To determine the effects of 10 years of enzyme replacement therapy (ERT) in adult patients with Pompe disease, focusing on individual variability in treatment response.
In this prospective, ...multicenter cohort study, we studied 30 patients from the Netherlands and France who had started ERT during the only randomized placebo-controlled clinical trial with ERT in late-onset Pompe disease (NCT00158600) or its extension (NCT00455195) in 2005 to 2008. Main outcomes were walking ability (6-minute walk test 6MWT), muscle strength (manual muscle testing using Medical Research Council MRC grading), and pulmonary function (forced vital capacity FVC in the upright and supine positions), assessed at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements.
Median follow-up duration on ERT was 9.8 years (interquartile range IQR 8.3-10.2 years). At the group level, baseline 6MWT was 49% of predicted (IQR 41%-60%) and had deteriorated by 22.2 percentage points (pp) at the 10-year treatment point (
< 0.001). Baseline FVC upright was 54% of predicted (IQR 47%-68%) and decreased by 11 pp over 10 years (
< 0.001). Effects of ERT on MRC sum score and FVC supine were similar. At the individual level, 93% of patients had initial benefit of ERT. Depending on the outcome measured, 35% to 63% of patients had a secondary decline after ≈3 to 5 years. Still, at 10 years of ERT, 52% had equal or better 6MWT and/or FVC upright compared to baseline.
The majority of patients with Pompe disease benefit from long-term ERT, but many patients experience some secondary decline after ≈3 to 5 years. Individual variation, however, is considerable.
This study provides Class IV evidence that for the majority of adults with Pompe disease, long-term ERT positively affects, or slows deterioration in, muscle strength, walking ability, and/or pulmonary function.
La maladie de Pompe est une glycogénose musculaire rare, de transmission autosomique récessive, liée à un déficit de l’activité lysosomale de l’alpha-glucosidase.
L’objectif de cette présentation est ...de présenter le Registre français des maladies de Pompe.
Avec les filières neuromusculaire (FILNEMUS) et métabolique (G2M), il a été colligé depuis 2004 les données fonctionnelles, cliniques et biologiques de tous les patients atteints de maladie de Pompe suivis dans les centres de référence français.
Parmi les 210 patients, 186 sont traités. Les premiers symptômes musculaires sont une faiblesse proximale des membres inférieurs à 38 ans en moyenne, associée à des symptômes respiratoires (17 %). À l’inclusion, 109 patients marchent sans aide technique et 29 ont recours au fauteuil roulant. Une assistance respiratoire est nécessaire pour 77 patients. Le dosage de l’activité enzymatique est réalisé chez 151 patients et la mutation « commune »c.-32-13T>G est identifiée pour 87 % des patients.
Cette large cohorte reflète l’état de patients atteints de maladie de Pompe. Ce registre a déjà permis de préciser les caractéristiques moléculo-épidémiologique de cette maladie, et évaluer le bénéfice de l’enzymothérapie substitutive par Myozyme®. L’arrivée prochaine de nouvelles thérapies (enzymothérapie, thérapie génique) renforce l’importance de poursuivre la collecte de données afin d’évaluer sur des bases académiques les effets des traitements.
Ce registre permet de suivre l’état de la population de patients français atteints de la maladie de Pompe et de les accompagner à l’ère de l’extension des options thérapeutiques.
Background
Pompe disease is a rare neuromuscular disorder caused by a deficiency of a lysosomal enzyme, acid α‐glucosidase. Macroglossia is a classic clinical sign of several inherited myopathies and ...has also been reported to occur progressively in late‐onset Pompe disease (LOPD).
Methods
We describe patients with LOPD and macroglossia included in the French national Pompe disease registry. Clinical, functional, and radiological data were collected during periodic follow‐up and analyzed retrospectively. These cases were compared with 15 previously reported cases.
Results
Five patients, three females and two males, aged 71–88 years, were included in this study. All but one of the patients suffered from symptoms related to macroglossia before the diagnosis of Pompe disease. Three had localized tongue atrophy and one had significant localized tongue hypertrophy which led to glossectomy 10 years before diagnosis. Two patients had severe dysphagia, one of whom underwent gastrostomy for enteral nutritional support. One patient experienced the persistence of numerous sleep apneas despite nocturnal bilevel positive airway pressure (BiPAP) ventilation. All our patients had dysarthria, and two required speech therapy. Four patients had a tongue hypersignal on magnetic resonance imaging (MRI) T1 sequences.
Conclusions
Detection of macroglossia should be part of the clinical diagnosis and follow‐up of patients with LOPD, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole‐body MRI with facial sections may facilitate the early diagnosis of Pompe disease with the “bright tongue sign”.
Detection of macroglossia should be part of the clinical diagnosis and follow‐up of patients with late‐onset Pompe disease, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole‐body magnetic resonance imaging with facial sections may facilitate the early diagnosis of Pompe disease with the “bright tongue sign”.
Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the
GAA
gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder ...(classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the
GAA
mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the
GAA
gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.
Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, ...long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.
Highlights • Birth by a Pompe patient in the absence of Cesarian section with multidisciplinary care. • Enzyme replacement therapy during pregnancy and uneventful vaginal birth. • Vaginal delivery ...despite severe respiratory failure.
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