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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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

These figures show the motor development of the sisters.A. Patient 1 (older sister) required neck and back supports when sitting at 1 year old.B. Patient 2 (younger sister) had normal development and could stand alone at 1 year old.C. Patient 1 was bedridden and required invasive ventilation for 24 h due to the gradual progression of muscle weakness at 6 years old.D. Patient 2 had independent walking at 1 year of age and achieved normal developmental milestones without cardiorespiratory failure through 3 years of age.
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f0030: These figures show the motor development of the sisters.A. Patient 1 (older sister) required neck and back supports when sitting at 1 year old.B. Patient 2 (younger sister) had normal development and could stand alone at 1 year old.C. Patient 1 was bedridden and required invasive ventilation for 24 h due to the gradual progression of muscle weakness at 6 years old.D. Patient 2 had independent walking at 1 year of age and achieved normal developmental milestones without cardiorespiratory failure through 3 years of age.

Mentions: Patient 1 had muscle weakness before initiation of ERT. She also had ptosis, a minor nasolabial fold, and sunken cheeks consistent with facial hypotonia (Fig. 5a). Motor development was severely delayed. As she was unable to hold her head up, she required head and back support while sitting at 1 year of age (Fig. 6A). Despite ERT, her muscle weakness progressed. She required tube feeding at 9 months of age and became bedridden at 2 years old (Figs. 5b, 6C). Patient 1 was only able to move her eyes, the corners of the mouth, and fingertips slightly. Brain MRI at 6 and 9 years old showed cerebral atrophy (data not shown).


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
These figures show the motor development of the sisters.A. Patient 1 (older sister) required neck and back supports when sitting at 1 year old.B. Patient 2 (younger sister) had normal development and could stand alone at 1 year old.C. Patient 1 was bedridden and required invasive ventilation for 24 h due to the gradual progression of muscle weakness at 6 years old.D. Patient 2 had independent walking at 1 year of age and achieved normal developmental milestones without cardiorespiratory failure through 3 years of age.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121151&req=5

f0030: These figures show the motor development of the sisters.A. Patient 1 (older sister) required neck and back supports when sitting at 1 year old.B. Patient 2 (younger sister) had normal development and could stand alone at 1 year old.C. Patient 1 was bedridden and required invasive ventilation for 24 h due to the gradual progression of muscle weakness at 6 years old.D. Patient 2 had independent walking at 1 year of age and achieved normal developmental milestones without cardiorespiratory failure through 3 years of age.
Mentions: Patient 1 had muscle weakness before initiation of ERT. She also had ptosis, a minor nasolabial fold, and sunken cheeks consistent with facial hypotonia (Fig. 5a). Motor development was severely delayed. As she was unable to hold her head up, she required head and back support while sitting at 1 year of age (Fig. 6A). Despite ERT, her muscle weakness progressed. She required tube feeding at 9 months of age and became bedridden at 2 years old (Figs. 5b, 6C). Patient 1 was only able to move her eyes, the corners of the mouth, and fingertips slightly. Brain MRI at 6 and 9 years old showed cerebral atrophy (data not shown).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus