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Disorders of Intracellular Cobalamin Metabolism

, PhD, MS, , MD, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: September 6, 2018.

Summary

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 compications, 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 diagnosis are possible.

GeneReview Scope

Disorders of Intracellular Cobalamin Metabolism: Included Phenotypes
  • cblC
  • cblD-combined
  • cblD-homocystinuria
  • cblE
  • cblF
  • cblG
  • cblJ
  • cblX

Diagnosis

The disorders of intracellular cobalamin metabolism result from deficient synthesis of the coenzymes derived from vitamin B12:

  • Adenosylcobalamin (AdoCbl) – the coenzyme for methylmalonyl-CoA mutase enzyme
  • Methylcobalamin (MeCbl) – the coenzyme for the enzyme methionine synthase (MTR) (Figure 1)
Figure 1. . Intracellular metabolism of cobalamin.

Figure 1.

Intracellular metabolism of cobalamin. The intracellular cobalamin metabolism and related pathways – including the complementation groups and corresponding genes – are shown. Endocytosis of cobalamin bound to its blood carrier transcobalamin (more...)

This GeneReview describes inborn errors of cobalamin metabolism, including disorders with combined methylmalonic acidemia and homocystinuria caused by AdoCbl and MeCbl deficiency (Table 1 – B) as well as disorders associated with homocystinuria (MeCbl deficiency) (Table 1 - C). For disorders associated with isolated methylmalonic acidemia (AdoCbl deficiency) (Table 1 – A) see Isolated Methylmalonic Acidemia).

Note: All the disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner except for cblX (associated with pathogenic variants in HCFC1), which is inherited in an X-linked manner.

Table 1.

Disorders of Intracellular Cobalamin Metabolism by Biochemical Phenotype

Biochemical PhenotypeComplementation Group 1Gene
A. Methylmalonic acidemia (AdoCbl deficiency) 2cblAMMAA
cblBMMAB
cblD-methylmalonic aciduriaMMADHC 3
B. Combined methylmalonic acidemia and homocystinuria 4 (AdoCbl and MeCbl deficiency)cblC 5MMACHC 6
PRDX1 7
HCFC1 8 (cblX)
THAP11 7
ZNF143 9
cblD-combinedMMADHC 3
cblFLMBRD1
cblJABCD4 10
C. Homocystinuria 4 (MeCbl deficiency)cblD-homocystinuriaMMADHC 3
cblEMTRR
cblGMTR

Note: The terms methylmalonic acidemia and methylmalonic aciduria are synonymous, as are the terms hyperhomocysteinemia and homocystinuria.

1.

The nomenclature for inherited disorders of intracellular cobalamin metabolism is based on cellular complementation analysis that defines cobalamin groups A-J (cblA - cblJ). The name of each disorder is prefixed with "cbl" (for cobalamin) followed by a unique capital letter for its complementation group determined by somatic cell analysis (e.g., cblC represents complementation group C).

2.

cblA, cblB, and cblD-methylmalonic aciduria are discussed in detail in Isolated Methylmalonic Acidemia and briefly under Differential Diagnosis.

3.
4.

The homocystinuria seen in disorders of intracellular cobalamin metabolism is associated with low/normal methionine in contrast to the homocystinuria seen in cystathionine beta-synthase deficiency, which is associated with high methionine (see Figure 1).

5.

Individuals with cblX can show a cblC complementation class.

6.

A rare complex variant of MMACHC and adjacent gene PRDX1 has been described [Guéant et al 2018]; see Molecular Genetics.

7.
8.
9.
10.

The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data. With the availability of molecular genetic testing, complementation group analysis is no longer frequently used.

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 Sheetsfor 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 (www.clir-r4s.org; 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.

Biochemical Testing

The identification of disorders of intracellular cobalamin metabolism relies on the following testing (Table 2):

  • Urine organic acid (UOA) analysis to screen for elevation of methylmalonic acid (MMA). Other secondary metabolites such as 3-hydroxypropionate, methylcitrate, and tiglylglycine may be seen transiently in symptomatic affected individuals.
  • Serum methylmalonic acid analysis is more quantitative than urine organic acid analysis.
  • Total plasma homocysteine (tHcy) analysis is the preferred method of detecting plasma homocysteine.
    Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [Ubbink 2000, Refsum et al 2004].
  • Plasma amino acid (PAA) analysis. Hypomethioninemia, seen in disorders with defective MeCbl synthesis, helps differentiate disorders of intracellular cobalamin metabolism from other causes of homocystinuria, such as cystathionine beta-synthase deficiency, in which methionine level is elevated (see Differential Diagnosis, Cystathionine beta-synthase deficiency).
    Other findings that can be seen on PAA analysis:
    • Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
    • Cystathionine (which is also excreted in the urine) in individuals with cblC
  • Serum vitamin B12 levels to exclude vitamin B12 deficiency
    Note: cblF and cblJ disorders are the exceptions and have been reported to have low B12 levels at diagnosis.
  • Plasma acylcarnitine analysis to detect elevation of propionylcarnitine (C3) or confirm the elevated propionylcarnitine following newborn screening

Table 2.

Metabolite Concentrations in Disorders of Intracellular Cobalamin Metabolism

Methylmalonic AcidPlasma Total Homocysteine (tHcy)Plasma Methionine
UrineBlood
Biochemical PhenotypeComplementation GroupNormal Values
<4 mmol/mol/Cr 1<0.27 µmol/L 13-13 µmol/L11-37 µmol/L
Values by Biochemical Phenotype
Combined AdoCbl & MeCbl deficiencycblC 1100s to low 1,000s of mmol/mol Cr when ill or at presentation; generally ranging from 10s to 100s mmol/mol Cr during treatment100s of µmol/L at presentation and when ill; 1-10 µmol/L when well & treated 2>100 when ill; 20-80 µmol/L when well & treated 2Low to normal
cblD-combined 3Can be >1,000 mmol/mol CrNR>100 µmol/L in some casesLow to normal
cblF 4200 mmol/mol/Cr when untreated; normal during treatmentNormal when treatedIncreased when untreated; normal when treatedNormal
cblJ 5IncreasedIncreasedIncreasedLow to normal
cblX 6, 7, 8IncreasedIncreasedNormal to increasedLow to normal
MeCbl deficiencycblD-homocystinuria 3NormalNormal>100 µmol/L in some casesLow to normal
cblENormal 9Normal>100 µmol/L when illLow 10
cblGNormalNormalIncreasedLow 10

NR = not reported

1.

Standard values have not been exclusively derived from children or neonates. Some laboratories report urine methylmalonic acid (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.

2.

Authors' experience with >50 affected individuals

3.

Values refer to cblD-combined and cblD-homocystinuria.

4.
5.
6.
7.
8.
9.

Mild elevation uncommon [Tuchman et al 1988]

10.

Molecular Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Individuals with the distinctive laboratory findings of a specific disorder of intracellular cobalamin metabolism described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas symptomatic individuals with nonspecific supportive clinical and laboratory findings in whom the diagnosis of a disorder of intracellular cobalamin metabolism has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

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 at the most reasonable cost 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.

Figure 2.

Testing algorithm to confirm the diagnosis of a disorder of intracellular cobalamin metabolism in a proband 1. While diagnostic testing is being performed, contact genetics/metabolic team and initiate treatment immediately.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by the wide of array of possible nonspecific clinical findings or an individual has atypical phenotypic features of a disorder of intracellular cobalamin metabolism, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 3.

Molecular Genetic Testing Used in Disorders of Intracellular Cobalamin Metabolism

Gene 1Complementation Group / DisorderProportion of Disorders of Intracellular Cobalamin Metabolism Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
MMACHCcblC80%96%-98% 5, 6, 7Unknown 8, 9
MMADHCcblD-combined; cblD-homocystinuria<5%22/22 10Unknown 8
MTRRcblE<5%21/22 11Unknown 8
LMBRD1cblF<5%23/24 12One reported 13
MTRcblG<5%64/74 11Unknown 8
ABCD4cblJ<<1%12/12 14Unknown 8
HCFC1cblX<1%14/17 15, 16Unknown 8
THAP11Not yet defined-cblX-like<1%Single case report 17Unknown 8
ZNF143Not yet defined-cblX-like<1%Single case report 18Unknown 8

Genes are listed in order of complementation group number.

