Clinical and Molecular Heterogeneity in Patients with the CblD Inborn Error of Cobalamin Metabolism

Miousse, Isabelle R.; Watkins, David; Coelho, David; Rupar, Tony; Crombez, Eric A.; Vilain, Eric; Bernstein, Jonathan A.; Cowan, Tina; Lee-Messer, Christopher; Enns, Gregory M.; Fowler, Brian; Rosenblatt, David S.

doi:10.1016/j.jpeds.2008.10.043

« Previous Next »The Journal of Pediatrics
Volume 154, Issue 4 , Pages 551-556, April 2009

Clinical and Molecular Heterogeneity in Patients with the CblD Inborn Error of Cobalamin Metabolism

Isabelle R. Miousse, BSc
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec
David Watkins, PhD
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec
- Reprint requests: David Watkins, PhD, Division of Medical Genetics, Room L3-319, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A4
David Coelho, PhD
- Metabolic Unit, University Children's Hospital, Basel, Switzerland
Tony Rupar, PhD
- Departments of Pediatrics, Biochemistry and the Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada
Eric A. Crombez, MD
- Department of Pediatrics, University of California Los Angeles, Los Angeles
Eric Vilain, MD
- Department of Pediatrics, University of California Los Angeles, Los Angeles
- Department of Urology, University of California Los Angeles, Los Angeles
- Department of Human Genetics, University of California Los Angeles, Los Angeles
Jonathan A. Bernstein, MD, PhD
- Department of Pediatrics, Division of Genetics, Stanford University, Palo Alto, CA
Tina Cowan, PhD
- Division of Pathology, Stanford University, Palo Alto, CA
Christopher Lee-Messer, MD, PhD
- Division of Neurology, Stanford University, Palo Alto, CA
Gregory M. Enns, MB, ChB
- Department of Pediatrics, Division of Genetics, Stanford University, Palo Alto, CA
Brian Fowler, PhD
- Metabolic Unit, University Children's Hospital, Basel, Switzerland
David S. Rosenblatt, MD
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec
- Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec

Received 21 May 2008; received in revised form 3 October 2008; accepted 27 October 2008. published online 08 December 2008.

Objectives

To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria.

Study design

Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA.

Results

Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients.

Conclusions

The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.

Abbreviations: AdoCbl, 5′-deoxyadenosylcobalamin, MeCbl, Methylcobalamin, MethylTHF, 5′-methyltetrahydrofolate, PCR, Polymerase chain reaction