Methylmalonyl-CoA Epimerase Deficiency

Mendelian MONDO:0009615 Pathograph 25 Show in embeddings browser Organic Aciduria Inborn Error of Metabolism

Methylmalonyl-CoA epimerase (MCEE) deficiency is an ultra-rare autosomal recessive defect of the propionate catabolic pathway. MCEE occupies the middle of three consecutive steps that carry propionyl-CoA into the TCA cycle: propionyl-CoA carboxylase makes D-methylmalonyl-CoA, MCEE epimerises it to the L-enantiomer, and methylmalonyl-CoA mutase converts that to succinyl-CoA. Deficiencies of the first and third steps are the well-characterised diseases propionic acidemia and isolated methylmalonic acidemia. The middle step is the one whose physiological importance was unclear until 2006, and whose clinical importance is still argued over. The reason is structural rather than evidential. The epimerisation MCEE catalyses can also proceed non-enzymatically, and a shunt through free methylmalonic acid provides a second bypass, so losing the enzyme produces a partial rather than a complete block. Knocking MCEE down by siRNA reduces pathway flux only slightly. That single fact explains the shape of the whole disorder: a persistent but mild-to-moderate methylmalonic aciduria, a biochemical profile dominated by 2-methylcitrate, 3-hydroxypropionate and C3 propionylcarnitine rather than by methylmalonate, and a clinical spectrum that runs from entirely asymptomatic through a single acute decompensation to severe intellectual disability and spasticity - with no genotype-phenotype correlation, and 83% of reported alleles being one nonsense variant. This entry therefore models the enzymatic block and its metabolite consequences as established, and keeps the neurological outcomes on an explicitly provisional branch. Two published patients had their symptoms fully explained by a second disorder, sepiapterin reductase deficiency, whose gene sits 1.8 Mb away on 2p13.3 and was co-inherited through consanguinity - a confounder that has to be excluded before any neurological finding is attributed to MCEE at all.

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1
Inheritance
6
Pathophys.
13
Phenotypes
3
Gaps
25
Pathograph
1
Genes
4
Variants
3
Medical Actions
3
Differentials
11
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
organic acidurias branched chain amino acids
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Inheritance

1
Autosomal recessive inheritance with unresolved clinical penetrance HP:0000007
Patients are homozygous or compound heterozygous for MCEE variants, most ascertained through consanguineous unions. Biallelic variants establish the biochemical phenotype but do not predict clinical outcome: siblings sharing the same homozygous null allele have been reported with and without symptoms, and a published review of the whole case series found no genotype-phenotype relationship. Obligate heterozygote parents excrete normal amounts of methylmalonic acid, so the carrier state is biochemically silent.
Autosomal recessive inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (4 references)
PMID:16752391 SUPPORT Human Clinical
"Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA)."
Establishes recessive inheritance and a biochemically silent carrier state.
PMID:38034150 SUPPORT Human Clinical
"We found no association between genotype and biochemical and clinical phenotypes."
Supports variable expressivity by recording the absence of any genotype-phenotype correlation across the reported series.
PMID:30682498 SUPPORT Human Clinical
"Cardiomyopathy. Sibling with similar biochemical profile but no symptoms"
Documents a sibling pair concordant for the biochemical phenotype and discordant for symptoms, supporting incomplete clinical penetrance.
+ 1 more reference
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Discussions and Knowledge Gaps

3
Is MCEE deficiency a disease, or a biochemical trait that has been ascertained through disease?
CONTROVERSY OPEN controversy_mcee_clinical_significance
Attached to
pathophysiology#Acute Encephalopathy and Neurological Injury disease#Methylmalonyl-CoA Epimerase Deficiency
The biochemical phenotype is not in dispute: biallelic null alleles, reduced propionate incorporation, complementation to the MCEE group, and rescue by wild-type cDNA. What is disputed is whether the clinical findings reported alongside it are caused by it. The case against is specific rather than general - two patients' neurological disease was fully explained by a co-inherited SPR defect and reversed by neurotransmitter replacement; two others were asymptomatic; siblings homozygous for the same null allele are discordant for symptoms; and the largest review found no genotype-phenotype relationship. The case for rests on the acute decompensations, which are hard to attribute to anything else and which follow catabolic stress in the way an intoxication-type block predicts. The most defensible current reading is that the enzymatic block and the acute crises are real, and that the chronic neurological burden is unproven.
Show evidence (1 reference)
PMID:27699154 SUPPORT Human Clinical
"The clinical significance and biochemical characteristics of this rare condition have been incompletely defined."
States the unresolved clinical significance that this controversy is about.
How does p.Lys60Gln cause disease when its protein behaves like wild type in every assay applied to it?
KNOWLEDGE GAP OPEN gap_mcee_lys60gln_mechanism
Attached to
pathophysiology#Two Molecular Routes to Enzyme Loss genetic#MCEE
p.Lys60Gln was reported homozygous in a patient, but it maps onto the wild-type structure without an obvious defect, is predicted tolerated by both SIFT and PolyPhen2, and its recombinant protein matches wild type in soluble level, unfolding and activity. Either the assays miss the defect - an interaction with a partner enzyme, a tissue-specific effect, an expression-level change not captured by over-expression - or the variant is not the cause of that patient's phenotype. Nothing published resolves it.
Show evidence (1 reference)
PMID:30682498 SUPPORT In Vitro
"By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation may cause disease."
States the unresolved discrepancy directly.
What actually carries the residual flux past the missing epimerase, and how much does it vary between people?
KNOWLEDGE GAP OPEN gap_mcee_residual_flux_route
Attached to
pathophysiology#Partial Block of the Propionate-to-Succinate Pathway
Two bypasses have been proposed - spontaneous non-enzymatic racemisation of the CoA ester, and a shunt through free methylmalonic acid - and the siRNA experiment shows something substantial is carrying flux, but neither has been quantified in humans and no second enzyme has been identified. This matters beyond mechanism: if bypass capacity varies between individuals it is the most obvious candidate explanation for why the same homozygous null allele produces everything from no symptoms to severe disease, which is the question the controversy above turns on.
Show evidence (1 reference)
PMID:27699154 SUPPORT BACKGROUND Other
"In contrast, the physiological significance of the second enzymatic step, catalysed by methylmalonyl-coA epimerase (MCE; also known as methylmalonyl-coA racemase), has remained less clear."
Records that the physiological weight of this step, and hence of its bypasses, is unsettled.
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Pathophysiology

6
MCEE Loss of Function
Mechanism confidence: Established
Biallelic MCEE variants abolish or greatly reduce methylmalonyl-CoA epimerase activity. Its loss was the first inborn error assigned to this step of propionate catabolism, and its identification is what established that the step has a physiological role in humans at all.
MCEE hgnc:16732 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MCEE (hgnc:16732). hgnc:16732 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
methylmalonyl-CoA epimerase activity GO:0004493 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylmalonyl-CoA epimerase activity (GO:0004493). GO:0004493 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Two Molecular Routes to Enzyme Loss The reported alleles do not all fail in the same way; the truncating, misfolding and active-site classes are separable at protein level.
Partial Block of the Propionate-to-Succinate Pathway Loss of the epimerase removes the enzymatic route from D-methylmalonyl-CoA to the L-enantiomer that methylmalonyl-CoA mutase requires.
Show evidence (3 references)
PMID:16752391 SUPPORT Human Clinical
"We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X)."
The founding molecular observation establishing MCEE loss of function as the lesion.
PMID:16752391 SUPPORT Human Clinical
"This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism."
Records that the human physiological role of the enzyme was established by the deficiency itself.
PMID:17823972 SUPPORT In Vitro
"Infection with wild-type MCEE cDNA resulted in correction of the biochemical phenotype in cells from both patients."
Functional rescue by wild-type cDNA demonstrates the biochemical defect is caused by loss of MCEE and not a linked lesion.
Two Molecular Routes to Enzyme Loss
Mechanism confidence: Established
The dominant allele by far, c.139C>T (p.Arg47*), truncates the protein inside the first beta-sheet, so essentially no protein survives. The missense alleles fail differently. p.Ile53Arg sits at the dimer interface and yields almost no soluble protein in either a recombinant system or patient fibroblasts, i.e. it misfolds. p.Arg143Cys is expressed at close to wild-type levels but its crystal structure shows two displaced loops that frame the active-site pocket, and its activity is nearly gone. So the same enzyme deficiency is reached either by losing the protein or by keeping it and breaking the site.
methylmalonyl-CoA epimerase activity GO:0004493 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylmalonyl-CoA epimerase activity (GO:0004493). GO:0004493 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Partial Block of the Propionate-to-Succinate Pathway Either route converges on the same absent enzymatic activity.
Show evidence (3 references)
PMID:30682498 SUPPORT In Vitro
"Loss of almost the entire protein is therefore the likely cause of enzymatic dysfunction due to this variation, assuming there is residual mRNA following nonsense-mediated decay."
Gives the molecular consequence of the common truncating allele.
PMID:30682498 SUPPORT In Vitro
"Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with..."
Establishes misfolding with loss of soluble protein as the mechanism for p.Ile53Arg.
PMID:30682498 SUPPORT In Vitro
"MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity."
Establishes the contrasting class, where protein is present but catalytically defective.
Partial Block of the Propionate-to-Succinate Pathway
Mechanism confidence: Established
This is the node that makes the disorder what it is. D-methylmalonyl-CoA accumulates behind the missing enzyme and less L-methylmalonyl-CoA reaches methylmalonyl-CoA mutase, so flux into succinyl-CoA and the TCA cycle falls. But it falls only partly. The D-to-L conversion also happens non-enzymatically, and a second bypass runs through free methylmalonic acid, so a complete genetic null still leaves measurable pathway activity - siRNA knockdown of MCEE reduced propionate incorporation only slightly. A partial block is why this disorder is biochemically milder than a mutase defect despite sitting on the same pathway, and why its methylmalonate elevation is modest and intermittent rather than massive and constant.
propionate catabolic process GO:0019543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased propionate catabolic process (GO:0019543). GO:0019543 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Accumulation of Propionate-Pathway Metabolites Substrate backs up behind the block and is disposed of through the alternative routes that generate the characteristic organic acids.
Show evidence (4 references)
PMID:30682498 SUPPORT BACKGROUND Other
"Located at the centre of this pathway, methylmalonyl CoA epimerase (MCEE) catalyzes the epimerization of d-methylmalonyl-CoA, generated from propionyl-CoA by propionyl-CoA carboxylase (PCC), to form l-methylmalonyl-CoA, subsequently converted into succinyl-CoA by methylmalonyl-CoA mutase (MUT)..."
States the position of the blocked reaction between the two flanking enzymes and its destination in the TCA cycle.
PMID:16697227 SUPPORT In Vitro
"However, siRNA only led to a small reduction in pathway activity, suggesting that previously postulated non-enzymatic conversion of D- to L-methylmalonyl-CoA may contribute to some flux through the pathway."
The direct experimental basis for calling this a partial rather than a complete block.
PMID:16697227 SUPPORT Human Clinical
"We conclude that the patient's MCEE defect was responsible for the mild methylmalonic aciduria, confirming a partial requirement for the enzymatic activity in humans."
States the partial requirement for MCEE activity in humans, the claim this node encodes.
+ 1 more reference
Accumulation of Propionate-Pathway Metabolites
Mechanism confidence: Established
Because the block is partial and sits one step below propionyl-CoA carboxylase, the accumulating pool is weighted toward propionyl-CoA-derived metabolites rather than toward methylmalonate. 2-methylcitrate, 3-hydroxypropionate and C3 propionylcarnitine dominate the profile while methylmalonic acid is only mildly and sometimes intermittently raised. Homocysteine and vitamin B12 stay normal, which separates this from the combined cobalamin defects. The consequence is diagnostic rather than merely descriptive: the profile reads as propionic acidemia, and published patients were investigated as such.
Downstream
Acute Metabolic Decompensation under Catabolic Stress The accumulated pool is tolerated at baseline and becomes an acute intoxication when catabolic load rises.
Methylmalonic aciduria Persistent mild-to-moderate urinary methylmalonate excretion is the defining laboratory finding.
Elevated urinary 2-methylcitric acid 2-methylcitrate is formed from the propionyl-CoA that backs up behind the partial block.
Elevated urinary 3-hydroxypropionic acid 3-hydroxypropionate is the other principal propionyl-CoA overflow metabolite.
Elevated circulating propionylcarnitine Propionyl-CoA is esterified to carnitine, raising the C3 acylcarnitine measured on newborn screening.
Show evidence (3 references)
PMID:38034150 SUPPORT Human Clinical
"Common biochemical findings in MCE deficiency are raised urinary excretion of MMA, methylcitrate (MCA), 3-hydroxypropionate (3-HP), and elevation of blood propionylcarnitine (C3), with normal vitamin B12 and homocysteine levels"
Gives the full accumulating metabolite set together with the normal B12 and homocysteine that exclude the combined cobalamin disorders.
PMID:27699154 SUPPORT Human Clinical
"At presentation, organic acid profiles were dominated by increased ketones and 3-hydroxypropionate, with moderately elevated methylcitrate and propionylglycine, and acylcarnitine profiles showed marked C3 (propionylcarnitine) elevation with normal C4DC (methylmalonylcarnitine + succinylcarnitine)."
Documents that the propionyl-CoA-derived metabolites dominate over the methylmalonyl-CoA-derived ones.
PMID:29104221 SUPPORT Human Clinical
"MCE deficiency could be considered a cause of mild and intermittent increases in methylmalonic acid."
States the modest and intermittent character of the methylmalonate elevation, which follows from the block being partial.
Acute Metabolic Decompensation under Catabolic Stress
Mechanism confidence: Established
Intercurrent illness, fasting or a protein load raises the endogenous propionyl-CoA load beyond what the partially bypassed pathway can clear, and the compensated steady state fails. The result is a high-anion-gap metabolic acidosis with ketosis, sometimes with hypoglycaemia and mild hyperammonaemia. That these crises can be severe in a disorder whose baseline biochemistry is mild is the strongest argument that the enzyme deficiency is clinically real.
propionate catabolic process GO:0019543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased propionate catabolic process (GO:0019543). GO:0019543 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Metabolic acidosis High-anion-gap acidosis is the defining biochemical event of the crisis.
Hyperammonemia Propionyl-CoA accumulation secondarily inhibits ureagenesis, producing mild hyperammonaemia.
Hypoglycemia Reduced anaplerotic supply to the TCA cycle impairs the response to catabolic stress.
Vomiting Vomiting and dehydration are the usual presenting features of the crisis and worsen it.
Acute Encephalopathy and Neurological Injury Severe or repeated crises are the proposed route from the metabolic lesion to fixed neurological deficit; the link is plausible but unproven here.
Show evidence (3 references)
PMID:27699154 SUPPORT Human Clinical
"We now describe a patient who presented acutely at 5 years of age with vomiting, dehydration, confusion, severe metabolic acidosis and mild hyperammonemia."
Documents the acute decompensation syndrome in a molecularly confirmed patient.
PMID:30682498 SUPPORT Human Clinical
"Severe metabolic acidosis and hypoglycemia following gastroenteritis, elevated propionyl-carnitine"
Records a decompensation precipitated by a specific intercurrent illness.
PMID:29104221 SUPPORT Human Clinical
"The reported clinical pictures of isolated MCE are variable, with two asymptomatic patients and two other patients presenting with metabolic acidosis attacks."
Places acute acidotic attacks alongside complete absence of symptoms within one disorder.
Acute Encephalopathy and Neurological Injury
Mechanism confidence: Provisional
Several patients have fixed neurological deficits - intellectual disability, spasticity, ataxia, seizures - and in some the deficit followed a documented decompensation with coma. The node is deliberately marked provisional rather than established, for two specific reasons and not out of general caution. First, two of the published patients with progressive neurological disease also carried homozygous nonsense variants in SPR, 1.8 Mb away on 2p13.3, and their course was fully explained by sepiapterin reductase deficiency and reversed by neurotransmitter replacement. Second, the largest review found no relationship between genotype and clinical phenotype, and asymptomatic individuals carry the same homozygous null allele as the most severely affected. The metabolic-injury mechanism is borrowed from the better-characterised organic acidemias; it has not been demonstrated in this disorder.
Downstream
Seizure Seizures occur both acutely during decompensation and as a chronic feature.
Intellectual disability Fixed cognitive impairment is reported at the severe end of the spectrum.
Spasticity Spastic paraparesis and spasticity are recurrent findings in the reported series.
Hypotonia Hypotonia and delayed motor milestones are reported in early-presenting patients.
Show evidence (3 references)
PMID:38034150 SUPPORT Human Clinical
"When first seen in our country, aged 10 and four years, respectively, both presented severe intellectual disability and spasticity."
Documents the severe end of the neurological spectrum in molecularly confirmed patients.
PMID:30682498 REFUTE Human Clinical
"For two patients, coincidental variations in the SPR gene causing sepiapterin reductase deficiency sufficiently explained their clinical symptoms"
Directly contradicts attributing the neurological phenotype to MCEE deficiency in the patients where it was most prominent, and is the reason this node is provisional.
PMID:25763508 REFUTE Human Clinical
"A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD."
Shows the neurological syndrome in a dually affected patient responded to neurotransmitter replacement, attributing it to sepiapterin reductase deficiency rather than to MCEE.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Methylmalonyl-CoA Epimerase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Cardiovascular 1
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30682498 SUPPORT Human Clinical
"Cardiomyopathy. Sibling with similar biochemical profile but no symptoms"
The single reported instance, together with the discordant sibling.
Digestive 1
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27699154 SUPPORT Human Clinical
"she presented acutely with vomiting, dehydration, confusion and visual hallucination"
Documents vomiting as a presenting feature.
Genitourinary 3
Methylmalonic aciduria HP:0012120 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Methylmalonic aciduria (HP:0012120). HP:0012120 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16752391 SUPPORT Human Clinical
"Here we present a 16-year-old female patient with persisting moderate MMA-uria (approximately 50 mmol/mol creatinine)."
Quantifies the persistent moderate methylmalonic aciduria in the index patient.
PMID:39051409 SUPPORT Human Clinical
"Increased MMA levels may be negligible at NBS as they may reach relevant values beyond the first days of life and thus could be identified only in confirmatory analyses."
Establishes that the defining analyte can be normal at newborn screening, so its absence early does not exclude the diagnosis.
Elevated urinary 2-methylcitric acid Elevated urine 2-methylcitric acid level HP:0034662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urine 2-methylcitric acid level (HP:0034662). HP:0034662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38034150 SUPPORT Human Clinical
"Common biochemical findings in MCE deficiency are raised urinary excretion of MMA, methylcitrate (MCA), 3-hydroxypropionate (3-HP), and elevation of blood propionylcarnitine (C3), with normal vitamin B12 and homocysteine levels"
Records raised urinary methylcitrate as a common finding.
Elevated urinary 3-hydroxypropionic acid Elevated urine 3-hydroxypropionic acid level HP:0034661 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urine 3-hydroxypropionic acid level (HP:0034661). HP:0034661 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27699154 SUPPORT Human Clinical
"organic acid profiles were dominated by increased ketones and 3-hydroxypropionate"
Documents 3-hydroxypropionate dominating the organic acid profile at presentation.
Metabolism 4
Elevated circulating propionylcarnitine Elevated circulating propionylcarnitine concentration HP:0033443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating propionylcarnitine concentration (HP:0033443). HP:0033443 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39051409 SUPPORT Human Clinical
"The NBS results showed increased levels of propionylcarnitine (C3) and 2-methylcitric acid (MCA), while methylmalonic acid (MMA) and homocysteine (Hcy) were within the reference limits."
Documents the C3 elevation on newborn screening in a molecularly confirmed patient.
PMID:31146325 SUPPORT Human Clinical
"Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin."
Documents persistent propionylcarnitine elevation, and its failure to respond to cobalamin, in an adult patient.
Metabolic acidosis HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942), qualified as temporality recurrent. HP:0001942 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:27699154 SUPPORT Human Clinical
"There was severe metabolic acidosis with increased anion gap"
Documents severe anion-gap acidosis during an acute presentation.
PMID:20301409 SUPPORT Human Clinical
"Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis."
GeneReviews states the clinical range of the epimerase-deficient form, from asymptomatic to severe acidosis.
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27699154 SUPPORT Human Clinical
"severe metabolic acidosis and mild hyperammonemia"
Documents mild hyperammonaemia during acute decompensation.
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:30682498 SUPPORT Human Clinical
"Severe metabolic acidosis and hypoglycemia following gastroenteritis, elevated propionyl-carnitine"
Documents hypoglycaemia in a molecularly confirmed patient during decompensation.
Musculoskeletal 2
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30682498 SUPPORT Human Clinical
"Slow motor development, hypotonia (inability to walk independently), spasticity of legs, eczema, episode of vomiting and diarrhea"
Reports spasticity of the legs in a molecularly confirmed MCEE-deficient patient.
Hypotonia 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:30682498 SUPPORT Human Clinical
"Slow motor development, hypotonia (inability to walk independently), spasticity of legs, eczema, episode of vomiting and diarrhea"
Documents hypotonia with delayed motor development.
Nervous System 2
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:30682498 SUPPORT Human Clinical
"Sepsis, psychomotor retardation, seizures, elevated C3-acylcarnitine, methyl-citrate in urine"
Documents seizures in a molecularly confirmed patient.
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:38034150 SUPPORT Human Clinical
"both presented severe intellectual disability and spasticity"
Documents severe intellectual disability in two molecularly confirmed siblings.
🧬

Genetic Associations

1
MCEE
Gene: MCEE hgnc:16732 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MCEE (hgnc:16732). hgnc:16732 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:38034150 SUPPORT Human Clinical
"Most patients were homozygous for that variant (83% of the alleles)."
Quantifies the dominance of the p.Arg47* allele in the reported series.
PMID:30682498 SUPPORT Human Clinical
"This remains by far the most common pathogenic variation identified in MCEE deficiency, with 16 out of 21 patients homozygous for this allele."
Independent quantification of the same allelic skew.
PMID:25763508 SUPPORT Human Clinical
"We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR)."
Establishes the physical proximity of MCEE and SPR and the co-inheritance that confounds phenotype attribution.
Variants (4)
c.139C>T (p.Arg47*)
The recurrent nonsense allele, truncating the protein within the first beta-sheet so that essentially no product survives nonsense-mediated decay. It accounts for the large majority of reported disease alleles.
Show evidence (1 reference)
PMID:30682498 SUPPORT In Vitro
"Loss of almost the entire protein is therefore the likely cause of enzymatic dysfunction due to this variation, assuming there is residual mRNA following nonsense-mediated decay."
States the functional consequence of the recurrent allele.
c.158T>G (p.Ile53Arg)
A misfolding missense allele at the dimer interface, absent from ExAC, yielding almost no soluble protein and no measurable activity.
Show evidence (1 reference)
PMID:30682498 SUPPORT In Vitro
"However, hMCEE containing p.Ile53Arg had very low levels of detectable protein (6 ± 1% of wt), similar to empty vector (4 ± 2% of wt)"
Quantifies the loss of soluble protein that defines this allele's mechanism.
c.427C>T (p.Arg143Cys)
An expressed but catalytically defective allele; the crystal structure of the variant protein shows displacement of two loops framing the active site. Reported only in the heterozygous state without an identified second allele, so its clinical role is not settled.
Show evidence (1 reference)
PMID:30682498 SUPPORT In Vitro
"We solved the structure of MCEE-Arg143Cys to 1.9 Å and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket."
Gives the structural basis for loss of activity in an allele that is normally expressed.
c.379-644A>G
A deep-intronic splicing variant found in trans with p.Arg47*, identified only by RNA study after exon sequencing found a single heterozygous allele. It is the reason a heterozygous-looking exome result does not exclude the diagnosis.
Show evidence (1 reference)
PMID:27699154 SUPPORT Human Clinical
"A heterozygous p.Arg47Ter (p.R47*) mutation in the MCEE gene was identified by sequencing of exons, and RNA studies identified a novel intronic splicing mutation, c.379-644A > G, confirming the diagnosis of MCE deficiency."
Documents the deep-intronic allele and the RNA study needed to find it.
💊

Medical Actions

3
Emergency management of acute metabolic decompensation
Action: metabolic emergency managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is metabolic emergency management, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Reversal of catabolism with intravenous glucose, correction of acidosis and dehydration, and temporary withdrawal of natural protein, as for the other intoxication-type organic acidemias. The published crises resolved with supportive metabolic management.
Mechanism Target:
Acute Metabolic Decompensation under Catabolic Stress — Reversing catabolism removes the propionyl-CoA load that precipitated the crisis.
Show evidence (1 reference)
PMID:20301409 SUPPORT Human Clinical
"When isolated MMA is suspected during the diagnostic evaluation due to elevated propionylcarnitine (C3) on a newborn blood spot, metabolic treatment should be initiated immediately, while the suspected diagnosis is being confirmed."
GeneReviews directs immediate metabolic treatment on suspicion, which is the management this treatment describes.
Natural protein restriction
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
Restriction of propiogenic amino acid precursors is the standard chronic management of isolated methylmalonic acidemia. Its necessity in MCEE deficiency specifically is unsettled: the best-documented patient with a severe initial crisis has remained well for six years on an essentially normal diet.
Mechanism Target:
Accumulation of Propionate-Pathway Metabolites — Reducing precursor intake lowers the propionyl-CoA flux arriving at the partial block.
Show evidence (1 reference)
PMID:20301409 SUPPORT Human Clinical
"restrict natural protein, particularly of propiogenic amino acid precursors, while maintaining a high-calorie diet"
States the dietary principle and its rationale in the isolated methylmalonic acidemias.
Show evidence (1 reference)
PMID:27699154 REFUTE Human Clinical
"Following the initial severe presentation, development has been normal and the clinical course over the subsequent six years has remained relatively uneventful on an essentially normal diet."
Contradicts a requirement for protein restriction in this disorder, in the patient with the best-documented long-term follow-up.
Hydroxocobalamin trial
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: hydroxocobalamin CHEBI:27786 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxocobalamin (CHEBI:27786). CHEBI:27786 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Cobalamin supplementation is standard practice in isolated methylmalonic acidemia because the cblA and cblB forms respond to it. MCEE deficiency does not: the enzyme is not cobalamin-dependent, and both the index patient and an adult patient on high-dose hydroxocobalamin failed to respond. A trial is still reasonable as part of the diagnostic work-up, but is recorded here as a treatment that does not work.
Show evidence (2 references)
PMID:16752391 REFUTE Human Clinical
"Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established."
Records the absence of a cobalamin response in the index patient.
PMID:31146325 REFUTE Human Clinical
"Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin."
Independent confirmation that high-dose hydroxocobalamin does not correct the biochemical phenotype.
🔬

Diagnosis

4
Urine organic acid analysis
The entry point. The profile shows methylmalonate that is mildly and sometimes intermittently raised, alongside more prominent 2-methylcitrate and 3-hydroxypropionate. Because the propionyl-CoA-derived acids dominate, the pattern reads as propionic acidemia and has led to that working diagnosis.
urine organic acid analysis
Results: Mild persistent methylmalonic aciduria with 2-methylcitrate, 3-hydroxypropionate and ketosis; normal homocysteine.
Show evidence (1 reference)
PMID:29104221 SUPPORT Human Clinical
"Metabolic investigations were consistent with propionic aciduria (PA). Unexpectedly, propionyl-CoA carboxylase activity was within the reference range."
Documents the diagnostic confusion the organic acid profile causes, and how it was resolved.
Newborn screening acylcarnitine profile
There is no dedicated screen for this disorder; it is picked up incidentally on the C3 propionylcarnitine marker used for propionic acidemia and mutase deficiency. The first screening-detected case showed raised C3 and 2-methylcitrate with methylmalonate and homocysteine still in range, which is a pattern worth recognising because the defining analyte is the one that is normal.
newborn screening
Results: Elevated C3 with slightly raised 2-methylcitrate; methylmalonate and homocysteine within reference limits.
Show evidence (2 references)
PMID:39051409 SUPPORT Human Clinical
"Elevated concentrations of C3 with a slight increase in MCA and normal MMA and Hcy during NBS should prompt the consideration of MCEE deficiency in differential diagnosis."
States the screening pattern that should raise the diagnosis.
PMID:39051409 SUPPORT Human Clinical
"A dedicated test for MCEE deficiency is not included in the newborn screening (NBS) panels but it can be incidentally identified when investigating methylmalonic acidemia and propionic acidemia."
Establishes that ascertainment is incidental to screening for the flanking enzyme defects.
MCEE molecular genetic testing
Sequencing MCEE, usually within a methylmalonic-pathway gene panel, is the practical confirmatory test and the one GeneReviews treats as establishing the diagnosis. Exon sequencing alone is not always sufficient: one patient was heterozygous on exon sequencing and required RNA study to find a deep intronic second allele.
molecular genetic testing
Results: Biallelic MCEE variants, most often homozygous c.139C>T (p.Arg47*).
Show evidence (2 references)
PMID:20301409 SUPPORT Human Clinical
"The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT"
GeneReviews states molecular testing as the diagnostic standard, with MCEE among the genes.
PMID:38034150 SUPPORT Human Clinical
"Patients present with overlapping clinical features with predominant neurological manifestations; genetic testing is indispensable for diagnosis."
States that the clinical and biochemical picture does not distinguish the disorder, so genetic testing is required.
Fibroblast propionate incorporation and complementation analysis
Cultured fibroblasts show moderately reduced incorporation of labelled propionate that is not corrected by hydroxocobalamin. Complementation analysis assigns the defect to the MCEE group and distinguishes it from mut, cblA and cblB. Available in specialist laboratories only, and now largely superseded by sequencing.
enzyme activity assay
Results: Moderately reduced propionate incorporation, no cobalamin response, complementation assigns to MCEE.
Show evidence (1 reference)
PMID:17823972 SUPPORT In Vitro
"the defect in these fibroblasts was complemented by mut, cblA, and cblB fibroblasts"
Establishes complementation analysis as the assay that assigns the defect to MCEE and separates it from the mutase and cobalamin groups.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population rate has been estimated and the disorder is not screened for directly. Published case counts are the only available measure: eleven cases were on record before the 2019 cohort screen added ten, and a 2023 review counted at least twenty-four including its own two patients.
Show evidence (2 references)
PMID:38034150 SUPPORT Human Clinical
"Including our two novel patients, at least 24 cases of MCE deficiency have been described, with a broad clinical spectrum ranging from asymptomatic to severely neurologically impaired patients."
Gives the published case count and the breadth of the clinical spectrum.
PMID:30682498 SUPPORT Human Clinical
"We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE."
Quantifies the yield of MCEE variants among unexplained methylmalonic aciduria, the only systematic ascertainment published.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Methylmalonyl-CoA Epimerase Deficiency:

Propionic acidemia
Overlapping Features The closest mimic and the one that has repeatedly been diagnosed first, because 2-methylcitrate, 3-hydroxypropionate and C3 dominate the profile while methylmalonate is only mildly raised. Normal propionyl-CoA carboxylase activity is what separates them.
Show evidence (1 reference)
PMID:29104221 SUPPORT Human Clinical
"We report isolated MCE deficiency in a boy who presented at five years of age with acute metabolic acidosis. Metabolic investigations were consistent with propionic aciduria (PA)."
A worked instance of the disorder being investigated as propionic aciduria.
Methylmalonyl-CoA mutase deficiency and the cblA/cblB cobalamin disorders
Overlapping Features The other isolated methylmalonic acidemias. They produce a far larger methylmalonate elevation, and the cobalamin defects respond at least partially to hydroxocobalamin, which MCEE deficiency does not. One patient was assigned to the cblA complementation group for years before MCEE sequencing corrected it.
Show evidence (1 reference)
PMID:16697227 SUPPORT Human Clinical
"A patient, formerly identified as belonging to the cblA complementation group of vitamin B12 disorders but lacking mutations in the affected gene, MMAA, was tested for mutations in the MCEE gene."
Documents a patient misassigned to cblA before MCEE was identified.
Sepiapterin reductase deficiency
Overlapping Features Not a biochemical mimic but a co-inheritance trap. SPR lies 1.8 Mb from MCEE on 2p13.3, and in consanguineous families homozygous null alleles in both have segregated together. Because sepiapterin reductase deficiency is a treatable neurotransmitter disorder, a patient with MCEE deficiency and progressive neurological disease needs it excluded before the neurology is attributed to the epimerase defect.
Show evidence (1 reference)
PMID:25763508 SUPPORT Human Clinical
"Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*."
Documents the co-inherited second disorder that explained the neurological course.
{ }

Source YAML

click to show 
name: Methylmalonyl-CoA Epimerase Deficiency
creation_date: '2026-09-22T00:00:00Z'
category: Mendelian
synonyms:
- MCEE deficiency
- MCE deficiency
- Methylmalonyl-CoA racemase deficiency
- Methylmalonic aciduria due to methylmalonyl-CoA epimerase deficiency
- Atypical methylmalonic aciduria
description: >-
  Methylmalonyl-CoA epimerase (MCEE) deficiency is an ultra-rare autosomal
  recessive defect of the propionate catabolic pathway. MCEE occupies the middle
  of three consecutive steps that carry propionyl-CoA into the TCA cycle:
  propionyl-CoA carboxylase makes D-methylmalonyl-CoA, MCEE epimerises it to the
  L-enantiomer, and methylmalonyl-CoA mutase converts that to succinyl-CoA.
  Deficiencies of the first and third steps are the well-characterised diseases
  propionic acidemia and isolated methylmalonic acidemia. The middle step is the
  one whose physiological importance was unclear until 2006, and whose clinical
  importance is still argued over.

  The reason is structural rather than evidential. The epimerisation MCEE
  catalyses can also proceed non-enzymatically, and a shunt through free
  methylmalonic acid provides a second bypass, so losing the enzyme produces a
  partial rather than a complete block. Knocking MCEE down by siRNA reduces
  pathway flux only slightly. That single fact explains the shape of the whole
  disorder: a persistent but mild-to-moderate methylmalonic aciduria, a
  biochemical profile dominated by 2-methylcitrate, 3-hydroxypropionate and C3
  propionylcarnitine rather than by methylmalonate, and a clinical spectrum that
  runs from entirely asymptomatic through a single acute decompensation to
  severe intellectual disability and spasticity - with no genotype-phenotype
  correlation, and 83% of reported alleles being one nonsense variant.

  This entry therefore models the enzymatic block and its metabolite
  consequences as established, and keeps the neurological outcomes on an
  explicitly provisional branch. Two published patients had their symptoms fully
  explained by a second disorder, sepiapterin reductase deficiency, whose gene
  sits 1.8 Mb away on 2p13.3 and was co-inherited through consanguinity - a
  confounder that has to be excluded before any neurological finding is
  attributed to MCEE at all.
classifications:
  icimd_category:
  - classification_value: organic_acidurias
    notes: >-
      MONDO places this disorder under methylmalonic acidemia, and the
      presenting abnormality is an organic aciduria on urine organic-acid
      analysis.
    evidence:
    - reference: PMID:38034150
      reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isolated methylmalonic aciduria (MMAuria) encompasses a group of
        autosomal recessive propionate degradation disorders resulting in
        methylmalonic acid (MMA) accumulation in body fluids.
      explanation: Places the disorder within the isolated methylmalonic acidurias, a group of organic acidurias.
  - classification_value: branched_chain_amino_acids
    notes: >-
      The blocked step is the common terminal route for the propiogenic amino
      acids valine, isoleucine, methionine and threonine, so the disorder is
      also a branched-chain amino acid catabolic defect.
    evidence:
    - reference: PMID:38034150
      reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Methylmalonyl coenzyme A (CoA) epimerase (MCE) converts
        D-methylmalonyl-CoA into L-methylmalonyl CoA in the final common
        degradation pathway of valine, isoleucine, methionine, threonine,
        odd-chain fatty acids, and cholesterol side chains.
      explanation: Names the branched-chain and other amino acid pathways that converge on the blocked step.
disease_term:
  preferred_term: methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
  term:
    id: MONDO:0009615
    label: methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
parents:
- Organic Aciduria
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance with unresolved clinical penetrance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Patients are homozygous or compound heterozygous for MCEE variants, most
    ascertained through consanguineous unions. Biallelic variants establish the
    biochemical phenotype but do not predict clinical outcome: siblings sharing
    the same homozygous null allele have been reported with and without
    symptoms, and a published review of the whole case series found no
    genotype-phenotype relationship. Obligate heterozygote parents excrete
    normal amounts of methylmalonic acid, so the carrier state is biochemically
    silent.
  evidence:
  - reference: PMID:16752391
    reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both parents were heterozygous for this mutation; they were found to
      excrete normal amounts of methylmalonic acid (MMA).
    explanation: Establishes recessive inheritance and a biochemically silent carrier state.
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found no association between genotype and biochemical and clinical phenotypes.
    explanation: Supports variable expressivity by recording the absence of any genotype-phenotype correlation across the reported series.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiomyopathy. Sibling with similar biochemical profile but no symptoms
    explanation: Documents a sibling pair concordant for the biochemical phenotype and discordant for symptoms, supporting incomplete clinical penetrance.
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If both parents are known to be heterozygous for an isolated
      MMA-causing pathogenic variant, each sib of an affected individual has at
      conception a 25% chance of being affected, a 50% chance of being an asymptomatic
      carrier, and a 25% chance of inheriting neither of the familial pathogenic
      variants.
    explanation: >-
      GeneReviews genetic-counseling recurrence risk for isolated MMA, which
      includes MCEE deficiency: 25% affected, 50% carrier per sib.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population rate has been estimated and the disorder is not screened for
    directly. Published case counts are the only available measure: eleven cases
    were on record before the 2019 cohort screen added ten, and a 2023 review
    counted at least twenty-four including its own two patients.
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Including our two novel patients, at least 24 cases of MCE deficiency have
      been described, with a broad clinical spectrum ranging from asymptomatic
      to severely neurologically impaired patients.
    explanation: Gives the published case count and the breadth of the clinical spectrum.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated a cohort of 150 individuals suffering from MMAuria of
      unknown origin, identifying ten new patients with pathogenic variations in
      MCEE.
    explanation: Quantifies the yield of MCEE variants among unexplained methylmalonic aciduria, the only systematic ascertainment published.
pathophysiology:
- name: MCEE Loss of Function
  conforms_to: metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic MCEE variants abolish or greatly reduce methylmalonyl-CoA
    epimerase activity. Its loss was the first inborn error assigned to this
    step of propionate catabolism, and its identification is what established
    that the step has a physiological role in humans at all.
  genes:
  - preferred_term: MCEE
    term:
      id: hgnc:16732
      label: MCEE
  molecular_functions:
  - preferred_term: methylmalonyl-CoA epimerase activity
    term:
      id: GO:0004493
      label: methylmalonyl-CoA epimerase activity
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:16752391
    reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a homozygous nonsense mutation (c.139C>T) in the
      methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating
      signal (p.R47X).
    explanation: The founding molecular observation establishing MCEE loss of function as the lesion.
  - reference: PMID:16752391
    reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first report of methylmalonyl-CoA epimerase deficiency,
      thereby unequivocally demonstrating the biochemical role of this enzyme in
      human metabolism.
    explanation: Records that the human physiological role of the enzyme was established by the deficiency itself.
  - reference: PMID:17823972
    reference_title: "Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Infection with wild-type MCEE cDNA resulted in correction of the
      biochemical phenotype in cells from both patients.
    explanation: Functional rescue by wild-type cDNA demonstrates the biochemical defect is caused by loss of MCEE and not a linked lesion.
  downstream:
  - target: Two Molecular Routes to Enzyme Loss
    description: >-
      The reported alleles do not all fail in the same way; the truncating,
      misfolding and active-site classes are separable at protein level.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These studies reveal ten new patients with MCEE deficiency and
        rationalize misfolding and loss of activity as molecular defects in
        MCEE-type MMAuria.
      explanation: States the two mechanistic classes by which reported MCEE alleles abolish function.
  - target: Partial Block of the Propionate-to-Succinate Pathway
    description: >-
      Loss of the epimerase removes the enzymatic route from
      D-methylmalonyl-CoA to the L-enantiomer that methylmalonyl-CoA mutase
      requires.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16752391
      reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Reduced incorporation of 14C-propionate into macromolecules suggested a
        defect in the propionate-to-succinate pathway.
      explanation: Links the MCEE lesion to measurably reduced flux through the propionate catabolic pathway.
- name: Two Molecular Routes to Enzyme Loss
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The dominant allele by far, c.139C>T (p.Arg47*), truncates the protein
    inside the first beta-sheet, so essentially no protein survives. The
    missense alleles fail differently. p.Ile53Arg sits at the dimer interface
    and yields almost no soluble protein in either a recombinant system or
    patient fibroblasts, i.e. it misfolds. p.Arg143Cys is expressed at close to
    wild-type levels but its crystal structure shows two displaced loops that
    frame the active-site pocket, and its activity is nearly gone. So the same
    enzyme deficiency is reached either by losing the protein or by keeping it
    and breaking the site.
  molecular_functions:
  - preferred_term: methylmalonyl-CoA epimerase activity
    term:
      id: GO:0004493
      label: methylmalonyl-CoA epimerase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Loss of almost the entire protein is therefore the likely cause of
      enzymatic dysfunction due to this variation, assuming there is residual
      mRNA following nonsense-mediated decay.
    explanation: Gives the molecular consequence of the common truncating allele.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant
      system as well as patient-derived fibroblasts revealed nearly undetectable
      soluble protein levels, defective globular protein behavior, and using a
      newly developed assay, lack of enzymatic activity - consistent with
      misfolded protein.
    explanation: Establishes misfolding with loss of soluble protein as the mechanism for p.Ile53Arg.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had
      slightly altered unfolding kinetics and greatly reduced activity.
    explanation: Establishes the contrasting class, where protein is present but catalytically defective.
  downstream:
  - target: Partial Block of the Propionate-to-Succinate Pathway
    description: Either route converges on the same absent enzymatic activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This is consistent with an inability to convert d-methylmalonyl-CoA to
        l-methylmalonyl-CoA due to a lack of correctly folded protein, as was
        demonstrated by Western blot analysis.
      explanation: Connects the protein-level defect to failure of the epimerisation reaction itself.
- name: Partial Block of the Propionate-to-Succinate Pathway
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    This is the node that makes the disorder what it is. D-methylmalonyl-CoA
    accumulates behind the missing enzyme and less L-methylmalonyl-CoA reaches
    methylmalonyl-CoA mutase, so flux into succinyl-CoA and the TCA cycle falls.
    But it falls only partly. The D-to-L conversion also happens
    non-enzymatically, and a second bypass runs through free methylmalonic acid,
    so a complete genetic null still leaves measurable pathway activity - siRNA
    knockdown of MCEE reduced propionate incorporation only slightly. A partial
    block is why this disorder is biochemically milder than a mutase defect
    despite sitting on the same pathway, and why its methylmalonate elevation is
    modest and intermittent rather than massive and constant.
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: (R)-methylmalonyl-CoA
    term:
      id: CHEBI:15465
      label: (R)-methylmalonyl-CoA
    modifier: INCREASED
  - preferred_term: (S)-methylmalonyl-CoA
    term:
      id: CHEBI:15466
      label: (S)-methylmalonyl-CoA
    modifier: DECREASED
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Located at the centre of this pathway, methylmalonyl CoA epimerase (MCEE)
      catalyzes the epimerization of d-methylmalonyl-CoA, generated from
      propionyl-CoA by propionyl-CoA carboxylase (PCC), to form
      l-methylmalonyl-CoA, subsequently converted into succinyl-CoA by
      methylmalonyl-CoA mutase (MUT) for entry into the TCA cycle.
    explanation: States the position of the blocked reaction between the two flanking enzymes and its destination in the TCA cycle.
  - reference: PMID:16697227
    reference_title: "Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, siRNA only led to a small reduction in pathway activity,
      suggesting that previously postulated non-enzymatic conversion of D- to
      L-methylmalonyl-CoA may contribute to some flux through the pathway.
    explanation: The direct experimental basis for calling this a partial rather than a complete block.
  - reference: PMID:16697227
    reference_title: "Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that the patient's MCEE defect was responsible for the mild
      methylmalonic aciduria, confirming a partial requirement for the enzymatic
      activity in humans.
    explanation: States the partial requirement for MCEE activity in humans, the claim this node encodes.
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      There is evidence that this reaction may be partially bypassed in vivo, by
      a shunt pathway proceeding via free methylmalonic acid
    explanation: Names the second bypass route that keeps the block partial.
  downstream:
  - target: Accumulation of Propionate-Pathway Metabolites
    description: >-
      Substrate backs up behind the block and is disposed of through the
      alternative routes that generate the characteristic organic acids.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38034150
      reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Methylmalonyl-CoA epimerase deficiency is an ultra-rare autosomal
        recessive disorder where methylmalonic acid, methylcitrate,
        3-hydroxypropionate, and propionylcarnitine are accumulated.
      explanation: Names the metabolites that accumulate downstream of the block.
- name: Accumulation of Propionate-Pathway Metabolites
  conforms_to: metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Because the block is partial and sits one step below propionyl-CoA
    carboxylase, the accumulating pool is weighted toward propionyl-CoA-derived
    metabolites rather than toward methylmalonate. 2-methylcitrate,
    3-hydroxypropionate and C3 propionylcarnitine dominate the profile while
    methylmalonic acid is only mildly and sometimes intermittently raised.
    Homocysteine and vitamin B12 stay normal, which separates this from the
    combined cobalamin defects. The consequence is diagnostic rather than merely
    descriptive: the profile reads as propionic acidemia, and published patients
    were investigated as such.
  chemical_entities:
  - preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
    modifier: INCREASED
  - preferred_term: 2-methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
    modifier: INCREASED
  - preferred_term: 3-hydroxypropionic acid
    term:
      id: CHEBI:33404
      label: 3-hydroxypropionic acid
    modifier: INCREASED
  - preferred_term: propionylcarnitine
    term:
      id: CHEBI:53210
      label: O-propanoyl-L-carnitine
    modifier: INCREASED
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical findings in MCE deficiency are raised urinary excretion
      of MMA, methylcitrate (MCA), 3-hydroxypropionate (3-HP), and elevation of
      blood propionylcarnitine (C3), with normal vitamin B12 and homocysteine
      levels
    explanation: Gives the full accumulating metabolite set together with the normal B12 and homocysteine that exclude the combined cobalamin disorders.
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At presentation, organic acid profiles were dominated by increased ketones
      and 3-hydroxypropionate, with moderately elevated methylcitrate and
      propionylglycine, and acylcarnitine profiles showed marked C3
      (propionylcarnitine) elevation with normal C4DC (methylmalonylcarnitine +
      succinylcarnitine).
    explanation: Documents that the propionyl-CoA-derived metabolites dominate over the methylmalonyl-CoA-derived ones.
  - reference: PMID:29104221
    reference_title: Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MCE deficiency could be considered a cause of mild and intermittent increases in methylmalonic acid.
    explanation: States the modest and intermittent character of the methylmalonate elevation, which follows from the block being partial.
  downstream:
  - target: Acute Metabolic Decompensation under Catabolic Stress
    description: >-
      The accumulated pool is tolerated at baseline and becomes an acute
      intoxication when catabolic load rises.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39051409
      reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Disease onset ranged from 1 month to 2.5 years of age; at least three
        patients presented symptoms following an intercurrent illness.
      explanation: Ties symptomatic presentation to intercurrent catabolic stress rather than to the baseline metabolite burden.
  - target: Methylmalonic aciduria
    description: Persistent mild-to-moderate urinary methylmalonate excretion is the defining laboratory finding.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16752391
      reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we present a 16-year-old female patient with persisting moderate
        MMA-uria (approximately 50 mmol/mol creatinine).
      explanation: Quantifies the persistent methylmalonic aciduria in the index patient.
  - target: Elevated urinary 2-methylcitric acid
    description: 2-methylcitrate is formed from the propionyl-CoA that backs up behind the partial block.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39051409
      reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Confirmatory analyses revealed altered levels of metabolites, including
        MCA and MMA, suggesting a block in the propionate degradation pathway.
      explanation: Records 2-methylcitrate elevation as a readout of the pathway block.
  - target: Elevated urinary 3-hydroxypropionic acid
    description: 3-hydroxypropionate is the other principal propionyl-CoA overflow metabolite.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27699154
      reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: organic acid profiles were dominated by increased ketones and 3-hydroxypropionate
      explanation: Documents 3-hydroxypropionate as a dominant organic acid at presentation.
  - target: Elevated circulating propionylcarnitine
    description: Propionyl-CoA is esterified to carnitine, raising the C3 acylcarnitine measured on newborn screening.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39051409
      reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The NBS results showed increased levels of propionylcarnitine (C3) and
        2-methylcitric acid (MCA), while methylmalonic acid (MMA) and
        homocysteine (Hcy) were within the reference limits.
      explanation: Documents the C3 elevation and the normal MMA that make this disorder look like propionic acidemia on screening.
- name: Acute Metabolic Decompensation under Catabolic Stress
  conforms_to: metabolic_intoxication_decompensation#Acute Metabolic Decompensation
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Intercurrent illness, fasting or a protein load raises the endogenous
    propionyl-CoA load beyond what the partially bypassed pathway can clear, and
    the compensated steady state fails. The result is a high-anion-gap metabolic
    acidosis with ketosis, sometimes with hypoglycaemia and mild hyperammonaemia.
    That these crises can be severe in a disorder whose baseline biochemistry is
    mild is the strongest argument that the enzyme deficiency is clinically real.
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now describe a patient who presented acutely at 5 years of age with
      vomiting, dehydration, confusion, severe metabolic acidosis and mild
      hyperammonemia.
    explanation: Documents the acute decompensation syndrome in a molecularly confirmed patient.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Severe metabolic acidosis and hypoglycemia following gastroenteritis, elevated propionyl-carnitine
    explanation: Records a decompensation precipitated by a specific intercurrent illness.
  - reference: PMID:29104221
    reference_title: Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The reported clinical pictures of isolated MCE are variable, with two
      asymptomatic patients and two other patients presenting with metabolic
      acidosis attacks.
    explanation: Places acute acidotic attacks alongside complete absence of symptoms within one disorder.
  downstream:
  - target: Metabolic acidosis
    description: High-anion-gap acidosis is the defining biochemical event of the crisis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27699154
      reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: There was severe metabolic acidosis with increased anion gap
      explanation: Documents the anion-gap acidosis during decompensation.
  - target: Hyperammonemia
    description: Propionyl-CoA accumulation secondarily inhibits ureagenesis, producing mild hyperammonaemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27699154
      reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: severe metabolic acidosis and mild hyperammonemia
      explanation: Records hyperammonaemia accompanying the acidotic crisis.
  - target: Hypoglycemia
    description: Reduced anaplerotic supply to the TCA cycle impairs the response to catabolic stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Seizures and hypoglycemia following viral infection, elevated proionyl-carnitine
      explanation: Documents hypoglycaemia during an infection-triggered decompensation.
  - target: Vomiting
    description: Vomiting and dehydration are the usual presenting features of the crisis and worsen it.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27699154
      reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: she presented acutely with vomiting, dehydration, confusion and visual hallucination
      explanation: Documents the presenting symptoms of acute decompensation.
  - target: Acute Encephalopathy and Neurological Injury
    description: >-
      Severe or repeated crises are the proposed route from the metabolic lesion
      to fixed neurological deficit; the link is plausible but unproven here.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38034150
      reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our patients are siblings of Arabic origin who presented with metabolic
        decompensation with coma and epilepsy during infancy.
      explanation: Documents decompensation with coma preceding the neurological outcome in two patients.
- name: Acute Encephalopathy and Neurological Injury
  conforms_to: metabolic_intoxication_decompensation#Acute Metabolic Encephalopathy
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Several patients have fixed neurological deficits - intellectual disability,
    spasticity, ataxia, seizures - and in some the deficit followed a documented
    decompensation with coma. The node is deliberately marked provisional rather
    than established, for two specific reasons and not out of general caution.
    First, two of the published patients with progressive neurological disease
    also carried homozygous nonsense variants in SPR, 1.8 Mb away on 2p13.3, and
    their course was fully explained by sepiapterin reductase deficiency and
    reversed by neurotransmitter replacement. Second, the largest review found no
    relationship between genotype and clinical phenotype, and asymptomatic
    individuals carry the same homozygous null allele as the most severely
    affected. The metabolic-injury mechanism is borrowed from the
    better-characterised organic acidemias; it has not been demonstrated in this
    disorder.
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When first seen in our country, aged 10 and four years, respectively, both
      presented severe intellectual disability and spasticity.
    explanation: Documents the severe end of the neurological spectrum in molecularly confirmed patients.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For two patients, coincidental variations in the SPR gene causing
      sepiapterin reductase deficiency sufficiently explained their clinical
      symptoms
    explanation: Directly contradicts attributing the neurological phenotype to MCEE deficiency in the patients where it was most prominent, and is the reason this node is provisional.
  - reference: PMID:25763508
    reference_title: "Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the
      dystonic posture, the mood and the hypersomnia, proving that the
      pathogenesis was due to SRD.
    explanation: Shows the neurological syndrome in a dually affected patient responded to neurotransmitter replacement, attributing it to sepiapterin reductase deficiency rather than to MCEE.
  downstream:
  - target: Seizure
    description: Seizures occur both acutely during decompensation and as a chronic feature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Sepsis, psychomotor retardation, seizures, elevated C3-acylcarnitine, methyl-citrate in urine
      explanation: Records seizures in a molecularly confirmed patient.
  - target: Intellectual disability
    description: Fixed cognitive impairment is reported at the severe end of the spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38034150
      reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: both presented severe intellectual disability and spasticity
      explanation: Documents severe intellectual disability in two affected siblings.
  - target: Spasticity
    description: Spastic paraparesis and spasticity are recurrent findings in the reported series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Slow motor development, hypotonia (inability to walk independently),
        spasticity of legs, eczema, episode of vomiting and diarrhea
      explanation: Reports spasticity of the legs in a molecularly confirmed MCEE-deficient patient.
  - target: Hypotonia
    description: Hypotonia and delayed motor milestones are reported in early-presenting patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Slow motor development, hypotonia (inability to walk independently),
        spasticity of legs, eczema, episode of vomiting and diarrhea
      explanation: Records hypotonia with delayed motor development in a molecularly confirmed patient.
phenotypes:
- category: Biochemical
  name: Methylmalonic aciduria
  description: >-
    Persistent but mild-to-moderate urinary methylmalonate excretion is the
    finding that brings patients to attention, and the one constant across the
    whole reported series. It may be intermittent, and at newborn-screening age
    it may not yet be detectable.
  context: Established biochemical phenotype; magnitude is modest relative to mutase deficiency.
  phenotype_term:
    preferred_term: Methylmalonic aciduria
    term:
      id: HP:0012120
      label: Methylmalonic aciduria
  evidence:
  - reference: PMID:16752391
    reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present a 16-year-old female patient with persisting moderate
      MMA-uria (approximately 50 mmol/mol creatinine).
    explanation: Quantifies the persistent moderate methylmalonic aciduria in the index patient.
  - reference: PMID:39051409
    reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased MMA levels may be negligible at NBS as they may reach relevant
      values beyond the first days of life and thus could be identified only in
      confirmatory analyses.
    explanation: Establishes that the defining analyte can be normal at newborn screening, so its absence early does not exclude the diagnosis.
- category: Biochemical
  name: Elevated urinary 2-methylcitric acid
  description: >-
    2-methylcitrate is formed when accumulated propionyl-CoA condenses with
    oxaloacetate, and in this disorder it is often more prominent than
    methylmalonate itself.
  context: Established biochemical phenotype.
  phenotype_term:
    preferred_term: Elevated urine 2-methylcitric acid level
    term:
      id: HP:0034662
      label: Elevated urine 2-methylcitric acid level
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical findings in MCE deficiency are raised urinary excretion
      of MMA, methylcitrate (MCA), 3-hydroxypropionate (3-HP), and elevation of
      blood propionylcarnitine (C3), with normal vitamin B12 and homocysteine
      levels
    explanation: Records raised urinary methylcitrate as a common finding.
- category: Biochemical
  name: Elevated urinary 3-hydroxypropionic acid
  description: >-
    3-hydroxypropionate is the other principal propionyl-CoA overflow
    metabolite, and at presentation it can dominate the organic acid profile.
  context: Established biochemical phenotype.
  phenotype_term:
    preferred_term: Elevated urine 3-hydroxypropionic acid level
    term:
      id: HP:0034661
      label: Elevated urine 3-hydroxypropionic acid level
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: organic acid profiles were dominated by increased ketones and 3-hydroxypropionate
    explanation: Documents 3-hydroxypropionate dominating the organic acid profile at presentation.
- category: Biochemical
  name: Elevated circulating propionylcarnitine
  description: >-
    The C3 acylcarnitine elevation is what newborn screening detects, and it is
    not specific: it is the same marker that flags propionic acidemia and
    mutase-deficient methylmalonic acidemia.
  context: Established biochemical phenotype; the newborn-screening handle for the disorder.
  phenotype_term:
    preferred_term: Elevated circulating propionylcarnitine concentration
    term:
      id: HP:0033443
      label: Elevated circulating propionylcarnitine concentration
  evidence:
  - reference: PMID:39051409
    reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The NBS results showed increased levels of propionylcarnitine (C3) and
      2-methylcitric acid (MCA), while methylmalonic acid (MMA) and homocysteine
      (Hcy) were within the reference limits.
    explanation: Documents the C3 elevation on newborn screening in a molecularly confirmed patient.
  - reference: PMID:31146325
    reference_title: "MCEE Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic work-up revealed intermittent MMA-uria and increased plasma
      levels of propionyl-carnitine not responsive to treatment with high-dose
      hydroxycobalamin.
    explanation: Documents persistent propionylcarnitine elevation, and its failure to respond to cobalamin, in an adult patient.
- category: Metabolic
  name: Metabolic acidosis
  description: >-
    High-anion-gap metabolic acidosis during decompensation, which can be severe
    even in patients whose baseline biochemistry and development are normal.
  context: Episodic rather than constant; present in a minority of reported patients.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
    temporality: RECURRENT
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was severe metabolic acidosis with increased anion gap
    explanation: Documents severe anion-gap acidosis during an acute presentation.
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methylmalonyl-CoA epimerase deficiency, in which findings range from
      complete absence of symptoms to severe metabolic acidosis.
    explanation: GeneReviews states the clinical range of the epimerase-deficient form, from asymptomatic to severe acidosis.
- category: Metabolic
  name: Hyperammonemia
  description: Mild hyperammonaemia accompanying acidotic crises, as in the other organic acidemias.
  context: Reported during decompensation; mild in degree.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe metabolic acidosis and mild hyperammonemia
    explanation: Documents mild hyperammonaemia during acute decompensation.
- category: Metabolic
  name: Hypoglycemia
  description: Hypoglycaemia reported during infection-triggered decompensation.
  context: Episodic; reported in a minority of patients.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Severe metabolic acidosis and hypoglycemia following gastroenteritis, elevated propionyl-carnitine
    explanation: Documents hypoglycaemia in a molecularly confirmed patient during decompensation.
- category: Gastrointestinal
  name: Vomiting
  description: Vomiting with dehydration is the usual presenting complaint of an acute crisis.
  context: Episodic, tied to decompensation.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she presented acutely with vomiting, dehydration, confusion and visual hallucination
    explanation: Documents vomiting as a presenting feature.
- category: Neurologic
  name: Seizure
  description: Seizures occur acutely during decompensation and, in severely affected patients, as epilepsy.
  context: Reported in a minority; causal attribution to MCEE is not established.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sepsis, psychomotor retardation, seizures, elevated C3-acylcarnitine, methyl-citrate in urine
    explanation: Documents seizures in a molecularly confirmed patient.
- category: Neurologic
  name: Intellectual disability
  description: Severe intellectual disability at the extreme end of the reported spectrum.
  context: Reported in a minority; the SPR confounder must be excluded before attributing it.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: both presented severe intellectual disability and spasticity
    explanation: Documents severe intellectual disability in two molecularly confirmed siblings.
- category: Neurologic
  name: Spasticity
  description: Spasticity of the legs and mild spastic paraparesis are recurrent findings.
  context: Reported in a minority of patients.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Slow motor development, hypotonia (inability to walk independently),
      spasticity of legs, eczema, episode of vomiting and diarrhea
    explanation: Reports spasticity of the legs in a molecularly confirmed MCEE-deficient patient.
- category: Neurologic
  name: Hypotonia
  description: Hypotonia with delayed motor milestones in early-presenting patients.
  context: Reported in a minority of patients.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Slow motor development, hypotonia (inability to walk independently),
      spasticity of legs, eczema, episode of vomiting and diarrhea
    explanation: Documents hypotonia with delayed motor development.
- category: Cardiovascular
  name: Cardiomyopathy
  description: >-
    Cardiomyopathy was the presenting feature in one patient, whose sibling had
    the same biochemical profile and no symptoms at all. Reported once; recorded
    here because that discordant sibling pair is the clearest single statement of
    the disorder's variable expressivity.
  context: Single reported patient; not an established feature of the disorder.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiomyopathy. Sibling with similar biochemical profile but no symptoms
    explanation: The single reported instance, together with the discordant sibling.
genetic:
- name: MCEE
  gene_term:
    preferred_term: MCEE
    term:
      id: hgnc:16732
      label: MCEE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    MCEE on 2p13.3 encodes mitochondrial methylmalonyl-CoA epimerase. Reported
    disease alleles are overwhelmingly one nonsense variant, c.139C>T
    (p.Arg47*), which accounts for 83% of alleles in the published series; the
    remainder are rare missense, frameshift and deep-intronic splicing changes.
    The locus matters clinically for a second reason: SPR, whose deficiency
    causes a treatable neurotransmitter disorder, lies 1.8 Mb away, and
    consanguineous families have been reported homozygous for null alleles in
    both.
  evidence:
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most patients were homozygous for that variant (83% of the alleles).
    explanation: Quantifies the dominance of the p.Arg47* allele in the reported series.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This remains by far the most common pathogenic variation identified in
      MCEE deficiency, with 16 out of 21 patients homozygous for this allele.
    explanation: Independent quantification of the same allelic skew.
  - reference: PMID:25763508
    reference_title: "Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the second patient presenting the combination of two
      homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb
      in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and
      the sepiapterin reductase gene (SPR).
    explanation: Establishes the physical proximity of MCEE and SPR and the co-inheritance that confounds phenotype attribution.
  variants:
  - name: c.139C>T (p.Arg47*)
    description: >-
      The recurrent nonsense allele, truncating the protein within the first
      beta-sheet so that essentially no product survives nonsense-mediated decay.
      It accounts for the large majority of reported disease alleles.
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Loss of almost the entire protein is therefore the likely cause of
        enzymatic dysfunction due to this variation, assuming there is residual
        mRNA following nonsense-mediated decay.
      explanation: States the functional consequence of the recurrent allele.
  - name: c.158T>G (p.Ile53Arg)
    description: >-
      A misfolding missense allele at the dimer interface, absent from ExAC,
      yielding almost no soluble protein and no measurable activity.
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, hMCEE containing p.Ile53Arg had very low levels of detectable
        protein (6 ± 1% of wt), similar to empty vector (4 ± 2% of wt)
      explanation: Quantifies the loss of soluble protein that defines this allele's mechanism.
  - name: c.427C>T (p.Arg143Cys)
    description: >-
      An expressed but catalytically defective allele; the crystal structure of
      the variant protein shows displacement of two loops framing the active
      site. Reported only in the heterozygous state without an identified second
      allele, so its clinical role is not settled.
    evidence:
    - reference: PMID:30682498
      reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We solved the structure of MCEE-Arg143Cys to 1.9 Å and found significant
        disruption of two important loop structures, potentially impacting
        surface features as well as the active-site pocket.
      explanation: Gives the structural basis for loss of activity in an allele that is normally expressed.
  - name: c.379-644A>G
    description: >-
      A deep-intronic splicing variant found in trans with p.Arg47*, identified
      only by RNA study after exon sequencing found a single heterozygous allele.
      It is the reason a heterozygous-looking exome result does not exclude the
      diagnosis.
    evidence:
    - reference: PMID:27699154
      reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A heterozygous p.Arg47Ter (p.R47*) mutation in the MCEE gene was
        identified by sequencing of exons, and RNA studies identified a novel
        intronic splicing mutation, c.379-644A > G, confirming the diagnosis of
        MCE deficiency.
      explanation: Documents the deep-intronic allele and the RNA study needed to find it.
diagnosis:
- name: Urine organic acid analysis
  diagnosis_term:
    preferred_term: urine organic acid analysis
  description: >-
    The entry point. The profile shows methylmalonate that is mildly and
    sometimes intermittently raised, alongside more prominent 2-methylcitrate
    and 3-hydroxypropionate. Because the propionyl-CoA-derived acids dominate,
    the pattern reads as propionic acidemia and has led to that working
    diagnosis.
  results: >-
    Mild persistent methylmalonic aciduria with 2-methylcitrate,
    3-hydroxypropionate and ketosis; normal homocysteine.
  evidence:
  - reference: PMID:29104221
    reference_title: Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic investigations were consistent with propionic aciduria (PA).
      Unexpectedly, propionyl-CoA carboxylase activity was within the reference
      range.
    explanation: Documents the diagnostic confusion the organic acid profile causes, and how it was resolved.
- name: Newborn screening acylcarnitine profile
  diagnosis_term:
    preferred_term: newborn screening
  description: >-
    There is no dedicated screen for this disorder; it is picked up incidentally
    on the C3 propionylcarnitine marker used for propionic acidemia and mutase
    deficiency. The first screening-detected case showed raised C3 and
    2-methylcitrate with methylmalonate and homocysteine still in range, which is
    a pattern worth recognising because the defining analyte is the one that is
    normal.
  results: Elevated C3 with slightly raised 2-methylcitrate; methylmalonate and homocysteine within reference limits.
  evidence:
  - reference: PMID:39051409
    reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated concentrations of C3 with a slight increase in MCA and normal MMA
      and Hcy during NBS should prompt the consideration of MCEE deficiency in
      differential diagnosis.
    explanation: States the screening pattern that should raise the diagnosis.
  - reference: PMID:39051409
    reference_title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A dedicated test for MCEE deficiency is not included in the newborn
      screening (NBS) panels but it can be incidentally identified when
      investigating methylmalonic acidemia and propionic acidemia.
    explanation: Establishes that ascertainment is incidental to screening for the flanking enzyme defects.
- name: MCEE molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
  description: >-
    Sequencing MCEE, usually within a methylmalonic-pathway gene panel, is the
    practical confirmatory test and the one GeneReviews treats as establishing
    the diagnosis. Exon sequencing alone is not always sufficient: one patient
    was heterozygous on exon sequencing and required RNA study to find a deep
    intronic second allele.
  results: Biallelic MCEE variants, most often homozygous c.139C>T (p.Arg47*).
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of isolated MMA is established in a proband by
      identification of biallelic pathogenic variants in MCEE, MMAA, MMAB,
      MMADHC, or MMUT
    explanation: GeneReviews states molecular testing as the diagnostic standard, with MCEE among the genes.
  - reference: PMID:38034150
    reference_title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients present with overlapping clinical features with predominant
      neurological manifestations; genetic testing is indispensable for
      diagnosis.
    explanation: States that the clinical and biochemical picture does not distinguish the disorder, so genetic testing is required.
- name: Fibroblast propionate incorporation and complementation analysis
  diagnosis_term:
    preferred_term: enzyme activity assay
  description: >-
    Cultured fibroblasts show moderately reduced incorporation of labelled
    propionate that is not corrected by hydroxocobalamin. Complementation
    analysis assigns the defect to the MCEE group and distinguishes it from mut,
    cblA and cblB. Available in specialist laboratories only, and now largely
    superseded by sequencing.
  results: Moderately reduced propionate incorporation, no cobalamin response, complementation assigns to MCEE.
  evidence:
  - reference: PMID:17823972
    reference_title: "Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the defect in these fibroblasts was complemented by mut, cblA, and cblB
      fibroblasts
    explanation: Establishes complementation analysis as the assay that assigns the defect to MCEE and separates it from the mutase and cobalamin groups.
differential_diagnoses:
- name: Propionic acidemia
  description: >-
    The closest mimic and the one that has repeatedly been diagnosed first,
    because 2-methylcitrate, 3-hydroxypropionate and C3 dominate the profile
    while methylmalonate is only mildly raised. Normal propionyl-CoA carboxylase
    activity is what separates them.
  evidence:
  - reference: PMID:29104221
    reference_title: Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report isolated MCE deficiency in a boy who presented at five years of
      age with acute metabolic acidosis. Metabolic investigations were consistent
      with propionic aciduria (PA).
    explanation: A worked instance of the disorder being investigated as propionic aciduria.
- name: Methylmalonyl-CoA mutase deficiency and the cblA/cblB cobalamin disorders
  description: >-
    The other isolated methylmalonic acidemias. They produce a far larger
    methylmalonate elevation, and the cobalamin defects respond at least
    partially to hydroxocobalamin, which MCEE deficiency does not. One patient
    was assigned to the cblA complementation group for years before MCEE
    sequencing corrected it.
  evidence:
  - reference: PMID:16697227
    reference_title: "Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A patient, formerly identified as belonging to the cblA complementation
      group of vitamin B12 disorders but lacking mutations in the affected gene,
      MMAA, was tested for mutations in the MCEE gene.
    explanation: Documents a patient misassigned to cblA before MCEE was identified.
- name: Sepiapterin reductase deficiency
  description: >-
    Not a biochemical mimic but a co-inheritance trap. SPR lies 1.8 Mb from MCEE
    on 2p13.3, and in consanguineous families homozygous null alleles in both
    have segregated together. Because sepiapterin reductase deficiency is a
    treatable neurotransmitter disorder, a patient with MCEE deficiency and
    progressive neurological disease needs it excluded before the neurology is
    attributed to the epimerase defect.
  evidence:
  - reference: PMID:25763508
    reference_title: "Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive dystonia and cataplexy narcolepsy led to diagnose the second
      homozygous mutation in the SPR gene: c.751A>T; p.Lys251*.
    explanation: Documents the co-inherited second disorder that explained the neurological course.
treatments:
- name: Emergency management of acute metabolic decompensation
  description: >-
    Reversal of catabolism with intravenous glucose, correction of acidosis and
    dehydration, and temporary withdrawal of natural protein, as for the other
    intoxication-type organic acidemias. The published crises resolved with
    supportive metabolic management.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: metabolic emergency management
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Acute Metabolic Decompensation under Catabolic Stress
    description: Reversing catabolism removes the propionyl-CoA load that precipitated the crisis.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        When isolated MMA is suspected during the diagnostic evaluation due to
        elevated propionylcarnitine (C3) on a newborn blood spot, metabolic
        treatment should be initiated immediately, while the suspected diagnosis
        is being confirmed.
      explanation: GeneReviews directs immediate metabolic treatment on suspicion, which is the management this treatment describes.
- name: Natural protein restriction
  description: >-
    Restriction of propiogenic amino acid precursors is the standard chronic
    management of isolated methylmalonic acidemia. Its necessity in MCEE
    deficiency specifically is unsettled: the best-documented patient with a
    severe initial crisis has remained well for six years on an essentially
    normal diet.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Accumulation of Propionate-Pathway Metabolites
    description: Reducing precursor intake lowers the propionyl-CoA flux arriving at the partial block.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        restrict natural protein, particularly of propiogenic amino acid
        precursors, while maintaining a high-calorie diet
      explanation: States the dietary principle and its rationale in the isolated methylmalonic acidemias.
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following the initial severe presentation, development has been normal and
      the clinical course over the subsequent six years has remained relatively
      uneventful on an essentially normal diet.
    explanation: Contradicts a requirement for protein restriction in this disorder, in the patient with the best-documented long-term follow-up.
- name: Hydroxocobalamin trial
  description: >-
    Cobalamin supplementation is standard practice in isolated methylmalonic
    acidemia because the cblA and cblB forms respond to it. MCEE deficiency does
    not: the enzyme is not cobalamin-dependent, and both the index patient and an
    adult patient on high-dose hydroxocobalamin failed to respond. A trial is
    still reasonable as part of the diagnostic work-up, but is recorded here as a
    treatment that does not work.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  evidence:
  - reference: PMID:16752391
    reference_title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established.
    explanation: Records the absence of a cobalamin response in the index patient.
  - reference: PMID:31146325
    reference_title: "MCEE Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic work-up revealed intermittent MMA-uria and increased plasma
      levels of propionyl-carnitine not responsive to treatment with high-dose
      hydroxycobalamin.
    explanation: Independent confirmation that high-dose hydroxocobalamin does not correct the biochemical phenotype.
references:
- reference: PMID:16752391
  title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
- reference: PMID:16697227
  title: "Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria."
- reference: PMID:17823972
  title: "Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE)."
- reference: PMID:27699154
  title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
- reference: PMID:29104221
  title: Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
- reference: PMID:30682498
  title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
- reference: PMID:31146325
  title: "MCEE Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid."
- reference: PMID:25763508
  title: "Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials."
- reference: PMID:38034150
  title: "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features."
- reference: PMID:39051409
  title: "Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report."
- reference: PMID:20301409
  title: Isolated Methylmalonic Acidemia.
  tags:
  - GeneReviews
discussions:
- discussion_id: controversy_mcee_clinical_significance
  prompt: >-
    Is MCEE deficiency a disease, or a biochemical trait that has been
    ascertained through disease?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Acute Encephalopathy and Neurological Injury
  - disease#Methylmalonyl-CoA Epimerase Deficiency
  rationale: >-
    The biochemical phenotype is not in dispute: biallelic null alleles, reduced
    propionate incorporation, complementation to the MCEE group, and rescue by
    wild-type cDNA. What is disputed is whether the clinical findings reported
    alongside it are caused by it. The case against is specific rather than
    general - two patients' neurological disease was fully explained by a
    co-inherited SPR defect and reversed by neurotransmitter replacement; two
    others were asymptomatic; siblings homozygous for the same null allele are
    discordant for symptoms; and the largest review found no genotype-phenotype
    relationship. The case for rests on the acute decompensations, which are hard
    to attribute to anything else and which follow catabolic stress in the way an
    intoxication-type block predicts. The most defensible current reading is that
    the enzymatic block and the acute crises are real, and that the chronic
    neurological burden is unproven.
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical significance and biochemical characteristics of this rare
      condition have been incompletely defined.
    explanation: States the unresolved clinical significance that this controversy is about.
- discussion_id: gap_mcee_lys60gln_mechanism
  prompt: >-
    How does p.Lys60Gln cause disease when its protein behaves like wild type in
    every assay applied to it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Two Molecular Routes to Enzyme Loss
  - genetic#MCEE
  rationale: >-
    p.Lys60Gln was reported homozygous in a patient, but it maps onto the
    wild-type structure without an obvious defect, is predicted tolerated by both
    SIFT and PolyPhen2, and its recombinant protein matches wild type in soluble
    level, unfolding and activity. Either the assays miss the defect - an
    interaction with a partner enzyme, a tissue-specific effect, an
    expression-level change not captured by over-expression - or the variant is
    not the cause of that patient's phenotype. Nothing published resolves it.
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By contrast, soluble protein levels, unfolding characteristics and activity
      of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation
      may cause disease.
    explanation: States the unresolved discrepancy directly.
- discussion_id: gap_mcee_residual_flux_route
  prompt: >-
    What actually carries the residual flux past the missing epimerase, and how
    much does it vary between people?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Partial Block of the Propionate-to-Succinate Pathway
  rationale: >-
    Two bypasses have been proposed - spontaneous non-enzymatic racemisation of
    the CoA ester, and a shunt through free methylmalonic acid - and the siRNA
    experiment shows something substantial is carrying flux, but neither has been
    quantified in humans and no second enzyme has been identified. This matters
    beyond mechanism: if bypass capacity varies between individuals it is the
    most obvious candidate explanation for why the same homozygous null allele
    produces everything from no symptoms to severe disease, which is the question
    the controversy above turns on.
  evidence:
  - reference: PMID:27699154
    reference_title: "Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      In contrast, the physiological significance of the second enzymatic step,
      catalysed by methylmalonyl-coA epimerase (MCE; also known as
      methylmalonyl-coA racemase), has remained less clear.
    explanation: Records that the physiological weight of this step, and hence of its bypasses, is unsettled.
notes: >-
  Curated for the metabolic WP-001 package (issue #5556, row 1.2.2.01), whose
  work hint was to review "Methylmalonic Acidemia" as a possible local home for
  this concept. It was curated as a separate entry rather than as a subtype of
  Methylmalonic_Acidemia, on three grounds. The lesion is a different enzyme at a
  different step, not an allelic or cofactor variant of methylmalonyl-CoA mutase,
  which is what that entry's existing subtypes describe. MONDO carries a distinct
  term for it. And the block is partial by construction, which makes the disease
  quantitatively and diagnostically unlike mutase deficiency - it presents
  looking like propionic acidemia rather than like the entry it would be nested
  under. The existing Methylmalonic_Acidemia entry's description scopes itself to
  MMUT, cblA and cblB and does not claim this form.

  No ORPHA cache was committed for ORPHA:308425: the Orphanet structured source
  needs the bulk Orphadata XML, which is not present in this checkout, so
  `just fetch-reference ORPHA:308425` fails rather than fetching a single record.
  There is no ClinGen Gene-Disease Validity assertion for MCEE in the committed
  ClinGen cache, so no CGGV evidence is cited; that is an absence in ClinGen's
  curation, not a judgement about the gene.

  Two PMIDs were written from memory during curation and both resolved to
  unrelated papers when fetched - an HDL/PI3K signalling study and a
  fructose-1,6-bisphosphatase cohort. Neither is cited here. The first had no
  cache file before this run and its file was removed; the second turned out to
  be an already-committed cache belonging to Fructose-1,6-Bisphosphatase
  Deficiency, so removing it would have broken that entry, and it was restored.
  Recorded because it is the exact failure mode CLAUDE.md describes for ontology
  CURIEs and it applies to PMIDs written from memory in the same way - and
  because the clean-up is its own hazard: a reference cache that looks like your
  own mistake may be another entry's evidence.
📚

References & Deep Research

References

11
PMID:16752391
A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
No top-level findings curated for this source.
PMID:16697227
Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria.
No top-level findings curated for this source.
PMID:17823972
Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE).
No top-level findings curated for this source.
PMID:27699154
Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene.
No top-level findings curated for this source.
PMID:29104221
Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.
No top-level findings curated for this source.
PMID:30682498
Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency.
No top-level findings curated for this source.
PMID:31146325
MCEE Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid.
No top-level findings curated for this source.
PMID:25763508
Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials.
No top-level findings curated for this source.
PMID:38034150
Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features.
No top-level findings curated for this source.
PMID:39051409
Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report.
No top-level findings curated for this source.
PMID:20301409
Isolated Methylmalonic Acidemia.
No top-level findings curated for this source.