Clinical characteristics.

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range:

• In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction
• Newborns, who can have microcephaly, poor feeding, and encephalopathy
• Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS)
• Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures
• Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord

Diagnosis/testing.

The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data. Evaluation of the methylmalonic acid (MMA) level in urine and blood and plasma total homocysteine (tHcy) level are the mainstays of biochemical testing. Diagnosis is confirmed by identification of biallelic pathogenic variants in one of the following genes (associated complementation groups indicated in parentheses): MMACHC (cblC), MMADHC (cblD-combined and cblD-homocystinuria), MTRR (cblE), LMBRD1 (cblF), MTR (cblG), ABCD4 (cblJ), THAP11(cblX-like), ZNF143(cblX-like), or a hemizygous variant in HCFC1 (cblX, which can show a cblC complementation class).

Management.

Treatment of manifestations: Critically ill individuals must be stabilized, preferably in consultation with a metabolic specialist, by treating acidosis, reversing catabolism, and initiating parenteral hydroxocobalamin. Treatment of thromboembolic complications (e.g., HUS and thrombotic microangiopathy) includes initiation of hydroxocobalamin (OHCbl) and betaine or an increase in their doses. Long-term management focuses on improving the metabolic derangement by lowering plasma tHcy and MMA concentrations and maintaining plasma methionine concentrations within the normal range. Gastrostomy tube placement for feeding may be required; infantile spasms, seizures, congenital heart malformations, and hydrocephalus are treated using standard protocols.

Prevention of primary manifestations: Early institution of injectable hydroxocobalamin improves survival and may reduce but not completely prevent primary manifestations. To prevent metabolic decompensations, patients are advised to avoid situations that result in catabolism, such as prolonged fasting and dehydration, and always remain on a weight-appropriate dose of hydroxocobalamin.

Surveillance: During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist to assess growth, nutritional status, feeding ability, and developmental and neurocognitive progress. Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and evaluate nutritional status. Teens and adults may be seen on a yearly basis. Routine ophthalmologic, neurologic, and cardiac evaluations may also be appropriate.

Agents/circumstances to avoid: Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids); dietary protein intake below the recommended dietary allowance for age or more than that prescribed by a metabolic specialist; methionine restriction including use of medical foods that do not contain methionine; and the anesthetic nitrous oxide.

Evaluation of relatives at risk: If the pathogenic variants in the family are known, at-risk sibs may be tested prenatally to allow initiation of treatment in utero or as soon as possible after birth.

If the newborn sib of an affected individual has not undergone prenatal testing, molecular genetic testing can be performed in the first week of life if the pathogenic variants in the family are known. Otherwise, evaluation of urine organic acids and plasma amino acids, measurement of total plasma homocysteine, serum methylmalonic acid analysis, and acylcarnitine profile analysis can be used for the purpose of early diagnosis and treatment.

Genetic counseling.

The majority of disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner. 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. The disorder of intracellular cobalamin metabolism caused by pathogenic variants in HCFC1 is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has an HCFC1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygous and will usually not be affected (no affected females have been described to date).

Once the pathogenic variant(s) have been identified in an affected family member, carrier testing for at-risk relatives, molecular genetic prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

A disorder of intracellular cobalamin metabolism should be suspected in individuals with the following physical and laboratory findings.

Physical findings

• In utero. Nonimmune hydrops, cardiomyopathy, intrauterine growth restriction
• Newborns. Microcephaly, poor feeding, encephalopathy
• Infants. Poor feeding and slow growth, hypotonia, developmental delay, seizures including infantile spasms, infantile maculopathy. Rarely, hemolytic uremic syndrome and obtundation.
• Toddlers. Poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, hypotonia, seizures
• Adolescents and adults. Neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, subacute combined degeneration of the spinal cord

Laboratory findings

• Macrocytic anemia with normal B₁₂ levels, thrombocytopenia, and/or neutropenia
• Hyperammonemia and/or metabolic acidosis in infancy (rare)

Newborn with abnormal newborn screening based on elevated C3 propionylcarnitine or decreased methionine (See ACMG ACT Sheets for C3 and methionine.)

