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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.


Electrocardiogram (ECG) at baseline in two siblings.A. Patient 1 at 4 months of age and before ERT. ECG shows short PR interval (0.10 s) and high voltage in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1.B. Patient 2 at birth and before ERT. ECG shows short PR interval (0.08 s), high voltages (maximum voltage of R + S was 7 mV on V2), and inverted T waves from V1 to V4.
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f0010: Electrocardiogram (ECG) at baseline in two siblings.A. Patient 1 at 4 months of age and before ERT. ECG shows short PR interval (0.10 s) and high voltage in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1.B. Patient 2 at birth and before ERT. ECG shows short PR interval (0.08 s), high voltages (maximum voltage of R + S was 7 mV on V2), and inverted T waves from V1 to V4.

Mentions: Chest X-ray showed cardiomegaly (cardiothoracic ratio of 65%) (Fig. 1A). Electrocardiogram (ECG) documented a short PR interval (0.10 s) and high voltages in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1 (Fig. 2A). Echocardiography (ECHO) demonstrated remarkable left ventricular wall thickening: the inter-ventricular septum end-diastolic thickness (IVSd) was 12 mm and the left ventricular end-diastolic posterior wall thickness (PWd) was 14 mm. The left ventricular myocardium mass index (LVMI) was calculated to be 392 g/m2 by ECHO. On the other hand, the left ventricular end-diastolic dimension (LVIDd) was 25.8 mm (98% of normal), and there was no left ventricular outflow stenosis. The left ventricular ejection fraction (EF) was decreased to 47% (Fig. 3A). Skeletal muscle biopsy histopathology showed many enlarged lysosomes, approximately 30 μm in diameter, in muscle fibers also filled with storage material and vacuolated fibers (Fig. 4A, B). GAA activity was low at 0.15 nmol-4MU/min/mg in lymphocytes (Normal range: 5.6 ± 1.87 nmol-4MU/mg/min) and 0.1 nmol-4MU/mg/30 min (Normal range: 14.6 ± 4.8 nmol-4MU/mg/30 min) in a muscle biopsy specimen. Mutation analysis of the GAA gene revealed compound heterozygosity for a frameshift mutation, c.483dupC (p.K162QfsX15) (very severe), and a missense mutation, c.1696 T > C (p.S566P) (potentially less severe).


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
Electrocardiogram (ECG) at baseline in two siblings.A. Patient 1 at 4 months of age and before ERT. ECG shows short PR interval (0.10 s) and high voltage in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1.B. Patient 2 at birth and before ERT. ECG shows short PR interval (0.08 s), high voltages (maximum voltage of R + S was 7 mV on V2), and inverted T waves from V1 to V4.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0010: Electrocardiogram (ECG) at baseline in two siblings.A. Patient 1 at 4 months of age and before ERT. ECG shows short PR interval (0.10 s) and high voltage in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1.B. Patient 2 at birth and before ERT. ECG shows short PR interval (0.08 s), high voltages (maximum voltage of R + S was 7 mV on V2), and inverted T waves from V1 to V4.
Mentions: Chest X-ray showed cardiomegaly (cardiothoracic ratio of 65%) (Fig. 1A). Electrocardiogram (ECG) documented a short PR interval (0.10 s) and high voltages in all chest leads (maximum voltage of R + S was 16 mV in V2) with elevated ST changes in V1 (Fig. 2A). Echocardiography (ECHO) demonstrated remarkable left ventricular wall thickening: the inter-ventricular septum end-diastolic thickness (IVSd) was 12 mm and the left ventricular end-diastolic posterior wall thickness (PWd) was 14 mm. The left ventricular myocardium mass index (LVMI) was calculated to be 392 g/m2 by ECHO. On the other hand, the left ventricular end-diastolic dimension (LVIDd) was 25.8 mm (98% of normal), and there was no left ventricular outflow stenosis. The left ventricular ejection fraction (EF) was decreased to 47% (Fig. 3A). Skeletal muscle biopsy histopathology showed many enlarged lysosomes, approximately 30 μm in diameter, in muscle fibers also filled with storage material and vacuolated fibers (Fig. 4A, B). GAA activity was low at 0.15 nmol-4MU/min/mg in lymphocytes (Normal range: 5.6 ± 1.87 nmol-4MU/mg/min) and 0.1 nmol-4MU/mg/30 min (Normal range: 14.6 ± 4.8 nmol-4MU/mg/30 min) in a muscle biopsy specimen. Mutation analysis of the GAA gene revealed compound heterozygosity for a frameshift mutation, c.483dupC (p.K162QfsX15) (very severe), and a missense mutation, c.1696 T > C (p.S566P) (potentially less severe).

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.