Figure 1. Pathways utilizing cobalamin derivatives. Cbl indicates cobalt atom and possible valence state (indicated by superscripted Roman numerals). (modified from Chandler & Venditti 2005)
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Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. The clinical manifestations of disorders of intracellular cobalamin metabolism, identified by complementation class as cblC, cblD, cblD variant 1, cblD variant 2, cblF, cblE, and cblG, can be highly variable even within a single complementation class. The prototype and best understood is cblC; it is also the most common of these disorders. The age of initial presentation of cblC ranges from (1) newborns who can be small for gestational age (SGA) and have microcephaly; to (2) infants who can have poor feeding, failure to thrive, pallor, and neurologic signs, and occasionally hemolytic uremic syndrome (HUS) and/or seizures including infantile spasms; to (3) toddlers who can have failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures; and to (4) young adults/adults who can have confusion, other mental status changes, cognitive decline, and megaloblastic anemia.
Diagnosis/testing. Metabolic screening tests such as urine organic acid analysis and plasma amino acid analysis help categorize the clinical syndrome. Analysis in specialized laboratories can establish the specific complementation class. The following three genes are the only ones known for disorders of intracellular cobalamin metabolism: MMACHC (cblC), MTRR (cblE), and MTR (cblG). Sequence analysis for these three genes is available on a clinical basis. The role of molecular genetic testing in diagnosis is evolving; molecular genetic testing may be faster and less expensive than complementation class analysis in establishing a specific diagnosis in a family.
Management. Treatment of manifestations: No therapy completely mitigates all disease manifestations. Critically ill individuals must be stabilized, preferably in consultation with a metabolic specialist, by treating acidosis and reversing catabolism. Disease exacerbations may be minimized using a high-calorie diet that is low in protein, especially propiogenic amino acid precursors, and, in some cases, cofactor therapy (hydroxycobalamin intramuscular injections). Gastrostomy tube placement for feeding is often required; seizures are treated using standard protocols. Prevention of primary manifestations: Intramuscular injections of 1 mg hydroxycobalamin approximately once every 1-3 days are used in responsive individuals. Surveillance: During the first year of life, infants may need to be evaluated once or twice a month. Routine medical care should include special attention to growth and development; neurologic evaluation for early signs of psychomotor retardation, behavioral disturbances, seizures, and myelopathy; and ophthalmologic evaluation for retinal and optic nerve changes. Agents/circumstances to avoid: prolonged fasting (longer than overnight without dextrose-containing intravenous fluids); excessive dietary protein intake. Testing of relatives at risk: For sibs of a proband: measure concentrations of methylmalonic acid, total plasma homocysteine, and/or related metabolites in urine and/or plasma as soon after birth as possible in order to institute treatment promptly in those found to be affected. Other: MedicAlert® bracelets; readily available emergency treatment protocols outlining fluid, electrolyte, and cofactor therapy.
Genetic counseling. All disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in a family are known. Enzyme analysis of cultured fetal cells can also be used for prenatal diagnosis if the diagnosis has been confirmed in an affected family member using biochemical methods.
Vitamin B12 (cobalamin) is a cofactor required by two enzymes, methionine synthase (MTR) and methylmalonyl-CoA mutase (MUT). Disorders of intracellular cobalamin metabolism may impair the function of either or both enzymes:
Clinical syndromes involving defects in MUT function alone are called methylmalonic acidemia. Such defects can be caused by defective MUT enzyme or missing B12 cofactor. Certain subtypes of methylmalonic acidemia may be further defined by complementation analysis. Complementation groups causing isolated methylmalonic acidemia include cblA and cblB (see Table 1).
Clinical syndromes involving defective MTR function can be caused by defective MTR enzyme, missing cofactor, or defects in an enzyme that regenerates MTR: methionine synthase reductase (MTRR). Defective MTR function is associated with variable hyperhomocysteinemia and/or homocystinuria.
Disorders that cause isolated defects in MTR function, as well as disorders that cause combined defects in both MTR and MUT function, are named by complementation group. MTR-only and combined MUT/MTR cobalamin disorders include cblC, cblD, cblD variant 1, cblD variant 2, cblE, cblF, and cblG (see Table 1).
