Abstracts

Rationale: Action myoclonus renal failure (AMRF) syndrome is a lethal inherited form of progressive myoclonus epilepsy associated with renal failure. It typically presents at 15 - 25 years with neurological symptoms (tremor, action myoclonus, seizures and later ataxia), or proteinuria evolving into renal failure requiring dialysis or transplantation. The autosomal recessive gene defect underlying AMRF was unknown and the lack of large pedigrees and lethality of the disorder precluded a conventional mapping strategy.Methods: We studied three Australian patients and their families: case A of Turkish-Cypriot origin whose parents were first cousins, and cases B and C whose ancestors came from different regions of Britain and no inbreeding loops were known for either family. Using SNP chips and a novel mapping strategy, homozygosity mapping of a known consanguineous case was conducted and then combined with analysis of affected and unaffected siblings in the other families.Results: Homozygosity mapping using all three cases identified a 5.3 cM critical region on chromosome 4 and a second 3.0 cM region on chromosome 20. Microsatellite analysis in these regions excluded the chromosome 20 locus and leaving the chromosome 4 locus as the region of interest. Microarray expression analysis of the two living AMRF patients and their unaffected same sex siblings as controls identified a lysosomal protein as the likely candidate. Sequencing revealed mutations predicted to truncate the protein in all three patients and a subsequent family. Western blotting showed absent expression of this lysosomal membrane protein in lymphocytes.Conclusions: Using only 3 affected individuals, we have identified the gene for this rare form of progressive myoclonus epilepsy. This will allow for earlier diagnosis of this condition and provides new insights into the biology of this disorder. This work was supported by a grant from the Australian National Health and Medical Research Council.