Identification of genetic heterogeneity in Refsum's disease

Refsum's disease (MIM 266500) is a recessive disorder characterised by defe ctive peroxisomal alpha-oxidation of phytanic acid. A Refsum's disease gene , phytanoyl-CoA hydroxylase (PAHX), has been localised to chromosome 10p13 between the markers D10S226-D10S223. This study investigated whether all ca ses of Refsum's disease were linked with chromosome 10p13. Eight geneticall y informative families comprising 92 individuals including 17 living patien ts with a Refsum's disease phenotype and initial plasma phytanic acid > 200 mu mol/L were recruited. Linkage to the 10pter-10p11.2 region was investig ated using a panel of eight dinucleotide repeat markers. Linkage analysis o f this phenotypically identical cohort suggested that Refsum's disease was genetically heterogeneous (Z(max) = 5.28, alpha = 0.45). Two subgroups were identified. One group of four families with eight affected individuals had a maximum multipoint lod score for linkage of 3.89 in the region D10S547 t o D10S191, whilst in another three families with nine affected individuals linkage to this region was definitely excluded. Our results show that Refsu m's disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. This suggests that Re fsum's disease, in common with other peroxisomal 'diseases', may be more ac curately described as a heterogeneous syndrome.