• Detection by newborn screening (NBS) depends on the C3 and C3/C2 ratio cutoff values used by reference laboratories and the availability of detection of low methionine [Chace et al 2001, Weisfeld-Adams et al 2010, Huemer et al 2015b]. cblD-homocystinuria, cblE, and cblG do not have elevated C3 and are often not identified on newborn screening. In some US states, detection of low methionine and the use of an NBS tool (clir.mayo.edu; registration required) in combination with measurement of homocysteine has sucessfully identified individuals with cblE and cblG [Wong et al 2016].
• Since NBS potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed before the onset of symptoms.

Establishing the Diagnosis

The diagnosis of a disorder of intracellular cobalamin metabolism is established in a proband with specific biochemical testing results (see Biochemical Testing and Table 2) and confirmed by identification of biallelic pathogenic variants in one of the genes listed in Table 3 – with the exception of HCFC1, in which a hemizygous pathogenic variant is confirmatory. For equivocal molecular genetic testing results, enzymatic testing on skin fibroblasts can be used.

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of a disorder of intracellular cobalamin metabolism, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

• Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of MMACHC first in individuals with biochemical findings of combined AdoCbl and MeCbl deficiency as it is by far the most commonly associated gene (Figure 2). If only one pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. If single-gene testing is nondiagnostic, a multigene panel is the next step.
• A multigene panel for inherited disorders of intracellular cobalamin metabolism that includes the genes listed in Table 3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Figure 2.

Testing algorithm to confirm the diagnosis of a disorder of intracellular cobalamin metabolism in a proband Footnotes:

Complementation Group Analysis

Complementation analysis is a method used historically to diagnose the specific defects of intracellular cobalamin metabolism using cultured skin fibroblasts [Watkins & Rosenblatt 1986]. Because of the availability of molecular genetic testing this method is now performed infrequently, but it may still be useful for individuals with equivocal molecular results.

Clinical Description

Disorders of intracellular cobalamin metabolism have a variable phenotype (Table 4) and age of onset that are influenced by the severity and location within the pathway of the defect.

Genotype-Phenotype Correlations

Genotype-phenotype correlations observed include the following:

cblC

• Infantile-presentation (early-onset), severe disease is associated with the MMACHC pathogenic variants c.271dupA or c.331C>T in the homozygous or compound heterozygous state.
• Noninfantile presentation (late onset) is usually associated with MMACHC pathogenic variants c.394C>T and MMACHC c.482G>A [Morel et al 2006, Nogueira et al 2008, Lerner-Ellis et al 2009, Wang et al 2009, Almannai et al 2017]. It may also be associated with MMACHC variant c.271dupA if individuals are compound heterozygotes for c.394C>T, c.347T>C, c.440 G>C, or c.482G>A [Morel et al 2006].

cblD. The location of pathogenic variants within MMADHC correlates with the type of enzyme deficiency:

• AdoCbl deficiency. Typically, pathogenic nonsense and frameshift variants are found in exons 3 and 4, encoding the region of the protein necessary for AdoCbl synthesis.
• MeCbl deficiency. Pathogenic missense variants are found in exons 6 and 8, encoding the C-terminal region of the protein necessary for MeCbl synthesis.
• AdoCbl and MeCbl deficiency. Pathogenic variants occur in exon 5, exon 8, and intron 7, encoding the middle of the protein [Stucki et al 2012].

cblE, caused by the MTRR c.1361C>T (p.Ser545Leu) Iberian pathogenic variant, has a milder phenotype than other reported pathogenic variants in MTRR with no evident neurologic involvement [Zavadáková et al 2002].

Clear genotype-phenotype correlations have not been described for cblF, cblG, cblJ, or cblX.

Prevalence

The true prevalence of the disorders of intracellular cobalamin metabolism is unknown.

• The incidence of cblC has been estimated at 1:200,000 births. Newborn screening suggested an incidence closer to 1:100,000 in New York State and 1:67,000 in California, where an incidence of 1:46,000 was estimated in the Hispanic population [Cusmano-Ozog et al 2007, Weisfeld-Adams et al 2010].
• Fewer than 40 cases have been described for cblE and cblG, and fewer than 20 cases each for cblD, cblF, cblJ, and cblX and its related types.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a disorder of intracellular cobalamin metabolism, the following evaluations are recommended.

In an unstable individual:

• Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes
• Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias
• Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)

Once the individual becomes stable:

• Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status
• Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias
• Echocardiogram to screen for cardiac defects and cardiomyopathy [Profitlich et al 2009, Tanpaiboon et al 2013]
• EEG and brain MRI in symptomatic individuals
• Ophthalmologic examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A set of guidelines for the diagnosis and management of cblC, cblD, cblE, cblF, cblG, cblJ, and MTHFR deficiency have been published [Huemer et al 2017].

