Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.
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 microM) 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.
Lamhonwah
Anne-Marie
AM
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Olpin
Simon E
SE
Pollitt
Rodney J
RJ
Vianey-Saban
Christine
C
Divry
Priscille
P
Guffon
Nathalie
N
Besley
Guy T N
GT
Onizuka
Russell
R
De Meirleir
Linda J
LJ
Cvitanovic-Sojat
Ljerka
L
Baric
Ivo
I
Dionisi-Vici
Carlo
C
Fumic
Ksenija
K
Maradin
Miljenka
M
Tein
Ingrid
I
D009202:Cardiomyopathies / Q000517:prevention & control*; D002331:Carnitine / Q000172:deficiency / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D027701:Organic Cation Transport Proteins; D010375:Pedigree; D000074058:Solute Carrier Family 22 Member 5; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D002331:Carnitine