AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG).

Abstract

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.

• Authors: Antonio F Martínez-Monseny, Mercè Bolasell, Laura Callejón-Póo, Daniel Cuadras, Verónica Freniche, Débora C Itzep, Susanna Gassiot, Pedro Arango, Didac Casas-Alba, Eugenia de la Morena, Javier Corral, Raquel Montero, Celia Pérez-Cerdá, Belén Pérez, Rafael Artuch, Jaak Jaeken, Mercedes Serrano, CDG Spanish Consortium
• Journal: Annals of neurology (Ann Neurol) Vol. 85 Issue 5 Pg. 740-751 (05 2019) ISSN: 1531-8249 [Electronic] United States
• PMID: 30873657 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Neurological Association.

Chemical References

• Carbonic Anhydrase Inhibitors
• Phosphotransferases (Phosphomutases)
• Acetazolamide

Topics

• Acetazolamide (pharmacology, therapeutic use)
• Adolescent
• Carbonic Anhydrase Inhibitors (pharmacology, therapeutic use)
• Cerebellar Diseases (diagnosis, drug therapy, genetics)
• Child
• Child, Preschool
• Congenital Disorders of Glycosylation (diagnosis, drug therapy, genetics)
• Female
• Glycosylation (drug effects)
• Humans
• Male
• Phosphotransferases (Phosphomutases) (deficiency, genetics)
• Single-Blind Method
• Treatment Outcome
• Young Adult