What is Methylmalonic Acidemia?

Methylmalonic Acidemia (MMA) is an autosomal recessive inherited organic acid metabolism disorder that typically manifests in the neonatal period or early infancy. The disease has an insidious onset and rapid progression, presenting with multisystem involvement. Characteristic neurological manifestations include intellectual disability, hypotonia, basal ganglia stroke-like lesions, and hyperammonemic encephalopathy. Metabolic disturbances may present as ketosis, hyperglycinemia, and metabolic acidosis. Multiorgan involvement can affect the kidneys (chronic renal failure), vision (optic atrophy), hearing (sensorineural deafness), bones (osteoporosis, short stature), and hematopoietic system (bone marrow failure). Patients often experience concurrent liver and kidney damage. Newborn screening data indicate a birth prevalence of approximately 1/28,000.

 

Image Source New insights into the pathophysiology of methylmalonic acidemia

 

Pathogenesis

MMA is primarily classified into two major categories: MCM-deficient type (Mut type) and cobalamin metabolism disorder type (cbl type). The Mut type results from mutations in the MMUT gene, including mut⁰ type with complete enzyme activity loss and mut⁻ type with partial deficiency. The cbl type involves mutations in various genes (such as MMAA, MMAB, MMACHC, etc.), leading to vitamin B12 metabolism abnormalities that subsequently affect MCM activity. Among these, cblC, cblD, and cblF type patients, who also exhibit homocystinemia, are classified as combined MMA, accounting for approximately 70% of Chinese patients.

In Chinese patients, the most common subtype is cblC type, primarily caused by mutations in the MMACHC gene. The most frequent mutation is c.609G>A (p.W203X), a nonsense mutation that generates a premature termination codon, resulting in truncated and inactivated functional protein.

The core pathogenesis of Methylmalonic Acidemia (MMA) can be summarized as functional defects in methylmalonyl-CoA mutase (MCM) or its coenzyme adenosylcobalamin (AdoCbl), which block the bioconversion of methylmalonyl-CoA to succinyl-CoA, leading to metabolic pathway abnormalities. This blockade causes accumulation of upstream metabolites propionyl-CoA and methylmalonyl-CoA, which are abnormally metabolized through alternative pathways to generate toxic organic acids such as methylmalonic acid, propionic acid, and methylcitric acid, as well as acylcarnitines including propionylcarnitine and methylmalonylcarnitine, resulting in abnormal accumulation of metabolic products in the body.

These toxic metabolites mediate cellular damage through multiple mechanisms, with mitochondrial dysfunction at the core: on one hand, they competitively inhibit key enzymes of the tricarboxylic acid cycle (TCA cycle), such as succinate dehydrogenase, causing impaired cellular energy (ATP) synthesis; on the other hand, they interfere with oxidative phosphorylation processes, inducing massive generation of reactive oxygen species (ROS) and triggering significant oxidative stress damage.

The central nervous system is the most significantly affected target organ system in the pathological process of MMA. The pathological mechanisms include: 1) synergistic effects of metabolic acidosis and propionic acid-mediated hyperammonemia directly leading to astrocyte edema and neuronal dysfunction, inducing acute metabolic encephalopathy; 2) long-term energy metabolism disorders and toxic environments interfering with neurodevelopmental processes, affecting neuronal differentiation, migration, and synapse formation, resulting in abnormal brain development; 3) oxidative stress impairing oligodendrocyte function, causing myelination disorders and white matter lesions; 4) gradual accumulation of these microscopic pathological changes ultimately manifesting macroscopically as abnormal brain network connectivity and progressive decline in higher brain functions such as cognition and motor skills.

The kidneys, as the primary excretory organs for methylmalonic acid, are chronically exposed to high organic acid loads and oxidative stress states, making them susceptible to renal tubular epithelial cell degeneration, necrosis, and interstitial inflammatory reactions, gradually progressing to chronic renal insufficiency and even renal failure.
 

