Format

Send to:

Choose Destination

Links from Gene

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

MedGen UID:
344424
Concept ID:
C1855114
Disease or Syndrome
Synonyms: Methylmalonic aciduria, mut type; MUT-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): MUT (6p12.3)
OMIM®: 251000

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. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (251100), caused by mutation in the MMAA gene (607481) on chromosome 4q31, and cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24. Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), and cblF (277380). See the comprehensive review of Ledley (1990).  http://www.omim.org/entry/251000
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

Nephropathy, tubulointerstitial
MedGen UID:
11952
Concept ID:
C0041349
Disease or Syndrome
A form of inflammation of the kidney affecting the interstitium of the kidneys surrounding the tubules.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Cerebellar hemorrhage
MedGen UID:
488779
Concept ID:
C0149854
Pathologic Function
Hemorrhage into the parenchyma of the cerebellum.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A disease of the heart muscle or myocardium proper. Cardiomyopathies may be classified as either primary or secondary, on the basis of etiology, or on the pathophysiology of the lesion: hypertrophic, dilated, or restrictive.
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.
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
INFLAMMATION of the PANCREAS. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of CHRONIC PANCREATITIS (International Symposium on Acute Pancreatitis, Atlanta, 1992). The two most common forms of acute pancreatitis are ALCOHOLIC PANCREATITIS and gallstone pancreatitis.
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.
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.
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.
Cerebellar hemorrhage
MedGen UID:
488779
Concept ID:
C0149854
Pathologic Function
Hemorrhage into the parenchyma of the cerebellum.
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.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Abnormality of the globus pallidus
MedGen UID:
425100
Concept ID:
CN002227
Finding
An abnormality of the globus pallidus.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
A decrease in the number of LEUKOCYTES in a blood sample below the normal range (LEUKOCYTE COUNT less than 4000).
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.
Cerebellar hemorrhage
MedGen UID:
488779
Concept ID:
C0149854
Pathologic Function
Hemorrhage into the parenchyma of the cerebellum.
Nephropathy, tubulointerstitial
MedGen UID:
11952
Concept ID:
C0041349
Disease or Syndrome
A form of inflammation of the kidney affecting the interstitium of the kidneys surrounding the tubules.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
A decrease in the number of LEUKOCYTES in a blood sample below the normal range (LEUKOCYTE COUNT less than 4000).
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
INFLAMMATION of the PANCREAS. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of CHRONIC PANCREATITIS (International Symposium on Acute Pancreatitis, Atlanta, 1992). The two most common forms of acute pancreatitis are ALCOHOLIC PANCREATITIS and gallstone pancreatitis.
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.
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.
Metabolic ketoacidosis
MedGen UID:
381478
Concept ID:
C1854704
Pathologic Function
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

Diagnosis

Xu S, Bhajoo SH, Jiang W
J Pediatr Endocrinol Metab 2013;26(9-10):903-8. doi: 10.1515/jpem-2013-0032. PMID: 23729607

Prognosis

Xu S, Bhajoo SH, Jiang W
J Pediatr Endocrinol Metab 2013;26(9-10):903-8. doi: 10.1515/jpem-2013-0032. PMID: 23729607

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...
Support Center