Combined Malonic and Methylmalonic Aciduria

Mendelian MONDO:0013661 Pathograph 9 Show in embeddings browser Organic Acidemia Inborn Error of Metabolism

Combined malonic and methylmalonic aciduria (CMAMMA) is an autosomal recessive metabolite-repair/proofreading disorder caused by biallelic ACSF3 variants. ACSF3 encodes a mitochondrial malonyl-CoA synthetase that also activates methylmalonate; loss of this activity impairs mitochondrial conversion of malonate and methylmalonate to their CoA thioesters. The biochemical signature is increased malonic acid and methylmalonic acid, usually with methylmalonic acid greater than malonic acid. Clinical expressivity is broad: selected clinical series include childhood metabolic and neurologic presentations and adult neurologic or psychiatric manifestations, while an unselected Quebec screening cohort had a favorable course in most patients.

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1
Inheritance
3
Pathophys.
5
Phenotypes
9
Pathograph
1
Genes
🏷

Classifications

👪

Inheritance

1
Autosomal recessive HP:0000007
CMAMMA is caused by biallelic ACSF3 pathogenic variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"First, seven additional probands harbored two mutations in ACSF3."
The discovery study supports biallelic ACSF3 variation in affected CMAMMA probands.
⚙

Pathophysiology

3
ACSF3 mitochondrial malonyl-CoA synthetase deficiency
Biallelic ACSF3 variants reduce mitochondrial malonyl-CoA synthetase / methylmalonyl-CoA synthetase activity. This removes a mitochondrial repair pathway that normally activates malonate and methylmalonate into CoA thioesters.
ACSF3 hgnc:27288
malonyl-CoA synthetase activity GO:0090409 ↓ DECREASED acid-thiol ligase activity GO:0016878 ↓ DECREASED
mitochondrion GO:0005739
Downstream
Malonate and methylmalonate activation failure Loss of ACSF3 prevents efficient ATP-dependent activation of malonate and methylmalonate to malonyl-CoA and methylmalonyl-CoA.
Show evidence (2 references)
PMID:21841779 SUPPORT Human Clinical
"We establish ACSF3 mutations as the cause of CMAMMA and describe the first disease association with a member of the acyl-CoA synthetase (ACS) family, enzymes that activate fatty acids for intermediary metabolism4."
Human sequencing and complementation data establish ACSF3 as the causal gene for CMAMMA.
PMID:21846720 SUPPORT In Vitro
"The human candidate protein ACSF3, which has a predicted N-terminal mitochondrial targeting sequence, was cloned, expressed, and characterized as a 65-kDa acyl-CoA synthetase with extremely high specificity for malonate and methylmalonate."
Biochemical characterization supports ACSF3 as a mitochondrial acyl-CoA synthetase for malonate and methylmalonate.
Malonate and methylmalonate activation failure
Failure to activate malonate and methylmalonate causes proximal substrate accumulation and reduced local mitochondrial production of malonyl-CoA from malonate.
malonyl-CoA biosynthetic process GO:2001295 ↓ DECREASED dicarboxylic acid metabolic process GO:0043648 ⚠ ABNORMAL
mitochondrion GO:0005739
Downstream
Combined malonic and methylmalonic aciduria The biochemical disease signature is increased urinary methylmalonic acid and malonic acid.
Mitochondrial metabolic inefficiency Malonate accumulation and reduced mitochondrial malonyl-CoA production impair mitochondrial metabolism and mitochondrial protein malonylation.
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"suggesting that malfunction of this enzyme causes accretion of the proximal substrates that manifests as methylmalonic and malonic aciduria."
The discovery paper links ACSF3 malfunction to malonic and methylmalonic aciduria.
Mitochondrial metabolic inefficiency
ACSF3 deficiency perturbs mitochondrial malonate disposal and malonyl-CoA dependent protein malonylation, providing a mechanistic bridge from the biochemical signature to variable neurologic or metabolic presentations.
mitochondrion GO:0005739
Downstream
Variable neurologic and metabolic manifestations Reported selected cases include neurologic, psychiatric, and childhood metabolic presentations, but screen-detected cohorts suggest many patients have a favorable or mild course.
Show evidence (1 reference)
PMID:28479296 SUPPORT In Vitro
"ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins."
The cell study supports reduced mitochondrial protein malonylation as a downstream consequence of ACSF3 loss.
⬡

Pathograph

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Referential integrity issues (1):
  • Target 'Combined malonic and methylmalonic aciduria' (from 'Malonate and methylmalonate activation failure') not found in named elements
Pathograph: causal mechanism network for Combined Malonic and Methylmalonic Aciduria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Nervous System 2
Seizure Seizure HP:0001250
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"four patients were diagnosed in adulthood with neurological manifestations (seizures, memory problems, psychiatric disease, and/or cognitive decline) without vitamin B12 deficiency."
Adult CMAMMA cases included seizures among neurologic manifestations.
Global developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay)."
Childhood CMAMMA presentations included developmental delay.
Growth 1
Failure to thrive Failure to thrive HP:0001508
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay)."
Childhood CMAMMA presentations included failure to thrive.
Other 2
Variable neurologic and metabolic manifestations
Show evidence (2 references)
PMID:21841779 SUPPORT Human Clinical
"four patients were diagnosed in adulthood with neurological manifestations (seizures, memory problems, psychiatric disease, and/or cognitive decline) without vitamin B12 deficiency."
Human clinical cases support adult neurologic and psychiatric presentations.
PMID:21841779 SUPPORT Human Clinical
"Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay)."
Human clinical cases support childhood metabolic and neurodevelopmental presentations.
Favorable screen-detected course
Show evidence (1 reference)
PMID:30740739 SUPPORT Human Clinical
"favorable outcome regardless of treatment."
The unselected cohort supports a generally favorable clinical course in screen-detected CMAMMA.
🧬

Genetic Associations

1
ACSF3
Gene: ACSF3 hgnc:27288 relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:21841779 SUPPORT Human Clinical
"We identified nine missense, one in-frame deletion and one nonsense mutation"
The discovery study describes multiple pathogenic ACSF3 variant classes in CMAMMA.
PMID:30740739 SUPPORT Human Clinical
"Causal ACSF3 mutations were identified in all patients for whom genotyping was performed (76% of cases)."
The unselected cohort confirms ACSF3 as the causal gene in genotyped patients.
🔬

Biochemical Markers

2
Methylmalonic acid (INCREASED)
Context: Methylmalonic acid is elevated in CMAMMA and usually exceeds malonic acid.
Pathograph Readouts
Readout Of Malonate and methylmalonate activation failure Positive Diagnostic
Increased methylmalonic acid reports failure to recycle methylmalonate through ACSF3.
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"Methylmalonic and malonic aciduria with urinary MMA/MA >5 was present in seven of nine affecteds"
The discovery cohort links increased methylmalonic aciduria to ACSF3-related CMAMMA.
Show evidence (1 reference)
PMID:21841779 SUPPORT Human Clinical
"Methylmalonic and malonic aciduria with urinary MMA/MA >5 was present in seven of nine affecteds"
The discovery cohort documents elevated methylmalonic acid together with malonic acid.
Malonic acid (INCREASED)
Context: Malonic acid is elevated with methylmalonic acid and is required to distinguish CMAMMA from classic methylmalonic acidemia.
Pathograph Readouts
Readout Of Malonate and methylmalonate activation failure Positive Diagnostic
Increased malonic acid reports failure to activate malonate through ACSF3.
Show evidence (1 reference)
PMID:26915364 SUPPORT Human Clinical
"The presence of increased urinary concentrations of both methylmalonic acid (MMA) and malonic acid (MA) is assumed to differentiate combined malonic and methylmalonic aciduria (CMAMMA), due to mutations in the ACSF3 gene, from other causes of methylmalonic aciduria (classic MMAemia)."
The diagnostic study supports malonic acid as part of the defining biochemical readout.
Show evidence (1 reference)
PMID:30740739 SUPPORT Human Clinical
"median urine malonic acid (MA) levels ranged from 9 to 280 mmol/mol creatinine (<5)."
The unselected cohort quantified elevated urinary malonic acid.
{ }

