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

Ann Neurol. 2019 May;85(5):740-751. doi: 10.1002/ana.25457. Epub 2019 Mar 22.


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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Carbonic Anhydrase Inhibitors
  • Phosphotransferases (Phosphomutases)
  • Acetazolamide

Supplementary concepts

  • Congenital disorder of glycosylation type 1A