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Definitions

1

Biochemical case definition of cblE

Raised plasma total homocysteine with low or normal methionine and normal methylmalonic acid, in a patient with megaloblastic anemia and/or developmental delay, confirmed by biallelic MTRR variants or by fibroblast complementation assigning the cblE group.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:20301503 SUPPORT Human Clinical

"The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data."

GeneReviews states the tripartite basis of diagnosis.

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic loss-of-function MTRR variants. Reported patients are homozygous or compound heterozygous, and carrier parents are unaffected; enzymatic and mutation analysis has been used for prenatal diagnosis in affected families.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:12555939 SUPPORT Human Clinical

"The cblE type of homocystinuria is a rare autosomal recessive disorder, which manifests with megaloblastic anaemia and developmental delay in early childhood."

States the autosomal recessive inheritance of cblE homocystinuria.

PMID:12555939 SUPPORT Human Clinical

"In the families of both patients, enzymatic and mutation analyses were successfully used for prenatal diagnosis."

Confirms biallelic Mendelian transmission tractable to prenatal testing.

PMID:20301503 SUPPORT Human Clinical

"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."

GeneReviews recurrence risk for the disorders of intracellular cobalamin metabolism, which is the genetic-counselling statement that follows from autosomal recessive inheritance.

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Discussions and Knowledge Gaps

2

Human cblE presents in infancy with megaloblastic anemia and progressive neurocognitive disease, yet the Mtrr(gt/gt) mouse becomes anemic only in late adult life, only in females, with a rising rather than falling reticulocyte count, and with no reported neurological phenotype. Does that reflect residual activity of the hypomorphic allele, a species difference in erythroid and cerebral folate handling, or a different mechanism reaching the same cell type - and can any model reproduce the infantile presentation?

HUMAN MODEL MISMATCH cble_mouse_model_mismatch

Attached to

pathophysiology#Impaired Erythropoiesis pathophysiology#Central Nervous System White Matter Injury

The mismatch is not that the mouse lacks the human phenotypes - it has an erythroid one - but that the two systems diverge in different ways, and the difference matters for what the model can be used to test. On the erythroid side the divergence is in timing and kinetics: the anemia appears late in adult life and is accompanied by reticulocytosis, whereas human folate-deficiency megaloblastic anemia is reticulocytopenic, and the authors could not establish that the murine anemia is megaloblastic at all. So a mouse that models the consequence of chronic MTRR deficiency does not model the neonatal marrow crisis. On the neurological side the divergence is starker and mechanistically specific: the entry attributes human white-matter injury to deficient S-adenosylmethionine-dependent methylation, and in this line the AdoMet/AdoHcy ratio is preserved in most tissues - unlike other murine hyperhomocysteinemia models, where it falls. Until a model reproduces the infantile presentation, the question that matters most clinically - whether earlier treatment prevents the neurocognitive injury, which is also what the newborn-screening gap turns on - cannot be tested in mouse.

Show evidence (5 references)

PMID:30024025 SUPPORT Model Organism

"Even though Mtrrgt/gt female mice display macrocytic anaemia, we were unable to determine whether the anaemia fulfils megaloblastic status."

The authors themselves decline to call the murine anemia megaloblastic, which is the precise point on which the model and the defining human phenotype part company.

PMID:30024025 SUPPORT Model Organism

"our finding that older Mtrrgt/gt female mice have increased reticulocyte counts contradicts most human cases of megaloblastic anaemia associated with folate deficiency wherein reticulocyte numbers are usually low"

A directional contradiction rather than a difference of degree - the murine marrow response goes the opposite way to the human one, which is why this is curated as a mismatch and not merely as incomplete modelling.

PMID:17369066 SUPPORT Model Organism

"Unexpectedly, Mtrr(gt/gt) mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues."

A mechanistic account of the neurological half of the mismatch. The entry attributes the human CNS white-matter injury to deficient S-adenosylmethionine-dependent methylation, and in this model that very ratio is preserved in most tissues - so the mouse does not reproduce the step the human neurological phenotype is proposed to run through.

+ 2 more references

Does presymptomatic detection of cblE by newborn screening improve neurocognitive outcome, and which analyte combination detects it reliably?

KNOWLEDGE GAP cble_newborn_screening_benefit

Attached to

pathophysiology#Central Nervous System White Matter Injury

The haematological features of cblE respond well to hydroxocobalamin while the neurological injury often does not, which is the usual argument for presymptomatic treatment. But the screening evidence for cblE specifically is weak: the systematic review that recommends newborn screening for CBS and severe MTHFR deficiency explicitly declines to extend that to cblE, both because benefit-of-early-treatment data are weaker and because analyte performance data are more limited. Whether the persistent neurocognitive morbidity reflects irreversible prenatal or early postnatal injury, or simply late treatment, is unresolved.

Show evidence (1 reference)

PMID:25762406 SUPPORT Human Clinical

"For the cblE and cblG defects, evidence for the benefit of early treatment is weaker; and data on performance of Met, Met/Phe and tHcy even more limited."

Directly states the twin evidence gaps for cblE newborn screening.

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Pathophysiology

7

MTRR Loss of Function

Biallelic pathogenic MTRR variants abolish or severely reduce methionine synthase reductase activity. Reported alleles include nonsense variants predicted to yield little or no MTRR protein, splice-disrupting insertions, and missense changes distributed across the FMN-, FAD- and NADPH-binding modules of this ferredoxin-NADP(+) reductase family flavoprotein.

MTRR hgnc:7473

methionine synthase reductase activity GO:0030586 ⇓ LOSS OF FUNCTION

Animal models

Mtrr gene-trap hypomorphic mouse Mouse partially recapitulates Reproduces reduced MTRR function and the expected one-carbon metabolic perturbation, but as a hypomorphic gene trap with residual activity rather than the biallelic loss-of-function alleles seen in patients.

Downstream

Methionine Synthase Trapped in Oxidised Cob(II)alamin State

Show evidence (3 references)

PMID:10484769 SUPPORT Human Clinical

"a defect in the MSR enzyme, which is required for the reductive activation of methionine synthase (MS)"

Identifies loss of MTRR/MSR enzyme function as the primary molecular lesion.

PMID:10484769 SUPPORT Human Clinical

"Of the eleven, three are nonsense mutations, allowing for the identification of two patients for whom little if any MSR protein should be produced."

Documents null alleles establishing loss of function as the mechanism.

PMID:12555939 SUPPORT Human Clinical

"supports the concept that this disorder is caused by mutations in the MTRR gene"

Confirms MTRR as the causal gene for the cblE complementation group.

Methionine Synthase Trapped in Oxidised Cob(II)alamin State

Methionine synthase turnover intermittently oxidises its cob(I)alamin cofactor to catalytically inert cob(II)alamin. MTRR normally performs the NADPH-dependent reductive methylation that restores the active form. Without it methionine synthase accumulates in the oxidised state, so cellular methylcobalamin is depleted while methionine synthase protein and its intrinsic activity are preserved - a functional, not structural, enzyme deficiency. This is why patient fibroblast MTR activity can measure normal under strong reducing conditions and only falls when the reducing agent is limited.

methionine synthase activity GO:0008705 ↓ DECREASED

Downstream

Impaired Homocysteine Remethylation

Show evidence (6 references)

PMID:10484769 SUPPORT Human Clinical

"These data demonstrate a unique requirement for MSR in the reductive activation of MS."

Establishes that methionine synthase depends on MTRR for reductive reactivation.

PMID:9427140 SUPPORT In Vitro

"methionine synthase activity was normal under high reducing conditions but decreased on limiting the reducing agent, dithiothreitol, to 5 mmol/L (18% of total, controls 51-81%)"

Directly demonstrates the functional nature of the defect - methionine synthase is intact but cannot be reactivated once the exogenous reductant is limiting.

PMID:9427140 SUPPORT In Vitro

"formation of methylcobalamin was low (4.5% of total cobalamins, control 57.5%) and complementation studies indicated the cblE defect"

Quantifies methylcobalamin depletion in cblE patient fibroblasts.

+ 3 more references

Impaired Homocysteine Remethylation

With methionine synthase functionally inactive, the folate- and cobalamin-dependent transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine fails. Homocysteine accumulates and methionine is not regenerated. Because the adenosylcobalamin limb serving methylmalonyl-CoA mutase is untouched, methylmalonic acid excretion stays normal - the discriminating feature against the combined cobalamin disorders.

homocysteine metabolic process GO:0050667 ↓ DECREASED cobalamin metabolic process GO:0009235 ↓ DECREASED

Downstream

Methyl-Group and Folate Trapping

Impaired Erythropoiesis

Homocysteine-Mediated Endothelial Injury

Show evidence (3 references)

PMID:25978498 SUPPORT Human Clinical

"Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine."

States the core metabolic block defining the disease.

PMID:35337626 SUPPORT Human Clinical

"inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria"

Establishes that the cblE block is confined to the remethylation limb, producing isolated homocystinuria without methylmalonic aciduria.

PMID:23430521 SUPPORT Human Clinical

"An urinary organic acid analysis revealed normal methylmalonic acid excretion."

Confirms in a genetically proven cblE patient that the adenosylcobalamin limb is spared.

Methyl-Group and Folate Trapping

Methionine synthase is the only reaction that regenerates tetrahydrofolate from 5-methyltetrahydrofolate. When it stalls, folate is sequestered as 5-methyltetrahydrofolate and becomes unavailable for one-carbon transfers - the classical methyl-folate trap. Reduced methionine also lowers S-adenosylmethionine, constraining the many downstream methylation reactions on which myelin maintenance and nucleotide synthesis depend. The trap explains the raised formiminoglutamate excretion seen in cblE and the partial biochemical response to pharmacological folate.

tetrahydrofolate metabolic process GO:0046653 ↓ DECREASED methylation GO:0032259 ↓ DECREASED one-carbon metabolic process GO:0006730 ↓ DECREASED

Downstream

Impaired Erythropoiesis

Central Nervous System White Matter Injury

Show evidence (3 references)

PMID:9427140 SUPPORT Human Clinical

"Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate."

Formiminoglutamate accumulates when tetrahydrofolate is unavailable for the formiminotransferase step, the expected consequence of methyl-folate trapping.

PMID:9427140 SUPPORT Human Clinical

"On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained."

Pharmacological folate partially relieves the trap biochemically, supporting folate sequestration as a real component - though the persistence of clinical disease shows it is not the whole mechanism.

PMID:27905001 SUPPORT Human Clinical

"impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions"

Links the remethylation block to generalized methylation failure.

Impaired Erythropoiesis

Folate trapping starves thymidylate synthesis of methylene-tetrahydrofolate, so erythroid precursors cannot complete DNA replication while cytoplasmic maturation continues. The result is nuclear-cytoplasmic dyssynchrony in the marrow - megaloblastic change - with macrocytic anemia and, when severe, extension to other lineages as pancytopenia. The marrow picture can be mistaken for congenital dyserythropoietic anemia before the biochemical diagnosis is made.

erythroid progenitor cell CL:0000038

erythrocyte differentiation GO:0030218 ↓ DECREASED

Animal models

Mtrr gene-trap hypomorphic mouse Mouse partially recapitulates Dedicated haematological phenotyping of this line shows that Mtrr(gt/gt) homozygotes do develop a macrocytic anemia with compensatory extramedullary haematopoiesis, so the erythroid consequence of MTRR deficiency is reproduced. It is reproduced partially: the murine anemia is late adult-onset and sex-limited, while human cblE presents with megaloblastic anemia in the first months of life in both sexes.

Show evidence (2 references)

PMID:25978498 SUPPORT Human Clinical

"We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them."

Documents megaloblastic marrow change in genetically confirmed cblE, including the diagnostic confusion with congenital dyserythropoietic anemia.

PMID:23430521 SUPPORT Human Clinical

"a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia"

Marrow-level confirmation of megaloblastic erythropoiesis in cblE.

Homocysteine-Mediated Endothelial Injury

Severe hyperhomocysteinemia damages vascular endothelium and promotes thrombotic microangiopathy. In neonatal-onset cblE this can present as an atypical haemolytic-uraemic syndrome, and post-mortem examination has shown myointimal proliferation with luminal narrowing in the kidney and microangiopathic change in the brain. This is the pathway that makes remethylation disorders part of the differential for unexplained thrombosis and atypical HUS.

endothelial cell CL:0000115

Downstream

Hemolytic-Uremic Syndrome The thrombotic microangiopathy this node describes is what presents clinically as an atypical haemolytic-uraemic syndrome.

Pancytopenia Microangiopathic haemolysis and platelet consumption contribute to the cytopenias alongside the megaloblastic marrow defect. Marked INDIRECT because two mechanisms converge on this phenotype and their relative contribution is not established.

Show evidence (3 references)

PMID:23430521 SUPPORT Human Clinical

"the histopathological examination of the kidneys showed marked myointimal proliferation and narrowing of the vascular lumen"

Histological demonstration of microangiopathic vascular injury in a cblE patient.

PMID:23430521 SUPPORT Human Clinical

"Microangiopathy was observed with an increase in vessel wall thickness, a reduction of the arterial inner diameter and capillary oedema."

Confirms generalized microangiopathy as a tissue-level consequence.

PMID:27905001 SUPPORT Human Clinical

"atypical haemolytic uraemic syndrome or unexplained vascular thrombosis"

Expert guidelines place atypical HUS and unexplained thrombosis among the presentations that should prompt testing for a remethylation disorder.

Central Nervous System White Matter Injury

Deficient S-adenosylmethionine-dependent methylation impairs myelin maintenance, and the resulting white matter disease underlies the developmental delay, microcephaly and seizures of cblE. Neuropathology in a fatal neonatal case showed diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis. Unlike the haematological features, the neurological injury often persists despite biochemical correction.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

white matter UBERON:0002316

Show evidence (2 references)

PMID:23430521 SUPPORT Human Clinical

"diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed"

Neuropathological confirmation of white matter injury in cblE.

PMID:9427140 SUPPORT Human Clinical

"At 17 years of age she remains severely mentally retarded."

Seventeen-year follow-up showing the neurological injury persists despite sustained biochemical treatment.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

16

Blood 4

Megaloblastic Anemia VERY_FREQUENT HP:0001889

Show evidence (2 references)

PMID:12555939 SUPPORT Human Clinical

"Case 1 involves a 20-year-old mentally retarded patient who presented with megaloblastic anaemia at 10 weeks of age."

Megaloblastic anemia as the presenting feature in a molecularly confirmed cblE patient.

PMID:10484769 SUPPORT Human Clinical

"Methionine synthase reductase (MSR) deficiency is an autosomal recessive disorder of folate/cobalamin metabolism leading to hyperhomocysteinemia"

Establishes MSR deficiency as the disorder in which this haematological phenotype occurs.

Macrocytic Anemia OCCASIONAL HP:0001972

Graded OCCASIONAL rather than VERY_FREQUENT on the strength of PMID:15714522, where the anemia was macrocytic in only 3 of 9 molecularly confirmed patients. This is deliberately lower than the strongest contrary source - which is not a narrative review but the 24-patient cblE/cblG cohort PMID:25526710, listing macrocytic anaemia among the most frequent symptoms. The two reconcile if macrocytosis is common but not obligatory; the grading follows the study that actually counted. The megaloblastic marrow change is graded separately and higher, and is the more reliable finding.

Show evidence (2 references)

PMID:25978498 SUPPORT Human Clinical

"It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment."

Names macrocytic anemia among the described presenting features of cobalamin E disorder.

PMID:15714522 SUPPORT Human Clinical

"They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases."

Qualifies the macrocytosis - in nine molecularly confirmed cblE patients the anemia was macrocytic in only three, so a normal MCV does not exclude the diagnosis.

Pancytopenia OCCASIONAL HP:0001876

Show evidence (1 reference)

PMID:23430521 SUPPORT Human Clinical

"hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement)"

Documents multilineage cytopenia in severe neonatal cblE.

Hemolytic Anemia in Adulthood VERY_RARE HP:0001878

Reported in one sibling pair. One of the two had a concurrent parvovirus B19 infection, which the authors note can cause erythroblastopenia even without immunocompromise, so the hemolysis and the viral trigger are not cleanly separable in that patient.

Show evidence (2 references)

PMID:38736634 SUPPORT Human Clinical

"We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by..."

The primary case description of adult-onset hemolytic anemia in treated cblE.

PMID:38736634 SUPPORT Human Clinical

"This is the first report of such complications in adulthood."

Graded PARTIAL because it establishes the phenotype from a single sibling pair, which is why the frequency here is VERY_RARE.

Digestive 1

Feeding Difficulties FREQUENT HP:0011968

Show evidence (1 reference)

PMID:25526710 SUPPORT Human Clinical

"failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms"

Lists feeding problems among the most frequent symptoms in the cblE/cblG cohort.

Eye 1

Nystagmus FREQUENT HP:0000639

Graded FREQUENT on the PMID:2688421 count of 5/11 (45%), which falls in the 30-79% band.

Show evidence (1 reference)

PMID:12555939 SUPPORT Human Clinical

"Case 2 involves an 8-year-old girl with nystagmus and developmental delay in whom megaloblastic anaemia was detected at 11 weeks of age."

Nystagmus as a presenting sign in a molecularly confirmed cblE patient.

Head and Neck 1

Microcephaly OCCASIONAL HP:0000252

Show evidence (1 reference)

PMID:9427140 SUPPORT Human Clinical

"Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia"

Lists microcephaly among the pre-treatment findings in a cblE patient.

Musculoskeletal 1

Hypotonia FREQUENT HP:0001252

Graded FREQUENT on the PMID:2688421 count of 7/11 (64%), which falls in the 30-79% band.

Show evidence (1 reference)

PMID:23430521 SUPPORT Human Clinical

"a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia"

Hypotonia in a neonatal-onset cblE presentation.

Nervous System 6

Cerebral Atrophy VERY_FREQUENT HP:0002059

PMID:25526710 pools cblE and cblG; the two share a final common metabolic block, so the imaging finding is expected to apply to cblE, but the fraction is not cblE-specific.

Show evidence (2 references)

PMID:25526710 SUPPORT Human Clinical

"Eighteen/22 patients presented with brain atrophy or white matter disease."

Quantifies structural brain involvement in the combined cblE/cblG cohort (18 of 22 imaged patients).

PMID:2688421 SUPPORT Human Clinical

"various neurological deficits including developmental retardation (10 patients), cerebral atrophy (8 patients), hypotonia (7 patients), EEG abnormalities (6 patients), and nystagmus (5 patients)"

Cerebral atrophy in 8 of the 11 patients in this functional methionine synthase deficiency series.

EEG Abnormality FREQUENT HP:0002353

Show evidence (1 reference)

PMID:2688421 SUPPORT Human Clinical

"various neurological deficits including developmental retardation (10 patients), cerebral atrophy (8 patients), hypotonia (7 patients), EEG abnormalities (6 patients), and nystagmus (5 patients)"

EEG abnormality in 6 of the 11 patients in this functional methionine synthase deficiency series.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:2688421 SUPPORT Human Clinical

"Hypertonia, seizures, blindness, and ataxia were less frequent."

Places seizures among the less frequent neurological deficits in functional methionine synthase deficiency, supporting the OCCASIONAL grading.

Global Developmental Delay VERY_FREQUENT HP:0001263

Graded VERY_FREQUENT on the PMID:2688421 count of developmental retardation in 10/11 (91%), which falls in the 80-100% band.

Show evidence (1 reference)

PMID:12555939 SUPPORT Human Clinical

"manifests with megaloblastic anaemia and developmental delay in early childhood"

States developmental delay as a defining early-childhood manifestation.

Intellectual Disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:9427140 SUPPORT Human Clinical

"At 17 years of age she remains severely mentally retarded."

Documents persistent severe intellectual disability on long-term follow-up.

Leukoencephalopathy OCCASIONAL HP:0002352

Show evidence (1 reference)

PMID:23430521 SUPPORT Human Clinical

"diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed"

Neuropathological documentation of leukoencephalopathy in cblE.

Growth 1

Failure to Thrive FREQUENT HP:0001508

Graded FREQUENT to match Feeding Difficulties, since both rest on the same PMID:25526710 "most frequent symptoms" sentence and cannot honestly carry different bands.

Show evidence (1 reference)

PMID:23430521 SUPPORT Human Clinical

"failure to thrive, hypotonia, pancytopaenia, HUS symptoms"

Failure to thrive at presentation in a neonatal cblE case.

Other 1

Hemolytic-Uremic Syndrome VERY_RARE HP:0005575

Show evidence (1 reference)

PMID:23430521 SUPPORT Human Clinical

"cblE should be considered when diagnosing patients presenting with HUS signs and symptoms during the newborn period."

Establishes HUS-like presentation as a recognized, if rare, cblE phenotype.

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Genetic Associations

1

MTRR

Gene: MTRR hgnc:7473 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:10484769 SUPPORT Human Clinical

"reveal 11 mutations in eight patients from seven families belonging to the cblE complementation group"

Original identification of MTRR as the cblE gene across multiple families.

PMID:10484769 SUPPORT Human Clinical

"Apart from an intronic substitution found in two unrelated patients, the mutations appear singular among individuals."

Documents the private, family-specific allelic spectrum.

PMID:10484769 SUPPORT Human Clinical

"distributed throughout the coding region, including proposed FMN, FAD and NADPH binding sites"

Maps the variant spectrum onto the flavoprotein cofactor-binding modules.

+ 2 more references

Variants (1)

c.1361C>T

Reported as associated with a milder, predominantly haematological presentation in homozygotes. This is the only genotype-phenotype link described for cblE, and it is contested - the larger 24-patient cblE/cblG survey found no genotype-phenotype correlations evident.

Show evidence (3 references)

PMID:15714522 SUPPORT Human Clinical

"Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected."

Places c.1361C>T among the recurrent MTRR alleles in a nine-patient cblE series.

DOI:10.1023/A:1025159103257 SUPPORT Human Clinical

"We propose that homozygosity for this novel mutation may be associated with a mild phenotype, although its long‐term deleterious neurological consequences remain possible."

The primary source for the mild-phenotype claim. Graded PARTIAL because the authors propose rather than establish it, on two patients, and explicitly leave long-term neurological consequences open.

DOI:10.1023/A:1025159103257 SUPPORT Human Clinical

"Genetic analysis confirmed that both patients are homozygous for a novel mutation c.1361C > T in the methionine synthase reductase gene leading to a replacement of serine by leucine (S454L) in a highly conserved FAD‐binding domain."

Locates the allele in a conserved FAD-binding domain, the structural basis for expecting reduced rather than abolished reductase activity.

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Medical Actions

5

Parenteral Hydroxocobalamin

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxocobalamin CHEBI:27786

Parenteral hydroxocobalamin is the first-line treatment and should be started without waiting for confirmatory testing in any suspected remethylation disorder.

Mechanism Target:

Impaired Homocysteine Remethylation — Supplying cobalamin in large excess raises the fraction of methionine synthase that is loaded with cofactor, partially compensating for the failed reductive reactivation.

Show evidence (7 references)

PMID:27905001 SUPPORT Human Clinical

"We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications."

Guideline-strength recommendation for parenteral hydroxocobalamin in remethylation disorders including cblE.

PMID:20301503 SUPPORT Human Clinical

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

GeneReviews on early treatment. Graded PARTIAL because it is explicitly qualified - survival improves but the primary manifestations are only reduced, not prevented, which matches the divergent haematological and neurological responses curated here.

PMID:20301503 SUPPORT Human Clinical

"Treatment of thromboembolic complications (e.g., HUS and thrombotic microangiopathy) includes initiation of hydroxocobalamin (OHCbl) and betaine or an increase in their doses."

GeneReviews management of the thrombotic microangiopathy complication, directly relevant because HUS is curated as a phenotype of this disorder.

+ 4 more references

Betaine

Action: Pharmacotherapy NCIT:C15986

Agent: betaine CHEBI:17750

Betaine provides an alternative, betaine-homocysteine methyltransferase-dependent route for remethylating homocysteine to methionine that bypasses methionine synthase entirely. Used in combination with hydroxocobalamin.

Mechanism Target:

Impaired Homocysteine Remethylation — Bypasses the blocked methionine synthase reaction by donating a methyl group through betaine-homocysteine methyltransferase.

Show evidence (2 references)

PMID:25978498 SUPPORT Human Clinical

"Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients."

Supports combined hydroxocobalamin plus betaine as the cblE regimen.

PMID:25526710 SUPPORT Human Clinical

"Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant."

Cohort-level confirmation that betaine-containing combinations produce a significant biochemical response.

Methylcobalamin

Action: Pharmacotherapy NCIT:C15986

Agent: methylcobalamin CHEBI:28115

Methylcobalamin supplies the methionine synthase cofactor in its already-methylated form. In one long-term case, substituting methylcobalamin for folate improved alertness, motor function, speech and EEG, with the best overall control on the two combined.

Mechanism Target:

Methionine Synthase Trapped in Oxidised Cob(II)alamin State — Delivers the methylated cofactor directly, reducing dependence on the MTRR-catalysed reductive methylation step that is missing.

Show evidence (2 references)

PMID:9427140 SUPPORT Human Clinical

"On replacement of folate with methylcobalamin, alertness, motor function, speech and the electroencephalogram improved"

Documents clinical and electrophysiological improvement on methylcobalamin.

PMID:9427140 SUPPORT Human Clinical

"The best control was observed on a combination of folate and methylcobalamin."

Supports combined folate plus methylcobalamin over either alone in this patient.

Folate Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: folic acid CHEBI:27470

High-dose folate relieves the methyl-folate trap biochemically. Its effect is partial - formiminoglutamate excretion and homocystinuria nearly normalized on folate alone while clinical and haematological abnormalities persisted - so it is adjunctive to cobalamin, not a substitute for it.

Mechanism Target:

Methyl-Group and Folate Trapping — Replenishes usable folate pools sequestered as 5-methyltetrahydrofolate.

Show evidence (1 reference)

PMID:9427140 SUPPORT Human Clinical

"On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained."

Explicitly partial - the biochemical response to folate alone was good but the clinical and haematological disease was not corrected.

Avoidance of Nitrous Oxide and Catabolic Stress

Action: Supportive Care NCIT:C15747

Nitrous oxide irreversibly oxidises the cobalamin cofactor of methionine synthase and is contraindicated. Prolonged fasting, protein intake below the age-appropriate recommended allowance, and methionine-free medical foods are likewise to be avoided.

Show evidence (2 references)

PMID:20301503 SUPPORT Human Clinical

"methionine restriction including use of medical foods that do not contain methionine; and the anesthetic nitrous oxide"

GeneReviews Agents/Circumstances to Avoid, naming nitrous oxide and methionine restriction as contraindicated in disorders of intracellular cobalamin metabolism.

PMID:20301503 SUPPORT Human Clinical

"Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)"

GeneReviews warning against catabolic stress.

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Biochemical Markers

5

Plasma Total Homocysteine (INCREASED)

Show evidence (2 references)

PMID:12555939 SUPPORT Human Clinical

"Biochemical features included severe hyperhomocysteinaemia and hypomethioninaemia"

Documents severe hyperhomocysteinemia in molecularly confirmed cblE.

PMID:27905001 SUPPORT Human Clinical

"We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms"

Guideline basis for total homocysteine as the first-line diagnostic marker.

Plasma Methionine (DECREASED)

Show evidence (2 references)

PMID:9427140 SUPPORT Human Clinical

"increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L)"

Quantifies the paired hyperhomocysteinemia and hypomethioninemia in cblE.

PMID:12555939 SUPPORT Human Clinical

"Severe hyperhomocysteinaemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cblE defect."

Qualifies the marker - a confirmed cblE patient with normal methionine, so hypomethioninemia is characteristic but not obligatory.

Urinary Homocystine (INCREASED)

Show evidence (1 reference)

PMID:35337626 SUPPORT Human Clinical

"inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria"

Defines the isolated-homocystinuria biochemical class to which cblE belongs.

Urinary Methylmalonic Acid (NORMAL)

Show evidence (2 references)

PMID:23430521 SUPPORT Human Clinical

"An urinary organic acid analysis revealed normal methylmalonic acid excretion."

Confirms normal MMA in a genetically proven cblE patient.

PMID:20301503 SUPPORT Human Clinical

"Evaluation of the methylmalonic acid (MMA) level in urine and blood and plasma total homocysteine (tHcy) level are the mainstays of biochemical testing."

GeneReviews establishes the paired MMA/tHcy measurement that discriminates the complementation groups.

Urinary Formiminoglutamate (INCREASED)

Show evidence (1 reference)

PMID:9427140 SUPPORT Human Clinical

"Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate."

Documents the folate-trapping marker in a cblE patient.

📈

Progression

4

Presentation

Age: 2 weeks to 3 years (median 4 weeks)

Onset is typically in early infancy with anemia and neurological involvement. Presentation after the first two years is unusual but described, including one patient who reached medical attention at 21 years with symptoms initially attributed to multiple sclerosis - a reminder that a remethylation defect belongs in the differential for unexplained adult subacute neurological disease.

Show evidence (2 references)

PMID:15714522 SUPPORT Human Clinical

"They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases."

Defines the age-at-presentation range and median in a molecularly confirmed cblE series.

PMID:2688421 SUPPORT Human Clinical

"Presentation has usually been in the first 2 years of life, but one patient came to medical attention at age 21 years with symptoms initially diagnosed as multiple sclerosis."

Documents both the usual infantile onset and a late-onset outlier.

Response to treatment

Age: After diagnosis

The two limbs of the disease diverge under treatment. Anemia and the biochemical abnormalities correct reliably on cobalamin; the neurological deficits resolve more slowly and often incompletely. Delay in diagnosis correlates with worse communication ability at follow-up, which is the main argument for early detection.

Show evidence (2 references)

PMID:2688421 SUPPORT Human Clinical

"All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities; neurological deficits resolved more slowly and in some cases incompletely."

States the divergent haematological and neurological treatment responses.

PMID:25526710 SUPPORT Human Clinical

"Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up."

Links diagnostic delay to worse neurocognitive outcome.

Long-term course

Age: Childhood to adulthood

Despite a biochemically stable or improving overall course in almost all patients, the burden of CNS symptoms accumulates over time and most patients end up developmentally delayed or severely handicapped. In vitro residual enzyme activity does not predict this outcome.