The phenotypes of the MTR-only and combined MUT/MTR cobalamin disorders are variable and can be seen in other related and unrelated conditions. Definitive diagnosis relies on specialized biochemical or molecular genetic testing (see Testing).
| Complementation Group | Gene Symbol | Biochemical Phenotype |
|---|---|---|
| cblA 1 | MMAA | Methylmalonic acidemia/aciduria |
| cblB 1 | MMAB | Methylmalonic acidemia/aciduria |
| cblC | MMACHC | Methylmalonic acidemia/aciduria and hyperhomocysteinemia/homocystinuria 2 |
| cblD | MMADHC | Methylmalonic acidemia/aciduria and hyperhomocysteinemia/homocystinuria 2 |
| cblD (variant 1) | Hyperhomocysteinemia/homocystinuria 2 | |
| cblD (variant 2) | Methylmalonic acidemia/aciduria | |
| cblE | MTRR | Hyperhomocysteinemia/homocystinuria 2 |
| cblF | Unknown | Methylmalonic acidemia/aciduria and hyperhomocysteinemia/homocystinuria 2 |
| cblG | MTR | Hyperhomocysteinemia/homocystinuria 2 |
1. CblA and cblB are discussed in detail in Methylmalonic Acidemia/Aciduria and briefly in the Differential Diagnosis. CblA and cblB have more severe methylmalonate excretion than the combined MUT/MTR disorders.
2. MTR = hyperhomocysteinemia/homocystinuria. The hyperhomocysteinemia seen in some cobalamin disorders is distinct from that seen in cystathionine beta synthase deficiency. The latter typically includes hypermethioninemia, whereas the former usually includes hypomethioninemia.
Specialized testing is used to exclude unrelated disorders and to place the enzyme defect in a known complementation group (see Table 1)
Note: Vitamin B12-deficiency states must first be ruled out as a matter of course.
Organic acid analysis. Initial diagnosis of inherited disorders of cobalamin metabolism relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography with confirmation of peaks by mass spectrometry (GC/MS). Approximate concentrations of methylmalonic acid (MMA) are shown in Table 2.
Nonspecific findings on urine organic acid analysis include the following:
For combined MUT/MTR disorders, secondary metabolites (including 3-hydroxypropionate, methylcitrate, and tiglylglycine) may be detected using GC/MS analysis when patients are ill. When patients are well controlled, the secondary metabolites generally disappear, leaving only elevated MMA excretion.
Methylglutaconic aciduria has been seen in at least one person with cblG [Adams et al 2006].
Mild methylmalonic aciduria has been seen in one person with cblE when acutely ill [Tuchman et al 1988].
| Complementation Group | Methylmalonic Acid Concentration | |
|---|---|---|
| Urine | Blood | |
| cblA | 100s to low 1000s of mg/g Cr when ill or at presentation; variable during treatment generally ranging from 10s to 100s | 100s of µM when ill; 10s of µM when well |
| cblB | ||
| cblC | 100s of µM when ill; 10s to within normal limits (most in the 10s range) when well 1 | |
| cblD 2, 3 | Can be greater than 1000 mg/g Cr | ND |
| cblE 3 | Mild elevation uncommon 4 | ND |
| cblF | 10s of mg/dL in untreated individuals; undetectable in some on therapy 5 | ND |
| cblG 3 | <4 mmol/mol/Cr | <0.27 µmol/L |
| Normal 4 | <4 mmol/mol/Cr 6 | <0.27 µmol/L 6 |
ND = not determined
1. Authors' experience with >20 patients
2. Values refer to cblD and cblD variant 2. CblD variant 1 may have a different pattern resembling cblC.
3. Individuals with complementation cblD variant 1 [Suormala et al 2004], cblE (methionine synthase reductase), and cblG (methionine synthase) generally have hyperhomocysteinemia/homocystinuria but no methylmalonic aciduria/emia.
4. Tuchman et al 1988
5. Rosenblatt et al 1986
6. Standard values have not been exclusively derived from pediatric patients or neonates. Some laboratories report urine MMA concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Plasma amino acid analysis
Hypomethioninemia and homocystinemia and mixed disulfide can be detected using plasma amino acid analysis (see Table 3).
Homocystine and the mixed disulfide of cysteine and homocysteine are excreted in the urine.
In individuals with cblC, cystathioninemia/uria can be present [Mudd et al 1969].
Total homocysteine concentration. Measurement of plasma or serum total homocysteine concentration is a sensitive test for the detection and monitoring of persons with cblC-cblF (see Table 3). When possible, measurement in plasma is preferable to measurement in serum.
Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase a total homocysteine result by as much as 10% an hour [Ubbink 2000, Refsum et al 2004].
Urine homocystine concentration. Measurement of urine homocystine concentration can be useful, especially in establishing the diagnosis initially. However, urine homocystine excretion is variable, making it potentially less sensitive than plasma total homocysteine concentration.
Note: Plasma homocysteine metabolism is discussed extensively in Cystathionine Beta Synthase Deficiency.
| Complementation Group | Metabolite 1 | |
|---|---|---|
| Urine Homocystine | Plasma Homocysteine | |
| cblA | 0 | Within normal limits |
| cblB | ||
| cblC | Increased | Hyperhomocysteinemia (>100 µM) when ill, most 30-90 µM when well 2 |
| cblD | Increased in some variants | Hyperhomocysteinemia has been described, with tHcy >100 µM, in some variants |
| cblE | Increased | Hyperhomocysteinemia when ill |
| cblF | Increased; can be normal on therapy 3 | Increased, can be normal on therapy 3 |
| cblG | Increased | Hyperhomocysteinemia when ill and some when treated |
| Normal | Not detected | Total 3-13 µM |
ND = not determined
1. Values for the rarest disorders are based on a small number of patients.
2. Authors' experience with >20 patients
3. Rosenblatt et al 1986
14C propionate and 14C MeTHF (14C formate) macromolecular incorporation studies are specialized biochemical laboratory investigations on patient-derived cell lines that can help establish the diagnosis of specific cobalamin disorders. Such assays rely on the incorporation of radiolabeled precursors into macromolecules. These tests are available clinically through specialized laboratories.
See Methylmalonic Acidemia for more information.
Complementation group analysis. This assay assigns a genetic group or class to the enzymatic block (i.e., cblA - cblG) using heterokaryon rescue or enzymatic cross correction [Gravel et al 1975]. In this assay the cell line from the affected individual is mixed with a panel of established cell lines of known status (e.g., cblC or cblF). Such testing is available clinically through specialized laboratories:
CblD variants 1 and 2 display isolated adeno- and methylcobalamin synthesis, respectively.
Complementation analysis is required to differentiate the cblC and cblF disorders.
Complementation analysis is used to differentiate cblE from cblG. CblE cells show sensitivity to reductant concentration in vitro [Rosenblatt et al 1984].
Cobalamin distribution. Cells are incubated in radio-labeled cyanocobalamin, following which various cobalamin derivatives are measured using HPLC to determine the ability of the cultured cells to carry out cobalamin-derivative interconversion.
Expanded newborn screening. In the past several years, the implementation of tandem mass spectrometry (MS/MS) in newborn screening by many states in the US and countries worldwide has identified newborns with methylmalonic acidemia through detection of elevated propionylcarnitine (C3), a metabolite increased in the blood of individuals with methylmalonic acidemia and the related disorder, propionic acidemia [Chace et al 2001].
Elevated C3 is usually observed during MS/MS testing of blood spots from individuals with MUT-only disorders.
MS/MS screening can detect persons with cblC and theoretically cblD variant 2 and cblF.
Although total homocysteine (tHcy) can be detected by MS/MS in newborn blood spots, it has not been used in newborn screening to date.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. The following genes and their complementation groups are the only ones known to be associated with MTR-only cobalamin disorders:
MMACHC (cblC)
MTRR (cblE)
MTR (cblG)
Clinical testing
Sequence analysis of MTR, MTRR, and MMACHC is available on a clinical basis.
Table 4 summarizes molecular genetic testing for these disorders.
| Gene Symbol | Complementation Group | Test Method | Mutation Detection Frequency by Gene and Test Method | Test Availability |
|---|---|---|---|---|
| MMACHC | cblC | Sequence analysis | Unknown | Clinical
 |
| MTRR | cblE | Unknown | Clinical
| |
| MTR | cblG | Unknown | Clinical
|
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Establishing the diagnosis of an MTR-only or combined MUT-MTR disorder in a proband
Metabolic screening tests such as urine organic acid analysis and plasma amino acid analysis help to categorize the clinical syndrome.
Urine organic acid analysis. If elevated MMA excretion is detected, then the following intracellular cobalamin-related inborn errors should be considered: cblA, cblB, cblC, cblD, cblD variant 1, and cblF.
Plasma amino acid analysis
Plasma concentrations of MMA, methylcitrate, free and total carnitine, and fractionated acylcarnitines (to document propionylcarnitine) should be obtained.
Plasma concentration of homocysteine should be measured as total homocysteine (not free homocysteine).
Note: Urine homocystine measurements can provide supportive data but are not as sensitive as plasma total homocysteine concentration.
Serum vitamin B12 analysis should be included to rule out vitamin B12 deficiency as a cause of elevated blood or urine MMA levels.
Molecular genetic testing. The role of molecular genetic testing in diagnosis is evolving. When molecular genetic testing identifies specific disease-causing mutations in a family, it may be faster and less expensive than complementation analysis; however, given the risk of identifying missense mutations of unknown significance, complementation analysis will be more definitive in some situations.
Skin biopsy to construct a primary fibroblast cell line should be obtained as soon as the affected individual is stable, or, in the event of poor suspected outcome, prior to death. Studies on the cell line are needed for definitive diagnosis through cellular biochemical studies.
Note: If the in vivo response to intramuscular vitamin B12 in the form of hydroxycobalamin (OH-Cbl) is questionable or borderline, OH-Cbl administration should be continued until the results of the in vitro studies are available.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in MTR, MTRR, or MMACHC.
The clinical manifestations of the disorders of intracellular cobalamin metabolism (cblC, cblD, cblD variant 1, cblD variant 2, cblF, cblE, and cblG) can be highly variable even within a single complementation class.
The prototype of the combined defect is cblC, which is also referred to as "methylmalonic acidemia and homocystinuria, cblC type," reflecting the fact that both the MTR and MUT cobalamin-requiring enzymes are affected. Because cblC is the most common of these disorders, most clinical experience derives from this condition.
In utero manifestations. Some infants with cblC are small for gestational age (SGA). SGA infants have been seen in cblF [Shih et al 1989].
Congenital microcephaly is seen in some affected newborns [Andersson et al 1999, Smith et al 2006].
Infantile presentation. Failure to thrive within the first two weeks of life is common. Acidosis is variably present. Pallor and neurologic signs, in addition to the universal observation of poor feeding, may be present.
Some infants have the hemolytic uremic syndrome and might be treated for suspected sepsis before a disorder of cobalamin metabolism is discovered [Geraghty et al 1992]. (See Atypical Hemolytic Uremic Syndrome.)
Seizures may be present and can manifest as infantile spasms.
Early presentation (first years of life). The next earliest presentation manifests as failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures.
Retinal changes and nystagmus that may be seen as early as age three months evolve, classically, into a "bull's-eye" macula within the first few years of life.
Cardiomyopathy has been described.
Cutaneous manifestations may occur [Howard et al 1997].
Young adult and adult presentation. Older individuals may present with confusion and other mental status changes accompanied by megaloblastic anemia. Adult onset of cognitive decline in the absence of other manifestations has been described [Boxer et al 2005]. Brain MRI may reveal leukodystrophy.
The presenting clinical picture may include signs of myelopathy. Post-mortem examination of one person showed cystic changes in the spinal cord [Bodamer et al 2001, Smith et al 2006].
Middle- to older-aged presentation dominated by neurologic syndrome with leukodystrophy was described in two previously healthy males in their 50s [Powers et al 2001].
A progressive microangiopathic renal syndrome may be present [Van Hove 2002]. Atypical glomerulopathy has been described [Brunelli et al 2002].
Secondary complications:
Cor pulmonale (rarely)
Retinal degeneration
Hydrocephalus
CblG is more common than cblE, which is more common than cblD variant 1.
As with cblC, some persons with cblG are severely affected whereas others may not be recognized until adulthood. As with other cobalamin disorders, some aspects of the presentation are highly variable, especially the neurologic signs and symptoms. Most children present in the first year of life with severe failure to thrive and megaloblastic anemia [Fowler et al 1997]. Developmental delays are common. Neurologic manifestations may include weakness, hypotonia, seizures, and/or mental status changes.
Other unusual presentations include an adult with megaloblastic anemia and progressive weakness [Carmel et al 1988] and an adult with neuropsychiatric illness [Hill 2004].
The two individuals with CblD variant 1 had cognitive impairment, neurologic signs, and megaloblastic anemia [Suormala et al 2004].
Secondary complications:
Clinically significant thrombophilia (rarely) causing renal artery thrombosis [Watkins & Rosenblatt 1989]
Hemolytic uremic syndrome and pulmonary hypertension [Labrune et al 1999]
Optic nerve atrophy [Poloschek et al 2005]
See Management. Prognosis and natural history have been difficult to assess for various reasons, including the following:
Small number of patients
Relatively recent availability of definitive diagnosis
Variable presentations
Variable treatment regimens
Differences in patient history before the institution of cobalamin therapy
Some affected individuals have early and severe symptoms; others, however, reach adulthood without evidence of ongoing disease progression. In some cases, severe neurologic symptoms and/or cognitive impairment persist. It is difficult to discern whether or not such impairments are sequelae of pretreatment disease progression or ongoing neurodegeneration.
No therapy has been shown to completely mitigate all disease manifestations. Some persons with cblC have developed optic atrophy, retinal degeneration, and neurologic decline despite treatment [Enns et al 1999, Patton et al 2000, Smith et al 2006]. Disease-related symptoms have appeared in persons who have been treated prenatally [Huemer et al 2005]. However, it appears that the earlier cobalamin therapy is initiated, the better the potential outcome.
Preliminary reports have discussed some association between disease manifestation and mutations.
Morel et al (2006) compiled a review of phenotype/genotype correlations among 37 previously reported individuals with cblC:
Of the 25 persons with early-onset disease, 17 were homozygous for c.271dupA or c.331C>T, or were compound heterozygotes for the two mutations.
Of the 12 persons with late-onset disease, nine had a primarily neurodegenerative disease onset. Of those nine, four were c.394C>T homozygotes, two were c.271dupA/c.394C>T compound heterozygotes, and three were c.271dupA/other missense mutation heterozygotes.
Precise delineation of these relationships requires additional study.
The nomenclature for inherited disorders of intracellular cobalamin transport and processing is based on cellular complementation analysis that defines cobalamin groups A-G (cblA - cblG).
In general, cobalamin disorders are classified into those that affect MUT only (causing methylmalonic aciduria), MTR only (causing homocystinuria/hypomethioninemia), or both MUT and MTR.
The true prevalence of the cobalamin disorders is unknown. Hundreds of cases have been described for cblC, tens of cases for cblE and cblG, and fewer than ten cases each for cblD (and variants) and cblF.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The highly variable presentations of the cobalamin disorders make for a large differential diagnosis. Selected conditions, notably those leading to detectable methylmalonyl acid excretion and hyperhomocysteinemia, are described below.
Because the infantile cblC presentation is heterogeneous, a high index of suspicion is needed to diagnose this disorder, especially when more common etiologies need to be considered in the initial workup.
Methylmalonic acidemia. As discussed in detail in Methylmalonic Acidemia, mutations in MUT, encoding methylmalonyl mutase (along with the cblA and cblB), cause a MUT-only phenotype.
"Benign" methylmalonic acidemia. Newborn screening in the province of Quebec identified infants with mild to moderate urinary MMA excretion. Follow-up revealed resolution in more than 50% of children, as well as an apparently benign, persistent, low-moderate hypermethylmalonic acidemia in some [Sniderman et al 1999]. Additional individuals with a relatively benign type of methylmalonic acidemia have been reported [Martens et al 2002].
Some of these individuals had a combined biochemical genetic phenotype of malonic and methylmalonic acidemia and therefore may not have a defect in methylmalonyl-CoA mutase activity or cobalamin metabolism [Sniderman et al 1999].
The long-term outcome and clinical phenotype of these individuals awaits further description.
SUCLA2 deficiency. Mild methylmalonic aciduria with Leigh syndrome is associated with deficiency in succinyl-CoA ligase [Ostergaard et al 2007, Carrozzo et al 2007].
Reye-like syndrome. A Reye-like syndrome of hepatomegaly and obtundation during a mild intercurrent infection is an unrecognized presentation of a number of inborn errors of metabolism, including methylmalonic acidemia [Chang et al 2000].
Other entities
Benign methylmalonic acidemia with distal renal tubular acidosis (one sibship) [Dudley et al 1998]
Malonyl-CoA decarboxylase deficiency, usually associated with significant MMA elevations and malonic acid increase relative to methylmalonic acidemia [Brown et al 1984]
Elevated MMA and malonic acid with MMA predominating [Gregg et al 1998]
Isolated methylmalonic acidemia, possibly caused by methylmalonic semialdehyde dehydrogenase deficiency [Roe et al 1998]
Isolated methylmalonic aciduria and normal plasma concentrations of methylmalonic acidemia (one family) [Martens et al 2002]
Cobalamin-unresponsive methylmalonic acidemia and progressive neurodegenerative disease with microcephaly and cataracts (two siblings) [Stromme et al 1995, Mayatepek et al 1996]
A mitochondrial deletion syndrome with a combined propionic and methylmalonic acidemia syndrome [Yano et al 2003]
Vitamin B12 deficiency. Individuals with vitamin B12 deficiency can have methylmalonic acidemia and homocystinuria, as can the newborns of mothers who have vitamin B12 deficiency. To establish the diagnosis of vitamin B12 deficiency, it is necessary to measure vitamin B12 serum concentration in both affected newborns and their mothers.
B12 deficiency can occur in a breast-fed infant of a vegan mother and in an infant born to a mother with subclinical pernicious anemia. The mother may not necessarily have a very low serum concentration of vitamin B12. Maternal vitamin B12 deficiency can produce a methylmalonic acidemia syndrome in an infant that ranges from severe encephalopathy [Higginbottom et al 1978] to elevated propionylcarnitine detected by newborn screening [Chace et al 2001].
Intramuscular replacement therapy to normalize vitamin B12 serum concentration reverses the metabolic abnormality.
Imerslund Gräsbeck syndrome. Features of this autosomal recessive disorder may include poor cobalamin absorption, abnormal renal tubular protein reabsorption, and urinary tract malformations. Two genes encoding intrinsic factor receptor components, CUBN encoding cubulin and AMN encoding amnionless, have been implicated [Grasbeck 2006].
Transcobalamin II deficiency. Transcobalamin II (distinguished from transcobalamin I AKA haptocorrin) is required for the movement of cobalamin from intestinal enterocytes into cells throughout the body. Transcobalamin II deficiency, a rare condition, is characterized by the infantile onset of megaloblastic anemia, failure to thrive, neurologic disease, and immunologic disease. Serum cobalamin concentrations are generally normal with a reduced (untreated) unsaturated B12 binding capacity (UBBS) and a reduced level of transcobalamin II (the latter detected by an immunoassay) [Kaikov et al 1991, Rosenblatt & Fenton 2001]
Cystathionine beta synthase deficiency (CBS, classic homocystinuria) is a disorder of homocysteine catabolism with a Marfan syndrome-like phenotype, soft skin, lens dislocation, developmental delays/cognitive impairment, and thromboembolism. CBS is progressive with onset typically in childhood. Biochemically it is characterized by elevated serum concentration of methionine and decreased serum concentration of cysteine.
Methylenetetrahydrofolate reductase (MTHFR) deficiency is a defect in folate-dependent methylation pathways that results in diminished conversion of homocysteine to methionine. The biochemical hallmarks are moderate homocystinuria/homocysteinemia with low to normal plasma methionine levels. In contrast to methionine biosynthetic defects like cblE and cblG, megaloblastic anemia does not occur. The clinical course is characterized by varying severity, cognitive impairment, and white-matter disease [Fenton et al 2001].
Mild hyperhomocysteinemia can result from folate deficiency, vitamin B12 deficiency, or mild mutations in enzymes in remethylation enzymes. It is thought to be a risk for premature vascular via thrombophilia.
To establish the extent of disease in an individual diagnosed with an MTR-only cobalamin syndrome, the following evaluations are recommended:
A serum chemistry panel (concentrations of Na+, K+, CI-, glucose, urea, creatinine, AST, ALT, alkaline phosphatase, bilirubin [T/U], triglycerides, and cholesterol)
A complete blood count with differential
Quantitative plasma amino acid analysis
Plasma MMA concentration
Urine organic acid analysis by GC/MS
Plasma total homocysteine concentration
Measurement of serum concentrations of vitamin B12 and RBC folate to determine if a nutritional deficiency is present and determine if folate trapping (as MeTHF) in the face of normal plasma B12 concentrations is occurring
For affected children with elevated MMA excretion, arterial (or venous) blood gas, plasma ammonium concentration, serum lactate concentration, and urine ketone measurements
Note: These investigations can be used to assess/follow disease in the presence of a known diagnosis.
Critically ill individuals must be stabilized, preferably in consultation with a metabolic specialist.
The severe acidotic/ketotic crises seen in isolated methylmalonic acidemia are less common in the combined MUT/MTR disorders. However, acute neurologic deterioration can punctuate a course marked by the insidious neurologic and developmental abnormalities seen in most patients. Aggressive therapy to both treat acidosis and reverse catabolism is warranted during acute deterioration:
Base deficits may be corrected with volume replacement and intravenous bicarbonate solutions if indicated.
Calories are initially supplied using dextrose-containing intravenous fluid given at high rates. During acute illness, adequate calories are important to arrest/prevent decompensation.
Dietary protein is initially restricted, then liberalized as tolerated. Most patients can tolerate more natural protein than patients with isolated mutase lesions.
Exacerbations can be minimized using a combination of dietary management (with a low-protein, high-calorie diet low in propiogenic amino acid precursors) and cofactor therapy. Dietary manipulation has not been systematically evaluated for MTR-only cobalamin disorders.
Cobalamin supplementation is the mainstay of therapy and must be provided after plasma vitamin B12 concentrations are measured and vitamin B12 responsiveness is determined. Hydroxycobalamin* (1-mg intramuscular injections daily) is a reasonable starting point for therapy. Dosing practices vary; some providers increase the interval between injections based on clinical assessment and MMA excretion.
* Note: Hydroxycobalamin (not the cyano form) is the preferred preparation for treatment of cobalamin disorders.
Other manifestations such as infantile spasms and seizures need specialized management.
Gastrostomy tube placement for feeding is often required when feeding problems and growth failure are present.
Dietary managment. Patients with combined MUT/MTR disorders may be able to tolerate a normal diet. The optimal management of such patients is under debate [Bartholomew et al 1988].
Patients with MTR-only cobalamin disorders generally do not need protein restriction.
Hydroxycobalamin injections. Intramuscular injections of 1 mg hydroxycobalamin approximately once every one to three days are usually required in responsive individuals. However, some individuals can be managed with less frequent injections.
Other therapies that are usually given but have not been systematically evaluated include the following:
Carnitine. For the combined MUT/MTR cobalamin disorders, carnitine can be given at a dose of 50-100 mg/kg/day. As a dietary supplement, carnitine may increase intracellular CoA pools and enhance the excretion of propionylcarnitine. However, the contribution of propionylcarnitine excretion to the total propionate load is small. The relief of intracellular CoA accretion may be the mechanism by which carnitine benefits some individuals.
Betaine. Betaine augments the nonmethionine synthase-dependent conversion of homocysteine to methionine. Some reports have questioned the efficacy of this therapy in persons with disorders of intracellular cobalamin metabolism. Further studies are required to examine dosing and useful monitoring.
Betaine is provided at the following doses:
Under age three years. 100 mg/kg/day, by mouth, divided into two doses
Over age three years. Up to 250 mg/kg/day, by mouth, divided into two doses [Bodamer & Lee 2006]
Pyridoxine. Vitamin B6 is a cofactor for cystathionine beta synthase and therefore has been proposed as a means of maximizing the removal of homocysteine. Persons with disorders of intracellular cobalamin metabolism generally do not respond to pyridoxine unless a dietary deficiency is present.
Folate and folinic acid. Folic acid and folinic acid can potentially augment remethylation. The adult dose of folate is 1 mg by mouth per day, titratable down to 0.5 mg for maintenance. Doses for children and infants are available in the Harriet Lane Handbook and other common reference texts.
Methionine supplementation. Hypomethioninemia associated with MUT/MTR and MTR-only disorders have been treated with methionine supplementation. The efficacy of this therapy is uncertain [Robb et al 1984, Smith et al 2006].
During the first year of life, infants may need to be evaluated once or twice a month. No guidelines recommend how often certain laboratory tests should be performed.
Routine medical care:
Ophthalmologic evaluation for retinal and optic nerve changes
Neurologic evaluation for early signs of psychomotor retardation, behavioral disturbances, seizures, and myelopathy
Special attention to growth and development
Potentially exacerbating circumstances:
Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
Excessive dietary protein intake (greater than RDA for age or more than prescribed by a metabolic specialist)
It is appropriate to measure the concentration of MMA, total plasma homocysteine, and/or related metabolites in urine and/or plasma of the sibs of a proband as soon as possible in order to institute treatment promptly in those who are affected.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
MedicAlert® bracelets and emergency treatment protocols outlining fluid, electrolyte, and cofactor therapy should be available for all affected individuals.
The use of cobalamin preparations other than hydroxycobalamin, including oral cyanocobalamin and intramuscular methylcobalamin injections (the latter for MTR-only types), has not been systematically evaluated.
Intramuscular cobalamin supplementation has been provided to pregnant women when the fetus is known to be affected by an intracellular cobalamin disorder. Several reports have documented the progression of disease-related complications in patients treated in utero [Patton et al 2000, Bodamer et al 2005].
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
All of the disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with a disorder of intracellular cobalamin metabolism are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Molecular genetic testing. Carrier testing using molecular genetic techniques is possible for some cobalamin disorders. Such testing requires that the disease-causing mutations in a family are known, and that clinical sequencing of the affected gene is available.
Biochemical genetic testing is not reliable enough for carrier testing.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when available testing is inconclusive or molecular genetic testing is available on a research basis only. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for cblC, cblE, or cblG is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Biochemical testing. Prenatal testing for pregnancies at 25% risk for MTR-only and MUT/MTR-combined cobalamin syndromes is possible by:
Enzyme analysis of cultured fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Biochemical confirmation of the diagnosis in an affected family member must be obtained before prenatal testing can be performed.
Amniotic fluid analysis of metabolites. The absolute positive predictive and negative predictive values of metabolite analysis only have yet to be determined but appear to aid the diagnosis in most cases [Morel et al 2005].
Prenatal diagnosis for both combined MUT/MTR and MTR-only cobalamin syndrome types has been demonstrated using complementation analysis of cultured amniocytes [Morel et al 2005]. Although clinical testing is available through specialized laboratories, examples of positive screens (thus confirming the efficacy of the method) have not been reported for all complementation classes.
Note: The most prudent recommendation is to perform both metabolite analysis AND enzymatic assays of cultured CVS or amniocytes.
No laboratories offering molecular genetic testing for prenatal diagnosis of cblD, cblD variant 1, cblD variant 2, or cblF are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| MMACHC | 1p34.1 | Methylmalonic aciduria and homocystinuria type C protein |
| MTR | 1q43 | Methionine synthase |
| MTRR | 5p15.3-p15.2 | Methionine synthase reductase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 156570 | 5-@METHYLTETRAHYDROFOLATE-HOMOCYSTEINE S-METHYLTRANSFERASE; MTR |
| 236270 | HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE |
| 250940 | METHYLCOBALAMIN DEFICIENCY, cblG TYPE |
| 277380 | METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblF TYPE |
| 277400 | METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE |
| 277410 | METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE |
| 602568 | METHIONINE SYNTHASE REDUCTASE; MTRR |
| 609831 | MMACHC GENE |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| MMACHC | 25974 (MIM No. 609831) | |
| MTR | 4548 (MIM No. 156570) | MTR |
| MTRR | 4552 (MIM No. 602568) | MTRR |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Figure 1. Pathways utilizing cobalamin derivatives. Cbl indicates cobalt atom and possible valence state (indicated by superscripted Roman numerals). (modified from Chandler & Venditti 2005)
Figure1)
MMACHC
Normal allelic variants: MMACHC is 11 kb and contains five exons [Lerner-Ellis et al 2006].
