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.

Figure 1

Kufs Disease Pedigrees and CLN6 Mutational Status (A) Mapping the set of four families with the mutant allele described with the symbol “m” and with different mutations indicated by varying superscripts. (B) Four pedigrees from the validation set with the mutations shown. The p.Ser308Thr variant in Ku8 (also found in one control) and the p.Ala34Thr variant in Ku12 are not shown.

Figure 2

LOD Scores Obtained by Four Individual Families in the Mapping Set and the Combined hLOD Score Across Chromosome 15

Figure 3

Overlap of the Critical Regions on Chromosome 15 from the Four Families in the Mapping Set The darker the rectangle is, the greater the contribution of this family to the LOD score.

Figure 4

Schematic Representation of CLN6 with Mutations The numbered blue boxes represent each exon. The numbers below each exon represent the amino acid number within the CLN6 protein. The symbols above, colored in red, are mutations reported here for Kufs disease. The grey symbols below are previously described mutations in CLN6 in variant late-infantile NCL (NCL Resource—A Gateway for Batten Disease). The black arrow indicates the mutation described in both phenotypes.