title: Localization of Refsum disease with increased pipecolic acidaemia to chromosome 10p by homozygosity mapping and carrier testing in a single nuclear family.
abstract: Adult Refsum disease (ARD) is a rare autosomal recessive neurologic disorder associated with the accumulation in blood and tissues of phytanic acid, a natural compound of exogenous origin whose catabolism is impaired in patients. We present here genome wide linkage analysis of an atypical Refsum disease family where L-pipecolic acid level in blood was also increased, suggesting that the patients suffer from a new peroxisomal disorder intermediate between ARD and Infantile Refsum Disease (IRD, a peroxisomal deficiency disease). We were able to demonstrate significant linkage (lod score = 3.6) between Refsum Disease with increased Pipecolic Acidaemia (RDPA) and the interval defined by D10S249 and D10S466 on 10p in this single consanguineous family by combining lod score values obtained from analysis of the multiple affected sibs, haplotype homozygosity and from discrimination between healthy carriers and non carriers based on phytanate oxidase measurements. This illustrates the power of homozygosity mapping with a dense map of microsatellite markers. A similar strategy will allow testing for homogeneity/heterogeneity between RDPA and ARD or the rare complementation groups of IRD.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP, Illkirch, France.
authors.forename: N
authors.initials: N
authors.lastname: Nadal
authors.forename: M O
authors.initials: MO
authors.lastname: Rolland
authors.forename: C
authors.initials: C
authors.lastname: Tranchant
authors.forename: L
authors.initials: L
authors.lastname: Reutenauer
authors.forename: G
authors.initials: G
authors.lastname: Gyapay
authors.forename: J M
authors.initials: JM
authors.lastname: Warter
authors.forename: J L
authors.initials: JL
authors.lastname: Mandel
authors.forename: M
authors.initials: M
authors.lastname: Koenig
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D004276:DNA, Satellite / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009679:Nuclear Family; D010375:Pedigree; D010875:Pipecolic Acids / Q000097:blood*; D016133:Polymerase Chain Reaction; D012035:Refsum Disease / Q000097:blood / Q000201:enzymology / Q000235:genetics*
chemical_list: D004276:DNA, Satellite; D010875:Pipecolic Acids; D006899:Mixed Function Oxygenases; C022397:phytanic acid alpha-oxidase; C031345:pipecolic acid