Early treatment with hydroxocobalamin injections improves survival and biochemical, hematologic, and microangiopathic symptoms in individuals with cblC. Both newborn screening (NBS) and early treatment are recommended by current guidelines [Huemer et al 2015b, Huemer et al 2017].

Institution of therapy during acute illness results in rapid improvement of clinical, biochemical, and hematologic manifestations in individuals with early- and late-onset cblC [Bartholomew et al 1988, Rosenblatt et al 1997, Bodamer et al 2001, Tomaske et al 2001, Kind et al 2002, Van Hove et al 2002, Fowler et al 2008].

Prevention of Primary Manifestations

Early institution of injectable hydroxocobalamin improves survival and may reduce but not completely prevent primary manifestations.

To prevent metabolic decompensations, affected individuals should be advised to avoid situations that result in catabolism, such as prolonged fasting and dehydration, and always remain on a weight-appropriate dose of hydroxocobalamin. Of note, during an intercurrent illness individuals may be treated with glucose-containing IV fluid.

Flu prevention (i.e., immunization) should be a routine part of health maintenance.

Surveillance

The following evaluations are performed at different intervals depending on age and disease severity:

• During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.
• Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.
• Teens and adults may be seen on a yearly basis.

Clinical evaluation should assess the following:

• Growth including weight, linear growth, and head circumference
• Nutritional status
• Feeding ability
• Developmental and neurocognitive progress, as age-appropriate

Laboratory evaluation should include the following:

• Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration
• CBC to monitor for cytopenias
• Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals

Routine evaluations should include the following:

• Ophthalmologic evaluation for retinal and optic nerve changes in those with cblC and cblG and if visual symptoms are present. Recommendations for the ophthalmologic follow up of individuals with cblC and related disorders have been published [Weisfeld-Adams et al 2015].
• Neurologic evaluations for early signs of developmental delays, behavioral disturbances, seizures, and myelopathy
• Brain MRI and/or EEG as clinically indicated
• Echocardiogram

Agents/Circumstances to Avoid

Potentially exacerbating circumstances:

• Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
• Dietary protein intake below the recommended dietary allowance (RDA) for age
• Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with cblC, cblD-combined, cblF, or cblJ
• Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth [Manoli et al 2016, Ahrens-Nicklas et al 2017], among other complications.
• Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B₁₂ and inhibits methionine synthase activity [Kondo et al 1981, Abels et al 1990, Drummond & Matthews 1994, Baum 2007]

Evaluation of Relatives at Risk

If the pathogenic variant(s) in the family are known, at-risk sibs may be tested prenatally to allow initiation of treatment in utero or as soon as possible after birth.

If the newborn sib of an affected individual has not undergone prenatal testing, molecular genetic testing can be performed in the first week of life if the pathogenic variant(s) in the family are known. If the pathogneic variant(s) are not known, evaluation of urine organic acids and plasma amino acids, measurement of total plasma homocysteine, serum methylmalonic acid analysis, and acylcarnitine profile analysis can be used for the purpose of early diagnosis and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

A good pregnancy outcome was reported in two women with cblC [Brunel-Guitton et al 2010, Liu et al 2015]. In addition, an unaffected infant was born to an asymptomatic woman with cblC who was diagnosed following her child's positive NBS for low carnitine [Lin et al 2009].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Disorders of intracellular cobalamin metabolism caused by pathogenic variants in ABCD4, LMBRD1, MMACHC, MMADHC, MTR, MTRR, THAP11, or ZNF143 are inherited in an autosomal recessive manner.

The disorder of intracellular cobalamin metabolism caused by pathogenic variants in HCFC1 is inherited in an X-linked manner.

A single report of a deceased child with a paternally inherited LMBRD1 pathogenic variant and a maternally inherited MTR pathogenic variant suggests that digenic inheritance may also be possible [Farwell Gonzalez et al 2015].

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with a disorder of intracellular cobalamin metabolism are obligate heterozygotes (carriers) for an ABCD4, LMBRD1, MMACHC, MMADHC, MTR, MTRR, THAP11, or ZNF143 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ABCD4, LMBRD1, MMACHC, MMADHC, MTR, MTRR, THAP11, or ZNF143 pathogenic variant.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizyous for the HCFC1 variant, and he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the HCFC1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo HCFC1 pathogenic variant, in which case the mother is not a heterozygote (carrier). Because very few families with HCFC1 pathogenic variants have been described, the frequency of de novo pathogenic variants is not known.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother.

