Henry Houlden, PhD, professor of neurology and molecular neuroscience at the University College of London's Neurological Institute, also studies the genetics of cerebellar ataxias. “This is an interesting finding in a very rare syndrome, but the important question is whether [these mutations] also cause other types of ataxia or dementias,” he commented.
PROBING GENETIC CAUSALITY
Exome sequencing of the primary patient revealed rare variants in both copies of 13 genes, two of which were also found in samples from the patient's two affected siblings, but not in unaffected family members.
The researchers then sequenced both of these proteins in samples from nine additional affected individuals from seven other families. One patient had two different RNF216 mutations, while four other subjects — two in the same family — had mutations in a single copy of that gene, but none had mutated versions of OTUD4.
All of the individuals with RNF216 mutations had similar medical histories, characterized by a lack of normal hormonal secretion, progressive ataxia and dementia; and all of those with mutations in both genes died in their 30s or 40s.
Neuroimaging revealed similar brain abnormalities in individuals with RNF216 mutations — including atrophy of the cerebellum and cortex. The four patients without RNF216 mutations had very different histories, with less severe symptoms.
Nonetheless, all developed progressive ataxia and dementia, and brain autopsies showed neuronal loss in cerebellar pathways and in the hippocampus, while surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were also found at the hypothalamic and pituitary levels of the reproductive endocrine axis.
“Despite a historical dichotomy between monogenic and complex traits, there exists a continuum of genetic causality, whereby mutations at a discrete number of loci cooperate to either cause the disease or modify its onset and severity,” said Dr. Katsanis.
“I think these findings show that we need to be as unbiased as possible with whole-exome data. In the past, when one genetic defect has been discovered it has been assumed to be responsible for a disorder, but what we have found is that there may be others involved that might be overlooked,” Dr. Katsanis told Neurology Today.
“My prediction is that we will find more and more conditions with similar segregation of genes, with an affecting driver and compounding influences by others,” he said.
Although exactly how these mutations lead to the symptoms seen in these individuals is unknown, the researchers noted that identifying these genes may someday lead to therapies — potentially including drugs currently being developed for other disorders involving ubiquitination, including Parkinson's disease — and enable genetic screening and counseling for affected families. They also hope to investigate whether less severe mutations in these genes may contribute to the presence of ataxia, dementia, or hypogonadism alone.
“This piggy-backing of biology and genomics is really just starting,” said Dr. Katsanis. “The next steps will involve investigating the collaboration of additional genes and trying to understand their influence on ubiquitination.”
The technology that made the study possible has only emerged within the past decade, said Brent L. Fogel, MD, PhD, assistant professor in the department of neurology program in neurogenetics at the David Geffen School of Medicine of the University of California, Los Angeles.
“The key step is the use of next-generation exome sequencing from the large affected family to identify potential disease genes. This is the future of clinical neurogenetics,” he told Neurology Today.
Whole-exome sequencing is becoming more mainstream, Dr. Fogel noted. The cost of exome sequencing is currently at around $5,000, with results usually available within a couple of months, similar to many individual gene tests already in use.
“Bioinformatics is still the main roadblock. Analysis can be very time-consuming, but with continuing improvements, the tests are going to start moving along more quickly.”
The researchers had “an ideal scenario” in the current study, he added. “They had a large consanguineous family to look for a recessive mutation, could also search in other families with similar phenotypes for confirmation, and then test their findings in an animal model. This is a good example of how to approach identifying a novel genetic disease.”
But then again, Dr. Fogel noted that it is still a challenge for such approaches to find novel genes in small families or individuals, dominantly inherited neurological conditions, or complex diseases involving multiple genes.
“What I find most encouraging is that physicians are realizing the value of exome testing and how this might be of great help to their patients, so more clinicians are paying close attention to studies like this.”
LINK UP FOR MORE INFORMATION:
•. Margolin DH, Seminara SB, Katsanis N, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. New Eng J Med
2013;368 (21):1992–2003. Epub 2013 May 8.
•. Seminara SB, Acierno JS Jr, Abdulwahid NA, et al. Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J Clin Endocrinol Metab
© 2013 American Academy of Neurology
•. Sailer A, Houlden H. Recent advances in the genetics of cerebellar ataxias. Curr Neurol Neurosci Rep
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