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 AE 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 AE 23.2 vs 40.7 AE 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 View this article online at wileyonlinelibrary.com.

New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach

“…Defects in the glycosylphosphatidylinositol (GPI)-anchor synthesis have more recently been added to this family [ 4 ]. CDG are mainly complex, multi-system disorders which—despite recent exciting therapeutic developments—still widely lack effective treatments [ 5 , 6 , 7 , 8 , 9 , 10 ]. PMM2-CDG (MIM: 212065) was the first reported N-glycosylation defect and it is the most common type with approximately 1000 patients reported worldwide [ 5 , 11 , 12 ].…”

Identification through exome sequencing of the first PMM2-CDG individual of Mexican mestizo origin

“…No curative treatment has been developed. A recent trial with acetazolamide, a long-known diuretic, showed a significant improvement of the motor cerebellar syndrome in PMM2-CDG [ 20 ]. This is a nice example of drug repositioning.…”

Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update

“…Acetazolamide shows efficacy in treating SLEs in CACNA1A familial hemiplegic migraine. 10,71 Remarkably, in PMM2 patients, coagulation parameters show improvement in addition to neurologic involvement. Enzymatic activity of PMM2 is dependent on Ca 2+ binding.…”

“…Recent reports demonstrated beneficial effects of acetazolamide in PMM2-CDG. 10 In patients with spasticity or dystonia, local injection of botulinum toxin may be useful. Aggressive treatment of increased body temperature (escalating fever), which often exacerbates seizures, myoclonus, and other movement disorders, and may provoke stroke-like episodes in many patients, is essential.…”

“…68 Recently, a clinical trial on oral acetazolamide therapy in PMM2-CDG patients presenting with neurologic involvement showed improvement of clinical severity, motor cerebellar involvement, and coagulation. 10 Transfer of the therapeutic agent through the blood-brain barrier is essential for treatment of neurologic involvement in CDG. PCs have been shown to travel across the blood-brain barrier and hold promise for alleviating central nervous system involvement, including Gaucher and Fabry disease.…”