Source YAML

click to show 
name: Combined Malonic and Methylmalonic Aciduria
category: Mendelian
creation_date: '2026-07-06T02:20:39Z'
synonyms:
- CMAMMA
- Combined malonic and methylmalonic acidemia
- ACSF3 deficiency
- Non-classic combined malonic and methylmalonic aciduria
description: >-
  Combined malonic and methylmalonic aciduria (CMAMMA) is an autosomal recessive
  metabolite-repair/proofreading disorder caused by biallelic ACSF3 variants.
  ACSF3 encodes a mitochondrial malonyl-CoA synthetase that also activates
  methylmalonate; loss of this activity impairs mitochondrial conversion of
  malonate and methylmalonate to their CoA thioesters. The biochemical signature
  is increased malonic acid and methylmalonic acid, usually with methylmalonic
  acid greater than malonic acid. Clinical expressivity is broad: selected
  clinical series include childhood metabolic and neurologic presentations and
  adult neurologic or psychiatric manifestations, while an unselected Quebec
  screening cohort had a favorable course in most patients.
classifications:
  icimd_category:
  - classification_value: metabolite_proofreading
    notes: >-
      ICIMD package WP-031 classifies ACSF3-related CMAMMA under Intermediary
      Metabolism: Others -> Disorders of metabolite repair/proofreading because
      the primary defect is failure to repair/recycle mitochondrial malonate and
      methylmalonate by thioesterification.
disease_term:
  preferred_term: combined malonic and methylmalonic aciduria
  term:
    id: MONDO:0013661
    label: combined malonic and methylmalonic acidemia
parents:
- Organic Acidemia
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    CMAMMA is caused by biallelic ACSF3 pathogenic variants.
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First, seven additional probands harbored two mutations in ACSF3.
    explanation: The discovery study supports biallelic ACSF3 variation in affected CMAMMA probands.
prevalence:
- population: Population incidence predicted from ACSF3 carrier frequency
  measure_type: UNKNOWN
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.333333
  notes: >-
    The estimate is predicted from ACSF3 mutant allele frequency rather than a
    population-based disease registry; clinical penetrance and ascertainment are
    still incompletely defined.
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACSF3 mutant alleles occur with a minor allele frequency (MAF) of 0.0058 in ~1,000 control individuals predicting a CMAMMA population incidence ~ 1:30,000.
    explanation: The discovery study estimates CMAMMA incidence from ACSF3 mutant allele frequency.
pathophysiology:
- name: ACSF3 mitochondrial malonyl-CoA synthetase deficiency
  description: >-
    Biallelic ACSF3 variants reduce mitochondrial malonyl-CoA synthetase /
    methylmalonyl-CoA synthetase activity. This removes a mitochondrial
    repair pathway that normally activates malonate and methylmalonate into
    CoA thioesters.
  genes:
  - preferred_term: ACSF3
    term:
      id: hgnc:27288
      label: ACSF3
  molecular_functions:
  - preferred_term: malonyl-CoA synthetase activity
    term:
      id: GO:0090409
      label: malonyl-CoA synthetase activity
    modifier: DECREASED
  - preferred_term: acid-thiol ligase activity
    term:
      id: GO:0016878
      label: acid-thiol ligase activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We establish ACSF3 mutations as the cause of CMAMMA and describe the first disease association with a member of the acyl-CoA synthetase (ACS) family, enzymes that activate fatty acids for intermediary metabolism4.
    explanation: Human sequencing and complementation data establish ACSF3 as the causal gene for CMAMMA.
  - reference: PMID:21846720
    reference_title: "Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The human candidate protein ACSF3, which has a predicted N-terminal mitochondrial targeting sequence, was cloned, expressed, and characterized as a 65-kDa acyl-CoA synthetase with extremely high specificity for malonate and methylmalonate.
    explanation: Biochemical characterization supports ACSF3 as a mitochondrial acyl-CoA synthetase for malonate and methylmalonate.
  downstream:
  - target: Malonate and methylmalonate activation failure
    description: >-
      Loss of ACSF3 prevents efficient ATP-dependent activation of malonate and
      methylmalonate to malonyl-CoA and methylmalonyl-CoA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21841779
      reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we examined purified, GST-tagged ACSF3 under MCS assay conditions and found that the enzyme activated malonate and methylmalonate, but not acetate, into the respective coenzyme thioesters
      explanation: The enzyme assay directly supports ACSF3-dependent activation of the accumulating substrates.
- name: Malonate and methylmalonate activation failure
  description: >-
    Failure to activate malonate and methylmalonate causes proximal substrate
    accumulation and reduced local mitochondrial production of malonyl-CoA from
    malonate.
  biological_processes:
