Advertisement

Journal of Inherited Metabolic Disease

, Volume 38, Issue 5, pp 957–967 | Cite as

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

  • M. Huemer
  • C. Bürer
  • P. Ješina
  • V. Kožich
  • M. A. Landolt
  • T. Suormala
  • B. Fowler
  • P. Augoustides- Savvopoulou
  • E. Blair
  • K. Brennerova
  • A. Broomfield
  • L. De Meirleir
  • G. Gökcay
  • J. Hennermann
  • P. Jardine
  • J. Koch
  • S. Lorenzl
  • A. S. Lotz-Havla
  • J. Noss
  • R. Parini
  • H. Peters
  • B. Plecko
  • F. J. Ramos
  • A. Schlune
  • K. Tsiakas
  • M. Zerjav Tansek
  • M. R. Baumgartner
Original Article

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.

Keywords

Cobalamin Macrocytic Anaemia Muscular Hypotonia Haemolytic Uremic Syndrome External Hydrocephalus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

10545_2014_9803_MOESM1_ESM.docx (16 kb)
ESM 1 (DOCX 15.9 kb)
10545_2014_9803_MOESM2_ESM.docx (19 kb)
ESM 2 (DOCX 18.5 kb)
10545_2014_9803_MOESM3_ESM.docx (17 kb)
ESM 3 (DOCX 16.8 kb)
10545_2014_9803_MOESM4_ESM.docx (18 kb)
ESM 4 (DOCX 18.2 kb)
10545_2014_9803_MOESM5_ESM.docx (16 kb)
ESM 5 (DOCX 15.7 kb)
10545_2014_9803_MOESM6_ESM.docx (37 kb)
ESM 6 (DOCX 37.4 kb)
10545_2014_9803_MOESM7_ESM.docx (39 kb)
ESM 7 (DOCX 38.5 kb)
10545_2014_9803_MOESM8_ESM.pdf (385 kb)
ESM 8 (PDF 384 kb)

References

  1. 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 318:1738–1741CrossRefPubMedGoogle Scholar
  2. 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):728–31CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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):329–330CrossRefPubMedGoogle Scholar
  4. 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 20:731–741CrossRefPubMedGoogle Scholar
  5. 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 23:487–489CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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 71:384–390CrossRefGoogle Scholar
  7. 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
  8. 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–e544Google Scholar
  9. Kvittingen EA, Spangen S, Lindemans J, Fowler B (1997) Methionine synthase deficiency without megaloblastic anaemia. Eur J Pediatr 156:925–930CrossRefPubMedGoogle Scholar
  10. 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 158:734–739CrossRefPubMedGoogle Scholar
  11. 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 219:361–367CrossRefPubMedGoogle Scholar
  12. Outteryck O, de Sèze J, Stojkovic T et al (2012) Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy. Neurology 79(4):386–388CrossRefPubMedGoogle Scholar
  13. 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 8:57–62CrossRefPubMedPubMedCentralGoogle Scholar
  14. Poloschek CM, Fowler F, Unsold R, Lorenz B (2005) Disturbed visual system function in methionine synthase deficiency. Graefe’s Arch Clin Exp Ophthalmol 243:497–500CrossRefGoogle Scholar
  15. Richard E, Desviat LR, Ugarte M, Perez B (2013) Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J Cell Biochem 114:183–191CrossRefPubMedGoogle Scholar
  16. 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):1127–1129CrossRefPubMedGoogle Scholar
  17. 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):137–145CrossRefPubMedGoogle Scholar
  18. 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 310:686–690CrossRefPubMedGoogle Scholar
  19. 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 20:705–706CrossRefPubMedGoogle Scholar
  20. 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 279:42742–9CrossRefPubMedGoogle Scholar
  21. Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157(Suppl 2):S118–21CrossRefPubMedGoogle Scholar
  22. 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):361–369CrossRefPubMedGoogle Scholar
  23. 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):143–153CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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):95CrossRefPubMedGoogle Scholar
  25. 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 25:239–247CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2014