Pathologic allelic variants: Lerner-Ellis et al (2006) detected 42 different mutations in 204 individuals. One mutation, 271dupA, accounted for 40% of disease alleles.
Normal gene product: The methylmalonic aciduria and homocystinuria type C protein is 282 amino acids and has a predicted molecular weight of 37.1 kd. The C-terminal region may fold similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. A putative vitamin B12-binding pocket may also be present.
Abnormal gene product: The most common 271dupA mutation results in a change of amino acid 91 from arginine to lysine followed by a frameshift causing a premature stop codon [Lerner-Ellis et al 2006].
MTR
Normal allelic variants: MTR is 105.24 kb and is made up of 33 exons [Brody et al 1999].
Pathologic allelic variants: Watkins et al (2002) studied 21 persons with methylcobalamin deficiency G (cblG) disorder, identifying 13 novel mutations. Truncations and nonsense mutations made up 7/13. They also found a previously described missense mutation, Pro1173Leu, in 16 persons in an expanded panel of 24 affected individuals. Maternal genotypes of 2576 AG or GG have been reported to be associated with an increased risk of cleft lip and palate [Mostowska et al 2006]. A subset of severe disease-causing mutations, including (IVS)-166A>G and 2112delTC, are thought to result in premature translation termination and mRNA instability [Wilson et al 1998]. Leclerc et al (1996) and Chen et al (1997) identified a common 2756A>G polymorphism in MTR. Further study has looked at a possible association with neural tube defects [Christensen et al 1999].
Normal gene product: The MTR enzyme has 1265 amino acids and weighs 140.5 kd. There are at least three functional domains. The 38-kd C-terminal domain binds AdoMet. A domain comprising amino acids 650 to 896 includes the binding domain for the required cofactor methylcobalamin. The 70-kd N-terminal domain binds homocysteine and methyltetrahydrofolate. The latter two activities may be on separate domains within this region [Goulding et al 1997].
Abnormal gene product: Leclerc et al (1996) identified two disease-causing mutations specifically near the cobalamin binding domain.
MTRR
Normal allelic variants: MTRR is 31.95 kb and contains 15 exons [Leclerc et al 1998].
Pathologic allelic variants: No clear single allele has been shown to predominate among the few that have been reported among affected individuals:
1675del4 [Leclerc et al 1998]
1726delTTG [Leclerc et al 1998]
1459G>A [Zavadakova et al 2002]
1623-1624insTA [Zavadakova et al 2002]
903>904ins140 [Zavadakova et al 2002]
1361C>T (5 alleles, with Iberian ancestry, among nine persons) [Zavadakova et al 2005]
Normal gene product: The MTRR protein contains 725 amino acids and has a mass of 80.4 kd. It shares 38% sequence identity with human cytochrome P450 reductase [LeClerc et al 1998]. MTRR has some chaperone-like activity with regard to MTR [Yamada et al 2006]. A mitochondrial isoform of MTRR has been predicted [LeClerc et al 1999].
Abnormal gene product: Most reported mutations have been nonconservative missense mutations. 903>904ins140 is likely to be a splice-affecting mutation in intron 6 of MTRR [Zavadakova et al 2002].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Methylmalonic acidemia
Organic Acidemia Association
13210 35th Avenue North
Plymouth MN 55441
Phone: 763-559-1797
Fax: 763-694-0017
Email: oaanews@aol.com
www.oaanews.org
Save Babies Through Screening Foundation, Inc
4 Manor View Circle
Malvern PA 19355-1622
Phone: 888-454-3383
Fax: 610-647-5757
Email: email@savebabies.org
www.savebabies.org/index.htm
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Dr. Adams is a pediatrician and biochemical geneticist. He is an assistant clinical investigator at the National Human Genome Research Institute at the National Institutes of Health.
Dr. Venditti is a pediatrician and biochemical geneticist. He is the director of the Organic Acid Disorder Research Unit at the National Human Genome Research Institute and an attending physician at the National Institutes of Health Clinical Center.
25 February 2008 (me) Review posted to live Web site
22 December 2006 (cpv) Original submission