Show evidence (2 references)

PMID:25526710 SUPPORT Human Clinical

"the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped"

Quantifies accumulating neurological burden despite treatment.

PMID:25526710 SUPPORT Human Clinical

"In vitro enzyme analysis data showed no correlation with outcome."

Residual fibroblast enzyme activity is not prognostic, which limits its use beyond complementation-group assignment.

Adult complications

Age: Adulthood

Treated cblE is not a static disease in adulthood. Hemolytic anemia has been reported in adult siblings who had been diagnosed neonatally and treated continuously, and it responded to hydroxocobalamin dose escalation - implying the maintenance dose adequate in childhood can become inadequate later. The same report proposes LDH as a monitoring biomarker for this.

Show evidence (2 references)

PMID:38736634 SUPPORT Human Clinical

"The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage."

Proposes ongoing LDH surveillance to guide dose adjustment across the adult course.

PMID:38736634 SUPPORT Human Clinical

"The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation."

States the clinical implication for long-term management of treated cblE.

📊

Prevalence

1

Worldwide (published cases)

Cases In Literature Ultra Rare

No population-based incidence or prevalence estimate exists. Published case counts are the only available measure, and the largest systematic survey assembled 11 cblE patients alongside 13 cblG. cblE is additionally not reliably detected by standard newborn screening, because the block spares the propionate pathway and so produces no propionylcarnitine (C3) elevation - meaning any case count is an undercount of unknown size, not merely a small number.

Show evidence (2 references)

PMID:25526710 SUPPORT Human Clinical

"In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms."

Gives the cohort size of the largest systematic survey of the disorder - 11 cblE patients - which is the basis for the ultra-rare classification.

PMID:2688421 SUPPORT Human Clinical

"Common findings among 11 patients (4 with cblE and 7 with cblG) have included megaloblastic anemia (all patients)"

An earlier series, again of single-digit cblE patient numbers.

🐁

Animal Models

1

Mtrr gene-trap hypomorphic mouse

The principal published Mtrr model is a gene-trap hypomorph rather than a null. It reproduces the upstream metabolic lesion - MTRR deficiency with hyperhomocysteinemia - and, on dedicated haematological characterisation, a macrocytic anemia. That anemia is late adult-onset and largely confined to females, however, so it maps onto the human erythroid phenotype in kind rather than in timing or sex distribution. The model's other reported phenotypes are reproductive and cardiac (embryonic resorption, growth restriction, ventricular septal defects, placental defects); the progressive neurocognitive disease that defines human cblE has not been reported in it.

Species

Mouse

Genotype

Mtrr(gt/gt) gene-trap homozygote

Genes

MTRR hgnc:7473

Publication

PMID:18413293

Pathograph links

MTRR Loss of Function partially recapitulates fidelity: moderate Reproduces reduced MTRR function and the expected one-carbon metabolic perturbation, but as a hypomorphic gene trap with residual activity rather than the biallelic loss-of-function alleles seen in patients.

Limitations: Hypomorphic, not null; the human disorder is caused by biallelic loss-of-function or severely hypomorphic alleles, and the mouse allele's residual activity is not calibrated against any patient genotype.

Show evidence (3 references)

PMID:18413293 SUPPORT Model Organism

"we used mice harboring a gene-trapped (gt) allele in Mtrr"

Identifies the allele as a gene trap in Mtrr, establishing the model's construction.

+ 2 more references

Impaired Erythropoiesis partially recapitulates fidelity: moderate Dedicated haematological phenotyping of this line shows that Mtrr(gt/gt) homozygotes do develop a macrocytic anemia with compensatory extramedullary haematopoiesis, so the erythroid consequence of MTRR deficiency is reproduced. It is reproduced partially: the murine anemia is late adult-onset and sex-limited, while human cblE presents with megaloblastic anemia in the first months of life in both sexes.

Limitations: Three specific divergences from the human phenotype. Onset - the murine defect is late adult-onset, whereas the human anemia is usually the presenting feature in infancy. Sex - female Mtrr(gt/gt) mice are anemic while males show erythrocytic macrocytosis without anemia; no comparable sex bias is reported in cblE. Morphology and kinetics - the authors state they could not establish whether the murine anemia meets megaloblastic criteria, and the reticulocytosis they observe runs opposite to the low reticulocyte count typical of human folate-deficiency megaloblastic anemia. The model is therefore informative for the erythroid consequence of MTRR deficiency but is not a surrogate for the infantile megaloblastic presentation that brings patients to attention.

Readouts

Peripheral erythrocyte count and cell volume in adult females

Direction: ALTERED

Interpretation: Anemia with enlarged erythrocytes - the murine counterpart of the human macrocytic anemia, attributed by the authors to defective erythroid differentiation rather than to haemolysis.

Show evidence (1 reference)

PMID:30024025 SUPPORT Model Organism

"Mtrrgt/gt female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis"

Reports the measurement and the authors' mechanistic reading of it - a production defect, which is what makes it a readout for the impaired-erythropoiesis node rather than for a haemolytic one.

Bone marrow cellularity and splenic extramedullary haematopoiesis

Direction: INCREASED

Interpretation: Compensatory expansion of erythropoiesis in response to the anemia, with raised renal Epo transcription driving it.

Show evidence (1 reference)

PMID:30024025 SUPPORT Model Organism

"This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis."

Establishes that the anemia provokes a normal compensatory response, so the lesion is in erythroid output rather than in the signal to produce red cells.

Show evidence (2 references)

PMID:30024025 SUPPORT Model Organism

"the hypomorphic Mtrrgt/gt mutation in mice results in late-onset and sex-specific blood defects, including macrocytic anaemia, extramedullary haematopoiesis and lymphopenia"

The study was designed to phenotype this line haematologically, and it reports a blood phenotype. That is what makes the model informative for this node at all.

+ 1 more reference

Show evidence (1 reference)

PMID:18413293 SUPPORT Model Organism

"We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice."

Supports the model as informative for MTRR-dependent one-carbon metabolism in development, while showing its readout is reproductive and cardiac rather than the human cblE syndrome.

