AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG)
Por:
Martinez-Monseny T, Bolasell M, Callejón L, Cuadras-Palleja D, Freniche V, Itzep DC, Gassiot S, Arango P, Casas-Alba D, de la Morena E, Corral J, Montero-Sanchez R, Pérez-Cerdá C, Pérez-Dueñas B, Artuch-Iriberri R, Jaeken J, and the CDG Spanish Consortium and Serrano M
Publicada:
1 may 2019
Ahead of Print:
22 mar 2019
Resumen:
Objective Phosphomannomutase deficiency (PMM2 congenital disorder of glycosylation [PMM2-CDG]) causes cerebellar syndrome and strokelike episodes (SLEs). SLEs are also described in patients with gain-of-function mutations in the CaV2.1 channel, for which acetazolamide therapy is suggested. Impairment in N-glycosylation of CaV2.1 promotes gain-of-function effects and may participate in cerebellar syndrome in PMM2-CDG. AZATAX was designed to establish whether acetazolamide is safe and improves cerebellar syndrome in PMM2-CDG. Methods A clinical trial included PMM2-CDG patients, with a 6-month first-phase single acetazolamide therapy group, followed by a randomized 5-week withdrawal phase. Safety was assessed. The primary outcome measure was improvement in the International Cooperative Ataxia Rating Scale (ICARS). Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PATA test), and cognitive scores. Results Twenty-four patients (mean age = 12.3 +/- 4.5 years) were included, showing no serious adverse events. Thirteen patients required dose adjustment due to low bicarbonate or asthenia. There were improvements on ICARS (34.9 +/- 23.2 vs 40.7 +/- 24.8, effect size = 1.48, 95% confidence interval [CI] = 4.0-7.6, p < 0.001), detected at 6 weeks in 18 patients among the 20 responders, on NPCRS (95% CI = 0.3-1.6, p = 0.013) and on the PATA test (95% CI = 0.5-3.0, p = 0.006). Acetazolamide improved prothrombin time, factor X, and antithrombin. Clinical severity, epilepsy, and lipodystrophy predicted greater response. The randomized withdrawal phase showed ICARS worsening in the withdrawal group (effect size = 1.46, 95% CI = 2.65-7.52, p = 0.001). Interpretation AZATAX is the first clinical trial of PMM2-CDG. Acetazolamide is well tolerated and effective for motor cerebellar syndrome. Its ability to prevent SLEs and its long-term effects on kidney function should be addressed in future studies. Ann Neurol 2019;85:740-751
Filiaciones:
Martinez-Monseny T:
Genetic Medicine Department and Pediatric Institute of Rare Diseases, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Bolasell M:
Genetic Medicine Department and Pediatric Institute of Rare Diseases, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Callejón L:
Neuropsychology Unit, Neuroesplugues, Esplugues de Llobregat, Barcelona, Spain
Cuadras-Palleja D:
Statistics Department, Sant Joan de Déu Foundation, Barcelona, Spain
Freniche V:
Neuropsychology Unit, Neuroesplugues, Esplugues de Llobregat, Barcelona, Spain
Itzep DC:
Neuropediatric Department, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Gassiot S:
Hematology Laboratory, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Arango P:
Nephrology Department, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Casas-Alba D:
Genetic Medicine Department and Pediatric Institute of Rare Diseases, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
de la Morena E:
Hematology and Medical Oncology Service, Morales Meseguer University Hospital, Regional Blood Donation Center, Murcia University, IMIB-Arrixaca, U-765, Center for Biomedical Research on Rare Diseases, Murcia, Spain
Corral J:
Hematology and Medical Oncology Service, Morales Meseguer University Hospital, Regional Blood Donation Center, Murcia University, IMIB-Arrixaca, U-765, Center for Biomedical Research on Rare Diseases, Murcia, Spain
Montero-Sanchez R:
Clinical Biochemistry Department, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
U-703, Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Sant Joan de Déu Hospital, Barcelona, Spain
Pérez-Cerdá C:
Diagnosis of Molecular Diseases Center, Autonomous University of Madrid, U-746, Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, IdiPAZ, Madrid, Spain
Pérez-Dueñas B:
Diagnosis of Molecular Diseases Center, Autonomous University of Madrid, U-746, Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, IdiPAZ, Madrid, Spain
Artuch-Iriberri R:
Clinical Biochemistry Department, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
U-703, Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Sant Joan de Déu Hospital, Barcelona, Spain
Jaeken J:
Center for Metabolic Disease, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
Serrano M:
Genetic Medicine Department and Pediatric Institute of Rare Diseases, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
Neuropediatric Department, Sant Joan de Déu Hospital Research Institute, Barcelona, Spain
U-703, Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Sant Joan de Déu Hospital, Barcelona, Spain
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