TY - JOUR
T1 - Clinical, enzymatic and molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency
AU - Salomons, G. S.
AU - Jakobs, C.
AU - Pope, Landegge
AU - Errami, A.
AU - Potter, M.
AU - Nowaczyk, M.
AU - Olpin, S.
AU - Manning, N.
AU - Raiman, J. A.J.
AU - Slade, T.
AU - Champion, M. P.
AU - Peck, D.
AU - Gavrilov, D.
AU - Hillman, R.
AU - Hoganson, G. E.
AU - Donaldson, K.
AU - Shield, J. P.H.
AU - Ketteridge, D.
AU - Wasserstein, M.
AU - Gibson, K. Michael
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33846458254&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846458254&partnerID=8YFLogxK
U2 - 10.1007/s10545-006-0514-6
DO - 10.1007/s10545-006-0514-6
M3 - Article
C2 - 17186413
AN - SCOPUS:33846458254
SN - 0141-8955
VL - 30
SP - 23
EP - 28
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 1
ER -