{ }

Source YAML

click to show

name: Methylcobalamin Deficiency Type cblE
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- cblE deficiency
- Cobalamin E disease
- Homocystinuria-megaloblastic anemia, cblE type
- Functional methionine synthase deficiency type cblE
- Methionine synthase reductase deficiency
- MTRR deficiency
- HMAE
description: >-
  Methylcobalamin deficiency type cblE is an autosomal recessive disorder of intracellular
  cobalamin metabolism caused by biallelic pathogenic variants in MTRR, which encodes
  methionine synthase reductase. Methionine synthase (MTR) uses methylcobalamin to transfer
  a methyl group from 5-methyltetrahydrofolate to homocysteine, regenerating methionine.
  Its cob(I)alamin cofactor is periodically oxidised to the inactive cob(II)alamin state,
  and MTRR is the flavoprotein that reductively remethylates it back to the active form.
  Losing MTRR therefore does not abolish methionine synthase protein or its intrinsic
  catalytic capacity; it strands the enzyme in an inactive oxidised state, which is why the
  defect is called a *functional* methionine synthase deficiency and why assaying MTR
  activity under strongly reducing conditions in vitro can appear normal.
  The block is confined to the remethylation limb of cobalamin metabolism, so patients show
  hyperhomocysteinemia and hypomethioninemia with normal methylmalonic acid - the
  biochemical signature that separates cblE and cblG from the combined disorders
  (cblC, cblD, cblF, cblJ). Clinically the disease presents in infancy with megaloblastic
  anemia and developmental delay, and can extend to microcephaly, nystagmus, seizures,
  leukoencephalopathy and, in severe neonatal cases, thrombotic microangiopathy resembling
  haemolytic-uraemic syndrome. Treatment is parenteral hydroxocobalamin with betaine as an
  alternative remethylation route; haematological response is generally good, but
  neurocognitive outcome can remain poor despite biochemical control.
disease_term:
  preferred_term: methylcobalamin deficiency type cblE
  term:
    id: MONDO:0009354
    label: methylcobalamin deficiency type cblE
parents:
- Inborn Error of Metabolism
- Homocystinuria
references:
- reference: PMID:20301503
  title: "Disorders of Intracellular Cobalamin Metabolism."
  tags:
  - GeneReviews
notes: >-
  GeneReviews mining (PMID:20301503): Genetic Counseling, Management and
  Diagnosis/Testing are mined into this entry. The CLINICAL CHARACTERISTICS section was
  deliberately NOT mined - that paragraph explicitly names cblC as the prototype and best
  understood phenotype, and its age-of-onset and manifestation lists are cblC-specific.
  Attributing them to cblE would be a Named Entity Confusion error. This is a curation
  decision, not an oversight.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic loss-of-function MTRR variants. Reported patients are homozygous or compound
    heterozygous, and carrier parents are unaffected; enzymatic and mutation analysis has
    been used for prenatal diagnosis in affected families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cblE type of homocystinuria is a rare autosomal recessive disorder, which manifests with megaloblastic anaemia and developmental delay in early childhood."
    explanation: States the autosomal recessive inheritance of cblE homocystinuria.
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the families of both patients, enzymatic and mutation analyses were successfully used for prenatal diagnosis."
    explanation: Confirms biallelic Mendelian transmission tractable to prenatal testing.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      GeneReviews recurrence risk for the disorders of intracellular cobalamin metabolism,
      which is the genetic-counselling statement that follows from autosomal recessive
      inheritance.
pathophysiology:
- name: MTRR Loss of Function
  description: >-
    Biallelic pathogenic MTRR variants abolish or severely reduce methionine synthase
    reductase activity. Reported alleles include nonsense variants predicted to yield
    little or no MTRR protein, splice-disrupting insertions, and missense changes
    distributed across the FMN-, FAD- and NADPH-binding modules of this
    ferredoxin-NADP(+) reductase family flavoprotein.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MTRR
    term:
      id: hgnc:7473
      label: MTRR
  molecular_functions:
  - preferred_term: methionine synthase reductase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0030586
      label: '[methionine synthase] reductase (NADPH) activity'
  downstream:
  - target: Methionine Synthase Trapped in Oxidised Cob(II)alamin State
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a defect in the MSR enzyme, which is required for the reductive activation of methionine synthase (MS)"
    explanation: Identifies loss of MTRR/MSR enzyme function as the primary molecular lesion.
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the eleven, three are nonsense mutations, allowing for the identification of two patients for whom little if any MSR protein should be produced."
    explanation: Documents null alleles establishing loss of function as the mechanism.
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supports the concept that this disorder is caused by mutations in the MTRR gene"
    explanation: Confirms MTRR as the causal gene for the cblE complementation group.
- name: Methionine Synthase Trapped in Oxidised Cob(II)alamin State
  description: >-
    Methionine synthase turnover intermittently oxidises its cob(I)alamin cofactor to
    catalytically inert cob(II)alamin. MTRR normally performs the NADPH-dependent reductive
    methylation that restores the active form. Without it methionine synthase accumulates in
    the oxidised state, so cellular methylcobalamin is depleted while methionine synthase
    protein and its intrinsic activity are preserved - a functional, not structural,
    enzyme deficiency. This is why patient fibroblast MTR activity can measure normal under
    strong reducing conditions and only falls when the reducing agent is limited.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: methionine synthase activity
    modifier: DECREASED
    term:
      id: GO:0008705
      label: methionine synthase activity
  chemical_entities:
  - preferred_term: methylcobalamin
    modifier: DECREASED
    term:
      id: CHEBI:28115
      label: methylcobalamin
  downstream:
  - target: Impaired Homocysteine Remethylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate a unique requirement for MSR in the reductive activation of MS."
    explanation: Establishes that methionine synthase depends on MTRR for reductive reactivation.
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "methionine synthase activity was normal under high reducing conditions but decreased on limiting the reducing agent, dithiothreitol, to 5 mmol/L (18% of total, controls 51-81%)"
    explanation: >-
      Directly demonstrates the functional nature of the defect - methionine synthase is
      intact but cannot be reactivated once the exogenous reductant is limiting.
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "formation of methylcobalamin was low (4.5% of total cobalamins, control 57.5%) and complementation studies indicated the cblE defect"
    explanation: Quantifies methylcobalamin depletion in cblE patient fibroblasts.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Methionine synthase specific activity in extracts of all cblE fibroblasts was normal or near-normal under standard reducing conditions"
    explanation: >-
      The defining in vitro discriminator between cblE and cblG. In cblE the methionine
      synthase apoenzyme is intact, so its measured activity is preserved when an exogenous
      reductant substitutes for the missing MTRR; in cblG the apoenzyme itself is defective
      and activity is low under all conditions.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts from patients with cblE (5 patients) and cblG (6 patients) all showed decreased intracellular levels of methylcobalamin (MeCbl)"
    explanation: Confirms depleted intracellular methylcobalamin as the shared cellular consequence.
  - reference: PMID:15714522
    reference_title: "cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect"
    explanation: >-
      Functional rescue - restoring wild-type MTRR to patient cells restores methionine
      synthesis, establishing MTRR loss as sufficient to cause the cellular defect.
- name: Impaired Homocysteine Remethylation
  description: >-
    With methionine synthase functionally inactive, the folate- and cobalamin-dependent
    transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine fails.
    Homocysteine accumulates and methionine is not regenerated. Because the adenosylcobalamin
    limb serving methylmalonyl-CoA mutase is untouched, methylmalonic acid excretion stays
    normal - the discriminating feature against the combined cobalamin disorders.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: homocysteine metabolic process
    modifier: DECREASED
    term:
      id: GO:0050667
      label: homocysteine metabolic process
  - preferred_term: cobalamin metabolic process
    modifier: DECREASED
    term:
      id: GO:0009235
      label: cobalamin metabolic process
  chemical_entities:
  - preferred_term: homocysteine
    modifier: INCREASED
    term:
      id: CHEBI:17230
      label: homocysteine
  - preferred_term: L-methionine
    modifier: DECREASED
    term:
      id: CHEBI:16643
      label: L-methionine
  downstream:
  - target: Methyl-Group and Folate Trapping
    causal_link_type: DIRECT
  - target: Impaired Erythropoiesis
    causal_link_type: DIRECT
  - target: Homocysteine-Mediated Endothelial Injury
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25978498
    reference_title: "Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine."
    explanation: States the core metabolic block defining the disease.
  - reference: PMID:35337626
    reference_title: "Inherited defects of cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria"
    explanation: >-
      Establishes that the cblE block is confined to the remethylation limb, producing
      isolated homocystinuria without methylmalonic aciduria.
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An urinary organic acid analysis revealed normal methylmalonic acid excretion."
    explanation: Confirms in a genetically proven cblE patient that the adenosylcobalamin limb is spared.
- name: Methyl-Group and Folate Trapping
  description: >-
    Methionine synthase is the only reaction that regenerates tetrahydrofolate from
    5-methyltetrahydrofolate. When it stalls, folate is sequestered as
    5-methyltetrahydrofolate and becomes unavailable for one-carbon transfers - the
    classical methyl-folate trap. Reduced methionine also lowers S-adenosylmethionine,
    constraining the many downstream methylation reactions on which myelin maintenance and
    nucleotide synthesis depend. The trap explains the raised formiminoglutamate excretion
    seen in cblE and the partial biochemical response to pharmacological folate.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: tetrahydrofolate metabolic process
    modifier: DECREASED
    term:
      id: GO:0046653
      label: tetrahydrofolate metabolic process
  - preferred_term: methylation
    modifier: DECREASED
    term:
      id: GO:0032259
      label: methylation
  - preferred_term: one-carbon metabolic process
    modifier: DECREASED
    term:
      id: GO:0006730
      label: one-carbon metabolic process
  downstream:
  - target: Impaired Erythropoiesis
    causal_link_type: DIRECT
  - target: Central Nervous System White Matter Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate."
    explanation: >-
      Formiminoglutamate accumulates when tetrahydrofolate is unavailable for the
      formiminotransferase step, the expected consequence of methyl-folate trapping.
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained."
    explanation: >-
      Pharmacological folate partially relieves the trap biochemically, supporting folate
      sequestration as a real component - though the persistence of clinical disease shows
      it is not the whole mechanism.
  - reference: PMID:27905001
    reference_title: "Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions"
    explanation: Links the remethylation block to generalized methylation failure.
- name: Impaired Erythropoiesis
  description: >-
    Folate trapping starves thymidylate synthesis of methylene-tetrahydrofolate, so
    erythroid precursors cannot complete DNA replication while cytoplasmic maturation
    continues. The result is nuclear-cytoplasmic dyssynchrony in the marrow - megaloblastic
    change - with macrocytic anemia and, when severe, extension to other lineages as
    pancytopenia. The marrow picture can be mistaken for congenital dyserythropoietic
    anemia before the biochemical diagnosis is made.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  evidence:
  - reference: PMID:25978498
    reference_title: "Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them."
    explanation: >-
      Documents megaloblastic marrow change in genetically confirmed cblE, including the
      diagnostic confusion with congenital dyserythropoietic anemia.
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia"
    explanation: Marrow-level confirmation of megaloblastic erythropoiesis in cblE.
- name: Homocysteine-Mediated Endothelial Injury
  description: >-
    Severe hyperhomocysteinemia damages vascular endothelium and promotes thrombotic
    microangiopathy. In neonatal-onset cblE this can present as an atypical
    haemolytic-uraemic syndrome, and post-mortem examination has shown myointimal
    proliferation with luminal narrowing in the kidney and microangiopathic change in the
    brain. This is the pathway that makes remethylation disorders part of the differential
    for unexplained thrombosis and atypical HUS.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  downstream:
  - target: Hemolytic-Uremic Syndrome
    causal_link_type: DIRECT
    description: >-
      The thrombotic microangiopathy this node describes is what presents clinically as
      an atypical haemolytic-uraemic syndrome.
  - target: Pancytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Microangiopathic haemolysis and platelet consumption contribute to the cytopenias
      alongside the megaloblastic marrow defect. Marked INDIRECT because two mechanisms
      converge on this phenotype and their relative contribution is not established.
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the histopathological examination of the kidneys showed marked myointimal proliferation and narrowing of the vascular lumen"
    explanation: Histological demonstration of microangiopathic vascular injury in a cblE patient.
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microangiopathy was observed with an increase in vessel wall thickness, a reduction of the arterial inner diameter and capillary oedema."
    explanation: Confirms generalized microangiopathy as a tissue-level consequence.
  - reference: PMID:27905001
    reference_title: "Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atypical haemolytic uraemic syndrome or unexplained vascular thrombosis"
    explanation: >-
      Expert guidelines place atypical HUS and unexplained thrombosis among the
      presentations that should prompt testing for a remethylation disorder.
- name: Central Nervous System White Matter Injury
  description: >-
    Deficient S-adenosylmethionine-dependent methylation impairs myelin maintenance, and
    the resulting white matter disease underlies the developmental delay, microcephaly and
    seizures of cblE. Neuropathology in a fatal neonatal case showed diffuse white matter
    lesions with spongiosis, necrosis and severe astrogliosis. Unlike the haematological
    features, the neurological injury often persists despite biochemical correction.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  locations:
  - preferred_term: white matter
    term:
      id: UBERON:0002316
      label: white matter
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed"
    explanation: Neuropathological confirmation of white matter injury in cblE.
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 17 years of age she remains severely mentally retarded."
    explanation: >-
      Seventeen-year follow-up showing the neurological injury persists despite sustained
      biochemical treatment.
prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based incidence or prevalence estimate exists. Published case counts are
    the only available measure, and the largest systematic survey assembled 11 cblE
    patients alongside 13 cblG. cblE is additionally not reliably detected by standard
    newborn screening, because the block spares the propionate pathway and so produces no
    propionylcarnitine (C3) elevation - meaning any case count is an undercount of unknown
    size, not merely a small number.
  evidence:
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms."
    explanation: >-
      Gives the cohort size of the largest systematic survey of the disorder - 11 cblE
      patients - which is the basis for the ultra-rare classification.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common findings among 11 patients (4 with cblE and 7 with cblG) have included megaloblastic anemia (all patients)"
    explanation: An earlier series, again of single-digit cblE patient numbers.
progression:
- phase: Presentation
  age_range: 2 weeks to 3 years (median 4 weeks)
  notes: >-
    Onset is typically in early infancy with anemia and neurological involvement.
    Presentation after the first two years is unusual but described, including one patient
    who reached medical attention at 21 years with symptoms initially attributed to
    multiple sclerosis - a reminder that a remethylation defect belongs in the differential
    for unexplained adult subacute neurological disease.
  evidence:
  - reference: PMID:15714522
    reference_title: "cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases."
    explanation: Defines the age-at-presentation range and median in a molecularly confirmed cblE series.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presentation has usually been in the first 2 years of life, but one patient came to medical attention at age 21 years with symptoms initially diagnosed as multiple sclerosis."
    explanation: Documents both the usual infantile onset and a late-onset outlier.
- phase: Response to treatment
  age_range: After diagnosis
  notes: >-
    The two limbs of the disease diverge under treatment. Anemia and the biochemical
    abnormalities correct reliably on cobalamin; the neurological deficits resolve more
    slowly and often incompletely. Delay in diagnosis correlates with worse communication
    ability at follow-up, which is the main argument for early detection.
  evidence:
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities; neurological deficits resolved more slowly and in some cases incompletely."
    explanation: States the divergent haematological and neurological treatment responses.
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up."
    explanation: Links diagnostic delay to worse neurocognitive outcome.
- phase: Long-term course
  age_range: Childhood to adulthood
  notes: >-
    Despite a biochemically stable or improving overall course in almost all patients, the
    burden of CNS symptoms accumulates over time and most patients end up developmentally
    delayed or severely handicapped. In vitro residual enzyme activity does not predict
    this outcome.
  evidence:
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped"
    explanation: Quantifies accumulating neurological burden despite treatment.
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In vitro enzyme analysis data showed no correlation with outcome."
    explanation: >-
      Residual fibroblast enzyme activity is not prognostic, which limits its use beyond
      complementation-group assignment.
- phase: Adult complications
  age_range: Adulthood
  notes: >-
    Treated cblE is not a static disease in adulthood. Hemolytic anemia has been reported
    in adult siblings who had been diagnosed neonatally and treated continuously, and it
    responded to hydroxocobalamin dose escalation - implying the maintenance dose adequate
    in childhood can become inadequate later. The same report proposes LDH as a monitoring
    biomarker for this.
  evidence:
  - reference: PMID:38736634
    reference_title: "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage."
    explanation: >-
      Proposes ongoing LDH surveillance to guide dose adjustment across the adult course.
  - reference: PMID:38736634
    reference_title: "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation."
    explanation: States the clinical implication for long-term management of treated cblE.
phenotypes:
- name: Megaloblastic Anemia
  category: Hematologic
  description: >-
    Macrocytic, megaloblastic anemia is the usual presenting feature, typically in the first
    weeks to months of life.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Megaloblastic anemia
    term:
      id: HP:0001889
      label: Megaloblastic anemia
  evidence:
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 1 involves a 20-year-old mentally retarded patient who presented with megaloblastic anaemia at 10 weeks of age."
    explanation: Megaloblastic anemia as the presenting feature in a molecularly confirmed cblE patient.
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Methionine synthase reductase (MSR) deficiency is an autosomal recessive disorder of folate/cobalamin metabolism leading to hyperhomocysteinemia"
    explanation: Establishes MSR deficiency as the disorder in which this haematological phenotype occurs.
- name: Macrocytic Anemia
  category: Hematologic
  description: >-
    Raised mean corpuscular volume is often described as characteristic, but it is not
    obligatory, and its absence must not be used to exclude cblE. In the largest single
    molecularly confirmed series the anemia was macrocytic in only three of nine patients,
    while megaloblastic marrow change was present in six of the seven examined. The marrow
    is the more reliable finding than the red cell indices.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:25978498
    reference_title: "Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment."
    explanation: Names macrocytic anemia among the described presenting features of cobalamin E disorder.
  - reference: PMID:15714522
    reference_title: "cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases."
    explanation: >-
      Qualifies the macrocytosis - in nine molecularly confirmed cblE patients the anemia
      was macrocytic in only three, so a normal MCV does not exclude the diagnosis.
  notes: >-
    Graded OCCASIONAL rather than VERY_FREQUENT on the strength of PMID:15714522, where
    the anemia was macrocytic in only 3 of 9 molecularly confirmed patients. This is
    deliberately lower than the strongest contrary source - which is not a narrative
    review but the 24-patient cblE/cblG cohort PMID:25526710, listing macrocytic anaemia
    among the most frequent symptoms. The two reconcile if macrocytosis is common but not
    obligatory; the grading follows the study that actually counted. The megaloblastic
    marrow change is graded separately and higher, and is the more reliable finding.
- name: Cerebral Atrophy
  category: Neurologic
  description: >-
    Brain atrophy or white matter disease is present on imaging in the large majority of
    patients with the cblE or cblG remethylation defect.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighteen/22 patients presented with brain atrophy or white matter disease."
    explanation: >-
      Quantifies structural brain involvement in the combined cblE/cblG cohort (18 of 22
      imaged patients).
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "various neurological deficits including developmental retardation (10 patients), cerebral atrophy (8 patients), hypotonia (7 patients), EEG abnormalities (6 patients), and nystagmus (5 patients)"
    explanation: >-
      Cerebral atrophy in 8 of the 11 patients in this functional methionine synthase
      deficiency series.
  notes: >-
    PMID:25526710 pools cblE and cblG; the two share a final common metabolic block, so the
    imaging finding is expected to apply to cblE, but the fraction is not cblE-specific.
- name: EEG Abnormality
  category: Neurologic
  description: Electroencephalographic abnormality, which can improve on cobalamin treatment.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "various neurological deficits including developmental retardation (10 patients), cerebral atrophy (8 patients), hypotonia (7 patients), EEG abnormalities (6 patients), and nystagmus (5 patients)"
    explanation: >-
      EEG abnormality in 6 of the 11 patients in this functional methionine synthase
      deficiency series.
- name: Feeding Difficulties
  category: Gastrointestinal
  description: Feeding problems in infancy, among the most frequent presenting symptoms.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms"
    explanation: Lists feeding problems among the most frequent symptoms in the cblE/cblG cohort.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures occur but are among the less frequent neurological features; infantile spasms
    with a West syndrome presentation have been reported.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertonia, seizures, blindness, and ataxia were less frequent."
    explanation: >-
      Places seizures among the less frequent neurological deficits in functional
      methionine synthase deficiency, supporting the OCCASIONAL grading.
- name: Global Developmental Delay
  category: Neurologic
  description: >-
    Developmental delay in early childhood is, with megaloblastic anemia, one of the two
    defining presentations; it frequently progresses to fixed intellectual disability.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifests with megaloblastic anaemia and developmental delay in early childhood"
    explanation: States developmental delay as a defining early-childhood manifestation.
  notes: >-
    Graded VERY_FREQUENT on the PMID:2688421 count of developmental retardation in 10/11 (91%), which falls in the 80-100% band.
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Persistent cognitive impairment, which in reported long-term follow-up has remained
    severe despite decades of biochemical treatment.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 17 years of age she remains severely mentally retarded."
    explanation: Documents persistent severe intellectual disability on long-term follow-up.
- name: Microcephaly
  category: Neurologic
  description: Reduced head circumference reported among the pre-treatment findings.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia"
    explanation: Lists microcephaly among the pre-treatment findings in a cblE patient.
- name: Nystagmus
  category: Ophthalmologic
  description: Nystagmus has been a presenting sign alongside developmental delay.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 2 involves an 8-year-old girl with nystagmus and developmental delay in whom megaloblastic anaemia was detected at 11 weeks of age."
    explanation: Nystagmus as a presenting sign in a molecularly confirmed cblE patient.
  notes: >-
    Graded FREQUENT on the PMID:2688421 count of 5/11 (45%), which falls in the 30-79% band.
- name: Hypotonia
  category: Neurologic
  description: Reported in neonatal-onset disease.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia"
    explanation: Hypotonia in a neonatal-onset cblE presentation.
  notes: >-
    Graded FREQUENT on the PMID:2688421 count of 7/11 (64%), which falls in the 30-79% band.
- name: Failure to Thrive
  category: Growth
  description: Poor growth in infantile presentations.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, hypotonia, pancytopaenia, HUS symptoms"
    explanation: Failure to thrive at presentation in a neonatal cblE case.
  notes: >-
    Graded FREQUENT to match Feeding Difficulties, since both rest on the same PMID:25526710 "most frequent symptoms" sentence and cannot honestly carry different bands.
- name: Pancytopenia
  category: Hematologic
  description: >-
    Severe disease can extend beyond the erythroid lineage to involve granulocytes and
    platelets.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement)"
    explanation: Documents multilineage cytopenia in severe neonatal cblE.
- name: Hemolytic-Uremic Syndrome
  category: Renal
