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Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

MedGen UID:
Concept ID:
Disease or Syndrome
Synonyms: MCEE-Related Methylmalonic Acidemia; METHYLMALONIC ACIDURIA III; Methylmalonyl-CoA epimerase deficiency; METHYLMALONYL-CoA RACEMASE DEFICIENCY
Gene (location): MCEE (2p13.3)
Monarch Initiative: MONDO:0009615
OMIM®: 251120
Orphanet: ORPHA308425

Disease characteristics

Excerpted from the GeneReview: Isolated Methylmalonic Acidemia
For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included: Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B12-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy. Partially deficient or B12-responsive phenotypes (mut– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer. [from GeneReviews]
Irini Manoli  |  Jennifer L Sloan  |  Charles P Venditti   view full author information

Additional description

From MedlinePlus Genetics
Methylmalonic acidemia is a group of inherited disorders that prevent the body from breaking down proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delays, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive). Long-term complications can include feeding problems, intellectual disabilities, movement problems, chronic kidney disease, and inflammation of the pancreas (pancreatitis). People with methylmalonic acidemia can have frequent episodes of excess acid in the blood (metabolic acidosis) that cause serious health complications.Without treatment, this disorder can lead to coma and death in some cases.  https://medlineplus.gov/genetics/condition/methylmalonic-acidemia

Clinical features

From HPO
MedGen UID:
Concept ID:
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Methylmalonic aciduria
MedGen UID:
Concept ID:
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Failure to thrive
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Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Gastroesophageal reflux
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A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
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Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Motor delay
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A type of Developmental delay characterized by a delay in acquiring motor skills.
MedGen UID:
Concept ID:
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Metabolic acidosis
MedGen UID:
Concept ID:
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
MedGen UID:
Concept ID:
An increased concentration of homocystine in the blood.
Elevated circulating palmitoleylcarnitine concentration
MedGen UID:
Concept ID:
An elevated level of propionylcarnitine in the circulation. Propionylcarnitine is present in high abundance in the urine of patients with Methylmalonyl-CoA mutase (MUT) deficiency.

Recent clinical studies


Yazıcı H, Canda E, Onay H, Uçar SK, Habif S, Çoker M
Turk J Pediatr 2022;64(5):946-950. doi: 10.24953/turkjped.2021.245. PMID: 36305448

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