Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6

Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
The American Journal of Human Genetics (Impact Factor: 10.99). 05/2011; 88(5):566-73. DOI: 10.1016/j.ajhg.2011.04.004
Source: PubMed

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.

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Available from: Stefano Meletti, Jul 28, 2015
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    • "NCLs are inherited in an autosomal recessive manner, except for one autosomal dominant adult form (Noskova et al., 2011; Velinov et al., 2012). According to the newly proposed classification scheme recently published by Williams and Mole (2012), nine NCL-causative genes have been identified and can be functionally grouped as " soluble lysosomal enzyme deficiencies " PPT1/CLN1 (Vesa et al., 1995), TPP1/CLN2 (Liu et al., 1998; Sleat et al., 1997), and CTSD/CLN10 (Siintola et al., 2006b; Steinfeld et al., 2006), or " nonenzyme deficiencies " CLN3 (The International Batten Disease Consortium, 1995), DNAJC 5 /CLN4 (Noskova et al., 2011; Velinov et al., 2012), CLN5 (Savukoski et al., 1998), CLN6 (Arsov et al., 2011; Gao et al., 2002; Wheeler et al., 2002), MFSD8/CLN7 (Siintola et al., 2007), and CLN8 (Ranta et al., 1999). Remaining genes whose classification is still uncertain are CLCN6 (Poet et al., 2006), SGSH (Sleat et al., 2009), CLN9 (Schulz et al., 2004), GRN/CLN11 (Smith et al., 2012), ATP13A2/CLN12 (Bras et al., 2012), CTSF/CLN13 (Tang et al., 2006), and KCTD7/CLN14 (Krabichler et al., 2012; Staropoli et al., 2012; van Bogaert et al., 2007). "
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    ABSTRACT: Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60-15.85nmol/h/mg (nr 110-476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at non-conserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity.
    Gene 12/2012; 516(1). DOI:10.1016/j.gene.2012.12.058 · 2.08 Impact Factor
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    • "Since loss-offunction CLN6 mutations are proven to underlie Egyptian/Indian variant of late infantile NCL (type 6), it has been hypothesized that the existence of different phenotypes with the same genetic basis depends on either ''milder'' mutations with partially retained CLN6 function in Kuf's disease or the action of modifying factors influencing the corresponding phenotype [16]. Ceroid inclusions in adult-onset NCL are often detected only in neurons, therefore, in the absence of a validated genetic test, brain biopsy (or sometimes rectal mucosa biopsy) is still the main diagnostic procedure [16]. Finnish variant late infantile form (type 5): hypotonia is generally observed by the age of 5, followed by visual impairment, ataxia, late myoclonus and GTCS. "
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