  description: >-
    Thrombotic microangiopathy with microangiopathic haemolysis, thrombocytopenia and renal
    involvement. cblE belongs in the differential for atypical HUS in the newborn period.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hemolytic-uremic syndrome
    term:
      id: HP:0005575
      label: Hemolytic-uremic syndrome
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cblE should be considered when diagnosing patients presenting with HUS signs and symptoms during the newborn period."
    explanation: Establishes HUS-like presentation as a recognized, if rare, cblE phenotype.
- name: Hemolytic Anemia in Adulthood
  category: Hematologic
  description: >-
    A late complication, first described in 2024 in two adult cblE siblings who had been
    diagnosed neonatally and treated throughout. Both developed hemolytic anemia with LDH
    above 11,000 U/L, undetectable haptoglobin and raised unconjugated bilirubin, which
    resolved on escalating the hydroxocobalamin dose rather than on any new agent. This is
    a different lesion from the presenting megaloblastic anemia and argues that treated
    cblE needs continued haematological surveillance into adult life.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:38736634
    reference_title: "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation."
    explanation: The primary case description of adult-onset hemolytic anemia in treated cblE.
  - reference: PMID:38736634
    reference_title: "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report of such complications in adulthood."
    explanation: >-
      Graded PARTIAL because it establishes the phenotype from a single sibling pair, which
      is why the frequency here is VERY_RARE.
  notes: >-
    Reported in one sibling pair. One of the two had a concurrent parvovirus B19 infection,
    which the authors note can cause erythroblastopenia even without immunocompromise, so
    the hemolysis and the viral trigger are not cleanly separable in that patient.
- name: Leukoencephalopathy
  category: Neurologic
  description: >-
    Diffuse white matter disease, demonstrated neuropathologically as spongiosis, necrosis
    and astrogliosis in a fatal neonatal case.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed"
    explanation: Neuropathological documentation of leukoencephalopathy in cblE.
biochemical:
- name: Plasma Total Homocysteine
  notes: >-
    Markedly raised plasma total homocysteine is the cardinal biochemical abnormality and
    the recommended first-line test in any suspected remethylation disorder.
  presence: INCREASED
  biomarker_term:
    preferred_term: Hyperhomocystinemia
    term:
      id: HP:0002160
      label: Hyperhomocystinemia
  evidence:
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical features included severe hyperhomocysteinaemia and hypomethioninaemia"
    explanation: Documents severe hyperhomocysteinemia in molecularly confirmed cblE.
  - reference: PMID:27905001
    reference_title: "Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms"
    explanation: Guideline basis for total homocysteine as the first-line diagnostic marker.
- name: Plasma Methionine
  notes: >-
    Low plasma methionine reflects failed regeneration by methionine synthase. It is not
    universal - one reported patient had severe hyperhomocysteinemia with normal methionine,
    so a normal methionine does not exclude cblE.
  presence: DECREASED
  biomarker_term:
    preferred_term: Hypomethioninemia
    term:
      id: HP:0003658
      label: Hypomethioninemia
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L)"
    explanation: Quantifies the paired hyperhomocysteinemia and hypomethioninemia in cblE.
  - reference: PMID:12555939
    reference_title: "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe hyperhomocysteinaemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cblE defect."
    explanation: >-
      Qualifies the marker - a confirmed cblE patient with normal methionine, so
      hypomethioninemia is characteristic but not obligatory.
- name: Urinary Homocystine
  notes: Homocystinuria without methylmalonic aciduria.
  presence: INCREASED
  biomarker_term:
    preferred_term: Homocystinuria
    term:
      id: HP:0002156
      label: Homocystinuria
  evidence:
  - reference: PMID:35337626
    reference_title: "Inherited defects of cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria"
    explanation: Defines the isolated-homocystinuria biochemical class to which cblE belongs.
- name: Urinary Methylmalonic Acid
  notes: >-
    Normal methylmalonic acid excretion, which is what separates cblE and cblG from the
    combined cobalamin disorders cblC, cblD, cblF and cblJ.
  presence: NORMAL
  evidence:
  - reference: PMID:23430521
    reference_title: "cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An urinary organic acid analysis revealed normal methylmalonic acid excretion."
    explanation: Confirms normal MMA in a genetically proven cblE patient.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evaluation of the methylmalonic acid (MMA) level in urine and blood and plasma total homocysteine (tHcy) level are the mainstays of biochemical testing."
    explanation: GeneReviews establishes the paired MMA/tHcy measurement that discriminates the complementation groups.
- name: Urinary Formiminoglutamate
  notes: >-
    Raised formiminoglutamate excretion, the expected marker of tetrahydrofolate
    unavailability in the methyl-folate trap.
  presence: INCREASED
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate."
    explanation: Documents the folate-trapping marker in a cblE patient.
genetic:
- name: MTRR
  notes: >-
    MTRR encodes methionine synthase reductase, a ferredoxin-NADP(+) reductase family
    flavoprotein carrying FMN-, FAD- and NADPH-binding modules. Reported cblE alleles are
    private to individual families and spread across the coding sequence, including
    nonsense, splice and missense changes.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MTRR
    term:
      id: hgnc:7473
      label: MTRR
  evidence:
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reveal 11 mutations in eight patients from seven families belonging to the cblE complementation group"
    explanation: Original identification of MTRR as the cblE gene across multiple families.
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apart from an intronic substitution found in two unrelated patients, the mutations appear singular among individuals."
    explanation: Documents the private, family-specific allelic spectrum.
  - reference: PMID:10484769
    reference_title: "Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distributed throughout the coding region, including proposed FMN, FAD and NADPH binding sites"
    explanation: Maps the variant spectrum onto the flavoprotein cofactor-binding modules.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MMACHC (cblC), MMADHC (cblD-combined and cblD-homocystinuria), MTRR (cblE), LMBRD1 (cblF), MTR (cblG), ABCD4 (cblJ)"
    explanation: >-
      GeneReviews assigns MTRR to the cblE complementation group in its diagnostic
      gene list, alongside the genes of the other complementation groups.
  - reference: PMID:15714522
    reference_title: "cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation."
    explanation: >-
      The one reported genotype-phenotype association - c.1361C>T homozygosity with a
      milder, predominantly haematological course. Graded PARTIAL because the same
      publication states no other correlation was apparent, and a later larger cohort found
      none at all.
  variants:
  - name: c.1361C>T
    description: >-
      Reported as associated with a milder, predominantly haematological presentation in
      homozygotes. This is the only genotype-phenotype link described for cblE, and it is
      contested - the larger 24-patient cblE/cblG survey found no genotype-phenotype
      correlations evident.
    evidence:
    - reference: PMID:15714522
      reference_title: "cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected."
      explanation: Places c.1361C>T among the recurrent MTRR alleles in a nine-patient cblE series.
    - reference: DOI:10.1023/A:1025159103257
      reference_title: "CblE type of homocystinuria: Mild clinical phenotype in two patients homozygous for a novel mutation in the <i>MTRR</i> gene"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We propose that homozygosity for this novel mutation may be associated with a mild phenotype, although its long‐term deleterious neurological consequences remain possible."
      explanation: >-
        The primary source for the mild-phenotype claim. Graded PARTIAL because the authors
        propose rather than establish it, on two patients, and explicitly leave long-term
        neurological consequences open.
    - reference: DOI:10.1023/A:1025159103257
      reference_title: "CblE type of homocystinuria: Mild clinical phenotype in two patients homozygous for a novel mutation in the <i>MTRR</i> gene"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis confirmed that both patients are homozygous for a novel mutation c.1361C > T in the methionine synthase reductase gene leading to a replacement of serine by leucine (S454L) in a highly conserved FAD‐binding domain."
      explanation: >-
        Locates the allele in a conserved FAD-binding domain, the structural basis for
        expecting reduced rather than abolished reductase activity.
treatments:
- name: Parenteral Hydroxocobalamin
  description: >-
    Parenteral hydroxocobalamin is the first-line treatment and should be started without
    waiting for confirmatory testing in any suspected remethylation disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  target_mechanisms:
  - target: Impaired Homocysteine Remethylation
    description: >-
      Supplying cobalamin in large excess raises the fraction of methionine synthase that
      is loaded with cofactor, partially compensating for the failed reductive reactivation.
  evidence:
  - reference: PMID:27905001
    reference_title: "Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications."
    explanation: Guideline-strength recommendation for parenteral hydroxocobalamin in remethylation disorders including cblE.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early institution of injectable hydroxocobalamin improves survival and may reduce but not completely prevent primary manifestations."
    explanation: >-
      GeneReviews on early treatment. Graded PARTIAL because it is explicitly qualified -
      survival improves but the primary manifestations are only reduced, not prevented,
      which matches the divergent haematological and neurological responses curated here.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of thromboembolic complications (e.g., HUS and thrombotic microangiopathy) includes initiation of hydroxocobalamin (OHCbl) and betaine or an increase in their doses."
    explanation: >-
      GeneReviews management of the thrombotic microangiopathy complication, directly
      relevant because HUS is curated as a phenotype of this disorder.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydroxycobalamin has been more effective than cyanocobalamin."
    explanation: >-
      Supports the choice of hydroxocobalamin specifically over cyanocobalamin, which is
      the reason the form of cobalamin is named in the treatment rather than left generic.
  - reference: PMID:2688421
    reference_title: "Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities; neurological deficits resolved more slowly and in some cases incompletely."
    explanation: Documents reliable haematological and biochemical response but incomplete neurological response.
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment."
    explanation: >-
      Tempers the treatment claim - biochemical correction is achievable but the clinical,
      and specifically neurocognitive, response is limited in most patients.
  - reference: PMID:38736634
    reference_title: "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation."
    explanation: >-
      States the rationale for the two-drug regimen - cobalamin to drive residual enzyme
      function, betaine to bypass it.
- name: Betaine
  description: >-
    Betaine provides an alternative, betaine-homocysteine methyltransferase-dependent route
    for remethylating homocysteine to methionine that bypasses methionine synthase
    entirely. Used in combination with hydroxocobalamin.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: betaine
      term:
        id: CHEBI:17750
        label: glycine betaine
  target_mechanisms:
  - target: Impaired Homocysteine Remethylation
    description: >-
      Bypasses the blocked methionine synthase reaction by donating a methyl group through
      betaine-homocysteine methyltransferase.
  evidence:
  - reference: PMID:25978498
    reference_title: "Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients."
    explanation: Supports combined hydroxocobalamin plus betaine as the cblE regimen.
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant."
    explanation: >-
      Cohort-level confirmation that betaine-containing combinations produce a significant
      biochemical response.
- name: Methylcobalamin
  description: >-
    Methylcobalamin supplies the methionine synthase cofactor in its already-methylated
    form. In one long-term case, substituting methylcobalamin for folate improved alertness,
    motor function, speech and EEG, with the best overall control on the two combined.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylcobalamin
      term:
        id: CHEBI:28115
        label: methylcobalamin
  target_mechanisms:
  - target: Methionine Synthase Trapped in Oxidised Cob(II)alamin State
    description: >-
      Delivers the methylated cofactor directly, reducing dependence on the MTRR-catalysed
      reductive methylation step that is missing.
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On replacement of folate with methylcobalamin, alertness, motor function, speech and the electroencephalogram improved"
    explanation: Documents clinical and electrophysiological improvement on methylcobalamin.
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The best control was observed on a combination of folate and methylcobalamin."
    explanation: Supports combined folate plus methylcobalamin over either alone in this patient.
- name: Folate Supplementation
  description: >-
    High-dose folate relieves the methyl-folate trap biochemically. Its effect is partial -
    formiminoglutamate excretion and homocystinuria nearly normalized on folate alone while
    clinical and haematological abnormalities persisted - so it is adjunctive to cobalamin,
    not a substitute for it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: folic acid
      term:
        id: CHEBI:27470
        label: folic acid
  target_mechanisms:
  - target: Methyl-Group and Folate Trapping
    description: Replenishes usable folate pools sequestered as 5-methyltetrahydrofolate.
  evidence:
  - reference: PMID:9427140
    reference_title: "Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained."
    explanation: >-
      Explicitly partial - the biochemical response to folate alone was good but the
      clinical and haematological disease was not corrected.
- name: Avoidance of Nitrous Oxide and Catabolic Stress
  description: >-
    Nitrous oxide irreversibly oxidises the cobalamin cofactor of methionine synthase and is
    contraindicated. Prolonged fasting, protein intake below the age-appropriate
    recommended allowance, and methionine-free medical foods are likewise to be avoided.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "methionine restriction including use of medical foods that do not contain methionine; and the anesthetic nitrous oxide"
    explanation: >-
      GeneReviews Agents/Circumstances to Avoid, naming nitrous oxide and methionine
      restriction as contraindicated in disorders of intracellular cobalamin metabolism.
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)"
    explanation: GeneReviews warning against catabolic stress.
definitions:
- name: Biochemical case definition of cblE
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Raised plasma total homocysteine with low or normal methionine and normal methylmalonic
    acid, in a patient with megaloblastic anemia and/or developmental delay, confirmed by
    biallelic MTRR variants or by fibroblast complementation assigning the cblE group.
  evidence:
  - reference: PMID:20301503
    reference_title: "Disorders of Intracellular Cobalamin Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data."
    explanation: GeneReviews states the tripartite basis of diagnosis.
animal_models:
- name: Mtrr gene-trap hypomorphic mouse
  species: Mouse
  genotype: Mtrr(gt/gt) gene-trap homozygote
  publication: PMID:18413293
  description: >-
    The principal published Mtrr model is a gene-trap hypomorph rather than a null. It
    reproduces the upstream metabolic lesion - MTRR deficiency with hyperhomocysteinemia -
    and, on dedicated haematological characterisation, a macrocytic anemia. That anemia is
    late adult-onset and largely confined to females, however, so it maps onto the human
    erythroid phenotype in kind rather than in timing or sex distribution. The model's
    other reported phenotypes are reproductive and cardiac (embryonic resorption, growth
    restriction, ventricular septal defects, placental defects); the progressive
    neurocognitive disease that defines human cblE has not been reported in it.
  genes:
  - preferred_term: MTRR
    term:
      id: hgnc:7473
      label: MTRR
  modeled_mechanisms:
  - target: MTRR Loss of Function
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces reduced MTRR function and the expected one-carbon metabolic perturbation,
      but as a hypomorphic gene trap with residual activity rather than the biallelic
      loss-of-function alleles seen in patients.
    limitations: >-
      Hypomorphic, not null; the human disorder is caused by biallelic loss-of-function or
      severely hypomorphic alleles, and the mouse allele's residual activity is not
      calibrated against any patient genotype.
    evidence:
    - reference: PMID:18413293
      reference_title: "Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we used mice harboring a gene-trapped (gt) allele in Mtrr"
      explanation: Identifies the allele as a gene trap in Mtrr, establishing the model's construction.
    - reference: PMID:17369066
      reference_title: "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate."
      explanation: >-
        The model reproduces the full human biochemical triad - hyperhomocysteinemia,
        hypomethioninemia, and folate trapped as methyltetrahydrofolate. This, rather than
        the genotype alone, is what makes the model informative for the metabolic lesion.
    - reference: PMID:17369066
      reference_title: "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity."
      explanation: >-
        Graded PARTIAL - the authors state the model is deliberately hypomorphic rather
        than null, which is the reason it is graded PARTIALLY_RECAPITULATES here.
  - target: Impaired Erythropoiesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Dedicated haematological phenotyping of this line shows that Mtrr(gt/gt) homozygotes
      do develop a macrocytic anemia with compensatory extramedullary haematopoiesis, so
      the erythroid consequence of MTRR deficiency is reproduced. It is reproduced
      partially: the murine anemia is late adult-onset and sex-limited, while human cblE
      presents with megaloblastic anemia in the first months of life in both sexes.
    limitations: >-
      Three specific divergences from the human phenotype. Onset - the murine defect is
      late adult-onset, whereas the human anemia is usually the presenting feature in
      infancy. Sex - female Mtrr(gt/gt) mice are anemic while males show erythrocytic
      macrocytosis without anemia; no comparable sex bias is reported in cblE. Morphology
      and kinetics - the authors state they could not establish whether the murine anemia
      meets megaloblastic criteria, and the reticulocytosis they observe runs opposite to
      the low reticulocyte count typical of human folate-deficiency megaloblastic anemia.
      The model is therefore informative for the erythroid consequence of MTRR deficiency
      but is not a surrogate for the infantile megaloblastic presentation that brings
      patients to attention.
    readouts:
    - name: Peripheral erythrocyte count and cell volume in adult females
      target: Impaired Erythropoiesis
      direction: ALTERED
      interpretation: >-
        Anemia with enlarged erythrocytes - the murine counterpart of the human macrocytic
        anemia, attributed by the authors to defective erythroid differentiation rather
        than to haemolysis.
      evidence:
      - reference: PMID:30024025
        reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mtrrgt/gt female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis"
        explanation: >-
          Reports the measurement and the authors' mechanistic reading of it - a production
          defect, which is what makes it a readout for the impaired-erythropoiesis node
          rather than for a haemolytic one.
    - name: Bone marrow cellularity and splenic extramedullary haematopoiesis
      target: Impaired Erythropoiesis
      direction: INCREASED
      interpretation: >-
        Compensatory expansion of erythropoiesis in response to the anemia, with raised
        renal Epo transcription driving it.
      evidence:
      - reference: PMID:30024025
        reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis."
        explanation: >-
          Establishes that the anemia provokes a normal compensatory response, so the
          lesion is in erythroid output rather than in the signal to produce red cells.
    evidence:
    - reference: PMID:30024025
      reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the hypomorphic Mtrrgt/gt mutation in mice results in late-onset and sex-specific blood defects, including macrocytic anaemia, extramedullary haematopoiesis and lymphopenia"
      explanation: >-
        The study was designed to phenotype this line haematologically, and it reports a
        blood phenotype. That is what makes the model informative for this node at all.
    - reference: PMID:30024025
      reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, the male response differed since Mtrrgt/gt male mice were not anaemic but did display erythrocytic macrocytosis and lymphopenia."
      explanation: >-
        Graded PARTIAL, and the reason the link is PARTIALLY_RECAPITULATES rather than
        RECAPITULATES - half the animals reproduce the macrocytosis without reproducing the
        anemia.
  evidence:
  - reference: PMID:18413293
    reference_title: "Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice."
    explanation: >-
      Supports the model as informative for MTRR-dependent one-carbon metabolism in
      development, while showing its readout is reproductive and cardiac rather than the
      human cblE syndrome.
discussions:
- discussion_id: cble_mouse_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Human cblE presents in infancy with megaloblastic anemia and progressive neurocognitive
    disease, yet the Mtrr(gt/gt) mouse becomes anemic only in late adult life, only in
    females, with a rising rather than falling reticulocyte count, and with no reported
    neurological phenotype. Does that reflect residual activity of the hypomorphic allele,
    a species difference in erythroid and cerebral folate handling, or a different
    mechanism reaching the same cell type - and can any model reproduce the infantile
    presentation?
  attaches_to:
  - pathophysiology#Impaired Erythropoiesis
  - pathophysiology#Central Nervous System White Matter Injury
  rationale: >-
    The mismatch is not that the mouse lacks the human phenotypes - it has an erythroid one
    - but that the two systems diverge in different ways, and the difference matters for
    what the model can be used to test. On the erythroid side the divergence is in timing
    and kinetics: the anemia appears late in adult life and is accompanied by
    reticulocytosis, whereas human folate-deficiency megaloblastic anemia is
    reticulocytopenic, and the authors could not establish that the murine anemia is
    megaloblastic at all. So a mouse that models the consequence of chronic MTRR deficiency
    does not model the neonatal marrow crisis. On the neurological side the divergence is
    starker and mechanistically specific: the entry attributes human white-matter injury to
    deficient S-adenosylmethionine-dependent methylation, and in this line the AdoMet/AdoHcy
    ratio is preserved in most tissues - unlike other murine hyperhomocysteinemia models,
    where it falls. Until a model reproduces the infantile presentation, the question that
    matters most clinically - whether earlier treatment prevents the neurocognitive injury,
    which is also what the newborn-screening gap turns on - cannot be tested in mouse.
  evidence:
  - reference: PMID:30024025
    reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Even though Mtrrgt/gt female mice display macrocytic anaemia, we were unable to determine whether the anaemia fulfils megaloblastic status."
    explanation: >-
      The authors themselves decline to call the murine anemia megaloblastic, which is the
      precise point on which the model and the defining human phenotype part company.
  - reference: PMID:30024025
    reference_title: "Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our finding that older Mtrrgt/gt female mice have increased reticulocyte counts contradicts most human cases of megaloblastic anaemia associated with folate deficiency wherein reticulocyte numbers are usually low"
    explanation: >-
      A directional contradiction rather than a difference of degree - the murine marrow
      response goes the opposite way to the human one, which is why this is curated as a
      mismatch and not merely as incomplete modelling.
  - reference: PMID:17369066
    reference_title: "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unexpectedly, Mtrr(gt/gt) mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues."
    explanation: >-
      A mechanistic account of the neurological half of the mismatch. The entry attributes
      the human CNS white-matter injury to deficient S-adenosylmethionine-dependent
      methylation, and in this model that very ratio is preserved in most tissues - so the
      mouse does not reproduce the step the human neurological phenotype is proposed to run
      through.
  - reference: PMID:17369066
    reference_title: "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation."
    explanation: >-
      The contrast that sharpens the mismatch - other hyperhomocysteinemia models do show
      impaired methylation, so the preserved ratio is specific to the Mtrr hypomorph rather
      than a general property of murine hyperhomocysteinemia.
  - reference: PMID:25526710
    reference_title: "Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment."
    explanation: >-
      States the human outcome the model would need to reproduce to be useful for testing
      treatment timing.
- discussion_id: cble_newborn_screening_benefit
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does presymptomatic detection of cblE by newborn screening improve neurocognitive
    outcome, and which analyte combination detects it reliably?
  attaches_to:
  - pathophysiology#Central Nervous System White Matter Injury
  rationale: >-
    The haematological features of cblE respond well to hydroxocobalamin while the
    neurological injury often does not, which is the usual argument for presymptomatic
    treatment. But the screening evidence for cblE specifically is weak: the systematic
    review that recommends newborn screening for CBS and severe MTHFR deficiency
    explicitly declines to extend that to cblE, both because benefit-of-early-treatment
    data are weaker and because analyte performance data are more limited. Whether the
    persistent neurocognitive morbidity reflects irreversible prenatal or early postnatal
    injury, or simply late treatment, is unresolved.
  evidence:
  - reference: PMID:25762406
    reference_title: "Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the cblE and cblG defects, evidence for the benefit of early treatment is weaker; and data on performance of Met, Met/Phe and tHcy even more limited."
    explanation: Directly states the twin evidence gaps for cblE newborn screening.