• If the mother of the proband has an HCFC1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygous and will usually not be affected (no affected females have been described to date).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the HCFC1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.

Offspring of a proband. Affected males transmit the HCFC1 variant to:

• All of their daughters, who will be carriers (heterozygotes) and will usually not be affected; and
• None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the HCFC1 pathogenic variant, and the aunts' offspring, depending on their sex, may be at risk of being heterozygotes for the pathogenic variant (carrier females) or of being affected (males).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the pathogenic variant(s) have been identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical testing. If the pathogenic variant(s) have not been identified in an affected family member, prenatal testing for pregnancies at risk for a disorder of intracellular cobalamin metabolism may be possible using these methods:

• Complementation analysis of cultured amniocytes [Morel et al 2005, Watkins & Rosenblatt 2014]
• Measurement of MMA and tHcy concentrations in amniotic fluid using mass spectrometric techniques [Morel et al 2005, Watkins & Rosenblatt 2014].

ABCD4

Gene structure. The longest transcript variant of ABCD4 is 3,157 bp with 19 exons (NM_005050.3) [Holzinger et al 1998]. Alternative splicing results in multiple transcript variants.

Pathogenic variants. Missense, frameshift, and splicing variants have been reported [Coelho et al 2012, Kim et al 2012].

Normal gene product. The ABCD4 protein contains 606 amino acids (NP_005041.1) and has a mass of 73 kd [Shani et al 1997]. It is an ATP-binding cassette (ABC) transporter that colocalizes with lysosomal proteins LAMP1 and LMBRD1 (cblF). It is thought that its ATPase activity may be involved in the intracellular processing of cobalamin [Coelho et al 2012].

Abnormal gene product. Pathogenic variants are expected to affect the lysosomal transport of cobalamin into the cytoplasm [Coelho et al 2012].

HCFC1

Gene structure. HCFC1 is a gene of about 24 kb; it comprises 26 exons.

Pathogenic variants. Five missense variants were identified in 14 individuals with cblX: c.202C>G, c.217G>A, c.218C>T, c.343G>A, and c.344C>T [Yu et al 2013]. These variants were located in the first two Kelch domains, which are conserved ~50-amino-acid sequences that interact to form a β-propeller structure and are involved in protein-protein interactions. An additional variant, c.307T>C, was reported in another family [Gérard et al 2015].

Other HCFC1 variants have been reported in individuals with intellectual disability with or without congenital malformations, in the absence of known biochemical abnormalities (although biochemical testing has not always been performed) [Huang et al 2012, Jolly et al 2015, Koufaris et al 2016].

Variants listed in Table 5 are only those HCFC1 variants reported to cause a cobalamin disorder phenotype.

Normal gene product. HCFC1 encodes host cell factor C-1 (aka HCF-1), a transcriptional coregulator. The protein is 2,035 amino acids long and is known to interact with transcription factors including those encoded by THAP11 and ZNF143. The HCFC1 complex has been reported to regulate hundreds of genes [Dejosez et al 2010].

Abnormal gene product. Fibroblasts from individuals with p.Ala73Val and p.Ala115Val showed decreased MMACHC RNA and protein expression, suggesting the failure of mutated HCFC1 protein to regulate MMACHC expression – potentially the result of disrupted protein-protein interactions via the Kelch domains.

LMBRD1

Gene structure. LMBRD1 is a gene of 121 kb; it comprises 16 exons [Rutsch et al 2009].

Pathogenic variants. Rutsch et al [2009] studied 12 unrelated individuals with cblF confirmed by complementation analysis. A common variant, c.1056delG, was seen in 18/24 independent alleles; this variant causes a frameshift yielding a premature stop codon in exon 11 [Rutsch et al 2009]. Altogether five different DNA variants accounted for 22 of 24 observed pathogenic variants. Eight additional variants have been reported including small deletions, splice site variants, and a large (6-kb) deletion, the latter described by Miousse et al [2011].

