Malonic Aciduria

Mendelian MONDO:0009556 Pathograph 14 Show in embeddings browser Organic Aciduria Inborn Error of Metabolism

Malonic aciduria is an ultra-rare autosomal recessive organic aciduria caused by biallelic loss-of-function variants in MLYCD, which encodes malonyl-CoA decarboxylase (MCD). MCD catalyses the conversion of malonyl-CoA to acetyl-CoA and CO2, and its loss allows malonyl-CoA to accumulate. Because cytosolic malonyl-CoA is the physiological inhibitor of carnitine palmitoyltransferase 1, its accumulation restricts mitochondrial long-chain fatty-acid uptake and beta-oxidation, so the disorder behaves biochemically like a hybrid of an organic aciduria and a fatty-acid oxidation defect. A second, non-canonical arm has been proposed in which excess malonyl-CoA drives protein lysine malonylation, itself impairing mitochondrial function and fatty-acid oxidation. Heart and skeletal muscle, which depend heavily on fatty-acid oxidation and express MLYCD most highly, are the principal targets: cardiomyopathy (most often dilated) is the leading cause of morbidity and mortality. Most patients present in the first months of life with developmental delay, hypotonia, seizures, metabolic acidosis, hypoglycaemia, and failure to thrive; a later-onset phenotype limited to cardiomyopathy has been described in adults. Elevated urinary malonic acid and plasma malonylcarnitine are the constant biochemical markers. A long-chain-triglyceride-restricted, medium-chain-triglyceride-supplemented diet with levocarnitine supplementation is the mainstay of treatment and can improve left ventricular function.

Ask OpenScientist

Ask a research question about Malonic Aciduria. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
16
Phenotypes
1
Hypotheses
1
Gaps
14
Pathograph
1
Genes
4
Medical Actions
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
organic acidurias
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Malonic aciduria segregates as an autosomal recessive trait; affected individuals carry biallelic MLYCD variants and heterozygous parents are unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:34884438 SUPPORT Human Clinical
"This enzyme is encoded by the MLYCD (Malonyl-CoA Decarboxylase) gene, and the disease has an autosomal recessive inheritance."
States the autosomal recessive mode of inheritance for MLYCD-related malonic aciduria.
◈

Mechanistic Hypotheses

1
Protein lysine malonylation as a pathogenic amplifier
lysine_malonylation_arm EMERGING
Evidence balance 1 support
Beyond CPT1 inhibition, accumulating malonyl-CoA malonylates lysine residues on mitochondrial and metabolic proteins. The hypothesis holds that this post-translational modification is itself pathogenic, further impairing mitochondrial function and fatty-acid oxidation and thereby amplifying the primary block. Support is currently limited to proteomic and functional work in MCD-deficient fibroblasts; the modification has not been shown to drive disease in patient heart or brain tissue.
Pathograph links
Protein Lysine Malonylation -> Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation INDIRECT UNKNOWN INTERMEDIATES Malonylation of mitochondrial proteins further impairs mitochondrial function and fatty-acid oxidation, reinforcing the primary block.
Show evidence (1 reference)
PMID:26320211 SUPPORT In Vitro
"Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases."
The authors frame the lysine-malonylation link to malonic aciduria as an association requiring further elucidation, matching an EMERGING status.
?

Discussions and Knowledge Gaps

1
Does the lysine-malonylation arm demonstrated in MCD-deficient fibroblasts operate in the human tissues that actually fail in malonic aciduria — heart and brain?
HUMAN MODEL MISMATCH OPEN mlycd_malonylation_model_fidelity
Attached to
pathophysiology#Protein Lysine Malonylation
The proteomic and functional evidence for pathogenic lysine malonylation comes entirely from cultured MCD-deficient fibroblasts, a cell type that is not clinically affected and that relies little on fatty-acid oxidation. The disease burden falls on cardiomyocytes and the developing brain, where malonyl-CoA concentrations, demalonylase (SIRT5) activity, and the relevant substrate proteome may differ substantially. Whether malonylation is a driver or an epiphenomenon of the fibroblast model therefore remains open, and it matters therapeutically: a demalonylation-directed strategy only makes sense if the modification is pathogenic in the target organs.
Proposed experiments
Lysine-malonylome of MLYCD-deficient heart and brain
mlycd_kmal_target_tissue_proteomics
Quantify the lysine-malonylome of myocardium and, where available, post-mortem brain from MLYCD-deficient patients or an MLYCD-null animal model, and compare site occupancy with the published fibroblast data.
Decision criterion
Substantial overlap of hyper-malonylated mitochondrial fatty-acid oxidation enzymes between target tissue and fibroblasts would support translational validity; a largely non-overlapping profile would argue the fibroblast result is model-specific.
SIRT5 rescue in MLYCD-null cardiomyocytes
mlycd_sirt5_rescue_cardiomyocytes
Test whether restoring demalonylation capacity (e.g. SIRT5 overexpression) rescues fatty-acid oxidation and contractile function in MLYCD-null iPSC-derived cardiomyocytes, separating the malonylation arm from direct malonyl-CoA inhibition of CPT1.
Decision criterion
Functional rescue without lowering malonyl-CoA would establish malonylation as an independent pathogenic arm; absence of rescue would place the burden of causation on CPT1 inhibition alone.
Show evidence (1 reference)
PMID:26320211 SUPPORT In Vitro
"We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency."
The malonylation evidence base is entirely fibroblast-derived, which is precisely the translational mismatch this discussion records.
⚙

Pathophysiology

8
Malonyl-CoA Decarboxylase Deficiency
Biallelic loss-of-function MLYCD variants — nonsense, frameshift, splice-altering, whole-exon deletion, and missense alleles — abolish or severely reduce malonyl-CoA decarboxylase activity. MCD normally catalyses the conversion of malonyl-CoA to acetyl-CoA and CO2 in the cytosol, peroxisome, and mitochondrion, so its loss removes the principal route of malonyl-CoA disposal.
MLYCD hgnc:7150 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MLYCD (hgnc:7150). hgnc:7150 is a gene from the HUGO Gene Nomenclature Committee.
malonyl-CoA decarboxylase activity GO:0050080 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased malonyl-CoA decarboxylase activity (GO:0050080). GO:0050080 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Malonyl-CoA Accumulation Loss of the only dedicated malonyl-CoA-degrading enzyme allows malonyl-CoA to accumulate.
Show evidence (3 references)
PMID:10455107 SUPPORT Human Clinical
"a malonyl-CoA decarboxylase-deficient patient has a severe mutation in the MCD gene (c.947-948delTT), confirming that this gene encodes human MCD"
Establishes MLYCD/MCD as the mutated gene in malonyl-CoA decarboxylase deficiency.
PMID:10455107 SUPPORT In Vitro
"Malonyl-CoA decarboxylase (MCD) catalyzes the proton-consuming conversion of malonyl-CoA to acetyl-CoA and CO(2)."
Defines the enzymatic reaction whose loss constitutes the initiating lesion.
PMID:37979716 SUPPORT Human Clinical
"Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
Demonstrates reduced MCD enzyme activity in patients, including the milder later-onset phenotype.
Malonyl-CoA Accumulation
Malonyl-CoA accumulates behind the enzymatic block and is hydrolysed and conjugated to the diagnostic derivatives malonic acid and malonylcarnitine. The accumulating thioester is not merely a marker: it is the physiological regulator whose excess produces the downstream disease, both by inhibiting mitochondrial fatty-acid uptake and by driving protein lysine malonylation.
Downstream
Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation Cytosolic malonyl-CoA is the endogenous inhibitor of carnitine palmitoyltransferase 1, so its accumulation blocks mitochondrial long-chain fatty-acid uptake and beta-oxidation.
Protein Lysine Malonylation Excess malonyl-CoA is the acyl donor for lysine malonylation of mitochondrial and metabolic proteins.
Show evidence (2 references)
PMID:34884438 SUPPORT Human Clinical
"Increased levels of malonic acid and malonylcarnitine were constant."
Confirms that malonyl-CoA-derived metabolites accumulate in essentially all reported patients.
PMID:22778304 SUPPORT Human Clinical
"MCD regulates fatty acid biosynthesis and converts malonyl-CoA to acetyl-CoA."
Establishes the substrate/product pair whose ratio shifts when MCD is deficient.
Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation
Accumulated cytosolic malonyl-CoA inhibits carnitine palmitoyltransferase 1 at the outer mitochondrial membrane, restricting entry of long-chain acyl-CoA into the mitochondrion and suppressing beta-oxidation. The resulting bioenergetic deficit is most consequential in cardiac and skeletal muscle, which express MLYCD most highly and derive much of their ATP from fatty-acid oxidation, and it explains why malonic aciduria phenocopies several features of the classical fatty-acid oxidation disorders.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED
carnitine O-palmitoyltransferase activity GO:0004095 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased carnitine O-palmitoyltransferase activity (GO:0004095). GO:0004095 is a molecular function from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomyocyte Energy Substrate Deficit Restricted fatty-acid oxidation deprives the myocardium of its dominant ATP source.
Metabolic Decompensation with Acidosis and Hypoglycaemia Impaired fatty-acid oxidation limits ketogenesis and gluconeogenic support during catabolic stress, precipitating hypoglycaemia and metabolic acidosis.
Neurodevelopmental Impairment and Cerebral White Matter Injury Chronic bioenergetic insufficiency during brain development contributes to the developmental delay, hypotonia, and white matter abnormalities seen in most patients.
Show evidence (2 references)
PMID:10455107 SUPPORT In Vitro
"MCD mRNA is most abundant in cardiac and skeletal muscles, tissues in which cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation and which derive significant amounts of energy from fatty acid oxidation"
Establishes malonyl-CoA as a potent inhibitor of mitochondrial fatty-acid oxidation in the tissues that express MCD most highly.
PMID:10455107 SUPPORT Human Clinical
"malonyl-CoA decarboxylase-deficient patients display a number of phenotypes that are reminiscent of mitochondrial fatty acid oxidation disorders"
Clinical corroboration that the fatty-acid-oxidation block is expressed in the patient phenotype.
Protein Lysine Malonylation
A proposed second, non-canonical arm of pathogenesis. Excess malonyl-CoA serves as the acyl donor for lysine malonylation (Kmal) of mitochondrial and metabolic proteins. In MCD-deficient patient fibroblasts hundreds of Kmal sites increase, and cells with raised Kmal show impaired mitochondrial function and fatty-acid oxidation, suggesting that post-translational malonylation amplifies the primary CPT1-mediated block rather than merely accompanying it. The evidence is in vitro and the arm should be treated as mechanistically plausible rather than established in patient tissue.
Protein lysine malonylation as a pathogenic amplifier
protein malonylation GO:0044394 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein malonylation (GO:0044394). GO:0044394 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation Malonylation of mitochondrial proteins further impairs mitochondrial function and fatty-acid oxidation, reinforcing the primary block. Protein lysine malonylation as a pathogenic amplifier
Show evidence (1 reference)
PMID:26320211 SUPPORT In Vitro
"Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria."
Directly proposes lysine malonylation as a pathogenic mechanism in malonic aciduria, with in vitro functional support.
Cardiomyocyte Energy Substrate Deficit
Cardiomyocytes, which normally derive the majority of their ATP from long-chain fatty-acid oxidation, sustain a chronic energy-substrate deficit when CPT1-dependent import is inhibited. This is the disease-specific primary cardiomyocyte insult that initiates maladaptive remodelling.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
generation of precursor metabolites and energy GO:0006091 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased generation of precursor metabolites and energy (GO:0006091). GO:0006091 is a biological process from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomyopathy and Ventricular Dysfunction Chronic myocardial energy deficit drives ventricular dilation and contractile failure.
Show evidence (2 references)
PMID:10455107 SUPPORT In Vitro
"MCD mRNA is most abundant in cardiac and skeletal muscles, tissues in which cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation and which derive significant amounts of energy from fatty acid oxidation"
Explains the cardiac tissue selectivity — the myocardium depends on the fatty-acid oxidation that malonyl-CoA blocks.
PMID:10455107 SUPPORT Human Clinical
"a lethal disorder characterized by cardiomyopathy and developmental delay"
Identifies cardiomyopathy as a defining consequence of the enzyme deficiency.
Cardiomyopathy and Ventricular Dysfunction
Structural and functional cardiac disease is the leading cause of morbidity and mortality. Dilated cardiomyopathy predominates, but hypertrophic cardiomyopathy, left ventricular non-compaction, and arrhythmia have all been reported; deaths in the published series are predominantly heart failure-related or arrhythmic. Cardiac involvement may be the sole manifestation in later-onset disease.
cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:22778304 SUPPORT Human Clinical
"Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder."
Establishes the clinical weight of the cardiac outcome.
PMID:37979716 SUPPORT Human Clinical
"After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death)."
Documents heart-failure and arrhythmic death as the principal mode of mortality.
Metabolic Decompensation with Acidosis and Hypoglycaemia
Episodic biochemical crisis, typically unmasked by intercurrent illness or fasting, with high-anion-gap metabolic acidosis, hypoglycaemia, vomiting and failure to thrive. Unlike the classical branched-chain organic acidaemias, decompensation episodes are not universal — a recent cohort reported that patients rarely decompensated — reflecting the largely energy-deficit rather than intoxication character of this disorder.
Show evidence (2 references)
PMID:34884438 SUPPORT Human Clinical
"Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
Enumerates the decompensation phenotype (metabolic acidosis, hypoglycaemia, failure to thrive).
PMID:39069445 SUPPORT Human Clinical
"rarely exhibited metabolic decompensation episodes or seizures"
Supports this node's own claim that decompensation is episodic rather than universal: the node description states that episodes are not obligate, and this cohort is the observation behind that statement.
Neurodevelopmental Impairment and Cerebral White Matter Injury
Developmental delay and hypotonia are near-universal, and seizures are common. Brain MRI in reported patients has shown deep and periventricular white matter signal abnormality and, in one case, diffuse pachygyria with periventricular heterotopia — a malformation of cortical development that suggests a prenatal contribution of the metabolic lesion to corticogenesis. The mechanistic link between the fatty-acid oxidation block and the structural brain findings remains incompletely defined.
white matter UBERON:0002316 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in white matter (UBERON:0002316). UBERON:0002316 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:24613099 SUPPORT Human Clinical
"Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared."
Documents the characteristic deep white matter MRI signature in a genetically confirmed patient.
PMID:16275149 SUPPORT Human Clinical
"We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development."
Reports white matter abnormality together with a cortical malformation in MCD deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Malonic 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

16
Cardiovascular 4
Dilated cardiomyopathy FREQUENT HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37979716 SUPPORT Human Clinical
"Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype."
Reports the 64% frequency of cardiovascular involvement with DCM predominant, supporting the FREQUENT band.
Hypertrophic cardiomyopathy OCCASIONAL HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37979716 SUPPORT Human Clinical
"The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction."
Documents hypertrophic cardiomyopathy as an alternative, less common cardiac presentation.
Ventricular pre-excitation HP:0004309 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular pre-excitation, annotated with Ventricular preexcitation (HP:0004309). HP:0004309 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37979716 SUPPORT Human Clinical
"The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction."
Documents ventricular pre-excitation in a molecularly confirmed adult with MLYCD deficiency.
Left ventricular noncompaction HP:0030682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction (HP:0030682). HP:0030682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22778304 SUPPORT Human Clinical
"Left ventricular noncompaction development was not prevented by dietary interventions."
Case evidence for left ventricular non-compaction as part of the cardiac spectrum.
Digestive 1
Abnormality of the digestive system HP:0025031 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is digestive symptoms, annotated with Abnormality of the digestive system (HP:0025031). HP:0025031 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:34884438 SUPPORT Human Clinical
"Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
Identifies digestive-system symptoms within the multisystem clinical presentation.
Genitourinary 1
Elevated urine malonic acid level VERY_FREQUENT HP:0034657 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urine malonic acid level (HP:0034657). HP:0034657 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34884438 SUPPORT Human Clinical
"Increased levels of malonic acid and malonylcarnitine were constant."
Reports malonic acid elevation as a constant finding across the reviewed literature.
Metabolism 3
Metabolic acidosis HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34884438 SUPPORT Human Clinical
"Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
Lists metabolic acidosis among the characteristic systemic features.
Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16275149 SUPPORT Human Clinical
"Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy."
Names hypoglycaemia as one of the presenting biochemical features.
Elevated circulating malonyl carnitine concentration VERY_FREQUENT HP:6001315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating malonyl carnitine concentration (HP:6001315). HP:6001315 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34884438 SUPPORT Human Clinical
"Both patients showed high levels of malonylcarnitine on acylcarnitine profiles and malonic acid on urinary organic acid chromatographies."
Documents raised plasma malonylcarnitine in confirmed patients.
PMID:37979716 SUPPORT Human Clinical
"Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
Confirms malonylcarnitine elevation persists, if attenuated, in the milder later-onset phenotype.
Musculoskeletal 2
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39069445 SUPPORT Human Clinical
"All patients exhibited varying degrees of developmental delay and hypotonia."
Hypotonia was present in all five patients of the cohort, supporting the VERY_FREQUENT band.
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39069445 SUPPORT Human Clinical
"A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness."
The reported treatment response documents muscle weakness as part of the clinical phenotype.
Nervous System 4
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39069445 SUPPORT Human Clinical
"All patients exhibited varying degrees of developmental delay and hypotonia."
All five genetically confirmed patients had developmental delay, supporting the VERY_FREQUENT band.
PMID:34884438 SUPPORT Human Clinical
"The most common signs were developmental delay and cardiomyopathy."
Literature review of 52 cases identifies developmental delay as one of the two commonest features.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24613099 SUPPORT Human Clinical
"We report long term follow up of a patient with MLYCD deficiency showing signs of neonatal hypoglycemia, mental retardation, developmental delay and rheumatoid arthritis."
Reports intellectual disability separately from developmental delay in a molecularly confirmed patient.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20549361 SUPPORT Human Clinical
"Malonyl coenzyme A (CoA) decarboxylase (EC 4.1.1.9, MCD) deficiency, or malonic aciduria, is a rare inborn error of metabolism characterised by a variable phenotype of developmental delay, seizures, cardiomyopathy and acidosis."
Lists seizures among the core clinical features of the disorder.
Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24613099 SUPPORT Human Clinical
"Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared."
MRI evidence of cerebral white matter abnormality in a confirmed patient.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34884438 SUPPORT Human Clinical
"Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
Lists failure to thrive among the characteristic systemic features.
🧬

Genetic Associations

1
MLYCD variants
Gene: MLYCD hgnc:7150 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MLYCD (hgnc:7150). hgnc:7150 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (5 references)
PMID:10417274 SUPPORT Human Clinical
"We have identified two different homozygous mutations in human MCD (hMCD) by using RT-PCR analysis of fibroblast RNA from two previously reported consanguineous Scottish patients with MCD deficiency."
The original identification of biallelic MLYCD/MCD mutations in patients with the disorder.
PMID:10417274 SUPPORT Human Clinical
"The first mutation is a 442C-->G transversion resulting in a premature stop codon (S148X) in the N-terminal half of the protein."
Documents a nonsense allele within the reported MLYCD variant spectrum.
PMID:39069445 SUPPORT Human Clinical
"MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion."
Extends the allelic spectrum with frameshift, nonsense, missense, and exon-deletion variants.
+ 2 more references
💊

Medical Actions

4
Long-chain-triglyceride-restricted, medium-chain-triglyceride-supplemented diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Restricting long-chain triglycerides reduces the substrate load on the blocked CPT1-dependent import step, while medium-chain triglycerides bypass CPT1 and provide mitochondrial acetyl-CoA directly. This dietary combination is the mainstay of management and has been shown to improve left ventricular function; deterioration on reducing MCT intake and recovery on reinstating it provide within-patient support for the mechanism.
Mechanism Target:
BYPASSES Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation — Medium-chain fatty acids enter mitochondria independently of the CPT1-dependent step that accumulated malonyl-CoA blocks, restoring mitochondrial acetyl-CoA supply.
Show evidence (3 references)
PMID:20549361 SUPPORT Human Clinical
"This case of malonic aciduria with cardiomyopathy demonstrates improvement in cardiac function attributable to LCT-restricted/MCT-supplemented diet."
Direct clinical evidence that the LCT-restricted/MCT-supplemented diet improves cardiac function.
PMID:20549361 SUPPORT Human Clinical
"During a period of low MCT intake, her cardiac function was noted to deteriorate."
Within-patient withdrawal and reinstatement supports a causal dietary effect on cardiac function.
PMID:22778304 REFUTE Human Clinical
"Left ventricular noncompaction development was not prevented by dietary interventions."
Recorded as REFUTE of a structural-prevention claim: in this newborn-screened infant the diet did not prevent left ventricular non-compaction from developing, so dietary management cannot be credited with preventing the structural cardiac lesion. The functional benefit of the diet is carried separately by the two PMID:20549361 items above.
Levocarnitine supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levocarnitine CHEBI:16347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levocarnitine, annotated with (R)-carnitine (CHEBI:16347). CHEBI:16347 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
L-carnitine is given alongside the modified diet, both to support conjugation and excretion of accumulated malonyl-CoA as malonylcarnitine and to correct secondary carnitine depletion. The combination of modified diet plus levocarnitine improved left ventricular systolic function in most reviewed patients.
Mechanism Target:
INHIBITS Malonyl-CoA Accumulation — Carnitine supports formation and excretion of malonylcarnitine, providing an alternative disposal route for accumulated malonyl groups without correcting the primary enzyme defect.
Show evidence (2 references)
PMID:37979716 SUPPORT Human Clinical
"A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases."
Systematic-review evidence that diet plus levocarnitine improves left ventricular systolic function.
PMID:39069445 SUPPORT Human Clinical
"A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness."
Cohort follow-up supporting the diet-plus-carnitine regimen for cardiomyopathy and muscle weakness.
ACE inhibitor therapy for cardiomyopathy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Standard heart-failure pharmacotherapy is added when ventricular function deteriorates. Angiotensin-converting enzyme inhibition, combined with further dietary adjustment, improved echocardiographic findings in reported patients.
Mechanism Target:
INHIBITS Cardiomyopathy and Ventricular Dysfunction — Neurohormonal blockade attenuates maladaptive ventricular remodelling downstream of the myocardial energy deficit.
Show evidence (1 reference)
PMID:22778304 SUPPORT Human Clinical
"Further restriction of long-chain triglycerides and medium-chain triglycerides supplementation in combination with angiotensin-converting enzyme inhibitors helped to improve echocardiogram findings."
Clinical evidence that ACE inhibition, added to diet, improved echocardiographic findings.
Cardiac surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because cardiomyopathy is the leading cause of death, can develop despite dietary treatment, and may be the sole manifestation of later-onset disease, ongoing echocardiographic monitoring is recommended for all patients.
Show evidence (1 reference)
PMID:22778304 SUPPORT Human Clinical
"Our case emphasizes the need for ongoing cardiac disease screening in patients with MCD deficiency and the benefits and limitations of current dietary interventions."
Explicit recommendation for ongoing cardiac screening in MCD deficiency.
🔬