📚

References & Deep Research

References

1

PMID:20301503

Disorders of Intracellular Cobalamin Metabolism.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Methylcobalamin Deficiency Type cblE (Methionine Synthase Reductase Deficiency) — Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 25 citations 2026-08-27T05:54:22.272429

Methylcobalamin Deficiency Type cblE (Methionine Synthase Reductase Deficiency) — Research Report

1. Disease Information

Overview

Methylcobalamin deficiency type cblE (also called homocystinuria-megaloblastic anemia, cblE type; HMAE) is a rare autosomal recessive inborn error of intracellular cobalamin (vitamin B12) metabolism. It results from biallelic pathogenic variants in MTRR, which encodes methionine synthase reductase — an enzyme required to periodically reactivate methionine synthase (MTR/MS) by reductive methylation. Loss of MTRR function causes functional deficiency of methionine synthase despite the enzyme itself being structurally normal, producing impaired remethylation of homocysteine to methionine. The clinical result is combined homocystinuria and megaloblastic anemia, typically with hypomethioninemia, in the absence of methylmalonic aciduria (distinguishing it from the "combined" cobalamin defects such as cblC/cblD/cblF) (GeneReviews, NBK1328; OMIM #236270).

Key Identifiers

OMIM phenotype: #236270 — Homocystinuria-Megaloblastic Anemia, cblE Type (HMAE)
OMIM gene: *602568 — METHIONINE SYNTHASE REDUCTASE; MTRR
MONDO: MONDO:0009354
Orphanet: ORPHA:2169 (methionine synthase reductase deficiency); grouped clinically with cblG and cblD-variant 1 under ORPHA:622 "Homocystinuria without methylmalonic aciduria"
MedGen: C1856057
HGNC: 7473 (MTRR)
UniProt: Q9UBK8 (MTRR protein, 698 amino acids, ~77.7 kDa)
Gene location: chromosome 5p15.31 (5p15.3–15.2 in older literature); gene spans ~34 kb, 15 exons
Inheritance: Autosomal recessive (Sources: OMIM #236270, OMIM *602568, NORD/MONDO, UniProt Q9UBK8, GeneReviews NBK1328)

Synonyms

Methionine synthase reductase deficiency
cblE-type homocystinuria / cblE disease
Homocystinuria-megaloblastic anemia, cblE type (HMAE)
Vitamin B12-responsive megaloblastic anemia due to methionine synthase reductase deficiency

Data Source Character

Nearly all available information is derived from case reports and small case series (individual patients and sibships), not large aggregated cohorts or EHR-based studies — reflecting the extreme rarity of the disease. The largest published cohort ("24 patients with the cblE or cblG remethylation defect") is a multi-center retrospective compilation (Huemer et al., J Inherit Metab Dis 2015; PMID not directly retrieved here, DOI 10.1007/s10545-014-9803-7), still a case-series design rather than population-level data.

2. Etiology

Disease Causal Factors

cblE is a purely genetic (Mendelian) disorder. Biallelic loss-of-function or hypomorphic variants in MTRR impair the reductive-methylation reactivation of methionine synthase (MTR), which uses methylcobalamin (MeCbl) as a cofactor to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, forming methionine. MTR undergoes occasional oxidative inactivation (cob(II)alamin state) during turnover; MTRR restores it to the active cob(I)alamin state using electrons from NADPH shuttled through FAD and FMN cofactors, with S-adenosylmethionine (SAM) as the methyl donor for reactivation. Without functional MTRR, MTR activity progressively declines, causing accumulation of homocysteine and depletion of methionine/SAM (WebSearch synthesis of MTRR mechanism; ScienceDirect topic pages; GeneReviews NBK1328).

Genetic Risk Factors

Causal variants: Biallelic pathogenic MTRR variants (missense, nonsense, splice-site, small indels, and a truncating frameshift). GeneReviews reports that sequence analysis detects the majority (21 of 22 reported variant types in one series) of pathogenic alleles (GeneReviews NBK1328).
Notable variants:
c.1361C>T (p.Ser454Leu), sometimes reported as p.Ser545Leu in different transcript numbering — an "Iberian-origin" founder-type variant associated with a milder phenotype with no evident neurologic involvement in homozygotes (ClinVar RCV000007449; GeneReviews NBK1328; ResearchGate case report "CblE type of homocystinuria: Mild clinical phenotype... novel mutation").
G487R (glycine-to-arginine at codon 487) — reported in homocystinuria-megaloblastic anemia patients.
A heterozygous truncating mutation in two siblings (OMIM 602568.0001) was among the first pathogenic MTRR alleles identified.
Additional ClinVar-curated variants include c.2073C>T (p.Arg691=, synonymous, uncertain significance in some records), c.1952+17C>A (intronic), and c.-119T>C (5′ UTR) (ClinVar RCV000907261, RCV003618859, RCV001530449).
No common susceptibility loci or modifier genes have been robustly established for cblE specifically, though the common MTRR polymorphism A66G (p.Ile22Met) has been studied extensively in the general population as a modifier of folate/homocysteine status and disease risk (neural tube defects, cardiovascular disease) — this is distinct from the rare biallelic pathogenic variants causing cblE disease itself.

Environmental Risk Factors

Maternal/dietary vitamin B12 or folate status: While cblE is a primary genetic enzyme defect (not a nutritional deficiency), functional cobalamin/folate status can modulate phenotypic severity, since MTRR partially rescues residual methionine synthase activity when cobalamin is abundant — this underlies the rationale for high-dose parenteral hydroxocobalamin therapy.
No infectious, occupational, or toxic environmental triggers have been described as causal for cblE; it is a monogenic disease that is fully penetrant when biallelic pathogenic variants are present, though age of onset and severity vary (GeneReviews NBK1328).

Protective Factors

No specific protective genetic variants against cblE disease itself have been reported (as opposed to studies of the common MTRR A66G polymorphism in other multifactorial contexts).
Vitamin B12 (hydroxocobalamin) responsiveness functions as a therapeutic/mitigating factor rather than a true "protective factor," since residual enzyme activity in hypomorphic alleles can be augmented pharmacologically.

Gene-Environment Interactions

The core gene-environment interaction in cblE pathophysiology is the substrate-driven rescue mechanism: supraphysiologic (pharmacologic) doses of hydroxocobalamin increase intracellular cobalamin pools sufficiently to partially bypass the reductive-reactivation defect in some hypomorphic MTRR variants, explaining "cobalamin responsiveness" as a treatment principle (GeneReviews NBK1328; multiple case reports).
Maternal folate/B12 status during pregnancy is relevant to the broader MTRR biology (e.g., mouse models — see Section 15) but is not established as a modifier of cblE disease severity in affected humans specifically.

3. Phenotypes

cblE produces a relatively narrow, well-defined phenotypic triad: megaloblastic anemia, neurologic/developmental impairment, and biochemical homocystinuria with hypomethioninemia — but with documented phenotypic heterogeneity in severity and organ involvement.

Hematologic

Megaloblastic anemia (macrocytic anemia with megaloblastic bone marrow changes) — the most consistent and often presenting feature. Reported as isolated in some patients.
HP suggestion: HP:0001889 (Megaloblastic anemia)
Pancytopenia / early-onset bone marrow failure has been reported, sometimes remaining isolated without neurologic involvement (WebSearch synthesis, PMC article on late-onset hemolytic anemia complication).
HP suggestion: HP:0001876 (Pancytopenia)
Late-onset refractory hemolytic anemia as a rare treatment-related/disease complication in siblings on long-term therapy, potentially preventable by hydroxocobalamin dose escalation (PMC11078714, "Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency").
HP suggestion: HP:0001878 (Hemolytic anemia)

Neurologic / Developmental

Developmental delay / delayed psychomotor development, frequently reported (HP:0002194)
Intellectual disability / cognitive dysfunction (HP:0001249)
Hypotonia (HP:0001252)
Seizures, described as "frequent" in some series (HP:0001250)
Cerebral atrophy on neuroimaging (HP:0002059)
Lethargy (HP:0001254)

Ophthalmologic

Nystagmus (HP:0000639)
Impaired visual acuity without lens dislocation — notably distinguishing cblE from classic CBS-deficiency homocystinuria, which characteristically causes ectopia lentis (HP:0000572, visual impairment)
Macular dysfunction, described as a rare feature (relevant HP term e.g. HP:0007754 macular dystrophy, if applicable per specific case)

Growth / Constitutional

Failure to thrive / feeding difficulties, often an early presenting sign (HP:0001508 / HP:0011968)
Severe growth failure — GeneReviews specifically states "most children with cblE present in the first two years of life with severe growth failure, megaloblastic anemia, and neurologic manifestations" (GeneReviews NBK1328)

Renal

Hemolytic uremic syndrome (HUS) — described as occurring in a subset of patients ("isolated megaloblastic anemia and HUS may also be seen")
HP suggestion: HP:0005575 (Hemolytic-uremic syndrome)
Atypical glomerulopathy — described in an adolescent-onset presentation (GeneReviews NBK1328)

Laboratory Abnormalities (biochemical phenotypes, distinct from clinical signs)

Elevated total plasma homocysteine (hyperhomocysteinemia) and homocystinuria (elevated urinary homocystine)
Low-to-normal plasma methionine (hypomethioninemia) and low S-adenosylmethionine (SAM)
Normal urine/plasma methylmalonic acid (MMA) — key distinguishing feature from combined (cblC/D/F) and isolated methylmalonic-acidemia cobalamin defects
No elevated propionylcarnitine (C3) on newborn screening acylcarnitine profile, which is why cblE and cblG are typically missed by standard newborn screening (GeneReviews NBK1328)

Phenotype Characteristics

Age of onset: Most commonly between 2 weeks and 3 years of age; GeneReviews specifies presentation "in the first two years of life" for the classic severe form; rarer adolescent-onset presentation with atypical glomerulopathy has also been described (GeneReviews NBK1328; multiple case-report sources).
Severity: Highly variable — from mild phenotype with isolated megaloblastic anemia and no neurologic involvement (e.g., homozygous c.1361C>T/p.Ser454Leu patients) to severe early-onset multisystem disease with profound developmental delay, seizures, and growth failure.
Progression: Generally chronic and, if untreated, progressive; treatment with parenteral hydroxocobalamin and betaine can stabilize biochemical parameters, but neurodevelopmental and ophthalmologic outcomes are only partially responsive.
Frequency among affected individuals: Formal frequency percentages for individual phenotypes are not well established given the very small published patient numbers (fewer than 40 cumulative cblE + cblG cases reported per GeneReviews).

