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Journal of Inherited Metabolic Disease

, Volume 37, Issue 5, pp 831–840 | Cite as

Clinical presentation and outcome in a series of 88 patients with the cblC defect

  • Sabine Fischer
  • Martina Huemer
  • Matthias Baumgartner
  • Federica Deodato
  • Diana Ballhausen
  • Avihu Boneh
  • Alberto B. Burlina
  • Roberto Cerone
  • Paula Garcia
  • Gülden Gökçay
  • Stephanie Grünewald
  • Johannes Häberle
  • Jaak Jaeken
  • David Ketteridge
  • Martin Lindner
  • Hanna Mandel
  • Diego Martinelli
  • Esmeralda G. Martins
  • Karl O. Schwab
  • Sarah C. Gruenert
  • Bernd C. Schwahn
  • László Sztriha
  • Maren Tomaske
  • Friedrich Trefz
  • Laura Vilarinho
  • David S. Rosenblatt
  • Brian FowlerEmail author
  • Carlo Dionisi-Vici
Original Article

Abstract

The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. Results: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with “overall impression” as judged by treating physicians. Physician’s impression of patient’s well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.

Keywords

Homocysteine Severity Score Total Homocysteine Onset Patient Methionine Level 
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

BF and MB were supported by the Swiss National Foundation, grant numbers 3200AO-109219/1 and 320000-122568/1. CD-V was supported by the grant “CCM 2010: Costruzione di percorsi diagnostico-assistenziali per le malattie oggetto di screening neonatale allargato” from the Italian Ministry of Health and by the grant R-12-92 from the “Fondazione Pierfranco e Luisa Mariani”. The clinical fellowship of DM was supported by the “Associazione la Vita è un Dono”.

Conflict of interest

Sabine Fischer, Martina Huemer, Federica Deodato, Diana Ballhausen, Avihu Boneh, Alberto B. Burlina, Roberto Cerone, Paula Garcia, Gülden Gökçay, Stephanie Grünewald, Johannes Häberle, Jaak Jaeken, David Ketteridge, Martin Lindner, Hanna Mandel, Esmeralda G. Martins, Karl O. Schwab, Sarah C. Gruenert, Bernd C. Schwahn, László Sztriha, Maren Tomaske, Friedrich Trefz, Laura Vilarinho and David S. Rosenblatt declare that they have no conflict of interest

Brian Fowler, Carlo Dionisi-Vici and Matthias Baumgartner and Diego Martinelli have received grants as listed in the acknowledgements.

Supplementary material

10545_2014_9687_MOESM1_ESM.doc (51 kb)
Supplementary Fig. 1 (DOC 51 kb)
10545_2014_9687_MOESM2_ESM.doc (43 kb)
Supplementary Table 1 (DOC 43 kb)
10545_2014_9687_MOESM3_ESM.doc (82 kb)
Supplementary Table 2 (DOC 82.5 kb)
10545_2014_9687_MOESM4_ESM.doc (68 kb)
Supplementary Table 3 (DOC 68 kb)

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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Sabine Fischer
    • 1
  • Martina Huemer
    • 2
    • 3
  • Matthias Baumgartner
    • 2
  • Federica Deodato
    • 4
  • Diana Ballhausen
    • 5
  • Avihu Boneh
    • 6
  • Alberto B. Burlina
    • 7
  • Roberto Cerone
    • 8
  • Paula Garcia
    • 9
  • Gülden Gökçay
    • 10
  • Stephanie Grünewald
    • 11
  • Johannes Häberle
    • 2
  • Jaak Jaeken
    • 12
  • David Ketteridge
    • 13
  • Martin Lindner
    • 14
  • Hanna Mandel
    • 15
  • Diego Martinelli
    • 4
  • Esmeralda G. Martins
    • 16
  • Karl O. Schwab
    • 17
  • Sarah C. Gruenert
    • 17
  • Bernd C. Schwahn
    • 18
  • László Sztriha
    • 19
  • Maren Tomaske
    • 2
    • 20
  • Friedrich Trefz
    • 21
  • Laura Vilarinho
    • 22
  • David S. Rosenblatt
    • 23
  • Brian Fowler
    • 1
    • 2
    Email author
  • Carlo Dionisi-Vici
    • 4
  1. 1.University Children’s Hospital BaselBaselSwitzerland
  2. 2.Division of Metabolic Diseases and Children’s Research CenterUniversity Children’s HospitalZürichSwitzerland
  3. 3.Department of PediatricsLandeskrankenhaus BregenzBregenzAustria
  4. 4.Division of MetabolismBambino Gesù Children’s Hospital, IRCCSRomeItaly
  5. 5.Pédiatrie MoléculaireCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  6. 6.The Murdoch Children’s Research Institute and Royal Children’s HospitalMelbourneAustralia
  7. 7.Division of Inherited Metabolic Diseases, Department of PediatricsUniversityHospitalPadovaItaly
  8. 8.Regional Center for Neonatal Screening and Diagnosis of Metabolic DiseasesUniversity Department of Pediatrics-Istituto Giannina GasliniGenovaItaly
  9. 9.Hospital Pediátrico do Centro Hospitalar e Universitário de CoimbraCoimbraPortugal
  10. 10.Istanbul Medical Faculty, Children’s Hospital, Division, Nutrition and MetabolismIstanbul UniversityIstanbulTurkey
  11. 11.Metabolic Unit, Great Ormond Street Hospital and Clinical & Molecular Genetics UnitUCL Institute of Child HealthLondonUK
  12. 12.Centre for Metabolic DiseaseUniversity Hospital GasthuisbergLeuvenBelgium
  13. 13.Metabolic UnitSA Pathology at the Women’s & Children’s HospitalNorth AdelaideAustralia
  14. 14.Division of Metabolic DiseasesUniversity Children’s HospitalHeidelbergGermany
  15. 15.Metabolic Unit, Department of Pediatrics, Technion Faculty of MedicineRambam Medical CenterHaifaIsrael
  16. 16.Unidade de MetabolismoCentro Hospitalar do PortoPortoPortugal
  17. 17.Centre for Pediatrics and Adolescent MedicineUniversity Hospital FreiburgFreiburgGermany
  18. 18.Royal Hospital for Sick ChildrenNHS Greater Glasgow and ClydeGlasgowUK
  19. 19.Department of Paediatrics, Division BUniversity of SzegedSzegedHungary
  20. 20.University Children’s Hospital TübingenTübingenGermany
  21. 21.MVZ Kreiskliniken ReutlingenCentre for Women, Children and AdolescentsGammertingGermany
  22. 22.Newborn Screening UnitNational Institute of HealthPortoPortugal
  23. 23.Department of Human Genetics, Department of MedicineMcGill UniversityMontrealCanada

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