title: Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state.
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 4 months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10 days of age and initiated ERT at Day 12. Patient 1, now 6 years 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 12 months of ERT. Her cardiac function and mobility were well-maintained for the first 3 years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3 years 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.
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuoka
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Miwa
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Tajika
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Sawada
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Fujimaki
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Showa University Northern Yokohama Hospital, Cardiovascular Center, Yokohama, Kanagawa, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Showa University Northern Yokohama Hospital, Cardiovascular Center, Yokohama, Kanagawa, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Uemura
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Faculty of Health and Medical Sciences, Tokoha University, Hamamatsu, Shizuoka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Sugie
authors.affiliation: Division of Medical Genetics, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Motomichi
authors.initials: M
authors.lastname: Kosuga
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Torayuki
authors.initials: T
authors.lastname: Okuyama
authors.affiliation: Showa University Northern Yokohama Hospital, Children Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Umeda