Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency.
Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common inherited disease of the mitochondrial long-chain fatty acid (LCFA) oxidation, may result in distinct clinical phenotypes, namely a mild adult muscular form and a severe hepatocardiomuscular disease with an onset in the neonatal period or in infancy. In order to understand the mechanisms underlying the difference in severity between these phenotypes, we analyzed a cohort of 20 CPT2-deficient patients being affected either with the infantile (seven patients) or the adult onset form of the disease (13 patients). Using a combination of direct sequencing and denaturing gradient gel electrophoresis, 13 CPT2 mutations were identified, including five novel ones, namely: 371G>A (R124Q), 437A>C (N146T), 481C>T (R161W), 983A>G (D328G), and 1823G>C (D608H). After updating the spectrum of CPT2 mutations (n=39) and genotypes (n=38) as well as their consequences on CPT2 activity and LCFA oxidation, it appears that both the type and location of CPT2 mutations and one or several additional genetic factors to be identified would modulate the LCFA flux and therefore the severity of the disease.
Thuillier
Laure
L
INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Paris, France.
Rostane
Hidayeth
H
Droin
Veronique
V
Demaugre
France
F
Brivet
Michèle
M
Kadhom
Noman
N
Prip-Buus
Carina
C
Gobin
Stéphanie
S
Saudubray
Jean-Marie
JM
Bonnefont
Jean-Paul
JP
D000328:Adult; D000595:Amino Acid Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency* / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007223:Infant; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction; D017386:Sequence Homology, Amino Acid
D005227:Fatty Acids; D004247:DNA; D002334:Carnitine O-Palmitoyltransferase