  - preferred_term: malonyl-CoA biosynthetic process
    term:
      id: GO:2001295
      label: malonyl-CoA biosynthetic process
    modifier: DECREASED
  - preferred_term: dicarboxylic acid metabolic process
    term:
      id: GO:0043648
      label: dicarboxylic acid metabolic process
    modifier: ABNORMAL
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  chemical_entities:
  - preferred_term: malonic acid
    term:
      id: CHEBI:30794
      label: malonic acid
    modifier: INCREASED
  - preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
    modifier: INCREASED
  - preferred_term: malonyl-CoA
    term:
      id: CHEBI:15531
      label: malonyl-CoA
    modifier: DECREASED
  - preferred_term: methylmalonyl-CoA
    term:
      id: CHEBI:16625
      label: methylmalonyl-CoA
    modifier: DECREASED
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggesting that malfunction of this enzyme causes accretion of the proximal substrates that manifests as methylmalonic and malonic aciduria.
    explanation: The discovery paper links ACSF3 malfunction to malonic and methylmalonic aciduria.
  downstream:
  - target: Combined malonic and methylmalonic aciduria
    description: The biochemical disease signature is increased urinary methylmalonic acid and malonic acid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26915364
      reference_title: "A New Approach for Fast Metabolic Diagnostics in CMAMMA."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The presence of increased urinary concentrations of both methylmalonic acid (MMA) and malonic acid (MA) is assumed to differentiate combined malonic and methylmalonic aciduria (CMAMMA), due to mutations in the ACSF3 gene, from other causes of methylmalonic aciduria (classic MMAemia).
      explanation: This diagnostic study supports the combined urinary biochemical signature and its ACSF3 association.
  - target: Mitochondrial metabolic inefficiency
    description: >-
      Malonate accumulation and reduced mitochondrial malonyl-CoA production
      impair mitochondrial metabolism and mitochondrial protein malonylation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased mitochondrial malonate.
    - Reduced ACSF3-derived mitochondrial malonyl-CoA and protein malonylation.
    evidence:
    - reference: PMID:28479296
      reference_title: "The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ACSF3 KO cells exhibited elevated malonate and impaired mitochondrial metabolism.
      explanation: ACSF3 knockout cells provide direct support for malonate accumulation and mitochondrial metabolic impairment.
- name: Mitochondrial metabolic inefficiency
  description: >-
    ACSF3 deficiency perturbs mitochondrial malonate disposal and malonyl-CoA
    dependent protein malonylation, providing a mechanistic bridge from the
    biochemical signature to variable neurologic or metabolic presentations.
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  chemical_entities:
  - preferred_term: malonic acid
    term:
      id: CHEBI:30794
      label: malonic acid
    modifier: INCREASED
  - preferred_term: malonyl-CoA
    term:
      id: CHEBI:15531
      label: malonyl-CoA
    modifier: DECREASED
  evidence:
  - reference: PMID:28479296
    reference_title: "The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins.
    explanation: The cell study supports reduced mitochondrial protein malonylation as a downstream consequence of ACSF3 loss.
  downstream:
  - target: Variable neurologic and metabolic manifestations
    description: >-
      Reported selected cases include neurologic, psychiatric, and childhood
      metabolic presentations, but screen-detected cohorts suggest many patients
      have a favorable or mild course.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21841779
      reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The age of diagnosis and symptoms were variable (Table 1).
      explanation: The selected discovery cohort supports broad variability in clinical expression.
    - reference: PMID:30740739
      reference_title: "Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, the favorable clinical course observed suggests that CMAMMA is probably a benign condition, although we cannot exclude the possibility that a small minority of patients may present symptoms attributable to CMAMMA
      explanation: The unselected Quebec cohort supports generally favorable course with possible symptomatic minority.
phenotypes:
- category: Clinical
  name: Variable neurologic and metabolic manifestations
  description: >-
    Selected patients may present in adulthood with neurologic or psychiatric
    manifestations, or in childhood with metabolic or neurodevelopmental
    features, but population-screened cohorts show favorable outcomes in most.
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four patients were diagnosed in adulthood with neurological manifestations (seizures, memory problems, psychiatric disease, and/or cognitive decline) without vitamin B12 deficiency.
    explanation: Human clinical cases support adult neurologic and psychiatric presentations.
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay).
