Skip to main content
Log in

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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine.

Methods

Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed.

Results

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. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96 % of patients, however 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. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype– phenotype correlations evident.

Conclusions

The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Carmel R, Watkins D, Goodman SI, Rosenblatt DS (1988) Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. New Eng J Med 318:1738–1741

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32(6):728–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dionisi-Vici C, Martinelli D, Ceravolo F, Boenzi S, Pastore A (2013) Optimizing the dose of hydroxocobalamin in cobalamin C (cblC) defect. Mol Genet Metab 109(4):329–330

    Article  CAS  PubMed  Google Scholar 

  • Fowler B, Schutgens RBH, Rosenblatt DS, Smit GPA, Lindemans J (1997) Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease). J Inher Metab Dis 20:731–741

    Article  CAS  PubMed  Google Scholar 

  • Greitz D (2007) Paradigm shift in hydrocephalus research in legacy of Dandy’s pioneering work: rationale for third ventriculostomy in communicating hydrocephalus. Childs Nerv Syst 23:487–489

    Article  PubMed  PubMed Central  Google Scholar 

  • Harding CO, Arnold G, Barness LA, Wolff JA, Rosenblatt DS (1997) Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. Am J Med Genetics 71:384–390

    Article  CAS  Google Scholar 

  • Kandula T, Peters H, Fahey M (2014) Cobalamin E defect, a rare inborn error of vitamin B12 metabolism: Value of early diagnosis and treatment. Clin Neurosci2014 May 17. pii: S0967-5868(14)00161-1. doi: 10.1016/j.jocn.2013.12.030

  • Kömhoff M, Roofthooft MT, Westra D, Teertstra TK, Losito A, van de Kar NC, Berger RM (2013) Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics 132(2):e540–e544

  • Kvittingen EA, Spangen S, Lindemans J, Fowler B (1997) Methionine synthase deficiency without megaloblastic anaemia. Eur J Pediatr 156:925–930

    Article  CAS  PubMed  Google Scholar 

  • Labrune P, Zittoun J, Duvaltier I, Trioche P, Marquet J, Niaudet P, Odievre M (1999) Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 158:734–739

    Article  CAS  PubMed  Google Scholar 

  • Müller P, Horneff G, Hennermann JB (2007) A rare inborn error of intracellular processing of cobalamin presenting with microcephalus and megaloblastic anemia: a report of 3 children. Klin Pädiatr 219:361–367

    Article  PubMed  Google Scholar 

  • Outteryck O, de Sèze J, Stojkovic T et al (2012) Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy. Neurology 79(4):386–388

    Article  PubMed  Google Scholar 

  • Palanca D, Garcia-Cazorla A, Ortiz J et al (2013) CblE-type homocystinuria presenting with features of haemolytic-uremic syndrome in the newborn period. JIMD Rep 8:57–62

    Article  PubMed  PubMed Central  Google Scholar 

  • Poloschek CM, Fowler F, Unsold R, Lorenz B (2005) Disturbed visual system function in methionine synthase deficiency. Graefe’s Arch Clin Exp Ophthalmol 243:497–500

    Article  CAS  Google Scholar 

  • Richard E, Desviat LR, Ugarte M, Perez B (2013) Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J Cell Biochem 114:183–191

    Article  CAS  PubMed  Google Scholar 

  • Rosenblatt DS, Cooper BA, Schmutz SM, Zaleski WA, Casey RE (1985) Prenatal vitamin B12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease). Lancet 1(8438):1127–1129

    Article  CAS  PubMed  Google Scholar 

  • Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H (2011) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34(1):137–145

    Article  CAS  PubMed  Google Scholar 

  • Schuh S, Rosenblatt DS, Cooper BA, Schroeder ML, Bishop AJ, Seargeant LE, Haworth JC (1984) Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy. New Engl J Med 310:686–690

    Article  CAS  PubMed  Google Scholar 

  • Steen C, Rosenblatt DS, Scheying H, Braeuer HC, Kohlschütter A (1997) Cobalamin E (CblE) disease: a severe neurological disorder with megaloblastic anaemia, homocystinuria and low serum methionine. J Inherit Metab Dis 20:705–706

    Article  CAS  PubMed  Google Scholar 

  • Suormala T, Baumgartner MR, Coelho D, Zavadakova P, Kozich V, Koch HG, Berghäuser M, Wraith JE, Burlina A, Sewell A, Herwig J, Fowler B (2004) The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279:42742–9

    Article  CAS  PubMed  Google Scholar 

  • Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157(Suppl 2):S118–21

    Article  CAS  PubMed  Google Scholar 

  • Vilaseca MA, Vilarinho L, Zavadakova P et al (2003) CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J Inherit Metab Dis 26(4):361–369

    Article  CAS  PubMed  Google Scholar 

  • Watkins D, Ru M, Hwang HY et al (2002) Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet 71(1):143–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilová K, Kozich V (2002) CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis 25(6):461–76, Erratum in: J Inherit Metab Dis 2003;26(1):95

    Article  CAS  PubMed  Google Scholar 

  • Zavadakova P, Fowler B, Suormala T et al (2005) cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum Mut 25:239–247

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all patients and their families who gave informed consent to include their data. This work was supported by the Swiss National Science Foundation [grant number 31003A_138521 to M.R.B. and B.F.] and the Rare Disease Initiative Zurich (radiz), a clinical research priority program for rare diseases of the University of Zurich, Switzerland. Institutional support to P.J and V.K. was provided by projects RVO VFN64165 and PRVOUK-P24/LF1/3.

Compliance with ethics guidelines

Conflict of interest

None.

Human and animal rights and informed consent

All procedures followed were in accordance with the ethical standards of theresponsible committee on human experimentation (institutional and national) and with the HelsinkiDeclaration of 1975, as revised in 2005. Informed consent was obtained from all patients for beingincluded in the study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Huemer.

Additional information

Communicated by: Carlo Dionisi-Vici

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 15.9 kb)

ESM 2

(DOCX 18.5 kb)

ESM 3

(DOCX 16.8 kb)

ESM 4

(DOCX 18.2 kb)

ESM 5

(DOCX 15.7 kb)

ESM 6

(DOCX 37.4 kb)

ESM 7

(DOCX 38.5 kb)

ESM 8

(PDF 384 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huemer, M., Bürer, C., Ješina, P. et al. 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. J Inherit Metab Dis 38, 957–967 (2015). https://doi.org/10.1007/s10545-014-9803-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-014-9803-7

Keywords

Navigation