1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.
7.

A rare complex variant of MMACHC and adjacent genes has been described [Guéant et al 2018].

8.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

9.

One consanguineous individual has been found to have biallelic MMACHC whole-gene deletions [Author, unpublished observation].

10.
11.
12.
13.

A deletion spanning exon 2 was reported by Miousse et al [2011].

14.
15.
16.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

17.
18.

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 Characteristics

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.

Table 4.

Clinical Manifestations of Disorders of Intracellular Cobalamin Metabolism

ManifestationsCombined AdoCbl and MeCbl DeficiencyMeCbl Deficiency
cblC 1cblD 2cblF 3cblJ 4cblX 5cblD 2cblE 6cblG 6
PerinatalIntrauterine growth retardation7X
MicrocephalyXXXX
Hydrops fetalisX
Dysmorphic features+/- 8+/-X
Congenital heart disease9XX
Fetal dilated cardiomyopathyX
HydrocephalusXX
Brain malformations+/-X
Cardiomyopathy w/left ventricular noncompactionX
Infantile & childhoodAcute metabolic decompensationXXX
LethargyXXXXX
Progressive encephalopathyXXX
SeizuresXXXXXXX
AtaxiaXX
HypotoniaXXXXXXX
Developmental delay / intellectual disabilityXXXXXXX
Demyelinating neuropathyX
DystoniaX
MicrocephalyXXX
Subdural hematoma10
Feeding difficultiesXXXXXX
Failure to thriveXXX
Nystagmus11XXX
Retinal degeneration11X
MaculopathyX
Optic atrophy11X
Megaloblastic anemia, cytopeniasXXXXXXXX
Recurrent infectionsX
Stomatitis, glossitisXX
Hemolytic uremic syndrome12X13
Cerebral atrophyXXX
Transient ischemic attackX
Dysmorphic featuresXX
Self-injurious behaviorsX
Infantile spasmsXXX
HyperammonemiaXX
Skin pigmentation abnormalitiesX
Adolescent & adulthoodProgressive encephalopathyX
Leukoencephalopathy14
Psychosis15X
Dementia15
Neuropsychiatric symptoms15X
Executive dysfunction14X
Subacute combined degeneration of the spinal cord1516
Glomerulopathy17X
Thromboembolic microangiopathy18
Deep venous thrombosis15X
Pulmonary thromboembolism19
Stroke20
Marfanoid features21

Combined Methylmalonic Acidemia and Homocystinuria

cblC and cblD-Combined Types

cblC, the most common of the disorders of intracellular cobalamin metabolism, is the best understood clinically and is described here as a prototype for combined methylmalonic acidemia and homocystinuria. In cblC, age of onset ranges from prenatal to adult. The infantile presentation is the most frequently recognized.

Perinatal manifestations. Intrauterine growth restriction (IUGR) has been seen in infants with cblC [Nogueira et al 2008, Frattini et al 2010] and cblF [Alfadhel et al 2011].

Other manifestations can include the following [Francis et al 2004, Smith et al 2006, Profitlich et al 2009]:

  • Microcephaly
  • Congenital heart malformation
  • Dilated cardiomyopathy
  • Hydrocephalus
  • Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [Cerone et al 1999]

Infantile presentation. This severe presentation is progressive and may be lethal unless treated. The absence of an acute metabolic presentation or the presence of a normal newborn screen result does not rule out the diagnosis of a disorder of intracellular cobalamin metabolism [Harding et al 2003, Ahrens-Nicklas et al 2015].

  • Infants may present with the following:
    • Failure to thrive, poor feeding, and hypotonia in the first weeks of life
    • An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
    • Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [Kind et al 2002, Sharma et al 2007, Carrillo-Carrasco & Venditti 2012]
  • Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
  • Maculopathy and progressive retinopathy develop in most individuals with infantile cblC.
    • The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
    • Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [Brooks et al 2016].
    • Note: Adolescent and adult (late-onset) presentations of cblC and other inborn errors of cobalamin metabolism do not typically have the ophthalmologic complications. Optic atrophy and other eye findings such as nystagmus and strabismus have been described in cblG [Poloschek et al 2005, Huemer et al 2015a].