    explanation: Human clinical cases support childhood metabolic and neurodevelopmental presentations.
- category: Neurological
  name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four patients were diagnosed in adulthood with neurological manifestations (seizures, memory problems, psychiatric disease, and/or cognitive decline) without vitamin B12 deficiency.
    explanation: Adult CMAMMA cases included seizures among neurologic manifestations.
- category: Developmental
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay).
    explanation: Childhood CMAMMA presentations included developmental delay.
- category: Clinical
  name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay).
    explanation: Childhood CMAMMA presentations included failure to thrive.
- category: Clinical
  name: Favorable screen-detected course
  description: >-
    In the unselected Quebec cohort, most patients came to attention through
    neonatal urine screening and had favorable outcomes regardless of treatment.
  evidence:
  - reference: PMID:30740739
    reference_title: "Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      favorable outcome regardless of treatment.
    explanation: The unselected cohort supports a generally favorable clinical course in screen-detected CMAMMA.
biochemical:
- name: Methylmalonic acid
  presence: INCREASED
  context: >-
    Methylmalonic acid is elevated in CMAMMA and usually exceeds malonic acid.
  biomarker_term:
    preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
  readouts:
  - target: Malonate and methylmalonate activation failure
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased methylmalonic acid reports failure to recycle methylmalonate through ACSF3.
    evidence:
    - reference: PMID:21841779
      reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Methylmalonic and malonic aciduria with urinary MMA/MA >5 was present in seven of nine affecteds
      explanation: The discovery cohort links increased methylmalonic aciduria to ACSF3-related CMAMMA.
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methylmalonic and malonic aciduria with urinary MMA/MA >5 was present in seven of nine affecteds
    explanation: The discovery cohort documents elevated methylmalonic acid together with malonic acid.
- name: Malonic acid
  presence: INCREASED
  context: >-
    Malonic acid is elevated with methylmalonic acid and is required to
    distinguish CMAMMA from classic methylmalonic acidemia.
  biomarker_term:
    preferred_term: malonic acid
    term:
      id: CHEBI:30794
      label: malonic acid
  readouts:
  - target: Malonate and methylmalonate activation failure
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased malonic acid reports failure to activate malonate through ACSF3.
    evidence:
    - reference: PMID:26915364
      reference_title: "A New Approach for Fast Metabolic Diagnostics in CMAMMA."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The presence of increased urinary concentrations of both methylmalonic acid (MMA) and malonic acid (MA) is assumed to differentiate combined malonic and methylmalonic aciduria (CMAMMA), due to mutations in the ACSF3 gene, from other causes of methylmalonic aciduria (classic MMAemia).
      explanation: The diagnostic study supports malonic acid as part of the defining biochemical readout.
  evidence:
  - reference: PMID:30740739
    reference_title: "Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      median urine malonic acid (MA) levels ranged from 9 to 280 mmol/mol creatinine (<5).
    explanation: The unselected cohort quantified elevated urinary malonic acid.
genetic:
- name: ACSF3
  gene_term:
    preferred_term: ACSF3
    term:
      id: hgnc:27288
      label: ACSF3
  relationship_type: CAUSATIVE
  variants:
  - name: Biallelic ACSF3 pathogenic variants
    description: >-
      Reported pathogenic variants include missense, in-frame deletion, and
      nonsense alleles affecting conserved acyl-CoA synthetase motifs.
  features: >-
    ACSF3 encodes the mitochondrial malonyl-CoA/methylmalonyl-CoA synthetase
    disrupted in CMAMMA.
  evidence:
  - reference: PMID:21841779
    reference_title: "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified nine missense, one in-frame deletion and one nonsense mutation
    explanation: The discovery study describes multiple pathogenic ACSF3 variant classes in CMAMMA.
  - reference: PMID:30740739
    reference_title: "Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Causal ACSF3 mutations were identified in all patients for whom genotyping was performed (76% of cases).
    explanation: The unselected cohort confirms ACSF3 as the causal gene in genotyped patients.
notes: >-
  WP-031 placement decision: curate CMAMMA as its own disease entry rather than
  as a subtype of classic methylmalonic acidemia, because independent sources
  and MONDO distinguish ACSF3-related combined malonic and methylmalonic
  aciduria from MUT/cobalamin-pathway methylmalonic acidemias. The package code
  is 12.1.22.01; the current ICIMD enum exposes the broader
  metabolite_proofreading value.