title: Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.
abstract: The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.forename: John
authors.initials: J
authors.lastname: Damiano
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Laura
authors.initials: L
authors.lastname: Canafoglia
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Bromhead
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Danya F
authors.initials: DF
authors.lastname: Vears
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Sulekha
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Alan
authors.initials: A
authors.lastname: McDougall
authors.forename: Vito
authors.initials: V
authors.lastname: Sofia
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Umberto
authors.initials: U
authors.lastname: Aguglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Zini
authors.forename: Stefano
authors.initials: S
authors.lastname: Meletti
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Saul
authors.initials: S
authors.lastname: Mullen
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D003704:Dementia / Q000473:pathology; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000209:etiology* / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: C447500:CLN6 protein, human; D008565:Membrane Proteins