The discovery of the gene responsible for Kufs disease, a rare but fatal inherited brain disorder, has paved the way for developing a blood test to diagnose the condition, rather than through brain biopsy, according to an Australian-led study published online in the American Journal of Human Genetics this week.
The researchers believe the innovative technology they developed for the study could help discover genetic causes of other epilepsy-related diseases, deafness and some inherited cancers.
Corresponding authors Professor Sam Berkovic, a neurologist and epilepsy specialist from the University of Melbourne and Dr Melanie Bahlo from the Bioinformatics division of the Walter and Eliza Hall Institute, and colleagues, developed new technology to discover that mutations in the CLN6 gene are the cause of inherited recessive Kufs type A disease. The gene lies on chromosome 15.
Kufs disease is a rare, hereditary and fatal disease that occurs in about 1 in a million people. It belongs to a group of disorders called neuronal ceroid lipofuscinoses (NCLs) that primarily affect the nervous system and cause problems with movement and intellectual function or cognition. People with the type A form of Kufs disease also have epilepsy and speech difficulties (dysarthria).
The signs and symptoms typically appear in early adulthood, but they can develop anytime between adolescence and late adulthood. They are caused by a build up of toxic fat in the brain and gradually worsen with time. Affected individuals usually survive about 10 years after symptoms first appear.
Genes accounting for most of the NCL disorders that begin in childhood have been identified, but this is the first discovery of a Kufs disease gene.
Berkovic and colleagues hope the discovery will lead to more efficient and less invasive ways of diagnosing Kufs disease earlier.
Diagnosis of Kufs disease is difficult because the characteristic fat deposits are largely present only in neurons or brain cells.
“Currently, the only way that we can reliably diagnose this disease is to do an invasive and dangerous brain biopsy, or at autopsy,” Berkovic told the press.
Now we know the gene behind the disease, we will be able to use a rapid and simple blood test to identify it genetically, and this will make it possible to screen for the disease in families that carry the gene, and to offer genetic counselling, which we already know is important for patients, he explained.
He and Bahlo described the discovery of the CLN6 gene as a “great outcome” for the team and the people affected by the disease.
However, Berkovic said the best possible outcome would be if the discovery led to a treatment for Kufs disease, which is currently untreatable and invariably leads to death. However, the possibility of a treatment is “still some time away”, he added.
For the study, the researchers used a technique called SNP genotyping which looks for patterns of genetic variations in “single nucleotide polymorphisms” or SNPs (called “snips”) in people’s DNA. Together with what Bahlo describes as “an innovative suite of highly specialised techniques and statistical algorithms”, that she and members of her team developed, they scanned the entire genetic code of a small number of people with Kufs disease to find which region had the mutations that cause it.
The method is new and unique because usually SNP genotyping is done with a much larger sample; however Kufs disease is so rare that it is not possible to find large samples of patients, and current models would not be sufficiently reliable to pinpoint the genetic mutations behind the disease.
Four families took part in the first phase of the study: three were affected by Kufs type A and one by type B. The researchers wrote that:
“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.”
To confirm the findings, they subsequently sequence CLN6 in eight other families and found mutations in CLN6 in three type A cases and in one family with an unclassified Kufs disease.
The discovery is good news for other patient group too. Bahlo said their study could also hold the key to finding the genes behind a number of other hereditary conditions, including other epilepsy-related diseases, deafness and some familial cancers.
Bahlo said the technology they developed for this study is at “the forefront of medical research today” and should help find more genes behind certain diseases, leading to new diagnostic tools and through better understanding of the biology, new treatments as well.
Australia’s Health and Medical Research Council and the Batten Disease Support and Research Association funded the study.
“Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6.”
Todor Arsov , Katherine R. Smith , John Damiano , Silvana Franceschetti , Laura Canafoglia , Catherine J. Bromhead , Eva Andermann , Danya F. Vears , Patrick Cossette , Sulekha Rajagopalan , Alan McDougall , Vito Sofia , Michael Farrell , Umberto Aguglia , Andrea Zini , Stefano Meletti , Michela Morbin , Saul Mullen , Frederick Andermann , Sara E. Mole , Melanie Bahlo and Samuel F. Berkovic.
DOI:10.1016/j.ajhg.2011.04.004
Additional sources: Walter and Eliza Hall Institute, Genetics Home Reference (NIH).
Written by: Catharine Paddock, PhD