Abstract
Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid α-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectancy of patients with IOPD. However, the efficacy of ERT in patients with IOPD is affected by the presence of symptoms and cross-reactive immunologic material (CRIM) status.We have treated two siblings with IOPD with ERT at different ages: the first was symptomatic and the second was asymptomatic. The female proband (Patient 1) was diagnosed with IOPD and initiated ERT at 4months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10days of age and initiated ERT at Day 12. Patient 1, now 6years old, is alive but bedridden, and requires 24-hour invasive ventilation due to gradually progressive muscle weakness. In Patient 2, typical symptoms of IOPD, including cardiac failure, respiratory distress, progressive muscle weakness, hepatomegaly and myopathic facial features were largely absent during the first 12months of ERT. Her cardiac function and mobility were well-maintained for the first 3years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3years of ERT. Both siblings have had low anti-rhGAA immunoglobulin G (IgG) antibody titers during ERT and have tolerated the treatment well.These results suggest that initiation of ERT during the pre-symptomatic period can prevent and/or attenuate the progression of IOPD, including cardiomyopathy, respiratory distress, and muscle weakness for first several years of ERT. However, to improve the long-term efficacy of ERT for IOPD, new strategies for ERT for IOPD, e.g. modifying the enzyme to enhance uptake into skeletal muscle and/or to cross the blood brain barrier (BBB), will be required.
Highlights
Pompe disease, known as glycogen storage disease type II (OMIM 232300), is an autosomal recessive, lysosomal storage disorder⁎ Corresponding author at: Division of Medical Genetics, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 1578535, Japan.T
No ECG was performed at birth in Patient 1, similar ECG abnormalities were observed in both siblings before initiation of Enzyme replacement therapy (ERT) and at all assessments thereafter, which consisted of a short PR interval, high voltages, and ST-wave abnormalities
The peak antibody titer in Patient 1 was 6400 after 3 months of ERT and in Patient 2 was 400 after 7 months of ERT. Both patients showed declining anti-rhGAA immunoglobulin G (IgG) antibody titers that remained low during ERT. It is well-recognized that ERT with rhGAA dramatically improves the prognosis and quality of life of patients with Infantile-onset Pompe disease (IOPD)
Summary
Known as glycogen storage disease type II (OMIM 232300), is an autosomal recessive, lysosomal storage disorder. ERT has been shown to dramatically improve the prognosis and quality of life of patients with IOPD. Initiation of ERT in IOPD reduces the risk of death and invasive ventilation in the first year of life. Newborn screening (NBS) is the best way to diagnose patients and enable initiation of treatment in a timely manner in the pre-symptomatic period [9,10]. NBS for Pompe disease has already started in Taiwan and in several US states, and it has been successful in improving the prognosis of patients with IOPD [11,12]. Several cases of ERT-treated siblings with IOPD have been reported [13,14]. We report our treatment experience in two Japanese sisters with IOPD. Long-term follow-up shows that current ERT has limitations with respect to efficacy in IOPD
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