Normal gene product. The probable lysosomal cobalamin transporter LMBR1 domain-containing one protein (LMBD1) is 540 amino acids and has a predicted molecular weight of 61.3 kd (the longest isoform). The predicted protein structure includes nine transmembrane regions and multiple potential glycosylation sites. The protein has been shown by immunocytofluorescence to colocalize with the lysosomal marker LAMP1. The protein is predicted to be a lysosomal membrane transporter [Rutsch et al 2009] and interacts in a complex with ABCD4 (cblJ) [Fettelschoss et al 2017].

Abnormal gene product. Pathogenic variants cause the defective release of cobalamin from lysosomes.

MMACHC

Gene structure. MMACHC is 11 kb and comprises four exons [Lerner-Ellis et al 2006].

Pathogenic variants. More than 90 variants have been identified in persons with cblC. Table 7 includes variants common in certain populations, such as c.609G>A, which is common in individuals of Chinese ancestry. The most common variant, present in an estimated 30%-50% of alleles, is c.271dupA, historically associated with infantile-onset disease.

Recently, three individuals who are double heterozygous for pathogenic variants in MMACHC and PRDX1 have been identified. PRDX1 is a neighboring gene on chromosome 1 transcribed from the reverse strand. Variants identified in PRDX1 located at the intron 5 splice acceptor site caused skipping of exon 6, transcription of antisense MMACHC, and hypermethylation of the MMACHC promoter/exon 1, resulting in no gene expression from that allele [Guéant et al 2018].

Normal gene product. The methylmalonic aciduria and homocystinuria type C (MMACHC) protein has 282 amino acids and a predicted molecular weight of 31.7 kd. The MMACHC protein has been crystallized and in vitro studies have shown that MMACHC removes the upper B-axial ligand of cobalamin derivatives (e.g., CN, OH, Ado, Me) through dealkylation or decyanation using glutathione; it is also thought to be involved in intracellular trafficking of cobalamins [Koutmos et al 2011]. MMACHC resides in a complex with MMADHC and other proteins in the pathway [Gherasim et al 2013, Bassila et al 2017].

Abnormal gene product. Defects in MMACHC disrupt its ability to process newly internalized cobalamins in the cytosol [Hannibal et al 2009].

MMADHC

Gene structure. MMADHC, previously known as C2orf25, is 18 kb and comprises eight exons (NM_015702.2) [Coelho et al 2008].

Pathogenic variants. There are no clearly identified common disease-causing variants; 13 variants have been reported to date. Pathogenic variants in MMADHC can result in three different phenotypes – cblD-MMA (AdoCbl deficiency), cblD-Hcy (MeCbl deficiency), and cblD-combined (AdoCbl and MeCbl deficiency). The pathogenic variants described to date are either missense or truncating (nonsense, splice, or frameshift) variants.

• Truncating variants in exons 3 and 4, encoding the N-terminus of the protein, cause AdoCbl deficiency (cblD-MMA) [Coelho et al 2008, Plesa et al 2011, Stucki et al 2012].
• Missense variants in exons 6 and 8, encoding the C-terminus, cause MeCbl deficiency (cblD-Hcy) [Coelho et al 2008, Stucki et al 2012].
• Truncating variants in exons 5, 7, and 8 and intron 7 cause combined AdoCbl and MeCbl deficiency [Coelho et al 2008, Stucki et al 2012].

Normal gene product. The MMADHC product is predicted to have 296 amino acids with a calculated molecular mass of 32.8 kd (NP_056517.1) [Stucki et al 2012]. There is an N-terminal mitochondrial leader sequence [Coelho et al 2008]. The C-terminus is thought to guide vitamin B₁₂ to methionine synthase [Plesa et al 2011]. In vitro studies suggest that MMADHC does not directly bind cobalamin but may act as a chaperone given that it binds to MMACHC [Deme et al 2012, Gherasim et al 2013]. The crystal structure showed that MMADHC is a modified nitroreductase fold with structural similarity to MMACHC [Froese et al 2015, Yamada et al 2015].

Abnormal gene product. The type and location of pathogenic variants within the protein is thought to determine whether the synthesis of AdoCbl, MeCbl, or both is affected. Variants in the region encoding the mitochondrial targeting sequence (amino acid position 1-61) affect AdoCbl synthesis.

MTR

Gene structure. MTR is 105.24 kb and comprises 33 exons [Brody et al 1999].

Pathogenic variants. About 40 pathogenic variants have been identified. The most common disease-causing allele in persons with cblG is a missense variant, c.3518C>T, accounting for 40% of alleles [Watkins et al 2002].

