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PubMed This is a summary of 6 peer-reviewed journal articles Updated
Medical Genetics · Phosphomannomutase 2 Congenital Disorder of Glycosylation

Emerging Treatments and Clinical Trials

At a Glance

While there is currently no FDA-approved cure for PMM2-CDG, promising research is underway. Experimental treatments include acetazolamide for ataxia management, pharmacological chaperones like govorestat to stabilize the PMM2 enzyme, and early-stage gene therapy to address the root cause.

While there is currently no FDA-approved cure for PMM2-CDG, we are in an era of unprecedented research. Scientists are moving beyond managing symptoms to developing therapies that target the root cause of the condition. It is important to remember that these treatments are experimental, but they represent a significant shift in the medical landscape for CDG families [1][2].

Targeted Symptom Management: The AZATAX Study

One of the most well-known recent studies for PMM2-CDG is the AZATAX study, which focused on an older medication called acetazolamide [3].

  • The Goal: To improve cerebellar ataxia (the balance and coordination issues associated with the brain’s cerebellum) [3].
  • The Findings: Patients in the study showed significant improvements in their ICARS scores (a measure of balance) and their ability to speak clearly [3]. It is important to note that acetazolamide is purely a symptomatic treatment for neurological symptoms; it alters fluid dynamics in the brain to help with ataxia, but it does not fix the underlying blood chemistry or coagulation risks [3].
  • The Trade-off: While generally safe, the medication can cause low bicarbonate levels in the blood or asthenia (feelings of weakness), which requires a doctor to carefully adjust the dosage [3].

Stabilizing the Enzyme: Pharmacological Chaperones

A newer area of research involves medications that interact directly with the faulty PMM2 enzyme. Drugs classified as aldose reductase inhibitors—specifically govorestat (also known as AT-007) and epalrestat—are currently being studied for their unique effects in PMM2-CDG [2][4].

  • How They Work: In the context of PMM2-CDG, these drugs are being investigated because they act as “pharmacological chaperones.” They essentially bind to and stabilize the defective PMM2 enzyme, preventing it from breaking down and boosting its overall activity [4][2].
  • Preliminary Results: Early data has shown promising improvements in clinical rating scales and certain biochemical markers [2].

The Future: Gene Replacement Therapy

The most “foundational” research involves gene therapy, specifically using a delivery vehicle called AAV9-PMM2 [5].

  • The Concept: This therapy uses a modified, harmless virus (AAV9) to “deliver” a healthy copy of the PMM2 gene directly into the patient’s cells [5].
  • Current Status: In the laboratory, this approach has successfully improved the “sugar tagging” (glycosylation) process in patient cells [5]. While this is still in the preclinical stages (not yet in human trials), it represents the long-term goal of correcting the genetic cause of PMM2-CDG at the source [5].

Understanding Clinical Endpoints

When you read about these trials, you will see doctors measuring “endpoints.” These are the benchmarks they use to see if a drug is working. Common endpoints in PMM2-CDG trials include:

  1. Biochemical Markers: Levels of liver enzymes and clotting factors like Antithrombin III [2][3].
  2. Clinical Scores: Improvements in the ICARS (balance scale) or the NPCRS (general health scale) [3][2].
  3. Functional Tests: Measures like the PATA test, which tracks how quickly and clearly a child can repeat syllables [3].

Before joining any trial, it is vital to discuss the benefit-risk profile with your metabolic geneticist to ensure the study is a good fit for specific health needs [6].

Common questions in this guide

Is there a cure for PMM2-CDG?
Currently, there is no FDA-approved cure for PMM2-CDG. However, researchers are actively studying new experimental therapies, such as pharmacological chaperones and gene therapy, which are designed to target the underlying cause of the condition.
What is the AZATAX study for PMM2-CDG?
The AZATAX study investigated a medication called acetazolamide to treat cerebellar ataxia, which causes balance and coordination issues. While it can improve balance and speech, it only manages symptoms and does not correct the underlying blood chemistry or coagulation risks.
How do pharmacological chaperones work for PMM2-CDG?
Pharmacological chaperones, such as govorestat, are experimental drugs that bind to the defective PMM2 enzyme. By stabilizing the faulty enzyme, these medications help prevent it from breaking down and increase its overall activity in the body.
Is gene therapy available for PMM2-CDG?
Gene therapy is currently being researched in laboratory settings using a delivery vehicle called AAV9-PMM2 to provide a healthy PMM2 gene. While it shows promise in correcting the genetic cause, it is still in the preclinical stage and not yet available for human trials.
How do doctors measure if an experimental PMM2-CDG treatment is working?
Doctors use clinical endpoints to track progress, such as testing blood levels of liver enzymes and clotting factors like Antithrombin III. They also use functional assessments like the ICARS balance scale and the PATA test to measure improvements in coordination and speech.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on my child's current ataxia (ICARS score), are they a candidate for the 'AZATAX' protocol with acetazolamide?
  2. 2.How do you monitor for low bicarbonate levels or 'asthenia' (weakness) if we start a trial of acetazolamide?
  3. 3.Are there any active clinical trials for pharmacological chaperones that our child might be eligible for?
  4. 4.What functional tests, like the PATA test, do you use to measure changes in my child's coordination over time?
  5. 5.What is the current status of gene therapy trials (AAV9-PMM2) for patients with PMM2-CDG?

Questions For You

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References

References (6)
  1. 1

    [Advances in the diagnosis and treatment of phosphomannomutase 2 deficiency].

    Zhou SY

    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2023; (25(2)):223-228 doi:10.7499/j.issn.1008-8830.2209049.

    PMID: 36854702
  2. 2

    Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.

    Jalazo ER, Weisenfeld LA, Ligezka A, et al.

    JIMD reports 2025; (66(6)):e70043 doi:10.1002/jmd2.70043.

    PMID: 41089670
  3. 3

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

    Martínez-Monseny AF, Bolasell M, Callejón-Póo L, et al.

    Annals of neurology 2019; (85(5)):740-751 doi:10.1002/ana.25457.

    PMID: 30873657
  4. 4

    Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

    Ligezka AN, Radenkovic S, Saraswat M, et al.

    Annals of neurology 2021; (90(6)):887-900 doi:10.1002/ana.26245.

    PMID: 34652821
  5. 5

    AAV9-based PMM2 gene replacement augments PMM2 expression and improves glycosylation in primary fibroblasts of patients with phosphomannomutase 2 deficiency (PMM2-CDG).

    Zhong M, Balakrishnan B, Guo AJ, Lai K

    Molecular genetics and metabolism reports 2024; (38()):101035 doi:10.1016/j.ymgmr.2023.101035.

    PMID: 38130891
  6. 6

    High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury.

    Hordeaux J, Lamontagne RJ, Song C, et al.

    Molecular therapy : the journal of the American Society of Gene Therapy 2024; (32(4)):952-968 doi:10.1016/j.ymthe.2024.02.002.

    PMID: 38327046

This page provides educational information about experimental treatments and clinical trials for PMM2-CDG. Always consult your metabolic geneticist before considering any new medical treatments or clinical trial participation for your child.

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