Image Source Animal models of methylmalonic acidemia: insights and challenges

 

Gene Therapy

AAV-mediated gene replacement therapy: This approach utilizes recombinant adeno-associated virus (AAV) vectors to deliver functional MMUT cDNA to primarily affected organs (mainly the liver), achieving long-term stable expression of methylmalonyl-CoA mutase (MCM). In 2021, the team led by Charles P. Venditti at the National Human Genome Research Institute developed a promoterless, nuclease-free AAV integration vector that precisely inserts the human codon-optimized MMUT gene upstream of the mouse albumin gene stop codon. This strategy achieved sustained therapeutic effects in MMA model mice, significantly reducing plasma methylmalonic acid levels and improving survival rates.

mRNA therapy: This approach utilizes delivery systems such as lipid nanoparticles (LNP) to deliver in vitro transcribed mRNA encoding normal MCM enzyme to target cells. mRNA-3705, an experimental therapeutic drug for MMA developed by Moderna, has entered Phase 1/2 clinical trials. This drug is administered via intravenous infusion and aims to restore MUT enzyme activity, thereby reducing the accumulation of toxic metabolites such as methylmalonic acid. In September 2025, Moderna announced interim data from this Phase I/II study, showing that mRNA-3705 demonstrated favorable safety and tolerability in MUT-deficient MMA patients.
 

Mouse Models

Mmut-KO mice: A classic Mut-type MMA model with complete knockout of the Mmut gene, simulating human mut⁰ type, exhibiting hypermethylmalonic acidemia, growth retardation, and multisystem damage.

Mmachcflox/flox;Pax6-Cre mice: These mice feature knockout of the Mmachc gene in specific cell types via Pax6-Cre, used to simulate the pathological process of cblC-type MMA.

W203X homozygous mutant mice: This model simulates the most common cblC-type MMACHC gene c.609G>A point mutation in Chinese populations, carrying the p.W203X nonsense mutation. This mutation causes premature termination of protein translation, producing truncated proteins. W203X homozygous mutant mice appear normal at birth but begin to show decreased responsiveness within 24 hours after birth, with significantly elevated serum propionylcarnitine (C3) levels.

MingCeler Biotech Supports Gene Therapy

While gene therapy offers hope for rare diseases, its development and validation depend critically on animal model support. MingCeler Biotech has developed multiple rare disease mouse models using its proprietary TurboMice™ technology. The TurboMice™ platform overcomes technical challenges associated with long mouse model generation cycles and low success rates for complex models, enabling editing at virtually any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various MMA mouse models according to client needs, including Mmut-KO mice, Mmachcflox/flox;Pax6-Cre mice, W203X homozygous mutant mice, and others. We welcome inquiries from researchers!
 

References:

[1] Head PE, Meier JL, Venditti CP. New insights into the pathophysiology of methylmalonic acidemia. J Inherit Metab Dis. 2023 May;46(3):436-449. doi: 10.1002/jimd.12617. PMID: 37078237; PMCID: PMC10715492.

[2] Chen T, Gao Y, Zhang S, Wang Y, Sui C, Yang L. Methylmalonic acidemia: Neurodevelopment and neuroimaging. Front Neurosci. 2023 Jan 26;17:1110942. doi: 10.3389/fnins.2023.1110942. PMID: 36777632; PMCID: PMC9909197.

[3] Ma F, Shi CC, Liang PP, Li ST, Gu X, Xiao X, Hao H. Construction of a methylmalonic acidemia cblC-type W203X mutant mouse model using CRISPR/Cas9. Zhongguo Dang Dai Er Ke Za Zhi. 2019 Aug;21(8):824-829. PMID: 31416512.

[4] Shan S, Liu M, Ma Y, Sun M, Wang Y, Zou H. Animal models of methylmalonic acidemia: insights and challenges. Orphanet J Rare Dis. 2025 Nov 14;20(1):583. doi: 10.1186/s13023-025-04101-8. PMID: 41239408; PMCID: PMC12619279.

[5] Chandler RJ, Venditti CP. Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future. Hum Gene Ther. 2019 Oct;30(10):1236-1244. doi: 10.1089/hum.2019.113. Epub 2019 Aug 16. PMID: 31303064; PMCID: PMC6763959.

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