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Methylmalonic aciduria, cblA type(MACA)

MedGen UID:
344422
Concept ID:
C1855109
Disease or Syndrome
Synonyms: MACA; Methylmalonic acidemia cblA type; Methylmalonic aciduria, vitamin B12-responsive; Methylmalonic aciduria, vitamin b12-responsive, due to defect in synthesis of adenosylcobalamin, cbla complementation type; MMA cbl A type; MMAA-Related Methylmalonic Acidemia; Vitamin B12-responsive methylmalonic acidemia type cblA
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): MMAA (4q31.21)
 
Monarch Initiative: MONDO:0009613
OMIM®: 251100
Orphanet: ORPHA79310

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]
Authors:
Irini Manoli  |  Jennifer L Sloan  |  Charles P Venditti   view full author information

Additional descriptions

From OMIM
Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblA and cblB (251110), which is caused by mutation in the MMAB gene (607568) on 12q24. See also cblH (277410), which may be a subset of cblA. The 'mut' form of MMA (251000) is caused by mutation in the MUT gene on chromosome 6p. In general, the mut form of MMA is unresponsive to vitamin B12 therapy. Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), cblF (277380), and cblJ (614857).  http://www.omim.org/entry/251100
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
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
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:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Elevated urine 3-hydroxypropionic acid level
MedGen UID:
1841876
Concept ID:
C5826570
Finding
Amount of 3-hydroxypropionic acid in the urine above the upper limit of normal.
Elevated urine 2-methylcitric acid level
MedGen UID:
1841959
Concept ID:
C5826571
Finding
Amount of 2-methylcitric acid in the urine above the upper limit of normal.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
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.
Ketosis
MedGen UID:
7206
Concept ID:
C0022638
Disease or Syndrome
Presence of elevated levels of ketone bodies in the body.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
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.
Hyperglycinemia
MedGen UID:
82817
Concept ID:
C0268559
Disease or Syndrome
An elevated concentration of glycine in the blood.
Methylmalonic acidemia
MedGen UID:
120654
Concept ID:
C0268583
Disease or Syndrome
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.
Decreased circulating adenosylcobalamin concentration
MedGen UID:
336369
Concept ID:
C1848556
Finding
The concentration of adenosylcobalam in the blood circulation is below the lower limit of normal. Adenosylcobalamin is one of the active forms of vitamin B12.
Decreased methylmalonyl-CoA mutase activity
MedGen UID:
336374
Concept ID:
C1848579
Finding
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of methylmalonyl-CoA mutase activity.
Abnormal circulating vitamin B12 concentration
MedGen UID:
866685
Concept ID:
C4021032
Finding
A deviation from the normal concentration of cobalamin (vitamin B12) in the blood. Vitamin B12 is one of the eight B vitamins.
Elevated serum anion gap
MedGen UID:
1671031
Concept ID:
C4732778
Finding
An abnormally high value of the serum anion gap (the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration).
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Recent clinical studies

Etiology

Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221
Lubrano R, Bellelli E, Gentile I, Paoli S, Carducci C, Carducci C, Santagata S, Pérez B, Ugarte M, Labriola D, Elli M
Am J Transplant 2013 Jul;13(7):1918-22. Epub 2013 May 24 doi: 10.1111/ajt.12282. PMID: 23711287

Diagnosis

Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221
Lubrano R, Bellelli E, Gentile I, Paoli S, Carducci C, Carducci C, Santagata S, Pérez B, Ugarte M, Labriola D, Elli M
Am J Transplant 2013 Jul;13(7):1918-22. Epub 2013 May 24 doi: 10.1111/ajt.12282. PMID: 23711287

Therapy

Peake RW
Clin Chem 2016 Oct;62(10):1410-2. doi: 10.1373/clinchem.2016.259705. PMID: 27683594

Prognosis

Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR
Mol Genet Metab 2013 Dec;110(4):472-6. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.08.021. PMID: 24095221
Lubrano R, Bellelli E, Gentile I, Paoli S, Carducci C, Carducci C, Santagata S, Pérez B, Ugarte M, Labriola D, Elli M
Am J Transplant 2013 Jul;13(7):1918-22. Epub 2013 May 24 doi: 10.1111/ajt.12282. PMID: 23711287

Clinical prediction guides

Lubrano R, Bellelli E, Gentile I, Paoli S, Carducci C, Carducci C, Santagata S, Pérez B, Ugarte M, Labriola D, Elli M
Am J Transplant 2013 Jul;13(7):1918-22. Epub 2013 May 24 doi: 10.1111/ajt.12282. PMID: 23711287

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

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