Quality of Life Impact

No disease-specific quality-of-life instrument data were identified in the literature searched. Neurodevelopmental impairment (intellectual disability, seizures) and visual impairment are the primary drivers of long-term functional impact; the JIMD cohort study (Huemer et al. 2015) explicitly notes that "the overall impact of treatment on neurodevelopmental disabilities and eye disease was at most moderate," implying persistent long-term QoL burden even with treatment (WebSearch synthesis of JIMD 2015 paper).

4. Genetic / Molecular Information

Causal Gene

MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase), HGNC:7473, chromosome 5p15.31, ~34 kb genomic span, 15 exons.
OMIM gene entry: *602568.

Protein / Function

MTRR is a diflavin oxidoreductase of the ferredoxin-NADP+ reductase family, structurally related to cytochrome P450 reductase and nitric oxide synthase reductase domains.
Domain architecture: N-terminal FMN-binding domain (flavodoxin-like) + C-terminal FAD/NADPH-binding domain (ferredoxin-NADP+ reductase-like).
Mechanism: Acquires electrons from NADPH, passes them sequentially through FAD → FMN, then to cob(II)alamin bound to methionine synthase (MTR), reducing it to cob(I)alamin, which is then remethylated by S-adenosylmethionine (SAM) to regenerate active methylcobalamin-bound MTR.
MTRR forms part of a multiprotein complex with MMACHC, MMADHC (the cblC/cblD gene products) and MTR itself, integrating it into the broader intracellular cobalamin-processing pathway.
(Sources: WebSearch synthesis of GeneCards/UniProt/PNAS cloning paper; ScienceDirect topic overview)

Pathogenic Variants

Gene: MTRR (HGNC:7473)
Variant classification: Reported alleles span pathogenic and likely pathogenic per ACMG/AMP in ClinVar; variant of uncertain significance for some synonymous/intronic changes (e.g., c.2073C>T p.Arg691=).
Variant types: Missense (majority; e.g., p.Ser454Leu/p.Ser545Leu, G487R), nonsense/truncating (e.g., the original heterozygous truncating mutation OMIM 602568.0001), splice-region (c.1952+17C>A), and regulatory/5′UTR (c.-119T>C).
Allele frequency: No large population allele-frequency data specific to disease-causing MTRR variants were retrieved; the disorder is exceedingly rare (fewer than 40 cumulative cblE+cblG cases reported), consistent with very low allele frequencies in gnomAD for the pathogenic alleles (not independently queried in this session).
Origin: Germline, autosomal recessive (biallelic).
Functional consequences: Loss-of-function or hypomorphic reduction of MTRR reductase activity → impaired reactivation of methionine synthase → functional methionine synthase deficiency despite normal MTR protein.
Genotype-phenotype correlation: The c.1361C>T (p.Ser454Leu) variant, described as of Iberian origin, is specifically associated with a milder phenotype without neurologic involvement in homozygotes — one of the few reasonably well-documented genotype-phenotype correlations in this disease (GeneReviews NBK1328; case report literature).

Modifier Genes

No confirmed modifier genes for cblE disease severity were identified in the literature retrieved. The common MTRR A66G (p.Ile22Met) polymorphism is studied as a population-level modifier of homocysteine/folate metabolism in unrelated contexts (e.g., neural tube defect risk, Down syndrome risk in some association studies) but is not established as a modifier of cblE disease phenotype in affected individuals.

Epigenetic Information

No disease-specific epigenetic (DNA methylation, histone modification) studies in human cblE patients were identified. However, mouse Mtrr hypomorphic models show that MTRR/folate-methionine pathway disruption causes DNA methylation dysregulation transgenerationally (see Section 15), suggesting a plausible but human-unconfirmed epigenetic dimension to pathophysiology, since SAM (whose production is impaired in cblE) is the universal methyl donor for DNA/histone methylation.

Chromosomal Abnormalities

No chromosomal-scale abnormalities (aneuploidy, translocations) are described as causal for cblE; it is a single-gene, point-mutation/small-indel disorder.

5. Environmental Information

Environmental factors: None established as independently causal; cblE is monogenic. However, functional cobalamin sufficiency (dietary/parenteral) modulates phenotype expression pharmacologically.
Lifestyle factors: Not applicable as causal factors; dietary protein restriction is specifically not recommended as part of management (see Section 12), distinguishing cblE from disorders like classic homocystinuria or organic acidemias where dietary protein restriction is standard.
Infectious agents: None implicated.

6. Mechanism / Pathophysiology

Causal Chain

Molecular trigger: Biallelic pathogenic MTRR variants → reduced/absent methionine synthase reductase activity.
Enzymatic consequence: Methionine synthase (MTR/MS), which cycles between active cob(I)alamin-bound and inactive cob(II)alamin-bound states during normal catalysis (~1 in 2,000 turnovers undergoes oxidative inactivation), cannot be efficiently reactivated by reductive methylation. MTR activity progressively declines despite the MTR protein itself and its bound cobalamin cofactor being intact.
Biochemical consequence: Impaired remethylation of homocysteine → methionine via the 5-methyltetrahydrofolate-homocysteine methyltransferase reaction. This causes:
Homocysteine accumulation (hyperhomocysteinemia/homocystinuria)
Methionine and SAM depletion (hypomethioninemia)
Folate trapping: as 5-methyltetrahydrofolate cannot be demethylated (the "methylfolate trap"), cellular folate becomes sequestered in a form unusable for purine/thymidylate synthesis.
Cellular consequence: Impaired thymidylate synthesis (via depleted folate cofactors needed for the thymidylate synthase cycle) → impaired DNA synthesis in rapidly dividing cells, especially hematopoietic precursors → megaloblastic changes and ineffective erythropoiesis (megaloblastic anemia).
Systemic/organismal consequence: SAM depletion impairs global transmethylation reactions (including neuronal myelin and neurotransmitter methylation pathways), contributing to neurodevelopmental impairment, hypotonia, and seizures. Elevated homocysteine itself is thought to contribute to vascular/endothelial and possibly neurologic toxicity, analogous to (but generally milder than) classic CBS-deficiency homocystinuria vasculopathy — although lens dislocation, a hallmark of CBS deficiency, is characteristically absent in cblE, suggesting distinct mechanisms of connective-tissue involvement (or its absence) between the disorders.

Upstream vs. Downstream

Upstream: MTRR loss-of-function (molecular/enzymatic).
Midstream: Functional methionine synthase deficiency; homocysteine/SAM/folate cycle disruption (cellular/metabolic).
Downstream: Megaloblastic hematopoiesis (cellular/tissue), CNS dysmyelination/developmental impairment (tissue/organism), possible renal microangiopathy/HUS (organism).

Cell Types and Biological Processes Involved

Hematopoietic precursor cells (erythroid lineage) — impaired DNA synthesis, megaloblastic change.
CL suggestion: CL:0000765 (erythroblast) or CL:0000038 (erythroid progenitor cell)
Neurons / glial cells — impaired methylation-dependent myelination and neurotransmitter metabolism.
CL suggestion: CL:0000540 (neuron)
Renal glomerular/endothelial cells — implicated in the rare HUS/atypical glomerulopathy phenotype, potentially via homocysteine-mediated endothelial injury (analogous to mechanisms proposed in cblC-associated HUS).
CL suggestion: CL:0002138 (endothelial cell of vascular tree) or CL:1001005 (glomerular visceral epithelial cell)

Molecular Pathways / GO Terms

One-carbon metabolism / folate cycle (KEGG: hsa00670 One carbon pool by folate; hsa00270 Cysteine and methionine metabolism)
GO Biological Process suggestions:
GO:0033353 (S-adenosylmethionine cycle)
GO:0009086 (methionine biosynthetic process)
GO:0050667 (homocysteine metabolic process)
GO:0032259 (methylation)
GO Molecular Function suggestions:
GO:0030350 (iron-responsive element binding — not relevant; correct term:)
GO:0050660 (flavin adenine dinucleotide binding)
GO:0010181 (FMN binding)
GO:0004489 (methylenetetrahydrofolate reductase [NAD(P)H] activity — for MTHFR, not MTRR; for MTRR specifically:)
GO:0016860 (intramolecular oxidoreductase activity) — verify against current GO for "methionine synthase reductase activity" annotation, e.g., GO:0030744 (methionine synthase reductase activity, if extant) — flag for verification with OAK/GO adapter before binding in KB entry.
GO Cellular Component: GO:0005829 (cytosol) — MTRR is a cytosolic enzyme.

Biochemical Abnormalities

Enzyme deficiency: methionine synthase reductase (EC 1.16.1.8) activity loss.
Functional/secondary enzyme deficiency: methionine synthase (EC 2.1.1.13) activity decreased under standard fibroblast assay conditions with suboptimal reducing agent — this is the key enzymatic distinguishing test between cblE and cblG: in cblE, MTR activity is preserved with excess exogenous reducing agent but falls under limiting conditions; in cblG, MTR activity is decreased under all conditions because the MTR apoenzyme itself is defective (WebSearch synthesis of Watkins 1989, AJMG; ScienceDirect topic page).

Immune System Involvement

No primary immune dysfunction is characteristic of cblE; it is not classified as a primary immunodeficiency.

Tissue Damage Mechanisms

Ineffective erythropoiesis (megaloblastic anemia) and possible endothelial/microvascular injury contributing to the rare HUS/glomerulopathy phenotype are the principal described tissue-damage mechanisms; direct evidence for oxidative-stress or fibrotic mechanisms specific to cblE was not identified in the literature retrieved.

Molecular Profiling / Advanced Technologies

No transcriptomic, proteomic, metabolomic, single-cell, or spatial-omics studies specific to human cblE patient tissue were identified in this search. Metabolomic characterization is largely limited to targeted amino acid/homocysteine/methylmalonic acid panels used diagnostically (see Section 10), not unbiased -omics profiling.

7. Anatomical Structures Affected

Organ Level

Primary: Bone marrow (hematopoietic system) — megaloblastic anemia/pancytopenia; Central nervous system — developmental delay, seizures, hypotonia, cerebral atrophy.
Secondary: Eye (nystagmus, visual impairment, rare macular dysfunction); Kidney (rare HUS, atypical glomerulopathy).
Body systems involved: Hematologic, nervous, ophthalmologic, and (rarely) renal systems.

UBERON suggestions: UBERON:0002371 (bone marrow), UBERON:0000955 (brain), UBERON:0000970 (eye), UBERON:0002113 (kidney).

Tissue and Cell Level

Erythroid precursor cells in bone marrow (megaloblastic changes)
Neural tissue — white matter/myelin-relevant cell populations
Renal glomerular capillary endothelium (in HUS/glomerulopathy presentations)

Subcellular Level

Cytosol: MTRR and MTR are cytosolic enzymes; the folate/methionine cycle operates in the cytosolic compartment.
GO Cellular Component: GO:0005829 (cytosol)

Localization

No specific lateralization pattern is described; CNS and hematologic involvement are systemic/bilateral by nature.

8. Temporal Development

Onset

Typical age: 2 weeks to 3 years of age (most common); classic presentation "in the first two years of life."
Rare atypical: Adolescent-onset presentation with atypical glomerulopathy has been described.
Onset pattern: Generally insidious/subacute, evolving over weeks to months in infancy, though acute presentations (e.g., with HUS) can occur.

Progression

Disease course pattern: Chronic, generally progressive if untreated; biochemically responsive (to varying degrees) to hydroxocobalamin/betaine therapy.
Progression rate: Variable — mild genotypes (e.g., p.Ser454Leu homozygotes) show slow/non-progressive isolated hematologic disease; severe genotypes show more rapid multisystem progression in infancy.
Disease duration: Chronic, lifelong (enzyme deficiency is permanent; management is lifelong).

Patterns

Remission: Biochemical parameters (homocysteine, methionine) can normalize or substantially improve with treatment; hematologic remission of megaloblastic anemia is generally achievable. Neurodevelopmental and ophthalmologic manifestations show only partial/moderate treatment response per the largest published cohort (JIMD 2015 paper).
Critical periods: Early infancy is considered a critical window for treatment initiation to minimize neurodevelopmental sequelae, though the evidence for this is characterized in the literature as "weak" ("only weak evidence for a response to treatment and for the specific value of early treatment in cblE defects" — WebSearch synthesis of JIMD 2015 cohort paper).

9. Inheritance and Population

Epidemiology

Prevalence/Incidence: No formal population-based incidence or prevalence rate has been established. The disease is characterized as ultra-rare, with GeneReviews stating "fewer than 40 cases have been described for cblE and cblG" combined, as of the most recent update reviewed. No newborn-screening-based incidence estimate exists because cblE (like cblG) is not reliably detected by standard newborn screening acylcarnitine profiles (no elevated propionylcarnitine/C3) (GeneReviews NBK1328).

Inheritance Pattern

Autosomal recessive. Per GeneReviews genetic counseling section: "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." Parents of an affected child are obligate heterozygous carriers (GeneReviews NBK1328).
Penetrance: Presumed complete for biallelic clearly pathogenic (loss-of-function) variants, though phenotypic severity is variable (variable expressivity), and hypomorphic alleles (e.g., p.Ser454Leu) produce milder, incompletely penetrant neurologic phenotypes.
Carrier detection: GeneReviews notes biochemical testing is not reliable for carrier detection; molecular (sequence-based) testing with a known familial variant is required.
Founder effects: The c.1361C>T (p.Ser454Leu) variant is specifically noted as being of Iberian origin, suggestive of a founder allele in that population.
Consanguinity: Not specifically quantified in the sources retrieved, but as an ultra-rare autosomal recessive disorder, consanguinity would be expected to increase local incidence in affected families/populations, as is typical for such disorders.
Carrier frequency: Not established in population databases for this session's search.

Population Demographics

No specific ethnic/geographic prevalence data beyond the Iberian-origin founder variant were identified.
Sex ratio: No sex predilection is described; autosomal recessive inheritance predicts equal male:female distribution.
Age distribution: Predominantly diagnosed in infancy/early childhood, consistent with typical age of onset.

10. Diagnostics

Clinical/Laboratory Tests

Complete blood count with peripheral smear: macrocytic/megaloblastic red cell morphology, possible pancytopenia.
Plasma total homocysteine (tHcy): elevated.
Urine homocystine: elevated (homocystinuria).
Plasma amino acid panel: low-to-normal methionine (hypomethioninemia); low SAM.
Urine and plasma methylmalonic acid (MMA): normal — key discriminating test versus combined cobalamin defects (cblC/D/F) and isolated methylmalonic acidemia disorders.
Newborn screening acylcarnitine profile: propionylcarnitine (C3) not elevated — explains why cblE/cblG are missed on standard NBS.

LOINC/SNOMED suggestions: standard plasma amino acid and homocysteine assay LOINC codes (specific codes not independently verified in this session).

Biomarkers

Elevated total homocysteine and low methionine/SAM ratio are the principal biochemical biomarkers.

Genetic Testing

Molecular confirmation: Identification of biallelic pathogenic MTRR variants by sequence analysis (detects the great majority of reported pathogenic alleles per GeneReviews — "21/22 reported variants" detectable by sequencing).
Approach: Given clinical/biochemical overlap between cblE and cblG (methionine synthase, MTR, deficiency) — "the clinical and biochemical features are virtually identical for both defects" — molecular testing (targeted gene sequencing or a remethylation-disorder gene panel including MTRR, MTR, MMACHC, MMADHC, MTHFR) is necessary to distinguish them, since biochemical testing alone cannot reliably differentiate cblE from cblG (WebSearch synthesis of Watkins 1989 AJMG paper; GeneReviews NBK1328).
Fibroblast complementation/enzyme studies: Historically used to assign the cblE complementation group — methionine synthase activity in cultured fibroblasts is preserved with excess exogenous reducing agent but falls under limiting reducing-agent conditions in cblE (vs. uniformly decreased in cblG), enabling functional discrimination prior to/alongside molecular testing.

Clinical Criteria / Differential Diagnosis

Per GeneReviews, cblE must be distinguished from: - Vitamin B12 deficiency (nutritional) — normalizes with B12 replacement; distinguished by dietary history, low serum B12, and absence of a genetic cause. - MTHFR deficiency — produces moderate homocystinuria with normal-to-low methionine but lacks megaloblastic anemia (a key distinguishing clinical feature, since MTHFR deficiency does not impair folate-independent hematopoiesis in the same way). - CBS (cystathionine beta-synthase) deficiency (classic homocystinuria) — elevated methionine together with elevated homocysteine (vs. low methionine in cblE); classically features ectopia lentis, marfanoid habitus, and thromboembolism, generally absent in cblE. - cblG (methionine synthase/MTR deficiency) — clinically and biochemically nearly indistinguishable; requires molecular/enzymatic complementation testing to differentiate. - cblC, cblD, cblF (combined remethylation + methylmalonic acidemia defects) — distinguished by presence of elevated methylmalonic acid, which is absent in cblE.

Screening

Not part of standard newborn screening panels due to lack of a distinguishing acylcarnitine signature; GeneReviews notes screening could theoretically be achieved by measuring methionine and the methionine-to-phenylalanine ratio in dried blood spots, with total homocysteine as a second-tier marker, but this is not currently standard practice (WebSearch synthesis).

11. Outcome / Prognosis

Survival/mortality: No specific mortality rate statistics were retrieved; the disorder is not classically described as acutely lethal when treated, though severe untreated cases with profound neurologic and hematologic compromise in infancy could carry significant morbidity/mortality risk (not independently quantified in sources retrieved).
Morbidity: Intellectual disability, seizures, and visual impairment represent the chief chronic morbidities. The JIMD 2015 cohort paper (24 patients) reports that even with treatment, neurodevelopmental and ophthalmologic outcomes show only "moderate" improvement at best, and that evidence for early-treatment benefit is "weak" — indicating that, unlike some other treatable inborn errors, cblE carries a persistent morbidity burden even under current standard-of-care management.
Positive outcome signal: A smaller subset (4 patients in one cited series) showed a clearer positive impact of early treatment on outcome, suggesting genotype- or presentation-dependent prognosis heterogeneity.
Complications: Late-onset refractory hemolytic anemia has been documented as a rare, potentially treatment-related long-term complication in siblings on chronic hydroxocobalamin/betaine therapy, possibly preventable by hydroxocobalamin dose escalation (PMC11078714).
Prognostic factors: Genotype (e.g., p.Ser454Leu associated with milder, non-neurologic phenotype); age/timing of treatment initiation; presence/absence of early neurologic involvement at diagnosis.

12. Treatment

Pharmacotherapy

Parenteral hydroxocobalamin (OHCbl) — the cornerstone of treatment. GeneReviews specifically emphasizes that only the parenteral hydroxocobalamin form is effective — cyanocobalamin and oral preparations are not adequate substitutes ("parenteral OHCbl (not the cyanocobalamin form or oral form) is the only effective preparation").
NCIT suggestion: NCIT:C15986 (Pharmacotherapy) as treatment_term, with therapeutic_agent bound to a CHEBI/NCIT term for hydroxocobalamin (CHEBI:20363, hydroxocobalamin, is a plausible CHEBI ID — verify against OAK before curation).
Betaine — supplementation (starting dose approximately 250 mg/kg/day cited in GeneReviews) to promote the alternative (cobalamin-independent) remethylation pathway via betaine-homocysteine methyltransferase (BHMT), lowering homocysteine and raising methionine.
CHEBI suggestion: CHEBI:17750 (betaine)
Folate/folinic acid supplementation — may be used adjunctively to support remethylation capacity.

Dietary Management

Normal dietary protein intake is appropriate; GeneReviews explicitly states that "low-protein diets and medical foods... are not recommended" — an important distinction from CBS-deficiency homocystinuria management, which often does involve protein/methionine restriction.

Surgical / Interventional

No surgical interventions are characteristic of cblE management.

Supportive / Rehabilitative

Developmental/early intervention services, physical/occupational therapy as indicated by neurodevelopmental impairment.
Ophthalmologic monitoring and supportive management of visual impairment.
Hematologic monitoring; transfusion support if severe anemia, though this is not typically the primary therapeutic modality given B12/betaine responsiveness.

Advanced Therapeutics / Experimental

No gene therapy, cell therapy, or RNA-based therapeutics specific to cblE were identified in the literature retrieved. "Functional correction by minigene expression" has been demonstrated as a research/proof-of-concept tool (Zavadáková et al. 2005, Human Mutation, PMID referenced in search results) to characterize variant pathogenicity in cultured cells, not as a clinical therapeutic.

Treatment Outcomes

Biochemical response (normalization/improvement of homocysteine, methionine, and hematologic parameters) is generally favorable with hydroxocobalamin + betaine.
Neurodevelopmental and ophthalmologic response to treatment is only moderate at best, per the largest published cohort, and evidence supporting early-treatment benefit specifically is characterized as weak.
Adverse events: Rare late-onset refractory hemolytic anemia has been documented as a treatment-era complication, discussed as potentially related to therapy dosing (PMC11078714).

Treatment Strategy

Lifelong parenteral hydroxocobalamin plus oral betaine is the standard combination approach; no formal published treatment algorithm/consensus guideline analogous to NCCN-style pathways was identified — management is guided by case-series experience and metabolic-disease expert consensus (e.g., within the broader "Disorders of Intracellular Cobalamin Metabolism" GeneReviews chapter, which covers cblE alongside cblA, cblB, cblC, cblD, cblF, and cblG under a shared general management framework).

13. Prevention

Primary prevention: Not applicable in the traditional sense (not preventable by lifestyle/vaccination), as cblE is a genetic disorder; the only "primary prevention" avenue is reproductive genetic counseling and prenatal/preimplantation genetic testing in families with a known pathogenic variant.
Secondary prevention / early detection: Because standard newborn screening does not reliably detect cblE, secondary prevention currently depends on clinical suspicion in infants presenting with unexplained megaloblastic anemia and/or developmental delay, prompting targeted biochemical (homocysteine/methionine) and molecular testing. Prenatal diagnosis has been performed in at-risk families with a known familial MTRR variant (referenced in the 2001 JIMD paper "CblE type of homocystinuria due to methionine synthase reductase deficiency: Clinical and molecular studies and prenatal diagnosis in two families").
Genetic counseling: Central to prevention in this autosomal recessive disorder — informing carrier parents of 25% recurrence risk per pregnancy, and offering carrier testing to at-risk relatives (with molecular, not biochemical, methods) and prenatal diagnosis in subsequent pregnancies.
Screening programs: A proposed but not widely implemented dried-blood-spot approach (methionine level / methionine-to-phenylalanine ratio, with second-tier homocysteine) could theoretically enable population newborn screening for cblE, per systematic-review literature on NBS for homocystinurias and methylation disorders (Huemer et al., PMID 25762406, cited in search results), but this is not current standard practice.
Prophylaxis: No prophylactic pharmacologic regimen (e.g., preemptive cobalamin supplementation in unaffected at-risk newborns pending testing) was described in the sources retrieved as a standardized practice, though early empiric treatment while confirmatory testing is pending is a reasonable clinical approach given the biochemical responsiveness of the disorder.

14. Other Species / Natural Disease

No naturally occurring veterinary or wildlife cases of MTRR-deficiency disease analogous to human cblE were identified in the literature searched (e.g., no OMIA entries were retrieved). The available animal data are exclusively engineered mouse models (below) rather than spontaneous natural disease in other species.

15. Model Organisms

Mouse Models (Mtrr)

The Mtrr gene-trap hypomorphic mouse model (Mtrr^gt) is the principal model system used to study MTRR/methionine-synthase-reductase pathway biology, though it models the broader folate/methionine metabolic consequences of MTRR deficiency rather than being validated specifically as a full recapitulation of the human cblE clinical syndrome (megaloblastic anemia + neurodevelopmental disease).

Reproductive/developmental phenotypes: "Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice" (Padmanabhan et al., PMID 18413293; PMC3110750). Mtrr deficiency produces hyperhomocysteinemia, dysregulated DNA methylation, and developmental phenotypes including neural tube defects, congenital heart defects, and placental defects.
Transgenerational effects: Notably, Mtrr-deficient mice show two distinct, separable phenotypes across generations: (1) adverse uterine-environment effects transmitted to wild-type daughters causing growth defects in wild-type grandprogeny, and (2) congenital malformations that persist independent of maternal environment for 5 generations — an unusual transgenerational epigenetic inheritance phenomenon (WebSearch synthesis of PMC/related papers).
Liver phenotype: "Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice" (PMID 32257815; PMC7109458) — Mtrr^gt/gt female mouse livers were enlarged, with eosinophilic hepatocytes and decreased glycogen content, associated with downregulation of glycogen synthesis genes.
Reproductive/fertility phenotype in males: "Analysis of spermatogenesis and fertility in adult mice with a hypomorphic mutation in the Mtrr gene" (PMC7116358) — Mtrr^gt/gt adult testes were more spherical in shape than wild-type, but serum testosterone was normal, spermatogenesis proceeded typically, and sperm morphology/count/viability/fertility were normal — indicating preserved male fertility despite altered testicular gross morphology, i.e., a phenotype that does not fully recapitulate a severe reproductive deficit.
Metabolic derangement: "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase" (PMC1973089) documents the core one-carbon-metabolism biochemical perturbations (elevated homocysteine, altered folate distribution) in this model, directly relevant to the biochemical phenotype of human cblE.

Model Limitations

The mouse Mtrr models are hypomorphic (gene-trap) rather than null, and the literature retrieved emphasizes developmental, reproductive, hepatic, and epigenetic-inheritance phenotypes rather than a hematologic (megaloblastic anemia) or neurologic phenotype directly paralleling the human cblE presentation. This represents a potential human-model translational gap: the mouse literature is dominated by reproductive/developmental and transgenerational-epigenetic findings, while the human disease is characterized primarily by megaloblastic anemia and neurodevelopmental impairment — suggesting the existing Mtrr mouse models may have uncertain fidelity for the core clinical hematologic/neurologic phenotype of human cblE disease, an important consideration for any HUMAN_MODEL_MISMATCH-type annotation if this disease is curated into a mechanistic knowledge base.

Resources

MGI: Mtrr, MGI:1891037 (Mouse Genome Informatics)
No zebrafish (ZFIN), Drosophila (FlyBase), C. elegans (WormBase), or yeast (SGD) MTRR-ortholog disease models were identified in this search.

Summary of Key Ontology Term Suggestions for KB Curation

Category	Suggested term
Disease	MONDO:0009354
Gene	hgnc:7473 (MTRR)
Phenotype: Megaloblastic anemia	HP:0001889
Phenotype: Developmental delay	HP:0002194
Phenotype: Seizures	HP:0001250
Phenotype: Hypotonia	HP:0001252
Phenotype: Nystagmus	HP:0000639
Phenotype: Failure to thrive	HP:0001508
Phenotype: Hemolytic-uremic syndrome	HP:0005575
Phenotype: Cerebral atrophy	HP:0002059
Cell type: Erythroid precursor	CL:0000765
Cell type: Neuron	CL:0000540
Anatomy: Bone marrow	UBERON:0002371
Anatomy: Brain	UBERON:0000955
Anatomy: Eye	UBERON:0000970
Anatomy: Kidney	UBERON:0002113
Treatment: Pharmacotherapy	NCIT:C15986
Chemical: Betaine	CHEBI:17750

(All ontology term suggestions should be independently verified via OAK/just validate-terms against current canonical labels before use in a curated KB entry, per standard practice — several GO term suggestions above in Section 6 are flagged as needing verification.)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	6
Quoted claims found in source	6
Quoted claims not found in source	0
References weighed for topical relevance	14
On topic	13
Off topic	0

All extracted references resolved successfully.

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Definitions

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Progression

Prevalence

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Methylcobalamin Deficiency Type cblE (Methionine Synthase Reductase Deficiency) — Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms

Data Source Character

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Hematologic

Neurologic / Developmental

Ophthalmologic

Growth / Constitutional

Renal

Laboratory Abnormalities (biochemical phenotypes, distinct from clinical signs)

Phenotype Characteristics

Quality of Life Impact

4. Genetic / Molecular Information

Causal Gene

Protein / Function

Pathogenic Variants

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

Causal Chain

Upstream vs. Downstream

Cell Types and Biological Processes Involved

Molecular Pathways / GO Terms

Biochemical Abnormalities

Immune System Involvement

Tissue Damage Mechanisms

Molecular Profiling / Advanced Technologies

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Population Demographics

10. Diagnostics

Clinical/Laboratory Tests

Biomarkers

Genetic Testing

Clinical Criteria / Differential Diagnosis

Screening

11. Outcome / Prognosis

12. Treatment

Pharmacotherapy

Dietary Management

Surgical / Interventional