Childhood presentation (first years of life). Failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures are typical. Renal thrombotic microangiopathy, HUS, pulmonary hypertension, and diffuse lung disease can also be seen [Kömhoff et al 2013, Beck et al 2017, Liu et al 2017].

Adolescent and adult presentation. Individuals with this presentation usually have predominant neurologic and neuropsychiatric manifestations including the following:

Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [Huemer et al 2014].

cblF and cblJ Types: Disorders of Lysosomal Cobalamin Transport

cblF. Individuals with cblF often present during infancy with symptoms similar to cblC – IUGR, poor postnatal growth, feeding difficulties, and developmental delay – but can also have stomatitis with or without glossitis and congenital heart malformations [Alfadhel et al 2011]. Additional features such as cleft palate, unilateral renal agenesis, hepatic ductopenia, and intraventricular hemorrhage have also been described [Gailus et al 2010, Constantinou et al 2016].

cblJ. Only five individuals with cblJ have been reported. Three presented neonatally with poor growth, feeding problems, respiratory distress, bone marrow suppression, and cardiac defect [Coelho et al 2012, Fettelschoss et al 2017] and two in early childhood with hyperpigmentation and premature graying; one of the two had a transient ischemic attack [Kim et al 2012, Takeichi et al 2015]. Retinopathy was described in one individual in early childhood [Fettelschoss et al 2017].

Note: cblF and cblJ can in some cases be distinguished from cblC and cblD-combined because the former present with low serum B12 levels.

Isolated Homocystinuria (cblE, cblG, cblD-Homocystinuria)

Methylcobalamin deficiency secondary to methionine synthase reductase deficiency (cblE), methionine synthase deficiency (cblG), and cblD-homocystinuria are rare syndromes that are not identified on newborn screening, resulting in a delayed diagnosis [Huemer et al 2015a].

cblE. Most children with cblE present in the first two years of life with severe growth failure, megaloblastic anemia, and neurologic manifestations; isolated megaloblastic anemia and HUS [Palanca et al 2013] may also be seen. Presentation in adolescence with atypical glomerulopathy has also been described [Paul et al 2013].

cblG. Individuals with cblG characteristically present in the first year of life with neurologic manifestations and megaloblastic anemia; however, phenotypic variability ranges from infantile to adult presentation. Neurologic manifestations may include weakness, hypotonia, seizures, mental status changes, and adult-onset leukoencephalopathy. Other unusual presentations of adult-onset cblG include megaloblastic anemia and progressive weakness (initially diagnosed as multiple sclerosis) [Carmel et al 1988], neuropsychiatric illness [Hill et al 2004], and thromobotic microangiopathy and atypical HUS [Vaisbich et al 2017]. Optic nerve atrophy, nystagmus, and strabismus have been described [Poloschek et al 2005, Huemer et al 2015a].

cblD-homocystinuria. Individuals with cblD-homocystinuria (isolated methylcobalamin deficiency) had cognitive impairment, neurologic signs, and megaloblastic anemia [Suormala et al 2004]. Thromboembolic complications including clinically significant thrombophilia causing renal artery thrombosis [Watkins & Rosenblatt 1989], HUS, and pulmonary hypertension [Labrune et al 1999] have also been described.

Genotype-Phenotype Correlations

Genotype-phenotype correlations observed include the following:

cblC

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.

Differential Diagnosis

The following disorders may cause clinical manifestations and laboratory abnormalities similar to those seen in disorders of intracellular cobalamin metabolism.

Disorders causing both methylmalonic acidemia and homocystinuria

  • 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 serum vitamin B12 concentrations in both affected newborns and their mothers.
    B12 deficiency can occur in a breastfed 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 result in elevated methylmalonic acid level in an infant with findings that range from severe encephalopathy [Higginbottom et al 1978, Dror & Allen 2008] to elevated propionylcarnitine detected by newborn screening (NBS) [Chace et al 2001].
    Intramuscular replacement therapy to normalize vitamin B12 serum concentration reverses the metabolic abnormality.
  • Imerslund Gräsbeck syndrome (OMIM 261100). Features of this autosomal recessive disorder may include poor cobalamin absorption, abnormal renal tubular protein reabsorption, and urinary tract malformations. The disorder is caused by biallelic pathogenic variants in one of two genes that encode intrinsic factor receptor components: CUBN (encoding cubulin) and AMN (encoding amnionless) [Gräsbeck 2006].
  • Transcobalamin II deficiency (OMIM 275350). Transcobalamin II (TCII) is required for the movement of cobalamin from intestinal enterocytes into cells throughout the body. Transcobalamin II deficiency, a rare autosomal recessive condition associated with biallelic pathogenic variants in TCN2, 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 and a reduced level of transcobalamin II (the latter detected by an immunoassay) [Kaikov et al 1991, Watkins & Rosenblatt 2014].
  • Transcobalamin receptor deficiency, also known as methylmalonic acidemia, TCblR type (OMIM 613646). Transcobalamin receptor deficiency is a defect in the cellular uptake of cobalamin bound to TCII. Inheritance is autosomal recessive and associated with biallelic variants in CD320, often a common in-frame deletion. This disorder may be a common defect in cobalamin metabolism based on the allele frequency in population databases (MAF 0.009), but few affected individuals have been identified and the clinical phenotype is not well described [Quadros et al 2010]. Affected individuals may be identified on NBS; metabolites may normalize with cobalamin therapy and some individuals are reported to be asymptomatic [Hannah-Shmouni et al 2018; Authors, unpublished observations].

Disorders causing primarily isolated homocystinuria

  • Cystathionine beta-synthase (CBS) deficiency (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 deficiency is progressive with onset typically in childhood. Biochemically it is characterized by elevated serum concentration of methionine and decreased serum concentration of cysteine. Inheritance is autosomal recessive and associated with biallelic variants in CBS.
  • Methylenetetrahydrofolate reductase (MTHFR) deficiency (OMIM 236250) is a defect in folate-dependent methylation pathways that results in diminished conversion of homocysteine to methionine. The biochemical hallmark is moderate homocystinuria 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]. Inheritance is autosomal recessive and associated with biallelic variants in MTHFR.
  • Mild homocystinuria can result from folate deficiency or vitamin B12 deficiency.

Disorders causing primarily methylmalonic acidemia

Management

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].

At the Time of Diagnosis

Goals of treatment are to reduce toxic metabolites and avoid low methionine levels.

  • Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted immediately when a disorder of intracellular cobalamin metabolism is suspected clinically or following positive NBS for propionylcarnitine.
  • Cyanocobalamin should not be used as it will not be effective in individuals with cblC.
  • Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
  • Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.

Acute Metabolic Decompensation

Although less common in the disorders of intracellular cobalamin metabolism than in isolated methylmalonic acidemia, severe acidotic/ketotic crises due to profound methylmalonic acidemia can occur, in particular at presentation or if untreated. Such critically ill individuals should be managed in consultation with a metabolic specialist. MedicAlert® bracelets and emergency treatment protocols outlining fluid and electrolyte therapy should be available for all affected individuals.

Treatment includes volume replacement with isotonic solutions containing high (10%-12.5%) glucose to reverse catabolism, correction of metabolic acidosis with sodium bicarbonate, and prompt reintroduction of feedings – preferably enterally, but parenterally if enteral route cannot be established. Parenteral hydroxocobalamin should be given immediately in the setting of an acute decompensation.

Thromboembolic Complications

Thromboembolic complications as a cause of mortality in cblC are likely associated with increasing plasma concentrations of tHcy [Carrillo-Carrasco & Venditti 2012]. The proper management of thromboembolic complications, such as HUS and thrombotic microangiopathy, should include initiation (or dosage increase) of OHCbl and betaine [Van Hove et al 2002, Sharma et al 2007].

Long-Term Management

The goals of long-term management include improving the metabolic derangement by lowering plasma tHcy and methylmalonic acid (MMA) concentrations and maintaining plasma methionine concentrations within the normal range. These are accomplished by the following.

