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Methylmalonic aciduria cblA type

MedGen UID:
344422
Concept ID:
C1855109
Disease or Syndrome
Synonyms: 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
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): MMAA (4q31.21)
OMIM®: 251100
Orphanet: ORPHA79310

Definition

Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut(0) enzymatic subtype or mut(–) enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. [from GTR]

Additional descriptions

From GeneReviews
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut(0) enzymatic subtype or mut(–) enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.  https://www.ncbi.nlm.nih.gov/books/NBK1231
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 GHR
Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain 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 delay, 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 disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases.  https://ghr.nlm.nih.gov/condition/methylmalonic-acidemia

Clinical features

Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies in the urine.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement 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
A profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused. Coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem RETICULAR FORMATION.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to DEPRESSION or DRUG ADDICTION.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
A finding of low numbers of red and white blood cells and platelets in the peripheral blood.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A laboratory test result indicating that there is an abnormally small number of platelets in the circulating blood.
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result demonstrating decreased levels of hemoglobin in a biological specimen.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
A decrease in the number of neutrophils in the peripheral blood.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
A pathological increase in the effort and frequency of breathing movements.
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies in the urine.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
A decrease in the 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
A condition characterized by an abnormally elevated concentration of KETONE BODIES in the blood (acetonemia) or urine (acetonuria). It is a sign of DIABETES COMPLICATION, starvation, alcoholism or a mitochondrial metabolic disturbance (e.g., MAPLE SYRUP URINE DISEASE).
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies in the urine.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Acid accumulation or depletion of base in the body due to buildup of metabolic acids.
Hyperammonaemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
A laboratory test result demonstrating an increased concentration of ammonia in the blood.
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
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut(0) enzymatic subtype or mut(–) enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Decreased adenosylcobalamin
MedGen UID:
336369
Concept ID:
C1848556
Finding
Decreased concentration of adenosylcobalamin. 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.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Abnormal serum cobalamin level
MedGen UID:
866685
Concept ID:
C4021032
Finding
A deviation from the normal concentration of cobalamin (vitamin B12) 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

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

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