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

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.

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).

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.