Parenteral hydroxocobalamin (OHCbl). The most experience derives from the treatment of individuals with cblC. Infants are usually started at a daily dose of 1.0 mg (~0.3 mg/kg/day) of OHCbl given intramuscularly or subcutaneously (SQ). Parenteral OHCbl (not the cyanocobalamin form or oral form) is the only effective preparation. Placement of a SQ catheter could be used to minimize cutaneous punctures [Maines et al 2017]; prefilled injections may increase compliance.

Weight-appropriate adjustment of OHCbl to 0.3 mg/kg/day to maintain the dosing in infancy is recommended and can be attained by the ability to concentrate OHCbl up to 30 mg/mL [Carrillo-Carrasco et al 2012]. Further titration of the dose may be empirically adjusted as needed for worsening clinical manifestations [Van Hove et al 2002] or for metabolic control of plasma tHcy, MMA, or methionine [Carrillo-Carrasco et al 2009]. Biochemical as well as clinical improvement has been demonstrated after increasing doses of OHCbl [Matos et al 2013], although clinical trials are needed to demonstrate long-term clinical outcomes [Dionisi-Vici et al 2013].

Betaine. Oral betaine (starting at ~250 mg/kg/day) is recommended in those with elevated plasma total homocysteine as it facilitates conversion of homocysteine to methionine through betaine homocysteine methyltransferase.

Folate and folinic acid. Folic acid and folinic acid can potentially augment remethylation and may help improve plasma tHcy and methionine concentrations. Folinic acid may be preferred as it crosses the blood-brain barrier more efficiently than folic acid. The adult dose of folate is 1.0 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 [Tschudy & Arcara 2012] and other common reference texts.

Dietary management. Individuals may be able to tolerate a normal diet.

  • Low-protein diets and medical foods designed for isolated methylmalonic acidemia are not recommended [Huemer et al 2017] as they can result in hypomethioninemia, which can be detrimental [Ribes et al 1990, Rossi et al 2001, De Bie et al 2009].
    • The use of low-protein diets correlated with lower height-for-age z-scores [Manoli et al 2016], and intake of medical foods (methionine-free formulas) was associated with decreased head circumference in two cohorts of individuals with cblC [Manoli et al 2016, Ahrens-Nicklas et al 2017].
    • Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
  • Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.

Other Therapeutic Considerations

The following have not been fully validated:

  • Methionine supplementation. Hypomethioninemia is usually responsive to appropriate treatment with OHCbl, betaine, and optimal dietary management. The need for exogenous methionine supplementation may be minimized by these strategies, as the efficacy of this therapy is uncertain [Smith et al 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 they have a dietary deficiency.
  • Levocarnitine. Indicated for low plasma carnitine levels. Most individuals take 50-200 mg/kg/day to aid in the removal of excess propionyl-CoA groups.
  • Metanx. A supplement that contains L-methylfolate (active form of folate), methylcobalamin, and pyridoxal-5'-phosphate (active form of vitamin B6) is prescribed as a treatment for neuropathy. It may be used in individuals with cobalamin disorders (in particular teens and adults with clinical indication for neuropathy) and also considered in all individuals with cobalamin disorders to replace individual folate and B6 supplements.
  • Aspirin. Antiplatelet doses of aspirin may be given to individuals with isolated homocystinuria to decrease the risk for thrombosis [Brunel-Guitton et al 2010].

Treatment of infantile spasms, seizures, congenital heart malformations, and hydrocephalus is done in a routine manner.

Prenatal Therapy

Prenatal therapy of an affected fetus by administration of intramuscular OHCbl to the mother may improve neurocognitive outcome; however, the ophthalmologic manifestations are often still present [Patton et al 2000, Huemer et al 2005, Brooks et al 2016, Trefz et al 2016].

  • The dose and frequency of OHCbl administration to pregnant mothers has not been established.
  • Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [Huemer et al 2005, Trefz et al 2016].

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 www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

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. —ED.

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].

Risk to Family Members – Autosomal Recessive Inheritance

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.

Carrier (Heterozygote) Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the ABCD4, LMBRD1, MMACHC, MMADHC, MTR, MTRR, THAP11, or ZNF143 pathogenic variants in the family.

Biochemical testing is not reliable for carrier detection.

