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

Area of Science:

• Genetics and rare diseases
• Lysosomal storage disorders
• Newborn screening

Background:

• Infantile-onset Pompe disease (IOPD) is a severe lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency.
• Newborn screening (NBS) for IOPD began in Japan in 2013 to enable early enzyme replacement therapy (ERT).
• This study examines ERT responses in the first NBS-identified Japanese IOPD case and a pre-NBS diagnosed case.

Purpose of the Study:

• To report and compare the outcomes of enzyme replacement therapy (ERT) in two infantile-onset Pompe disease (IOPD) patients in Japan.
• To discuss challenges in achieving timely ERT initiation for IOPD in Japan.
• To highlight the importance of early diagnosis and intervention through newborn screening (NBS).

Main Methods:

• Acid alpha-glucosidase (GAA) activity was measured using a fluorometric assay.
• GAA gene sequencing (next-generation, Sanger, or PCR-based) confirmed IOPD diagnosis.
• Clinical data and treatment responses were analyzed for both patients.

Main Results:

• The NBS-identified infant with novel and pathogenic GAA variants showed prompt clinical and biochemical improvement with ERT initiated at 58 days, remaining well at 14 months.
• The pre-NBS diagnosed patient with a CRIM-negative genotype (homozygous p.R608X) survived 12 years with ERT and respiratory support but developed anti-rhGAA antibodies.
• Early ERT initiation in the NBS case demonstrated effective management of cardiac and biochemical markers.

Conclusions:

• Enzyme replacement therapy (ERT) for infantile-onset Pompe disease (IOPD) should be initiated before 2 months of age to ensure reversible cardiac function.
• While NBS facilitates early ERT, cross-reactive immunological material (CRIM)-negative genotypes can complicate rapid treatment initiation.
• Prompt ERT is vital for favorable outcomes in IOPD, emphasizing the value of newborn screening programs.