MTR – Methylcobalamin Deficiency Type cblG

Methionine synthase (MTR) deficiency, also known as cobalamin type G (cblG), is an autosomal recessive inborn error of cobalamin metabolism characterized by impaired remethylation of homocysteine to methionine. Clinical presentation typically includes megaloblastic anemia and neurodevelopmental delay, with occasional misdiagnosis as thrombotic microangiopathy (TMA) or atypical hemolytic uremic syndrome due to overlapping hematologic findings.

Genetic evidence for MTR in cblG is strong. Two unrelated probands with novel MTR variants presented in infancy with megaloblastic anemia and failure to respond to cyanocobalamin, later confirmed by exome sequencing to carry biallelic deleterious MTR mutations ([PMID:28210839])(PMID:31951343). A larger cohort of 21 cblG patients was screened, identifying 13 novel truncating and splice‐site mutations and confirming the recurrent P1173L allele in 16 individuals ([PMID:12068375]). Additional functional null “cblG-variant” cases (n=3) demonstrated complete loss of MS activity in fibroblasts ([PMID:9683607]).

Inheritance is autosomal recessive, with segregation documented in a sibship (1 additional affected relative). Case series include at least 24 probands across 23 families, harboring missense (n=5), nonsense (n=7), frameshift (n=8), and splice‐site (n=3) variants. The recurrent founder allele c.3518C>T (p.Pro1173Leu) was observed on multiple haplotypes and accounts for ~40% of alleles in cblG cohorts ([PMID:12068375]).

Functionally, all pathogenic MTR alleles result in loss of enzyme activity, either via premature termination codons leading to mRNA instability or disruption of catalytic domains. Fibroblast assays in cblG-variant patients show absent methylcobalamin incorporation and MS activity, consistent with a loss-of-function mechanism ([PMID:9683607]). Treatment with hydroxycobalamin restores methionine levels and hematologic parameters but requires early initiation to prevent irreversible neurologic damage.

Phenotypically, affected infants present with megaloblastic anemia (HP:0001889), failure to thrive (HP:0001508), microcephaly (HP:0000252), hypotonia (HP:0001252), chronic diarrhea (HP:0002028) and oral ulcers (HP:0000155). One patient developed TMA and acute renal failure, initially managed as aHUS with eculizumab without improvement until the underlying cblG diagnosis was made ([PMID:28210839]).

Integration of genetic and experimental data supports a Strong ClinGen gene–disease association: 24 probands, multi‐family segregation, and functional concordance. Genetic evidence reaches a Strong tier (biallelic null alleles in >20 probands), and functional studies provide a Moderate tier (consistent loss-of-function assays). Early molecular diagnosis enables targeted hydroxycobalamin therapy and guides genetic counseling. Key take-home: MTR testing should be included in early evaluation of unexplained megaloblastic anemia and neurodevelopmental delay to direct lifesaving cobalamin treatment.

References

• Pediatric Nephrology (Berlin, Germany) • 2017 • Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls PMID:28210839
• Turk J Pediatr • 2019 • An infant with an extremely rare cobalamin disorder: Methionine synthase deficiency and importance of early diagnosis and treatment PMID:31951343
• American Journal of Human Genetics • 1998 • Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency PMID:9683607
• American Journal of Human Genetics • 2002 • Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L PMID:12068375

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