Pompe disease in adulthood: effects of antibody formation on enzyme replacement therapy.

PURPOSE: To determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation. METHODS: We used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function. RESULTS: Of 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250-1:31,250) in 40%, and none or low (0-1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy. CONCLUSIONS: In adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype.Genet Med 19 1, 90-97.

Increased aortic stiffness and blood pressure in non-classic Pompe disease.

Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p < 0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20%), more Pompe patients had a history of hypertension (36%, p = 0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p < 0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly.

The ACE I/D polymorphism does not explain heterogeneity of natural course and response to enzyme replacement therapy in Pompe disease.

The majority of children and adults with Pompe disease in the population of European descent carry the leaky splicing GAA variant c.-32-13T>G (IVS1) in combination with a fully deleterious GAA variant on the second allele. The phenotypic spectrum of this patient group is exceptionally broad, with symptom onset ranging from early infancy to late adulthood. In addition, the response to enzyme replacement therapy (ERT) varies between patients. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been suggested to be a modifier of disease onset and/or response to ERT. Here, we have investigated the effect of the ACE I/D polymorphism in a relatively large cohort of 131 children and adults with Pompe disease, of whom 112 were followed during treatment with ERT for 5 years. We assessed the use of wheelchair and mechanical ventilation, muscle strength assessed via manual muscle testing and hand-held dynamometry (HHD), distance walked on the six-minute walk test (6MWT), forced vital capacity (FVC) in sitting and supine position and daily-life activities assessed by R-PAct. Cross sectional analysis at first visit showed no differences between the genotypes with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use. Also response to ERT over 5 years assessed by linear mixed model analyses showed no significant differences between ACE groups for any of the outcome measures. The patient cohort contained 24 families with 54 siblings. Differences in ACE genotype could neither explain inter nor intra familial differences. We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant.

Long-term benefit of enzyme replacement therapy in Pompe disease: A 5-year prospective study.

OBJECTIVE: To determine the effect of enzyme replacement therapy (ERT) after 5 years and to identify predictors for a favorable response because few data are available on the long-term efficacy of ERT in Pompe disease. METHODS: We included 102 adult patients with Pompe disease in a nationwide, prospective cohort study. We assessed muscle strength (manual muscle testing with Medical Research Council [MRC] grading, handheld dynamometry [HHD]), muscle function (6-minute walk test, Quick Motor Function Test), daily life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale), and pulmonary function (forced vital capacity [FVC] in upright and supine positions, maximum inspiratory and expiratory pressures) at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements. RESULTS: Median follow-up duration was 6.1 years (range 0.4-7.9 years), of which 5.0 years (range 0.2-7.3 years) were during ERT. Treated patients had better muscle strength (MRC sum score +6.6 percentage points [pp]; HHD sum score +9.6 pp, both p < 0.0001), activity levels (R-PAct +10.8 pp, p < 0.002), and pulmonary function (FVC upright +7.3 pp, FVC supine +7.6 pp, both p < 0.0003) than expected for their untreated disease course. Walking distance improved (416 vs 376 m at baseline, p = 0.03). The largest increase was seen during the first 2 to 3 years of treatment. Response to treatment was similar between groups regardless of sex, age, or disease duration. CONCLUSIONS: Long-term ERT positively affects muscle strength, pulmonary function, and daily life activities in adult patients with Pompe disease, with a peak effect at ≈2 to 3 years of treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with Pompe disease, long-term ERT positively affects muscle strength, pulmonary function, and daily life activities.