A subset of severe pathogenic variants (including frameshifting deletions and nonsense variants) [Watkins et al 2002] and a variant resulting in a cryptic splice site are thought to result in premature translation termination and mRNA instability [Wilson et al 1998, Watkins et al 2002].

Leclerc et al [1996] identified two pathogenic variants specifically near the cobalamin-binding domain.

Normal gene product. The MTR enzyme has 1,265 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. Pathogenic variants are expected to decrease enzymatic activity.

MTRR

Gene structure. The longest transcript variant of MTRR (NM_002454.2) comprises 15 exons and encodes the shorter protein isoform of 698 amino acids (NP_002445.2). In comparison, the transcript variant NM_024010.2 uses an alternate splice site in the 5' region and initiates translation at an alternate start codon. The encoded protein isoform NP_076915.2 has 725 amino acids with a longer N-terminus.

Pathogenic variants. More than 25 variants in MTRR have been reported.

• The most common disease-causing variant, accounting for 25% of alleles, is a deep intronic variant in intron 6 (c.903+469T>C) that activates a splice enhancer site in a pseudoexon resulting in its inclusion [Zavadáková et al 2002, Zavadáková et al 2005, Homolova et al 2010].
• The c.1361C>T variant is common in persons of Iberian ancestry. Reports suggest a milder phenotype with no neurologic involvement [Zavadáková et al 2005].

Other variants have been described [Leclerc et al 1999, Zavadáková et al 2002]. Most reported variants have been nonconservative missense variants.

Normal gene product. The MTRR protein isoform NP_002445.2 has 698 amino acids. MTRR shares homology with human cytochrome P450 reductase [Leclerc et al 1999]. MTRR has some chaperone-like activity with regard to MTR [Yamada et al 2006]. The longer N-terminus isoform NP_076915.2 was initially predicted to have a mitochondrial leader sequence [Leclerc et al 1999], but in vitro experiments suggest that the protein is primarily cytosolic [Froese et al 2008].

Abnormal gene product. Pathogenic variants are expected to decrease enzymatic activity.

THAP11

Gene structure. The THAP11 transcript NM_020457.2 is ~2 kb and contains a single exon.

Pathogenic variants. A single variant, NM_020457.2:c.240C>G (p.Phe80Leu), was identified in the homozygous state in a single individual with a cblX-like clinical and biochemical phenotype [Quintana et al 2017].

Normal gene product. The transcript (NM_020457) encodes a 314-amino-acid protein (NP_065190.2). THAP11 (THAP containing protein 11) is a transcription factor located in a complex with HCFC1, ZNF143, and other proteins that regulate the expression of hundreds of genes including MMACHC.

Abnormal gene product. The variant reported may interfere with DNA binding or disrupt the interactions with HCFC1, ZNF143, and other proteins in the complex, resulting in decreased expression of MMACHC and other genes.

ZNF143

Gene structure. The gene is 67 kb and is composed of 16 exons.

Pathogenic variants. The two variants shown in Table 11 have been reported in a single case [Pupavac et al 2016].

Normal gene product. The longest transcript is 2.9 kb (NM_003442) encoding a protein of 638 amino acids. ZNF143 is a transcription factor located in a complex with HCFC1, THAP11, and other proteins that regulate the expression of hundreds of genes.

Abnormal gene product. The variants reported may interfere with DNA binding or disrupt the interactions with HCFC1, ZNF143, and other proteins in the complex, resulting in decreased expression of MMACHC and other genes.

Author Notes

Dr Sloan is a genetic counselor and researcher at the National Human Genome Research Institute at the National Institutes of Health.

Dr Carrillo is a pediatrician and biochemical geneticist. She is an attending physician at the National Human Genome Research Institute at the National Institutes of Health.

Dr Adams is a pediatrician and biochemical geneticist. He is an attending physician 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, a Senior Investigator in the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.

Revision History

• 16 December 2021 (js) Revision: Figure 2 corrected
• 6 September 2018 (ha) Comprehensive update posted live
• 21 November 2013 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: targeted mutation analysis for c.271dupA mutation in cblC and prenatal diagnosis for cblD and variants available clinically.
• 2 June 2009 (cd) Revision: sequence analysis available clinically for MMADHC mutations causing cblD, cblD variant 1, and cblD variant 2
• 25 February 2008 (me) Review posted live
• 22 December 2006 (cpv) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Disorders of Intracellular Cobalamin Metabolism" is in the public domain in the United States of America.

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