Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.
OBJECTIVE
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.


METHODS
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.
Miousse
Isabelle R
IR
Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
Watkins
David
D
Coelho
David
D
Rupar
Tony
T
Crombez
Eric A
EA
Vilain
Eric
E
Bernstein
Jonathan A
JA
Cowan
Tina
T
Lee-Messer
Christopher
C
Enns
Gregory M
GM
Fowler
Brian
B
Rosenblatt
David S
DS
D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D003038:Cobamides / Q000172:deficiency*; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006712:Homocystinuria / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008764:Methylmalonic Acid / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics; D010641:Phenotype; D014806:Vitamin B 12 Deficiency / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology
D003038:Cobamides; D047908:Intracellular Signaling Peptides and Proteins; C527938:MMADHC protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D008764:Methylmalonic Acid