title: Clinical, enzymatic and molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency.
abstract: We report nine new patients with malonic aciduria associated with enzyme-confirmed malonyl-CoA decarboxylase (MCD) deficiency in eight. Clinical details were available on eight, and molecular genetic characterization was obtained for nine. As for 15 previously described patients, cardinal clinical manifestations included developmental delay and cardiomyopathy; metabolic perturbations (e.g. acidosis) and seizures, however, were infrequent or not observed in our patients. For all, detection of elevated malonic acid in urine (+/- increased C3DC acylcarnitine by analysis employing tandem mass spectrometry) led to pursuit of enzyme studies. MCD activities (nmol/h PER mg protein) revealed: control (n = 22), 16.2 +/- 1.8 (SEM; range 5.7-46.2); patients (n = 8, assayed in duplicate), 1.7 +/- 0.3 (10% of parallel control; range 0.6-2.8). Molecular characterization by DNA sequence analysis and multiplex ligation-dependent probe amplification revealed nine novel mutations (c.796C>T; p.Gln266X, c.481delC; p.Leu161CysfsX18, c.1367A>C; p.Tyr456Ser, c.1319G>T; p.Ser440Ile, c.1430C>T; p.Ser477Phe, c.899G>T; p.Gly300Val, c.799-1683_949-1293del3128, and two other large genomic deletions comprising exons 1 or the complete gene) and two known mutations in the MLYCD gene. Our findings increase the number of enzyme-confirmed MCD-deficient patients by >50%, and expand our understanding of the phenotypic and molecular heterogeneity of this rare disorder.
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G S
authors.initials: GS
authors.lastname: Salomons
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: L Landegge
authors.initials: LL
authors.lastname: Pope
authors.forename: A
authors.initials: A
authors.lastname: Errami
authors.forename: M
authors.initials: M
authors.lastname: Potter
authors.forename: M
authors.initials: M
authors.lastname: Nowaczyk
authors.forename: S
authors.initials: S
authors.lastname: Olpin
authors.forename: N
authors.initials: N
authors.lastname: Manning
authors.forename: J A J
authors.initials: JA
authors.lastname: Raiman
authors.forename: T
authors.initials: T
authors.lastname: Slade
authors.forename: M P
authors.initials: MP
authors.lastname: Champion
authors.forename: D
authors.initials: D
authors.lastname: Peck
authors.forename: D
authors.initials: D
authors.lastname: Gavrilov
authors.forename: R
authors.initials: R
authors.lastname: Hillman
authors.forename: G E
authors.initials: GE
authors.lastname: Hoganson
authors.forename: K
authors.initials: K
authors.lastname: Donaldson
authors.forename: J P H
authors.initials: JP
authors.lastname: Shield
authors.forename: D
authors.initials: D
authors.lastname: Ketteridge
authors.forename: M
authors.initials: M
authors.lastname: Wasserstein
authors.forename: K M
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000293:Adolescent; D002262:Carboxy-Lyases / Q000172:deficiency* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008297:Male; D008314:Malonates / Q000652:urine; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D008314:Malonates; C030290:malonic acid; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase