A Prospective Study of Pediatric Participants up to 16 Years of Age With Methylmalonic Acidemia (MMA) Due to Mutations in the MMUT Gene

February 19, 2026 updated by: Genespire Srl

A Prospective, Longitudinal, Observational, Multi-centre Study of Pediatric Participants up to 16 Years of Age With Methylmalonyl-CoA Mutase Deficiency Caused by Mutations in the MMUT Gene That Results in a Diagnosis of Isolated Methylmalonic Acidemia (MMA).

Methylmalonic Acidemia (MMA) is a severe and rare condition that affects how the body turns food into energy. In people with MMA, the body is missing or has a very low activity of a specific protein (an enzyme called methylmalonyl-CoA mutase (MMUT)) needed to break down certain proteins and fats in everyday food. Because this process does not work properly, a harmful substance called methylmalonic acid builds up in the blood and tissues, causing damage in the body.

Most people with MMA have an altered MMUT gene, which affects the enzyme methylmalonyl-CoA mutase. MMA often appears in infancy or early childhood, but some people are diagnosed later.

MMA affects approximately 1 in every 100,000 babies born and primarily impacts the liver, brain and kidneys. MMA poses significant challenges as it can result in complications such as dangerous acid levels in the blood, problems with the brain and nerves, visions problems, problems with how the pancreas, liver, and the kidneys work, as well as growth and development delays.

The main purpose of this observational study that tracks how the disease develops over time is to gather necessary data and evidence to confirm which signs in the body and blood test results can reliably show disease activity related to MMA. These confirmed signs and blood test results will be used for future research into developing new treatments for MMA. The data will be collected from participants with severe symptoms with and without liver transplant.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

The term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to metabolize methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid (Manoli 2016).

Although, the diagnosis of isolated MMA can result from identification of biallelic pathogenic variants in either MCEE, MMAA, MMAB, MMADHC, or MMUT, this study will focus on better understanding clinical outcomes of participants with the MMUT biallelic mutation only.

Isolated MMA, associated with MMUT gene is the most common cause of Isolated MMA, exists as a continuous spectrum of disease depending on the amount of residual enzyme activity and clinical symptoms. Historically, the disease has been categorized as either complete (mut0) or partial (mut-) deficiency of the enzyme methylmalonyl-CoA mutase. (Kruszka 2013, Manoli 2016) In modern practice, severe and non-severe forms of MMA are described rather than describing patient subtype by genotype. This is because the phenomenon of interallelic complementation makes prediction of genotype/phenotype/enzyme activity difficult because some individuals who have two pathogenic variants can have a mut- enzymatic subtype in the compound state but a mut0 enzymatic subtype in the homozygous state (Acquaviva 2005). Severity of disease is therefore distinguished primarily by the type of genetic mutation but also the severity of symptoms. Severe MMA is often associated with mutations that completely eliminate the activity of the enzyme methylmalonyl-CoA mutase (typically mut0 form) which presents early in infancy and has more pronounced clinical features such as severe metabolic acidosis, developmental delays, and frequent metabolic crises. Non-severe MMA more frequently involves mutations that reduce but do not eliminate enzyme activity (typically mut- form) and may present later with milder features (Forny 2021).

The routine management of MMA involves strict dietary restrictions, specifically limiting certain amino acids (isoleucine, valine, methionine, threonine), carnitine supplementation, and treatment of hyperammonemia with ammonia scavengers and limiting the endogenous production of odd-chain fatty acids. Early diagnosis and prompt initiation of treatment are crucial to minimize metabolic crises, improve growth and development, and reduce neurological complications. However, despite these interventions, MMA remains a progressive and life-limiting condition. Liver and kidney transplants are the only effective treatments available for severe cases of MMA. These procedures, while offering hope come with their own set of risks, including the need for compatible donors, the risk of rejection, the requirement for long-term immunosuppression, and the possibility of other clinical complications.

Severe MMA is managed with dietary management, specific therapies and patients may receive liver transplant while patients with non-severe MMA are unlikely to receive liver transplant. Long-term without liver transplantation patients with severe MMA will develop higher rates of irreversible morbidity and mortality (Forny 2021).

Study Type

Observational

Enrollment (Estimated)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Milan, Italy, 20132
      • Roma, Italy, 00146
        • OBGP (Bambino Gesu Ospedale Pediatrico)
        • Contact:
        • Principal Investigator:
          • Martinelli, PhD
  • Spain
      • Barcelona, Spain, 08950
        • SJD_San Joan de Deù Children's Hospital
        • Contact:
        • Principal Investigator:
          • García Cazorla, PhD
      • Madrid, Spain, 28041
  • United Kingdom
      • London, United Kingdom, WC1N 3JH
        • GOSH NHS (Great Ormond Street Hospital for Children)
        • Contact:
        • Principal Investigator:
          • Anupam, PhD
      • Manchester, United Kingdom, M13 9WL
  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • CHOP (Children's hospital of Philadelphia)
        • Contact:
        • Principal Investigator:
          • can Ficicioglu, PhD
      • Pittsburgh, Pennsylvania, United States, 15224
        • UPMC (Children's hospital of Pittsburgh)
        • Contact:
        • Principal Investigator:
          • Gerard Vockley, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The participants will come from the participating hospital where they are routinely follow up for their disease and their routine care

Description

Inclusion Criteria:

  1. Aged ≤16 years at screening visit
  2. With or without previous liver (or combined liver/kidney) transplantation at time of screening (note: number of transplanted participants capped at n=15) 3. Confirmed laboratory diagnosis of Isolated MMA caused by mutations in the MMUT gene (NOTE: if a historical genetic mutational analysis report was available at Screening visit but was not from a CLIA/ISO15189 approved laboratory, a confirmatory sample will be taken during the study. However the original lab report will be adequate for study eligibility consideration)..

4. Severe MMA phenotype.

  • For untransplanted participants, all of the following criteria (a-c) must be met to qualify as "severe" MMA phenotype:

    1. Serum methylmalonic acid (sMMA) level of >100 µmol/L at the Screening visit
    2. An unscheduled ER visit, hospitalization or requirement for use of the sick day diet regimen in the 12 months prior to the screening visit
    3. Considered to potentially require future liver transplantation to improve metabolic stability in accordance with MMA transplantation guidelines (Baumgartner 2014, Forny 2021, Sen 2023)

  • For participants with previous liver or combined liver and kidney transplantation, the phenotype of the participant will be judged by the Investigator to be severe if both of the following were applicable prior to transplantation:

    1. Pre-transplant serum methylmalonic acid (sMMA) level of >100 µmol/L AND
    2. Transplantation was conducted to improve metabolic stability in accordance with MMA transplantation guidelines (Baumgartner 2014, Forny 2021, Sen 2023).

NOTE: sMMA pre-transplant measure must have been obtained within 6 months prior to transplant. An alternative blood MMA concentration may be used (e.g. plasma MMA, or dry blood spot), if sMMA is unavailable. Details of the assay used must be provided and additional samples will be collected during the study to allow comparison to sMMA results.

Exclusion Criteria:

  1. Participant/parent/legal guardian/caregiver not willing to consent to participate
  2. Current participation in another interventional or therapeutic study
  3. Prior participation in a gene therapy clinical trial including mRNA therapy
  4. Participants who, in the opinion of the Site Investigator, would be unable or unsuitable to participate in the demands of the study, for example but not limited to participants unable to travel to protocol study visits or participants under palliative care.
  5. For participants who are post-liver transplant only, participant will be excluded if no prior pre-liver transplant measurements of blood MMA are available.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Unstransplanted severe MMA
without previous liver (or combined liver/kidney) transplantation at time of screening
Transplanted severe MMA
with previous liver (or combined liver/kidney) transplantation at time of screening

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of disease progression using biochemical biomarkers
Time Frame: Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36
Change over time in biomarkers to evaluate disease progression and/or organ transplantation.
Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate metabolic stability
Time Frame: Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36
Number of metabolic decompensation episodes (MDEs) assessed longitudinally to evaluate disease progression, with or without organ transplantation
Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36
Evaluate disease trajectory outcomes
Time Frame: Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36
Disease outcomes assessed longitudinally to evaluate disease progression, with or without organ transplantation
Baseline, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Genespire Srl

Investigators

  • Study Director: simon Hawkins, Genespire Srl

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

May 1, 2030

Study Completion (Estimated)

May 1, 2030

Study Registration Dates

First Submitted

January 28, 2026

First Submitted That Met QC Criteria

February 19, 2026

First Posted (Actual)

February 25, 2026

Study Record Updates

Last Update Posted (Actual)

February 25, 2026

Last Update Submitted That Met QC Criteria

February 19, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MMA-OBS-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

May 2031

IPD Sharing Supporting Information Type

  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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