Authors and Affiliations

  • M. Huemer
    • 1
    • 2
    • 3
  • C. Bürer
    • 1
    • 2
  • P. Ješina
    • 4
  • V. Kožich
    • 4
  • M. A. Landolt
    • 5
    • 6
  • T. Suormala
    • 1
    • 2
  • B. Fowler
    • 1
    • 2
  • P. Augoustides- Savvopoulou
    • 7
  • E. Blair
    • 8
  • K. Brennerova
    • 9
  • A. Broomfield
    • 10
  • L. De Meirleir
    • 11
  • G. Gökcay
    • 12
  • J. Hennermann
    • 13
  • P. Jardine
    • 14
  • J. Koch
    • 15
  • S. Lorenzl
    • 16
  • A. S. Lotz-Havla
    • 17
  • J. Noss
    • 18
  • R. Parini
    • 19
  • H. Peters
    • 20
  • B. Plecko
    • 21
    • 22
  • F. J. Ramos
    • 23
  • A. Schlune
    • 24
  • K. Tsiakas
    • 25
  • M. Zerjav Tansek
    • 26
  • M. R. Baumgartner
    • 1
    • 2
  1. 1.Division of Metabolic Diseases and Children’s Research CenterUniversity Children’s Hospital ZürichZurichSwitzerland
  2. 2.radiz – Rare Disease Initiative ZürichUniversity of ZürichZurichSwitzerland
  3. 3.Department of PaediatricsLandeskrankenhaus BregenzBregenzAustria
  4. 4.Institute of Inherited Metabolic DiseasesCharles University-1st Faculty of Medicine and General University HospitalPragueCzech Republic
  5. 5.Department of Psychosomatics and PsychiatryUniversity Children’s Hospital ZürichZurichSwitzerland
  6. 6.Department of Child and Adolescent Health Psychology, Institute of PsychologyUniversity of ZurichZurichSwitzerland
  7. 7.1st Paediatric Department, Metabolic LaboratoryAristotle University of ThessalonikiThessalonikiGreece
  8. 8.Department of Clinical GeneticsChurchill Hospital, Oxford University Hospital NHS TrustOxfordUK
  9. 9.Ist Paediatric ClinicUniversity Children’s Hospital BratislavaBratislavaSlovakia
  10. 10.Willink Biochemical Genetics UnitManchester Centre for Genomic Medicine, St Mary’s HospitalManchesterUK
  11. 11.Department of Paediatric Neurology and MetabolicsUZ Brussel lBrusselBelgium
  12. 12.Istanbul Medical Faculty, Children’s Hospital, Division of Nutrition and Metabolism, IstanbulIstanbul UniversityIstanbulTurkey
  13. 13.Department of Paediatric and Adolescent Medicine, Villa MetabolicaUniversity Medical Center MainzMainzGermany
  14. 14.University of BristolBristolUK
  15. 15.Department of PaediatricsParacelsus Medical University SalzburgSalzburgAustria
  16. 16.Endowed Professorship for Interdisciplinary Research in Palliative Care Institute of Nursing Science and PracticeParacelsus Medical UniversitySalzburgAustria
  17. 17.Dr. von Hauner Children’s HospitalLudwig Maximilians University MunichMunichGermany
  18. 18.Department of PaediatricsKlinikum Dritter OrdenMunichGermany
  19. 19.Rare Metabolic Diseases UnitAzienda Ospedaliera San GerardoMonzaItaly
  20. 20.Victorian Clinical Genetics Services, Murdoch Childrens Research InstituteRoyal Children’s HospitalMelbourneAustralia
  21. 21.Division of Child NeurologyUniversity Children’s Hospital ZurichZurichSwitzerland
  22. 22.Department of PaediatricsUniversity Children’s Hospital GrazGrazAustria
  23. 23.Department of NeurologyHospital Sant Joan de DeuBarcelonaSpain
  24. 24.Department of General Paediatrics, Neonatology and Pediatric CardiologyUniversity Children’s Hospital, Heinrich-Heine UniversityDüsseldorfGermany
  25. 25.Departments of PaediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  26. 26.Department of Diabetes, Endocrinology and Metabolic DiseasesUniversity Children’s Hospital, UMC LjubljanaLjubljanaSlovenia

Personalised recommendations