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2012 ANCL Smith, Dahl, Damiano. Bahlo &Berkovic

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Adult Batten Disease: New Genes, Better Diagnosis

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2012 ANCL Smith, Dahl, Damiano. Bahlo &Berkovic

  1. 1. What is adult Batten disease? Adult Batten disease (also known as adult onset neuronal ceroid lipofuscinosis or ANCL) is a diverse group of diseases with different genetic causes. The age of onset can range from the late teens to the sixties; symptoms include seizures, poor balance (ataxia) and intellectual decline. Some forms involve blindness, while others, known as Kufs disease, do not. Some forms show recessive inheritance, where disease is caused by mistakes (mutations) in two copies of a gene, while others show dominant inheritance, in which mistakes in a single copy of a gene suffices to cause disease. How is it diagnosed? ANCL is much more difficult to diagnose using skin biopsies or other accessible tissues than childhood forms of Batten disease. This is because the diagnostic findings may be sparse and difficult to distinguish from normal changes of ageing. Reliable diagnosis using microscopy may require examination of a small piece of brain tissue surgically removed from the patient (a brain biopsy). If a patient has a form of ANCL for which the genetic basis has been discovered, then diagnosis can be performed by simply examining the patient’s DNA from a blood sample. Adult Batten Disease: New Genes, Better Diagnosis Katherine R Smith1, Hans-Henrik Dahl2, John Damiano2, Melanie Bahlo1, Samuel F Berkovic2 (1) Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne VIC 3052, Australia (2) Epilepsy Research Centre, University of Melbourne, Melbourne VIC 3084, Australia. Contact s.berkovic@unimelb.edu.au BDSRA 2012 At the start of 2010, the genetic basis of ANCL was completely unknown, so genetic testing was not an option for patients suspected to have ANCL. Fortunately, great progress has been made since that time; the genetic basis of at least four different types of ANCL have been discovered (Figure 1 and Table 1). Our research group has identified three such genes. One is not yet published and is described as ‘Gene B’ in this poster. The other two genes are: The CLN6 gene - recessive Kufs disease, type A We have identified mutations in the CLN6 gene as the major cause of Type A Kufs disease. It has been known since 2002 that mutations in both copies of CLN6 can cause a form of childhood Batten disease called variant late infantile NCL. We discovered that mutations in both copies of this gene can also cause ANCL - a surprising finding, since the two forms of Batten disease have different ages of onset, and only the childhood form involves blindness. The progranulin gene (GRN) - recessive ANCL with blindness So far, mutations in this gene have only been detected in two ANCL patients, a pair of siblings, so mutations in this gene do not appear to be a common cause of ANCL. The siblings developed symptoms at the ages of 22 and 23, including visual problems. They were found to have mutations in both copies of the GRN gene. It has been known since 2006 that mutations in a single copy of the GRN gene can cause a form of late onset intellectual decline called frontotemporal lobar degeneration (FTLD). This research finding provides an unexpected link between ANCL, which is a rare disease, and FTLD, which is relatively common. What does this mean for patients? The recent advances in ANCL mutation identification means that most patients with a form of ANCL caused by mutations in CLN6, DNAJC5, ‘Gene B’ or GRN can now be diagnosed by examining DNA obtained from a blood sample. These patients will be able to avoid surgery to remove brain tissue to be used for diagnosis. A genetic diagnosis will inform genetic counseling of patients and their relatives, helping them to understand the risk of disease faced by themselves and any children they might have. We hope that these findings will encourage research into the function of the proteins produced by these four genes, and ultimately lead to therapies being developed for these types of ANCL. Conclusion Our research has revealed unexpected connections between a form of ANCL and a form of childhood onset Batten disease, and between a second form of ANCL and a relatively common late onset cognitive impairment. ANCL is rare compared to childhood onset Batten disease, which is itself a rare disease. We hope that the links we have discovered will allow ANCL patients to benefit from research being undertaken into these other conditions. Great progress has been made in identifying genes in which mutations cause ANCL. However, it is thought that several genes still remain to be discovered. References 1. Arsov T, Smith KR, Damiano J, et al. The American Journal of Human Genetics 2011;88:566-73. 2. Benitez BA, Alvarado D, Cai Y, et al. PLoS ONE 2011;6:e26741. 3. Nosková L, Stránecký V, Hartmannová H, et al. The American Journal of Human Genetics 2011;89:241-52. 4. Velinov M, Dolzhanskaya N, Gonzalez M, et al. PLoS ONE 2012;7:e29729. 5. Smith KR, Damiano J, Franceschetti S, et al. The American Journal of Human Genetics 2012;90:1102-7. Figure 1. Different forms of adult Batten disease and their genetic basis (where known ) Gene Ages of onset No. families or unrelated patients with mutations in this gene No. patients with mutations in this gene (can be related) No. different mutations discovered CLN61 16-51 7 10 9 DNAJC52-4 24-46 9 >=23 2 GRN5 22-23 1 2 1 ‘Gene B’ 20-35 3 4 5 Table 1. Summary of genes implicated in ANCL - age of onset, number of patients and number of mutations

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