Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy

Forsha, Daniel; Li, Jennifer S.; Smith, P. Brian; Ploeg, Ans T. van der; Kishnani, Priya S.; Pasquali, Sara K.

doi:10.1097/gim.0b013e3182142966

Cited by 41 publications

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References 42 publications

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“…We agree with Forsha et al 1 that further studies are needed to evaluate cardiac effects of ERT in late-onset Pompe disease and would like to emphasize that they should include childhoodand juvenile-onset cases.…”

supporting

confidence: 59%

“…Forsha et al 's study 1 is one of the first to report on the cardiac response to ERT in patients with late-onset Pompe disease. Although they found that cardiovascular parameters were not affected by ERT, it is unclear in the paper whether the PR interval of two patients improved after 78 weeks of ERT or if they simply dropped out of the study.…”

mentioning

confidence: 99%

“…

Forsha et al 1 . Ninety patients were randomized 2:1 to enzyme replacement therapy (ERT) or placebo in a double-blind protocol.

…”

mentioning

confidence: 99%

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Correction of a short cardiac PR interval in a 12-year-old girl with late-onset Pompe disease following enzyme replacement therapy

Fernández

Legido

Jethva

et al. 2012

Genetics in Medicine

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Forsha et al. 1 . Ninety patients were randomized 2:1 to enzyme replacement therapy (ERT) or placebo in a double-blind protocol. Electrocardiograms and echocardiograms were obtained at baseline and scheduled intervals over a 78-week study period. Eighty-seven adult patients (median age 44 years; 51% male) were included in the final analysis of the results. At baseline 10% of the patients had a short PR interval (<120 milliseconds). Other cardiac dysfunction included ventricular hypertrophy (12%), decreased ejection fraction (7%), and enlarged left-ventricular mass (5%). These findings are in contrast to those described in infantile Pompe disease in which electrocardiograms abnormalities are universal and cardiac hypertrophy is much more prevalent and severe. The study suggested that cardiovascular parameters, including short PR interval, may not be impacted by ERT. However, the authors recognized that the relatively small sample size could be a limiting factor in detecting small differences between baseline and follow-up data. The authors concluded that long-term evaluation of the cardiac effect of ERT in a larger cohort of late-onset Pompe patients is necessary.Because of the authors' conclusion, we would like to contribute our experience with a patient with late-onset Pompe disease, in whom ERT had a quick and prominent effect in the recovery of a short PR interval. We evaluated a 12-yearold girl for failure to thrive, proximal weakness, and fatigue of 2 years duration. Neurological examination revealed diffuse decrease of muscle mass in both the upper and lower extremities. Proximal muscle strength was 4+/5 in the upper extremities and 4/5 in the lower extremities. Deep tendon reflexes were normal in upper extremities, absent in the patellas, and decreased in the Achilles tendons. Laboratory evaluation revealed creatine phosphokinase 563U/L, aldolase 19U/L, aspartate aminotranferase 249U/L, and alanine aminotraferase 216U/L. Electromyogram and nerve conduction velocity studies were normal. Cardiac exam revealed a short PR interval of 70 milliseconds in leads II, III, V2, V4, V5, and V6. An echocardiogram was also performed, which demonstrated an intact atrial septum with no evidence of septal or free wall hypertrophy. There was adequate myocardial performance with a fractional shortening of the left ventricle of 0.42 seconds. The diagnosis of late-onset Pompe disease was confirmed by an abnormal low acid alpha glucosidase activity of 1.3 pmol/punch/hour in dried blood spot (normal range 10-49 pmol/punch/hour) and genetic studies. The patient had a c3213 T>G mutation within the first intron of the GAA gene (carried by her mother) and a mutation in exon 11 (c1636g>c), carried by her father, compatible with Pompe disease. Our patient remained clinically stable for 2 years with nutritional restrictions and physical therapy. ERT was initiated after an elevation of creatine phosphokinase and glucose tetrasaccharides in urine. She was treated with biweekly intravenous infusions of Lumizyme at a dose of 20 mg/kg body...

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confidence: 59%

mentioning

confidence: 99%

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Correction of a short cardiac PR interval in a 12-year-old girl with late-onset Pompe disease following enzyme replacement therapy

Fernández

Legido

Jethva

et al. 2012

Genetics in Medicine

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“…In untreated late onset patients, muscle strength and pulmonary function usually deteriorate, leading in a large majority of patients to wheelchair and need of respiratory support [4,5]. Cardiac involvement, characterized by decreased left ventricular systolic function or elevated left ventricular or septum mass on echocardiogram, has been recently reported in few adult patients [6].…”

Section: Introductionmentioning

confidence: 99%

Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years

et al. 2011

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The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.

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“…Recently, a relatively large cohort of adults (87 patients, median age 44 years old, 51% males) with Pompe disease has been described. 40 A short PR interval was present in 10% of the patients, 7% showed a decreased left ventricular systolic function, and 5% had cardiomyopathy (increased left ventricular mass by echocardiography). Interestingly, no changes in cardiovascular status associated with ERT were observed.…”

Section: The Point Of View Of the Pulmonologistmentioning

confidence: 99%

Molecular Basis and Clinical Management of Pompe Disease

et al. 2013

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Pompe disease (glycogenosis type II) is a rare autosomal recessive lysosomal storage disorder due to mutations of the GAA gene, leading to the deficiency of acid α-glucosidase and consequent glycogen storage in various tissues, mainly in the skeletal muscle, heart and liver. The consequent clinical picture is mainly due to the muscle and heart involvement, although clinical manifestations may be multi-systemic. The phenotype of patients is heterogeneous and the severity is inversely related to the residual enzymatic activity of acid α-glucosidase. More than 200 different mutations of GAA gene have been described and genotype/phenotype correlations have been established for some of them. Traditionally three forms have been described, i.e. early onset classical and non-classical forms and late onset attenuated forms. A severe hypertrophic cardiomyopathy in combination with conduction disorder in newborns represents a typical feature in the classic infantile presentation, while clinical picture in late onset forms is dominated by skeletal muscle dysfunction, resulting in mobility and respiratory problems. Enzyme replacement therapy with recombinant human GAA is the approved therapeutic approach in Pompe disease patients. Clinical trials on enzyme replacement therapy (ERT) support the efficacy in improving survival and hypertrophic cardiomyopathy, while efficacy seems to be variable on manifestations due to skeletal muscle involvement, mainly in lateonset patients. Considering the limitations of ERT and its high costs, innovative therapeutic approaches are now under development

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Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy

Cited by 41 publications

References 42 publications

Correction of a short cardiac PR interval in a 12-year-old girl with late-onset Pompe disease following enzyme replacement therapy

Correction of a short cardiac PR interval in a 12-year-old girl with late-onset Pompe disease following enzyme replacement therapy

Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years

Molecular Basis and Clinical Management of Pompe Disease

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