TY - JOUR
T1 - Novel OCTN2 mutations
T2 - No genotype-phenotype correlations: Early carnitine therapy prevents cardiomyopathy
AU - Lamhonwah, Anne Marie
AU - Olpin, Simon E.
AU - Pollitt, Rodney J.
AU - Vianey-Saban, Christine
AU - Divry, Priscille
AU - Guffon, Nathalie
AU - Besley, Guy T N
AU - Onizuka, Russell
AU - De Meirleir, Linda J.
AU - Cvitanovic-Sojat, Ljerka
AU - Baric, Ivo
AU - Dionisi-Vici, Carlo
AU - Fumic, Ksenija
AU - Maradin, Miljenka
AU - Tein, Ingrid
PY - 2002/8/15
Y1 - 2002/8/15
N2 - Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 μM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G>A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype.
AB - Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 μM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G>A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype.
KW - Carnitine transporter
KW - Cultured skin fibroblasts
KW - Fatty acid oxidation
KW - Hypertrophic cardiomyopathy
KW - Organic cation transporter
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U2 - 10.1002/ajmg.10585
DO - 10.1002/ajmg.10585
M3 - Article
C2 - 12210323
AN - SCOPUS:4243325434
VL - 111
SP - 271
EP - 284
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 3
ER -