Abstract
Primary systemic carnitine deficiency (SCD) is a rare hereditary disorder transmitted by an autosomal recessive mode of inheritance. The disorder includes cardiomyopathy, muscle weakness, hypoketotic coma with hypoglycemia, and hyperammonemia. In this study, we conducted a linkage analysis of a Japanese SCD family with a proband-a 9-year-old girl-and 26 members. The serum and urinary carnitine levels were determined for all members. The entire genome was searched for linkage to the gene locus for SCD, by use of a total of approximately 300 polymorphic markers located approximately 15-20 cM apart. In the family, there were two significantly different phenotypes, in terms of serum free-carnitine levels: low serum free-carnitine level (29.5+/-5.0 microM; n=14) and normal serum free-carnitine level (46.8+/-6.2 microM; n=12). There was no correlation of urinary free-carnitine levels with the low serum-level phenotype (putative heterozygote), but in normal phenotypes (wild type) urinary levels decreased as the serum levels decreased; renal resorption of free carnitine appeared to be complete in wild-type individuals, when the serum free-carnitine level was <36 microM. Linkage analysis using an autosomal dominant mode of inheritance of heterozygosity revealed a tight linkage between the disease allele and D5S436 on chromosome 5q, with a two-point LOD score of 4.98 and a multipoint LOD score of 5.52. The haplotype analysis revealed that the responsible genetic locus lies between D5S658 and D5S434, which we named the "SCD" locus. This region was syntenic with the jvs locus, which is responsible for murine SCD. Phylogenic conversion of the SCD locus strongly suggests involvement of a single gene, in human SCD.
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- Engel A. G., Rebouche C. J., Wilson D. M., Glasgow A. M., Romshe C. A., Cruse R. P. Primary systemic carnitine deficiency. II. Renal handling of carnitine. Neurology. 1981 Jul;31(7):819–825. doi: 10.1212/wnl.31.7.819. [DOI] [PubMed] [Google Scholar]
- Garavaglia B., Uziel G., Dworzak F., Carrara F., DiDonato S. Primary carnitine deficiency: heterozygote and intrafamilial phenotypic variation. Neurology. 1991 Oct;41(10):1691–1693. doi: 10.1212/wnl.41.10.1691. [DOI] [PubMed] [Google Scholar]
- Golper T. A., Wolfson M., Ahmad S., Hirschberg R., Kurtin P., Katz L. A., Nicora R., Ashbrook D., Kopple J. D. Multicenter trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects. Kidney Int. 1990 Nov;38(5):904–911. doi: 10.1038/ki.1990.289. [DOI] [PubMed] [Google Scholar]
- Koizumi T., Nikaido H., Hayakawa J., Nonomura A., Yoneda T. Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2(0) strain of mouse with similarities to Reye's syndrome. Lab Anim. 1988 Jan;22(1):83–87. doi: 10.1258/002367788780746511. [DOI] [PubMed] [Google Scholar]
- Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
- Kuwajima M., Kono N., Horiuchi M., Imamura Y., Ono A., Inui Y., Kawata S., Koizumi T., Hayakawa J., Saheki T. Animal model of systemic carnitine deficiency: analysis in C3H-H-2 degrees strain of mouse associated with juvenile visceral steatosis. Biochem Biophys Res Commun. 1991 Feb 14;174(3):1090–1094. doi: 10.1016/0006-291x(91)91532-h. [DOI] [PubMed] [Google Scholar]
- Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nikaido H., Horiuchi M., Hashimoto N., Saheki T., Hayakawa J. Mapping of jvs (juvenile visceral steatosis) gene, which causes systemic carnitine deficiency in mice, on chromosome 11. Mamm Genome. 1995 May;6(5):369–370. doi: 10.1007/BF00364804. [DOI] [PubMed] [Google Scholar]
- Rinaldo P., Stanley C. A., Hsu B. Y., Sanchez L. A., Stern H. J. Sudden neonatal death in carnitine transporter deficiency. J Pediatr. 1997 Aug;131(2):304–305. doi: 10.1016/s0022-3476(97)70171-9. [DOI] [PubMed] [Google Scholar]
- Stanley C. A., DeLeeuw S., Coates P. M., Vianey-Liaud C., Divry P., Bonnefont J. P., Saudubray J. M., Haymond M., Trefz F. K., Breningstall G. N. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol. 1991 Nov;30(5):709–716. doi: 10.1002/ana.410300512. [DOI] [PubMed] [Google Scholar]
- Takahashi M., Ueda S., Misaki H., Sugiyama N., Matsumoto K., Matsuo N., Murao S. Carnitine determination by an enzymatic cycling method with carnitine dehydrogenase. Clin Chem. 1994 May;40(5):817–821. [PubMed] [Google Scholar]
- Tein I., De Vivo D. C., Bierman F., Pulver P., De Meirleir L. J., Cvitanovic-Sojat L., Pagon R. A., Bertini E., Dionisi-Vici C., Servidei S. Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy. Pediatr Res. 1990 Sep;28(3):247–255. doi: 10.1203/00006450-199009000-00020. [DOI] [PubMed] [Google Scholar]
- Tripp M. E., Katcher M. L., Peters H. A., Gilbert E. F., Arya S., Hodach R. J., Shug A. L. Systemic carnitine deficiency presenting as familial endocardial fibroelastosis: a treatable cardiomyopathy. N Engl J Med. 1981 Aug 13;305(7):385–390. doi: 10.1056/NEJM198108133050707. [DOI] [PubMed] [Google Scholar]