ARTICLE IN BRIEF
Mutations in a major epigenetic regulator have now been observed in a growing number of patients and neurological disorders, prompting calls for clinical neurologists to be on the lookout for a variety of associated phenotypes, including a triad of symptoms: sensory neuropathy, hearing loss, and dementia.
WASHINGTON—Four years after being first identified, mutations in a major epigenetic regulator have now been observed in a growing number of patients and neurological disorders, prompting calls for clinical neurologists to be on the lookout for a variety of associated phenotypes, according to a presentation here at the AAN Annual Meeting.
At the same time, research into mutations of the regulator, DNA maintenance methyltransferase (DNMT1), may shed light on a fundamental new mechanism underlying age-related neurodegeneration, said the senior author of the paper, Christopher J. Klein, MD, a professor of neurology at the Mayo Clinic in Rochester, MN.
“We think this mechanism is important in neurodegeneration of many types, including brain, nerve, and cerebellar,” Dr. Klein told Neurology Today in an interview preceding his talk. “These patients are dying on average at age 54. It's almost as if they're having accelerated aging. They have hearing loss, dementia, and neuropathy. If we live long enough, we will all have hearing loss, we will all have memory loss and neuropathy. So this relatively rare disorder may help us understand a number of neurodegenerative diseases.”
DNMT1 is necessary for maintenance of methylation, gene regulation, and chromatin stability, Dr. Klein and colleagues noted in a 2011 paper published in Nature Genetics. “DNMT1, comprised of a large regulatory N-terminal region and a smaller catalytic C-terminal region, is the sole maintenance methyltransferase and an essential component of cellular epigenetic regulation. It is indispensable in embryonic development and performs crucial functions in chromatin structure, neuronal survival and cell regulations,” they explained in the study.
The 2011 paper was the first to identify DNMT1 mutations through exome sequencing in one Japanese, one European, and two American kindreds. The two mutations identified in that paper were shown to cause both central and peripheral neurodegeneration in a form of hereditary sensory and neuropathy (HSAN1E) with dementia and hearing loss.
Three years later, an Italian study led by Giuseppe Plazzi, MD, PhD, of the University of Bologna, reported that five patients carrying DNMT1 mutations, from four kindreds, presented with two distinct autosomal dominant diseases: HSAN1E or autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). They concluded that the two phenotypes were both manifestations of the same underlying DNMT1 methylopathy, both of them marked by narcolepsy with or without cataplexy.
“There's much more overlap between these two apparently distinguishable phenotypes than previously recognized,” a coauthor of that paper, Valerio Carelli, MD, PhD, a professor of neurology and chief of the laboratory of neurogenetics at the University of Bologna, told Neurology Today.
In the latest study, published ahead of print in Brain on Feb. 11 and presented here on April 22, Dr. Klein and colleagues from around the world identified nine new kindreds and five novel mutations with DNMT1, including 45 affected patients.
“We thought these cases would be so rare we would never see one again,” Dr. Klein said. “So we now know they're more common than we ever imagined.”
Already Dr. Klein has heard from three other physicians who also have patients with what are now being called “DNMT1 complex disorders.”
“A lot of these patients saw multiple doctors before getting a proper diagnosis,” he said. “If neurologists would keep in mind that all patients have a triad of sensory neuropathy, hearing loss, and cognitive decline, they will be able to order one genetic test.”
The average survival age of the patients in Dr. Klein's latest study was 53.6 years (range: 43-75), with an average onset age of 37.7 years (range: 18-51). All patients presented with sensory axonal neuropathy, hearing loss, and cognitive decline. But other symptoms also frequently occurred — myoclonus, seizures, auditory hallucinations, sleep disorders, and renal failure — and these often delayed the diagnosis.
“Usually these patients first see an audiologist due to hearing loss, but the audiologist doesn't do a nerve exam,” Dr. Klein said. “Then they might see a psychiatrist, because they develop frontotemporal dementia-like symptoms. Eventually the neurologist gets involved when they have an ulcer on their foot or gait problems.”
Because of the neuropathy, he said, “About half of our patients ended up getting foot ulcers or amputations.”
Responding to the Italian study's conclusion that HSAN1E and ADCA-DN are two sides of the same coin, Dr. Klein's paper reported that “to date, all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain.” Whether the locations of mutations have something to do with the phenotypes remains to be discovered.
Unlike the 2011 Italian paper, which found narcolepsy in all patients, Dr. Klein's study identified hypersomnia, REM sleep disorder, and/or narcolepsy in only 11 of the 45 patients. They found global brain atrophy in 12 out of 14 patients who underwent brain MRI. Five of the six patients who had had EEGs showed low amplitude (delta) frontal-predominant abnormality.
Although there was marked variability in cognitive deficits, Dr. Klein reported that 89 percent of the patients developed significant cognitive deficits by the age of 45. Cognitive function decline often started with personality changes and psychiatric manifestations.
In searching for a mechanism by which the mutations cause the disorders, Dr. Klein's group found misfolding in all the mutant DNMT1 proteins, which reduced enzyme activity and led to premature degradation. Moreover, cytoplasm aggresomes wre observed in transfected cells.
“Aggresome-induced autophagy is implicated in the pathogenesis in combination with an aberrant genome methylation pattern,” the study authors concluded.
Thomas D. Bird, MD, FAAN, a professor of neurology and medical genetics and chief of the division of neurogenetics at the University of Washington in Seattle, said the discovery of so many new patients and kindreds was the paper's most important finding.
“It's not a disease that's on the tip of the tongue for most neurologists,” said Dr. Bird, who was not involved with the study. “This paper shows it's probably under-recognized and more common than we knew. The reason is that it has so many different clinical features, so it's not recognized as a single genetic disease.”
He recalled seeing a patient in Seattle some years ago who presented with a combination of cognitive difficulties and ataxia. “No one was sure what the man had,” Dr. Bird said. “He was thought to have Alzheimer's with coincidental ataxia. It was only when we saw family members with neuropathy, deafness, and cognitive dysfunction that we figured out that the symptoms must be related. Then I read Klein's first paper and realized, ‘Oh my God, that's what our family must have,’ and indeed they did.”
Dr. Carelli said he found the data on cytoplasmic accumulation provocative but not definitive. “I strongly believe we need to study very carefully how the nuclear genome and perhaps the mitochondrial DNA behave,” he said.
Dr. Klein agreed that cytoplasmic accumulation has yet to be proven as a pathogenic mechanism, adding, “We've created a heterozygous knockout mouse model to try to answer that question.”
Although all the DNMT1 complex disorders are marked by substantially reduced methylation, Dr. Klein said it would be unwise to attempt to raise methylation levels throughout the body.
“Elevated methylation could increase the person's risk for cancer,” he said, noting, “We now know of about a hundred affected people in all, and we have yet to find a single malignancy. So we're going to need a much more targeted therapy that targets methylation only in the brain and peripheral nerves.”
For now, neurologists have no treatment to offer patients, he said, adding that even so, “It's kind of amazing how thankful the patients are to have a diagnosis. At least they know what they're dealing with.”
EXPERTS: ON THE ASSOCIATION BETWEEN MUTANT DNMT1 AND NEUROLOGIC DISORDERS