Biochemical Markers

2
Urinary malonic acid (INCREASED)
Context: Elevated urinary malonic acid on organic acid chromatography is the defining biochemical abnormality and gives the disorder its name. Modest methylmalonic acid elevation may accompany it.
Pathograph Readouts
Readout Of Malonyl-CoA Accumulation Positive Diagnostic
Urinary malonic acid reports the accumulated intracellular malonyl-CoA pool behind the enzymatic block and is used diagnostically.
Show evidence (1 reference)
PMID:20549361 SUPPORT Human Clinical
"She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene."
Links elevated urinary malonic acid directly to a deleterious MLYCD genotype.
Plasma malonylcarnitine (INCREASED)
Context: Malonylcarnitine on the plasma or dried-blood-spot acylcarnitine profile is the marker detected by expanded newborn screening and the one that remains abnormal, though only mildly, in attenuated later-onset disease.
Pathograph Readouts
Readout Of Malonyl-CoA Accumulation Positive Diagnostic
Plasma malonylcarnitine reports the malonyl-CoA burden and is the screening and diagnostic analyte.
Show evidence (1 reference)
PMID:37979716 SUPPORT Human Clinical
"Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
Pairs the malonylcarnitine readout with directly measured residual enzyme activity.
🔬

Diagnosis

4
Newborn screening by acylcarnitine profiling
Newborn screening can detect the characteristic malonylcarnitine elevation before clinical presentation and supports earlier diagnostic evaluation.
Results: Elevated malonylcarnitine on the newborn-screening acylcarnitine profile.
Show evidence (2 references)
PMID:24613099 SUPPORT Human Clinical
"Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.9) deficiency is a rare autosomal recessive disorder that is widely diagnosed by neonatal screening."
Establishes neonatal screening as a common route to diagnosis.
PMID:39069445 SUPPORT Human Clinical
"Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder."
Supports the clinical value of newborn screening for early recognition.
Urine organic acid analysis
Urine organic acid analysis detects the defining malonic acid elevation; methylmalonic acid may also be elevated.
Results: Elevated urinary malonic acid, sometimes accompanied by methylmalonic acid.
Show evidence (1 reference)
PMID:20549361 SUPPORT Human Clinical
"She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene."
Documents the diagnostic urinary organic-acid pattern in an affected infant.
Malonyl-CoA decarboxylase activity assay
Measurement of enzyme activity can biochemically confirm deficient MLYCD function.
Results: Reduced malonyl-CoA decarboxylase activity.
Show evidence (1 reference)
PMID:37979716 SUPPORT Human Clinical
"Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
Shows reduced enzyme activity alongside the diagnostic acylcarnitine abnormality.
MLYCD molecular genetic testing
Sequence and copy-number analysis can confirm biallelic pathogenic MLYCD variants.
Results: Identification of biallelic pathogenic or likely pathogenic MLYCD variants.
Show evidence (2 references)
PMID:39069445 SUPPORT Human Clinical
"Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents."
Documents Sanger sequencing as a molecular diagnostic method for affected families.
PMID:39069445 SUPPORT Human Clinical
"MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion."
Demonstrates molecular confirmation across a five-patient cohort, including a multi-exon deletion.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Fewer than 60 genetically or biochemically confirmed patients have been reported since the first description in 1984; a 2021 literature review counted 52 cases, and a 2023 systematic review of cardiovascular involvement identified 33 individuals with a genetic diagnosis.
Show evidence (2 references)
PMID:34884438 SUPPORT Human Clinical
"A review of the literature yielded 52 cases described since 1984."
Provides the published case count underpinning the ultra-rare occurrence class.
PMID:37979716 SUPPORT Human Clinical
"The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD"
Independent systematic review confirming the very small size of the reported patient population.
{ }

Source YAML

click to show 
name: Malonic Aciduria
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- Malonyl-CoA decarboxylase deficiency
- MLYCD deficiency
- MCD deficiency
- MLYCDD
- Malonic acidemia
description: >
  Malonic aciduria is an ultra-rare autosomal recessive organic aciduria caused
  by biallelic loss-of-function variants in MLYCD, which encodes malonyl-CoA
  decarboxylase (MCD). MCD catalyses the conversion of malonyl-CoA to
  acetyl-CoA and CO2, and its loss allows malonyl-CoA to accumulate. Because
  cytosolic malonyl-CoA is the physiological inhibitor of carnitine
  palmitoyltransferase 1, its accumulation restricts mitochondrial long-chain
  fatty-acid uptake and beta-oxidation, so the disorder behaves biochemically
  like a hybrid of an organic aciduria and a fatty-acid oxidation defect. A
  second, non-canonical arm has been proposed in which excess malonyl-CoA
  drives protein lysine malonylation, itself impairing mitochondrial function
  and fatty-acid oxidation. Heart and skeletal muscle, which depend heavily on
  fatty-acid oxidation and express MLYCD most highly, are the principal
  targets: cardiomyopathy (most often dilated) is the leading cause of
  morbidity and mortality. Most patients present in the first months of life
  with developmental delay, hypotonia, seizures, metabolic acidosis,
  hypoglycaemia, and failure to thrive; a later-onset phenotype limited to
  cardiomyopathy has been described in adults. Elevated urinary malonic acid
  and plasma malonylcarnitine are the constant biochemical markers. A
  long-chain-triglyceride-restricted, medium-chain-triglyceride-supplemented
  diet with levocarnitine supplementation is the mainstay of treatment and can
  improve left ventricular function.
classifications:
  icimd_category:
  - classification_value: organic_acidurias
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Organic acidurias"
      under category "Disorders of amino acid metabolism". MONDO:0009556 is
      classified is_a MONDO:0000688 "inborn organic aciduria". The disorder
      also has substantial mechanistic overlap with the ICIMD group
      "Mitochondrial fatty acid oxidation" because accumulating malonyl-CoA
      inhibits carnitine palmitoyltransferase 1; only the primary
      organic-aciduria assignment is recorded here.
disease_term:
  preferred_term: malonic aciduria
  term:
    id: MONDO:0009556
    label: malonic aciduria
parents:
- Organic Aciduria
- Inborn Error of Metabolism
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 60 genetically or biochemically confirmed patients have been
    reported since the first description in 1984; a 2021 literature review
    counted 52 cases, and a 2023 systematic review of cardiovascular
    involvement identified 33 individuals with a genetic diagnosis.
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A review of the literature yielded 52 cases described since 1984."
    explanation: Provides the published case count underpinning the ultra-rare occurrence class.
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD"
    explanation: Independent systematic review confirming the very small size of the reported patient population.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Malonic aciduria segregates as an autosomal recessive trait; affected
    individuals carry biallelic MLYCD variants and heterozygous parents are
    unaffected.
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This enzyme is encoded by the MLYCD (Malonyl-CoA Decarboxylase) gene, and the disease has an autosomal recessive inheritance."
    explanation: States the autosomal recessive mode of inheritance for MLYCD-related malonic aciduria.
pathophysiology:
- name: Malonyl-CoA Decarboxylase Deficiency
  biological_scale: MOLECULAR
  conforms_to: "metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism"
  description: >
    Biallelic loss-of-function MLYCD variants — nonsense, frameshift,
    splice-altering, whole-exon deletion, and missense alleles — abolish or
    severely reduce malonyl-CoA decarboxylase activity. MCD normally catalyses
    the conversion of malonyl-CoA to acetyl-CoA and CO2 in the cytosol,
    peroxisome, and mitochondrion, so its loss removes the principal route of
    malonyl-CoA disposal.
  genes:
  - preferred_term: MLYCD
    term:
      id: hgnc:7150
      label: MLYCD
  molecular_functions:
  - preferred_term: malonyl-CoA decarboxylase activity
    term:
      id: GO:0050080
      label: malonyl-CoA decarboxylase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a malonyl-CoA decarboxylase-deficient patient has a severe mutation in the MCD gene (c.947-948delTT), confirming that this gene encodes human MCD"
    explanation: Establishes MLYCD/MCD as the mutated gene in malonyl-CoA decarboxylase deficiency.
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Malonyl-CoA decarboxylase (MCD) catalyzes the proton-consuming conversion of malonyl-CoA to acetyl-CoA and CO(2)."
    explanation: Defines the enzymatic reaction whose loss constitutes the initiating lesion.
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
    explanation: Demonstrates reduced MCD enzyme activity in patients, including the milder later-onset phenotype.
  downstream:
  - target: Malonyl-CoA Accumulation
    description: Loss of the only dedicated malonyl-CoA-degrading enzyme allows malonyl-CoA to accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26320211
      reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins."
      explanation: Directly documents malonyl-CoA accumulation as the consequence of MCD deficiency in patient-derived cells.
- name: Malonyl-CoA Accumulation
  biological_scale: MOLECULAR
  conforms_to: "metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit"
  description: >
    Malonyl-CoA accumulates behind the enzymatic block and is hydrolysed and
    conjugated to the diagnostic derivatives malonic acid and malonylcarnitine.
    The accumulating thioester is not merely a marker: it is the physiological
    regulator whose excess produces the downstream disease, both by inhibiting
    mitochondrial fatty-acid uptake and by driving protein lysine malonylation.
  chemical_entities:
  - preferred_term: malonyl-CoA
    term:
      id: CHEBI:15531
      label: malonyl-CoA
    modifier: INCREASED
  - preferred_term: acetyl-CoA
    term:
      id: CHEBI:15351
      label: acetyl-CoA
    modifier: DECREASED
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of malonic acid and malonylcarnitine were constant."
    explanation: Confirms that malonyl-CoA-derived metabolites accumulate in essentially all reported patients.
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD regulates fatty acid biosynthesis and converts malonyl-CoA to acetyl-CoA."
    explanation: Establishes the substrate/product pair whose ratio shifts when MCD is deficient.
  downstream:
  - target: Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation
    description: >-
      Cytosolic malonyl-CoA is the endogenous inhibitor of carnitine
      palmitoyltransferase 1, so its accumulation blocks mitochondrial
      long-chain fatty-acid uptake and beta-oxidation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10455107
      reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cytoplasmic MCD is positioned to play a role in the regulation of cytoplasmic malonyl-CoA abundance and, thus, of mitochondrial fatty acid uptake and oxidation."
      explanation: Links cytoplasmic malonyl-CoA abundance to control of mitochondrial fatty-acid uptake and oxidation.
  - target: Protein Lysine Malonylation
    description: >-
      Excess malonyl-CoA is the acyl donor for lysine malonylation of
      mitochondrial and metabolic proteins.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26320211
      reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency."
      explanation: Quantifies the increase in protein lysine malonylation caused by MCD deficiency.
- name: Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation
  biological_scale: CELLULAR
  description: >
    Accumulated cytosolic malonyl-CoA inhibits carnitine palmitoyltransferase 1
    at the outer mitochondrial membrane, restricting entry of long-chain
    acyl-CoA into the mitochondrion and suppressing beta-oxidation. The
    resulting bioenergetic deficit is most consequential in cardiac and
    skeletal muscle, which express MLYCD most highly and derive much of their
    ATP from fatty-acid oxidation, and it explains why malonic aciduria
    phenocopies several features of the classical fatty-acid oxidation
    disorders.
  molecular_functions:
  - preferred_term: carnitine O-palmitoyltransferase activity
    term:
      id: GO:0004095
      label: carnitine O-palmitoyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MCD mRNA is most abundant in cardiac and skeletal muscles, tissues in which cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation and which derive significant amounts of energy from fatty acid oxidation"
    explanation: Establishes malonyl-CoA as a potent inhibitor of mitochondrial fatty-acid oxidation in the tissues that express MCD most highly.
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malonyl-CoA decarboxylase-deficient patients display a number of phenotypes that are reminiscent of mitochondrial fatty acid oxidation disorders"
    explanation: Clinical corroboration that the fatty-acid-oxidation block is expressed in the patient phenotype.
  downstream:
  - target: Cardiomyocyte Energy Substrate Deficit
    description: Restricted fatty-acid oxidation deprives the myocardium of its dominant ATP source.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22778304
      reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder."
      explanation: Establishes the myocardium as the principal target organ of the metabolic block.
  - target: Metabolic Decompensation with Acidosis and Hypoglycaemia
    description: >-
      Impaired fatty-acid oxidation limits ketogenesis and gluconeogenic
      support during catabolic stress, precipitating hypoglycaemia and
      metabolic acidosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16275149
      reference_title: "Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy."
      explanation: Links the enzyme deficiency to the decompensation triad of acidosis and hypoglycaemia alongside cardiomyopathy.
  - target: Neurodevelopmental Impairment and Cerebral White Matter Injury
    description: >-
      Chronic bioenergetic insufficiency during brain development contributes
      to the developmental delay, hypotonia, and white matter abnormalities
      seen in most patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39069445
      reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients exhibited varying degrees of developmental delay and hypotonia."
      explanation: Documents the near-universal neurodevelopmental phenotype in a genetically confirmed cohort.
- name: Protein Lysine Malonylation
  biological_scale: MOLECULAR
  description: >
    A proposed second, non-canonical arm of pathogenesis. Excess malonyl-CoA
    serves as the acyl donor for lysine malonylation (Kmal) of mitochondrial
    and metabolic proteins. In MCD-deficient patient fibroblasts hundreds of
    Kmal sites increase, and cells with raised Kmal show impaired mitochondrial
    function and fatty-acid oxidation, suggesting that post-translational
    malonylation amplifies the primary CPT1-mediated block rather than merely
    accompanying it. The evidence is in vitro and the arm should be treated as
    mechanistically plausible rather than established in patient tissue.
  biological_processes:
  - preferred_term: protein malonylation
    term:
      id: GO:0044394
      label: protein malonylation
    modifier: INCREASED
  evidence:
  - reference: PMID:26320211
    reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria."
    explanation: Directly proposes lysine malonylation as a pathogenic mechanism in malonic aciduria, with in vitro functional support.
  downstream:
  - target: Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation
    description: >-
      Malonylation of mitochondrial proteins further impairs mitochondrial
      function and fatty-acid oxidation, reinforcing the primary block.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lysine_malonylation_arm
    evidence:
    - reference: PMID:26320211
      reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria."
      explanation: Supports a feed-forward contribution of protein malonylation to the fatty-acid-oxidation defect.
- name: Cardiomyocyte Energy Substrate Deficit
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >
    Cardiomyocytes, which normally derive the majority of their ATP from
    long-chain fatty-acid oxidation, sustain a chronic energy-substrate deficit
    when CPT1-dependent import is inhibited. This is the disease-specific
    primary cardiomyocyte insult that initiates maladaptive remodelling.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: generation of precursor metabolites and energy
    term:
      id: GO:0006091
      label: generation of precursor metabolites and energy
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MCD mRNA is most abundant in cardiac and skeletal muscles, tissues in which cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation and which derive significant amounts of energy from fatty acid oxidation"
    explanation: Explains the cardiac tissue selectivity — the myocardium depends on the fatty-acid oxidation that malonyl-CoA blocks.
  - reference: PMID:10455107
    reference_title: "MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a lethal disorder characterized by cardiomyopathy and developmental delay"
    explanation: Identifies cardiomyopathy as a defining consequence of the enzyme deficiency.
  downstream:
  - target: Cardiomyopathy and Ventricular Dysfunction
    description: Chronic myocardial energy deficit drives ventricular dilation and contractile failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37979716
      reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype."
      explanation: Quantifies the frequency and predominant form of the cardiac outcome across reported patients.
- name: Cardiomyopathy and Ventricular Dysfunction
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >
    Structural and functional cardiac disease is the leading cause of morbidity
    and mortality. Dilated cardiomyopathy predominates, but hypertrophic
    cardiomyopathy, left ventricular non-compaction, and arrhythmia have all
    been reported; deaths in the published series are predominantly heart
    failure-related or arrhythmic. Cardiac involvement may be the sole
    manifestation in later-onset disease.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder."
    explanation: Establishes the clinical weight of the cardiac outcome.
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death)."
    explanation: Documents heart-failure and arrhythmic death as the principal mode of mortality.
- name: Metabolic Decompensation with Acidosis and Hypoglycaemia
  biological_scale: ORGANISM
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  description: >
    Episodic biochemical crisis, typically unmasked by intercurrent illness or
    fasting, with high-anion-gap metabolic acidosis, hypoglycaemia, vomiting
    and failure to thrive. Unlike the classical branched-chain organic
    acidaemias, decompensation episodes are not universal — a recent cohort
    reported that patients rarely decompensated — reflecting the largely
    energy-deficit rather than intoxication character of this disorder.
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
    explanation: Enumerates the decompensation phenotype (metabolic acidosis, hypoglycaemia, failure to thrive).
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rarely exhibited metabolic decompensation episodes or seizures"
    explanation: >-
      Supports this node's own claim that decompensation is episodic rather than
      universal: the node description states that episodes are not obligate, and
      this cohort is the observation behind that statement.
- name: Neurodevelopmental Impairment and Cerebral White Matter Injury
  biological_scale: ORGANISM
  description: >
    Developmental delay and hypotonia are near-universal, and seizures are
    common. Brain MRI in reported patients has shown deep and periventricular
    white matter signal abnormality and, in one case, diffuse pachygyria with
    periventricular heterotopia — a malformation of cortical development that
    suggests a prenatal contribution of the metabolic lesion to corticogenesis.
    The mechanistic link between the fatty-acid oxidation block and the
    structural brain findings remains incompletely defined.
  locations:
  - preferred_term: white matter
    term:
      id: UBERON:0002316
      label: white matter
  evidence:
  - reference: PMID:24613099
    reference_title: "Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared."
    explanation: Documents the characteristic deep white matter MRI signature in a genetically confirmed patient.
  - reference: PMID:16275149
    reference_title: "Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development."
    explanation: Reports white matter abnormality together with a cortical malformation in MCD deficiency.
mechanistic_hypotheses:
- hypothesis_group_id: lysine_malonylation_arm
  hypothesis_label: Protein lysine malonylation as a pathogenic amplifier
  status: EMERGING
  description: >
    Beyond CPT1 inhibition, accumulating malonyl-CoA malonylates lysine
    residues on mitochondrial and metabolic proteins. The hypothesis holds that
    this post-translational modification is itself pathogenic, further
    impairing mitochondrial function and fatty-acid oxidation and thereby
    amplifying the primary block. Support is currently limited to proteomic and
    functional work in MCD-deficient fibroblasts; the modification has not been
    shown to drive disease in patient heart or brain tissue.
  evidence:
  - reference: PMID:26320211
    reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases."
    explanation: The authors frame the lysine-malonylation link to malonic aciduria as an association requiring further elucidation, matching an EMERGING status.
discussions:
- discussion_id: mlycd_malonylation_model_fidelity
  prompt: >-
    Does the lysine-malonylation arm demonstrated in MCD-deficient fibroblasts
    operate in the human tissues that actually fail in malonic aciduria — heart
    and brain?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Protein Lysine Malonylation
  rationale: >-
    The proteomic and functional evidence for pathogenic lysine malonylation
    comes entirely from cultured MCD-deficient fibroblasts, a cell type that is
    not clinically affected and that relies little on fatty-acid oxidation. The
    disease burden falls on cardiomyocytes and the developing brain, where
    malonyl-CoA concentrations, demalonylase (SIRT5) activity, and the relevant
    substrate proteome may differ substantially. Whether malonylation is a
    driver or an epiphenomenon of the fibroblast model therefore remains open,
    and it matters therapeutically: a demalonylation-directed strategy only
    makes sense if the modification is pathogenic in the target organs.
  proposed_experiments:
  - experiment_id: mlycd_kmal_target_tissue_proteomics
    name: Lysine-malonylome of MLYCD-deficient heart and brain
    description: >-
      Quantify the lysine-malonylome of myocardium and, where available,
      post-mortem brain from MLYCD-deficient patients or an MLYCD-null animal
      model, and compare site occupancy with the published fibroblast data.
    decision_criterion: >-
      Substantial overlap of hyper-malonylated mitochondrial fatty-acid
      oxidation enzymes between target tissue and fibroblasts would support
      translational validity; a largely non-overlapping profile would argue the
      fibroblast result is model-specific.
  - experiment_id: mlycd_sirt5_rescue_cardiomyocytes
    name: SIRT5 rescue in MLYCD-null cardiomyocytes
    description: >-
      Test whether restoring demalonylation capacity (e.g. SIRT5
      overexpression) rescues fatty-acid oxidation and contractile function in
      MLYCD-null iPSC-derived cardiomyocytes, separating the malonylation arm
      from direct malonyl-CoA inhibition of CPT1.
    decision_criterion: >-
      Functional rescue without lowering malonyl-CoA would establish
      malonylation as an independent pathogenic arm; absence of rescue would
      place the burden of causation on CPT1 inhibition alone.
  evidence:
  - reference: PMID:26320211
    reference_title: "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency."
    explanation: The malonylation evidence base is entirely fibroblast-derived, which is precisely the translational mismatch this discussion records.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  frequency: FREQUENT
  description: >
    The predominant cardiac phenotype; cardiovascular involvement of some kind
    was present in about two-thirds of genetically diagnosed patients in a
    systematic review, with dilated cardiomyopathy the commonest form.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype."
    explanation: Reports the 64% frequency of cardiovascular involvement with DCM predominant, supporting the FREQUENT band.
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  frequency: OCCASIONAL
  description: >
    A minority cardiac presentation, described in later-onset disease alongside
    ventricular pre-excitation.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction."
    explanation: Documents hypertrophic cardiomyopathy as an alternative, less common cardiac presentation.
- category: Cardiovascular
  name: Ventricular pre-excitation
  description: >
    Ventricular pre-excitation can accompany the later-onset hypertrophic
    cardiomyopathy presentation.
  phenotype_term:
    preferred_term: Ventricular pre-excitation
    term:
      id: HP:0004309
      label: Ventricular preexcitation
  evidence:
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction."
    explanation: Documents ventricular pre-excitation in a molecularly confirmed adult with MLYCD deficiency.
- category: Cardiovascular
  name: Left ventricular noncompaction
  description: >
    Reported in an infant identified by newborn screening whose non-compaction
    developed despite early dietary intervention.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular noncompaction development was not prevented by dietary interventions."
    explanation: Case evidence for left ventricular non-compaction as part of the cardiac spectrum.
- category: Neurologic
  name: Global developmental delay
  frequency: VERY_FREQUENT
  description: >
    Developmental delay is among the two most common signs across the reported
    literature and was present in every patient of a five-patient
    genetically-confirmed cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited varying degrees of developmental delay and hypotonia."
    explanation: All five genetically confirmed patients had developmental delay, supporting the VERY_FREQUENT band.
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common signs were developmental delay and cardiomyopathy."
    explanation: Literature review of 52 cases identifies developmental delay as one of the two commonest features.
- category: Neurologic
  name: Intellectual disability
  description: Intellectual disability has been reported in the neurodevelopmental phenotype.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:24613099
    reference_title: "Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report long term follow up of a patient with MLYCD deficiency showing signs of neonatal hypoglycemia, mental retardation, developmental delay and rheumatoid arthritis."
    explanation: Reports intellectual disability separately from developmental delay in a molecularly confirmed patient.
- category: Neurologic
  name: Hypotonia
  frequency: VERY_FREQUENT
  description: Generalised hypotonia accompanying the developmental delay.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited varying degrees of developmental delay and hypotonia."
    explanation: Hypotonia was present in all five patients of the cohort, supporting the VERY_FREQUENT band.
- category: Neuromuscular
  name: Muscle weakness
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness."
    explanation: The reported treatment response documents muscle weakness as part of the clinical phenotype.
- category: Neurologic
  name: Seizure
  description: >
    Seizures are part of the classical phenotype, though a recent cohort found
    them to be infrequent.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20549361
    reference_title: "Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonyl coenzyme A (CoA) decarboxylase (EC 4.1.1.9, MCD) deficiency, or malonic aciduria, is a rare inborn error of metabolism characterised by a variable phenotype of developmental delay, seizures, cardiomyopathy and acidosis."
    explanation: Lists seizures among the core clinical features of the disorder.
- category: Neurologic
  name: Abnormal cerebral white matter morphology
  description: >
    Deep and periventricular white matter signal abnormality on brain MRI; one
    reported patient additionally had diffuse pachygyria and periventricular
    heterotopia.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:24613099
    reference_title: "Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared."
    explanation: MRI evidence of cerebral white matter abnormality in a confirmed patient.
- category: Metabolic
  name: Metabolic acidosis
  description: High-anion-gap metabolic acidosis during decompensation.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
    explanation: Lists metabolic acidosis among the characteristic systemic features.
- category: Metabolic
  name: Hypoglycemia
  description: Hypoglycaemia, reflecting the impaired fatty-acid oxidation and ketogenesis.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:16275149
    reference_title: "Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy."
    explanation: Names hypoglycaemia as one of the presenting biochemical features.
- category: Growth
  name: Failure to thrive
  description: Poor weight gain and growth in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
    explanation: Lists failure to thrive among the characteristic systemic features.
- category: Gastrointestinal
  name: Abnormality of the digestive system
  phenotype_term:
    preferred_term: digestive symptoms
    term:
      id: HP:0025031
      label: Abnormality of the digestive system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy."
    explanation: Identifies digestive-system symptoms within the multisystem clinical presentation.
- category: Metabolic
  name: Elevated urine malonic acid level
  frequency: VERY_FREQUENT
  description: >
    Urinary malonic acid elevation is the biochemical hallmark and was constant
    across reported cases.
  phenotype_term:
    preferred_term: Elevated urine malonic acid level
    term:
      id: HP:0034657
      label: Elevated urine malonic acid level
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of malonic acid and malonylcarnitine were constant."
    explanation: Reports malonic acid elevation as a constant finding across the reviewed literature.
- category: Metabolic
  name: Elevated circulating malonyl carnitine concentration
  frequency: VERY_FREQUENT
  description: >
    Plasma malonylcarnitine elevation is the acylcarnitine marker used for
    newborn screening and diagnosis; it was constant in reviewed cases and is
    mildly elevated even in the attenuated later-onset phenotype.
  phenotype_term:
    preferred_term: Elevated circulating malonyl carnitine concentration
    term:
      id: HP:6001315
      label: Elevated circulating malonyl carnitine concentration
  evidence:
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients showed high levels of malonylcarnitine on acylcarnitine profiles and malonic acid on urinary organic acid chromatographies."
    explanation: Documents raised plasma malonylcarnitine in confirmed patients.
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
    explanation: Confirms malonylcarnitine elevation persists, if attenuated, in the milder later-onset phenotype.
biochemical:
- name: Urinary malonic acid
  presence: INCREASED
  context: >
    Elevated urinary malonic acid on organic acid chromatography is the
    defining biochemical abnormality and gives the disorder its name. Modest
    methylmalonic acid elevation may accompany it.
  biomarker_term:
    preferred_term: malonic acid
    term:
      id: CHEBI:30794
      label: malonic acid
  readouts:
  - target: Malonyl-CoA Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary malonic acid reports the accumulated intracellular malonyl-CoA
      pool behind the enzymatic block and is used diagnostically.
    evidence:
    - reference: PMID:20549361
      reference_title: "Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene."
      explanation: Links elevated urinary malonic acid directly to a deleterious MLYCD genotype.
- name: Plasma malonylcarnitine
  presence: INCREASED
  context: >
    Malonylcarnitine on the plasma or dried-blood-spot acylcarnitine profile is
    the marker detected by expanded newborn screening and the one that remains
    abnormal, though only mildly, in attenuated later-onset disease.
  biomarker_term:
    preferred_term: malonylcarnitine
    term:
      id: CHEBI:73028
      label: O-malonylcarnitine
  readouts:
  - target: Malonyl-CoA Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Plasma malonylcarnitine reports the malonyl-CoA burden and is the
      screening and diagnostic analyte.
    evidence:
    - reference: PMID:37979716
      reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
      explanation: Pairs the malonylcarnitine readout with directly measured residual enzyme activity.
diagnosis:
- name: Newborn screening by acylcarnitine profiling
  description: >
    Newborn screening can detect the characteristic malonylcarnitine elevation
    before clinical presentation and supports earlier diagnostic evaluation.
  results: Elevated malonylcarnitine on the newborn-screening acylcarnitine profile.
  evidence:
  - reference: PMID:24613099
    reference_title: "Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.9) deficiency is a rare autosomal recessive disorder that is widely diagnosed by neonatal screening."
    explanation: Establishes neonatal screening as a common route to diagnosis.
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder."
    explanation: Supports the clinical value of newborn screening for early recognition.
- name: Urine organic acid analysis
  description: >
    Urine organic acid analysis detects the defining malonic acid elevation;
    methylmalonic acid may also be elevated.
  results: Elevated urinary malonic acid, sometimes accompanied by methylmalonic acid.
  evidence:
  - reference: PMID:20549361
    reference_title: "Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene."
    explanation: Documents the diagnostic urinary organic-acid pattern in an affected infant.
- name: Malonyl-CoA decarboxylase activity assay
  description: Measurement of enzyme activity can biochemically confirm deficient MLYCD function.
  results: Reduced malonyl-CoA decarboxylase activity.
  evidence:
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity."
    explanation: Shows reduced enzyme activity alongside the diagnostic acylcarnitine abnormality.
- name: MLYCD molecular genetic testing
  description: Sequence and copy-number analysis can confirm biallelic pathogenic MLYCD variants.
  results: Identification of biallelic pathogenic or likely pathogenic MLYCD variants.
  evidence:
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents."
    explanation: Documents Sanger sequencing as a molecular diagnostic method for affected families.
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion."
    explanation: Demonstrates molecular confirmation across a five-patient cohort, including a multi-exon deletion.
genetic:
- name: MLYCD variants
  gene_term:
    preferred_term: MLYCD
    term:
      id: hgnc:7150
      label: MLYCD
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:22778304
      reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Malonyl coenzyme A (CoA) decarboxylase (MCD) deficiency is a rare autosomal recessive organic acidemia characterized by varying degrees of organ involvement and severity."
      explanation: States the autosomal recessive inheritance of MCD deficiency.
  relationship_type: CAUSATIVE
  features: >
    Reported pathogenic MLYCD alleles span nonsense (S148X, p.Gln116*,
    p.Arg310*), frameshift (c.947-948delTT, c.60delG), splice-altering
    (IVS4-14A>G, creating a novel splice acceptor), start-loss (p.M1K),
    missense (p.H152N, p.Ser241Pro, p.Trp431Cys), and multi-exon deletion
    (exons 4-5) changes. Genotype-phenotype correlation is poor, and the same
    homozygous genotype has produced markedly different clinical courses within
    a single consanguineous family.
  evidence:
  - reference: PMID:10417274
    reference_title: "The molecular basis of malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified two different homozygous mutations in human MCD (hMCD) by using RT-PCR analysis of fibroblast RNA from two previously reported consanguineous Scottish patients with MCD deficiency."
    explanation: The original identification of biallelic MLYCD/MCD mutations in patients with the disorder.
  - reference: PMID:10417274
    reference_title: "The molecular basis of malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first mutation is a 442C-->G transversion resulting in a premature stop codon (S148X) in the N-terminal half of the protein."
    explanation: Documents a nonsense allele within the reported MLYCD variant spectrum.
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion."
    explanation: Extends the allelic spectrum with frameshift, nonsense, missense, and exon-deletion variants.
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, there is no correlation between various genotypes and phenotypes."
    explanation: Supports the absence of a usable genotype-phenotype correlation.
  - reference: PMID:34884438
    reference_title: "Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here two index cases belonging to the same family that, despite an identical genotype, present very different clinical pictures."
    explanation: Demonstrates intrafamilial variability at identical genotype, reinforcing the poor genotype-phenotype correlation.
treatments:
- name: Long-chain-triglyceride-restricted, medium-chain-triglyceride-supplemented diet
  description: >
    Restricting long-chain triglycerides reduces the substrate load on the
    blocked CPT1-dependent import step, while medium-chain triglycerides bypass
    CPT1 and provide mitochondrial acetyl-CoA directly. This dietary
    combination is the mainstay of management and has been shown to improve
    left ventricular function; deterioration on reducing MCT intake and
    recovery on reinstating it provide within-patient support for the
    mechanism.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Malonyl-CoA-Mediated Inhibition of Mitochondrial Fatty Acid Oxidation
    treatment_effect: BYPASSES
    description: >-
      Medium-chain fatty acids enter mitochondria independently of the
      CPT1-dependent step that accumulated malonyl-CoA blocks, restoring
      mitochondrial acetyl-CoA supply.
  evidence:
  - reference: PMID:20549361
    reference_title: "Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case of malonic aciduria with cardiomyopathy demonstrates improvement in cardiac function attributable to LCT-restricted/MCT-supplemented diet."
    explanation: Direct clinical evidence that the LCT-restricted/MCT-supplemented diet improves cardiac function.
  - reference: PMID:20549361
    reference_title: "Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During a period of low MCT intake, her cardiac function was noted to deteriorate."
    explanation: Within-patient withdrawal and reinstatement supports a causal dietary effect on cardiac function.
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular noncompaction development was not prevented by dietary interventions."
    explanation: >-
      Recorded as REFUTE of a structural-prevention claim: in this
      newborn-screened infant the diet did not prevent left ventricular
      non-compaction from developing, so dietary management cannot be credited
      with preventing the structural cardiac lesion. The functional benefit of
      the diet is carried separately by the two PMID:20549361 items above.
- name: Levocarnitine supplementation
  description: >
    L-carnitine is given alongside the modified diet, both to support
    conjugation and excretion of accumulated malonyl-CoA as malonylcarnitine
    and to correct secondary carnitine depletion. The combination of modified
    diet plus levocarnitine improved left ventricular systolic function in most
    reviewed patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levocarnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
  target_mechanisms:
  - target: Malonyl-CoA Accumulation
    treatment_effect: INHIBITS
    description: >-
      Carnitine supports formation and excretion of malonylcarnitine, providing
      an alternative disposal route for accumulated malonyl groups without
      correcting the primary enzyme defect.
  evidence:
  - reference: PMID:37979716
    reference_title: "Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases."
    explanation: Systematic-review evidence that diet plus levocarnitine improves left ventricular systolic function.
  - reference: PMID:39069445
    reference_title: "Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness."
    explanation: Cohort follow-up supporting the diet-plus-carnitine regimen for cardiomyopathy and muscle weakness.
- name: ACE inhibitor therapy for cardiomyopathy
  description: >
    Standard heart-failure pharmacotherapy is added when ventricular function
    deteriorates. Angiotensin-converting enzyme inhibition, combined with
    further dietary adjustment, improved echocardiographic findings in reported
    patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
  target_mechanisms:
  - target: Cardiomyopathy and Ventricular Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade attenuates maladaptive ventricular remodelling
      downstream of the myocardial energy deficit.
  evidence:
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further restriction of long-chain triglycerides and medium-chain triglycerides supplementation in combination with angiotensin-converting enzyme inhibitors helped to improve echocardiogram findings."
    explanation: Clinical evidence that ACE inhibition, added to diet, improved echocardiographic findings.
- name: Cardiac surveillance
  description: >
    Because cardiomyopathy is the leading cause of death, can develop despite
    dietary treatment, and may be the sole manifestation of later-onset
    disease, ongoing echocardiographic monitoring is recommended for all
    patients.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:22778304
    reference_title: "Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case emphasizes the need for ongoing cardiac disease screening in patients with MCD deficiency and the benefits and limitations of current dietary interventions."
    explanation: Explicit recommendation for ongoing cardiac screening in MCD deficiency.
notes: >-
  WP-001 (IEMbase metabolic) new-entry increment for issue 5556, row 1.2.23.01
  (MLYCD / OMIM:248360 / ORPHA:943), following Carbonic_Anhydrase_VA_Deficiency
  (row 1.1.09.01) and 3-Methylglutaconic_Aciduria_Type_I (row 1.2.12.01). The
  WP-001 seed table short-alias-matched MLYCD to Migraine_with_Aura; that match
  was confirmed to be a false positive (an unrelated channelopathy entry) and
  discarded, so this is a genuinely new entry rather than an edit.

  NEC preflight passed: MONDO:0009556 "malonic aciduria" names malonyl-CoA
  decarboxylase in its Orphanet-sourced definition, carries OMIM:248360 and
  Orphanet:943 xrefs matching the seed row, lists "malonyl-CoA decarboxylase
  deficiency" as an exact synonym, and asserts RO:0004003 to HGNC:7150 (MLYCD)
  — the gene named throughout the cited literature.

  Newborn screening and the biochemical and molecular confirmation pathway are
  modelled under diagnosis. The reported case of maternal uniparental
  isodisomy of the telomeric end of chromosome 16
  (PMID:17535268) is a notable genetic mechanism but that abstract was not
  fetched in this pass, so it is not cited. PMID:31395333 (nine-patient cohort,
  Chapel-Crespo 2019) is the largest clinical series but has no abstract
  available in PubMed, so no snippet could be quoted from it.