Gene for Lou Gehrig’s Disease and Frontotemporal Dementia Identified
Frontotemporal dementia and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease – two fatal neurodegenerative disease with distinct symptoms – are triggered by a common mutation in many cases, according to researchers who say they have identified the mutated gene.
In the study, reported in the September 21 online issue of Neuron, the scientists described the discovery of a genetic mutation that is accountable for almost 12 percent of familial FTD and more than 22 percent of familial ALS samples studied.
They also report that the defect is the strongest genetic risk factor found to date for the more common, non-inherited, sporadic forms of these diseases. It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS samples in the largest clinical patient series.
The study was led by scientists at the Mayo Clinic in Florida, in collaboration with researchers at UCSF, the University of British Columbia and UCLA. The finding emerged from the identification and study of a family stricken by both ALS and FTD, reported last year. In that study, led by the UCSF scientists and published in the Journal of Neurology, Neurosurgery and Psychiatry, the researchers honed in on the region in which the gene was located.
“Both clinically and at the molecular level this discovery is going to significantly improve our understanding of these diseases,” said co-author Adam Boxer, MD, PhD, of the UCSF Memory and Aging Center, the lead author on the 2010 paper. The discovery makes it possible to develop a diagnostic test for the mutation, as well as to create animal models that may be used to help unravel the molecular mysteries connecting the mutation to the diseases, he said.
What is Frontotemporal Dementia ?
Frontotemporal dementia (FTD) describes a clinical syndrome associated with shrinking of the frontal and temporal anterior lobes of the brain. Originally known as Pick’s disease, the name and classification of FTD has been a topic of discussion for over a century. The current designation of the syndrome groups together Pick’s disease, primary progressive aphasia, and semantic dementia as FTD. Some doctors propose adding corticobasal degeneration and progressive supranuclear palsy to FTD and calling the group Pick Complex. These designations will continue to be debated. As it is defined today, the symptoms of FTD fall into two clinical patterns that involve either (1) changes in behavior, or (2) problems with language. The first type features behavior that can be either impulsive (disinhibited) or bored and listless (apathetic) and includes inappropriate social behavior; lack of social tact; lack of empathy; distractability; loss of insight into the behaviors of oneself and others; an increased interest in sex; changes in food preferences; agitation or, conversely, blunted emotions; neglect of personal hygiene; repetitive or compulsive behavior, and decreased energy and motivation. The second type primarily features symptoms of language disturbance, including difficulty making or understanding speech, often in conjunction with the behavioral type’s symptoms. Spatial skills and memory remain intact. There is a strong genetic component to the disease; FTD often runs in families.
In the current study, a detailed molecular genetic characterization of the family that Boxer described was done in the laboratory of senior author Rosa Rademakers, PhD, from the Mayo Clinic. She and colleagues identified the gene and the specific mutation within it.
What is amyotrophic lateral sclerosis?
Amyotrophic lateral sclerosis, or ALS, is a disease in which certain nerve cells in the brain and spinal cord slowly die. These nerve cells are called motor neurons, and they control the muscles that allow you to move the parts of your body. ALS is also called Lou Gehrig’s disease.
People with ALS gradually become more disabled. How quickly the disease gets worse is different for everyone. Some people live with ALS for several years. But over time, ALS makes it hard to walk, speak, eat, swallow, and breathe. These problems can lead to injury, illness, and eventually death. In most cases, death will occur within 3 to 5 years after symptoms begin, although some people do live for many years, even decades.
It can be very scary to learn that you have ALS. Talking with your doctor, getting counseling, or joining a support group may help you deal with your feelings. Your family members may also need support or counseling as your disease gets worse.
ALS is rare. Each year in the United States and most of the world, only 1 to 2 people out of 100,000 get ALS. Men get ALS slightly more often than women do. ALS can occur at any age, but it most often starts in middle-aged and older adults.
The mutation consists of from hundreds to thousands of extra copies of a six-letter DNA sequence GGGGCC strung end to end within a region of human chromosome nine. The mutation occurs within a gene of unknown function called C9ORF72.
Frontotemporal Dementia Signs and Symptoms
In the past, patients with frontotemporal dementia (FTD) often were misdiagnosed with depression, schizophrenia or Alzheimer’s disease. Because some FTD cases still may be misidentified, doctors at the UCSF Center for Memory and Aging say it’s difficult to determine the prevalence of the disorder but they believe FTD is the most common dementia diagnosed in patients under age 60 and is as common as Alzheimer’s disease among patients age 45 to 64.
Early symptoms typically involve personality or mood changes such as depression and withdrawal, sometimes obsessive behavior and language difficulties. Many patients lose their inhibitions and exhibit antisocial behavior.
Doctors at UCSF have identified a small group of patients who develop extraordinary visual or musical creativity, while experiencing language and social impairment.
