion of PD on NBS. Almost all HCPs (93.3%) feel their state has sufficient resources to provide follow-up medical care for IOPD; however, only three-fourths (74.6%) believed this for LOPD. Common barriers included time lag between NBS and confirmatory results, insurance difficulties for laboratory testing, and family difficulties in seeking medical care. HCPs more frequently encountered barriers providing care for LOPD than IOPD (53.9% LOPD identified ≥3 barriers, 31.1% IOPD). HCPs also believe creation of a population of presymptomatic individuals with LOPD creates a psychological burden on the family (87.3% agree/strongly agree), unnecessary medicalization of the child (63.5% agree/strongly agree), and parental hypervigilance (68.3% agree/strongly agree). Opinions were markedly divided on the use of reproductive benefit as a justification for NBS. Participants believe additional education for pediatricians and other specialists would be beneficial in providing care for patients with both IOPD and LOPD, in addition to the creation of evidence-based official guidelines for care and supportive resources for families with LOPD. [ABSTRACT FROM AUTHOR]

The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m2). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]