Risk to Family Members – X-Linked Inheritance

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 gender, may be at risk of being heterozygotes for the pathogenic variant (carrier females) or of being affected (males).

Carrier (Heterozygote) Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the HCFC1 pathogenic variant in the family. Note: Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected.

Biochemical testing is not reliable for carrier testing.

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 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 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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 diagnosis 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:

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • HCU Network America
    623 Creek Lane
    Flourtown PA 19031
    Phone: 630-360-2087
    Email: hcunetworkamerica@gmail.com
  • Organic Acidemia Association
    Phone: 763-559-1797
    Fax: 866-539-4060 (toll-free)
    Email: kstagni@oaanews.org; menta@oaanews.org
  • European Network and Registry for Homocystinurias and Methylation Defects (E-HOD)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Disorders of Intracellular Cobalamin Metabolism (View All in OMIM)

1565705-@METHYLTETRAHYDROFOLATE-HOMOCYSTEINE S-METHYLTRANSFERASE; MTR
236270HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE; HMAE
250940HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE; HMAG
277380METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblF TYPE; MAHCF
277400METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE; MAHCC
277410METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE; MAHCD
300019HOST CELL FACTOR C1; HCFC1
309541METHYLMALONIC ACIDEMIA AND HOMOCYSTEINEMIA, cblX TYPE
602568METHIONINE SYNTHASE REDUCTASE; MTRR
603214ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 4; ABCD4
603433ZINC FINGER PROTEIN 143; ZNF143
609119THAP DOMAIN-CONTAINING PROTEIN 11; THAP11
609831MMACHC GENE; MMACHC
611935MMADHC GENE; MMADHC
612625LMBR1 DOMAIN-CONTAINING PROTEIN 1: LMBRD1

See Figure1. For detailed summaries of gene and protein information for the genes discussed in this section, see Table A, Gene.

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.

Table 5.

HCFC1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.202C>Gp.Gln68GluNM_005334​.2
NP_005325​.2
c.217G>Ap.Ala73Thr
c.218C>Tp.Ala73Val
c.307T>Cp.Tyr103His
c.343G>Ap.Ala115Thr
c.344C>Tp.Ala115Val

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

Table 6.

LMBRD1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1056delGp.Asn353IlefsTer18NM_018368​.3
NP_060838​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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.

Table 7.

MMACHC Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change 1Predicted Protein ChangeReference Sequences
c.271dupA 2p.Arg91LysfsTer140NM_015506​.2
NP_056321​.2
c.331C>T 3p.Arg111Ter
c.347T>Cp.Leu116Pro
c.394C>T 4p.Arg132Ter
c.440G>Cp.Gly147Ala
c.482G>A 5p.Arg161Gln
c.609G>A 6p.Trp203Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Accounts for approximately 30%-50% of disease alleles in individuals of European ancestry [Lerner-Ellis et al 2006, Lerner-Ellis et al 2009, Fischer et al 2014]

3.

Common in people of Cajun and French Canadian ancestry [Lerner-Ellis et al 2009]

4.

Common in people of Indian and Middle Eastern ancestry [Lerner-Ellis et al 2009]; associated with a late-onset phenotype

5.

Associated with milder disease, and may be more common in individuals of Hispanic descent [Almannai et al 2017]

6.

Common in people of Chinese ancestry [Liu et al 2010]

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.

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.

Table 8.

MTR Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.3518C>Tp.Pro1173LeuNM_000254​.2
NP_000245​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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.

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

Table 9.

MTRR Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change (Alias 1)Predicted Protein ChangeReference Sequences
c.903+469T>C
(903_904ins140)
--NM_002454​.2
NP_002445​.2
c.1361C>Tp.Ser545Leu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

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].

Table 10.

THAP11 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.240C>Gp.Phe80LeuNM_020457​.2
NP_065190​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org).See Quick Reference for an explanation of nomenclature.

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].

Table 11.

ZNF143 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReferenceSequences
c.851T>Gp.Leu284TerNM_003442​.5
NP_003433​.3
c.1019C>Tp.Thr340Ile

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org).See Quick Reference for an explanation of nomenclature.

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.

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Chapter Notes

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

  • 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

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