As FTD progresses, it takes a toll on mental abilities, affecting memory and other functions that are more common in Alzheimer’s disease and other dementias. In Alzheimer’s, one of the first symptoms is memory loss. With FTD, unusual or antisocial behavior as well as loss of speech or language are usually the first symptoms.
In later stages, patients develop movement disorders such as unsteadiness, rigidity, slowness, twitches, muscle weakness or difficulty swallowing. Some patients develop Lou Gherig’s disease or amyotrophic lateral sclerosis (ALS). People in the final stages of FTD cannot care for themselves.
After identifying the mutation, the Mayo researchers searched for it in DNA from other patients with both familial and sporadic forms of the diseases, where they found the strong associations.
FTD is characterized by disturbances in decision making, language skills, behavior and emotional expression, and is as common as Alzheimer’s disease in people younger than 65, according to Boxer. ALS is a neuromuscular disease, leading to muscle paralysis and respiratory failure, often within three to five years. However, it is not unusual for patients diagnosed with one of the two diseases to exhibit symptoms of the other.
Since 2006, six separate groups have reported evidence for a genetic link between the disorders and the same chromosomal region. In the study led by Boxer last year, the researchers described clinical aspects of the disease within the family, and homed in more closely to the gene than others had.
Amyotrophic lateral sclerosis (a-mi-oh-TROH-fik LAT-ur-ul skluh-ROH-sis), or ALS, is a serious neurological disease that causes muscle weakness, disability and eventually death. ALS is often called Lou Gehrig’s disease, after the famous baseball player who was diagnosed with it in 1939. In the U.S., ALS and motor neuron disease (MND) are sometimes used interchangeably.
Worldwide, ALS occurs in 1 to 3 people per 100,000. In the vast majority of cases – 90 to 95 percent – doctors don’t yet know why ALS occurs. About 5 to 10 percent of ALS cases are inherited.
ALS often begins with muscle twitching and weakness in an arm or leg, or with slurring of speech. Eventually, ALS affects your ability to control the muscles needed to move, speak, eat and breathe.
The pattern of protein deposition in the brains of family members in the study may eventually shed light on common aspects of the neurodegenerative process that occurs in both diseases, Boxer said.
There is only one standard medical treatment for ALS, riluzole, which extend life for about six months, he said.
There is no known effective treatment to slow FTD. However, neurologists have generally become much better at recognizing the degenerative disorder, according to Boxer.
Boxer and Bruce Miller, MD, the director of the UCSF Memory and Aging Center and a co-author of both studies, are leaders in FTD research, diagnosis and patient care.
“Ten years ago some neurologists did not acknowledge the existence of FTD,” Boxer says. “Today we are much better at diagnosing the disease, although sometimes it still takes an expert to distinguish it from Alzheimer’s or from psychiatric disorders.
Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)
There is increasing clinical, imaging and neurophatological evidence that amyotrophic lateral sclerosis (ALS) represents a multisystem neurodegenerative disease. Neurodegeneration is not restricted to motor neurons, but also includes parts of the brain other than the motor cortex, especially the prefrontal and/or anterior temporal lobe, that contribute to the clinical syndrome. In some cases an evident dementia that resembles frontotemporal degeneration (FTD) was observed. It is now suggested that ALS and FTD are closely related conditions with overlapping clinical, pathological, radiological, and genetic characteristics. The presence of a frontal dementia in ALS has also crucial practical consequences for management of the patients, whose disorder requires critical life decisions for enteral nutrition and respiratory complications. It is our intent to provide a brief overview of the relationships between ALS and FTD.
“We’re actively trying to develop treatments for FTD, and we believe this discovery will pave the way for major advances in these efforts.”
The researchers used a technique called linkage analysis to narrow the search for the gene by comparing affected and unaffected family members. Another group of scientists – reporting in the same online edition of Neuron on the same gene – found that C9ORF72 emerged as being significantly associated with FTD and ALS in a genome-wide scan of patients in Finland.
The Mayo portion of the study was funded by the National Institutes of Health and the ALS association (ALSA). The UCSF portion was funded by the NIH, the John Douglas French Foundation; the Hellman Family Foundation and the Tau Research Consortium and the Larry Hillblom Foundation and the state of California.
Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve, Adam L. Boxer, Matt Baker, Nicola J. Rutherford, Alexandra M. Nicholson, NiCole A. Finch, Heather Flynn, Jennifer Adamson, Naomi Kouri, Aleksandra Wojtas, Pheth Sengdy, Ging-Yuek R. Hsiung, Anna Karydas, William W. Seeley, Keith A. Josephs, Giovanni Coppola, Daniel H. Geschwind, Zbigniew K. Wszolek, Howard Feldman, David S. Knopman, Ronald C. Petersen, Bruce L. Miller, Dennis W. Dickson, Kevin B. Boylan, Neill R. Graff-Radford, and Rosa Rademakers. Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron, 2011; DOI: 10.1016/j.neuron.2011.09.011