C9ORF72 mutation is most common cause of familial ALS, FTD
Two independent research teams have identified a mutation in the gene for chromosome 9 open reading frame 72 (C9ORF72) as the most common cause found to date of familial (inherited) ALS, frontotemporal dementia (FTD) and ALS with FTD (ALS-FTD).
The investigators further determined that the mutation — an expanded section of DNA known as a repeat expansion — also accounts for a small percentage of cases of sporadic (noninherited) ALS.
The mutation appears to be responsible for approximately 30 percent of familial ALS cases and, conservatively, 4 percent of sporadic ALS cases in North America.
Familial ALS accounts for about 5 to 10 percent of all ALS cases, with the other 90 to 95 percent occurring sporadically (without a family history of the disease). Approximately 50 percent of people with ALS have some degree of cognitive or behavioral impairment, but only about 10 to 30 percent of patients meet the criteria for a clinical diagnosis of ALS-FTD.
Results of the two studies were published online Sept. 21, 2011, in Neuron.
One team was coordinated by neurologist Bryan Traynor at the National Institutes of Health in Bethesda, Md. The other team included corresponding authors Ian R. Mackenzie, a professor of pathology and laboratory medicine at the University of British Columbia, Vancouver, Canada, and Rosa Rademakers, associate professor of molecular science at the Mayo Clinic Florida in Jacksonville.
This is the first time a repeat expansion mutation has been found to directly cause ALS, although a repeat expansion in the ataxin 2 gene was recently identified as a significant contributor to the risk of developing ALS.
Because this type of mutation has been implicated in a number of other diseases, it’s been the subject of a great deal of research.
Both teams reported that the C9ORF72 mutation is the most common known cause of inherited ALS and FTD. Data from the studies indicate that the C9ORF72 mutation is more than twice as common as mutations in the superoxide dismutase 1 (SOD1) gene as a cause of familial ALS, and more than three times as common as mutations in TAR DNA-binding protein 43 (TARDBP, or TDP43), fused in sarcoma (FUS), optineurin (OPTN) and valosin-containing protein (VCP) genes combined.
“Until now we knew that mutations in SOD1 accounted for approximately 20 percent of familial ALS and that mutations in all other known ALS-associated genes combined accounted for, at most, another 10 percent,” said neurologist Michael Benatar at the University of Miami Miller School of Medicine. “Mutations in C9ORF72 probably account for 20 to 30 percent of patients with familial ALS.
Benatar, who received MDA funding for his contribution to this work, added, “Moreover, we now know the genetic cause of ALS in the majority — 50 to 60 percent — of patients with familial ALS.”
Whether, and how frequently, mutations in C9ORF72 cause sporadic ALS in the United States is not known, but is an area of active research, Benatar said.
“If the finding that this mutation in C9ORF72 is responsible for a significant proportion of patients with sporadic ALS, then a whole new array of approaches to developing treatments for patients with ALS becomes apparent.”
An immediate implication of the new findings will be the development of a genetic test for the C9ORF72 repeat expansion. Genetic test results could inform individuals, families, caregivers and physicians about the probable course of the disease and aid in early decision-making. (Genetic testing always should be discussed with a physician, and genetic counseling may be recommended.)
For more on frontotemporal dementia in ALS, see When the Thinking Parts of the Brain Go Awry in ALS.
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Ubiquilin 2 flaws connected to ALS
Abnormalities in the ubiquilin 2 gene and protein have been shown to be important contributors to several forms of ALS, including an X-linked form of juvenile and adult-onset familial ALS, as well as ALS with dementia (cognitive impairment).
The ubiquilin 2 protein plays a role in a cellular maintenance mechanism called the ubiquitin-proteasome pathway, which normally disposes of damaged proteins.
The study team, led by Teepu Siddique at Northwestern University Feinberg School of Medicine in Chicago, published its findings online Aug. 21, 2011, in the prestigious journal Nature.
The study investigators showed that abnormal, coil-like accumulations of the ubiquilin 2 protein can occur in the spinal cords of people with ALS without dementia, and in the brains of people with ALS/dementia — whether or not there is a mutation in the ubiquilin 2 gene.
These ubiquilin 2 protein accumulations appear to be associated with development of ALS, perhaps by tying up ubiquilin 2 and keeping it from its normal duties, the new findings suggest. However, a definitive causative connection between ubiquilin 2 protein accumulations and ALS has not yet been established.
The new findings should open new avenues for exploration by ALS researchers. Likely first steps are the development of cells and mice that have ubiquilin 2 mutations, so that the ubiquilin 2 pathways in health and disease can be studied and potential targets for therapies identified.
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Sigma R1 gene mutation causes juvenile ALS
A mutation on chromosome 9 in the gene for a protein called sigma intracellular receptor 1 (sigma R1) has been identified as a cause of familial juvenile ALS, a team of researchers from Riyadh, Saudi Arabia, has reported.
The average age of onset of ALS in the United States and Europe is 56 to 63 years. Juvenile onset tends to manifest in the teens or early 20s, but symptoms can appear earlier.
Previous studies have shown that sigma 1 receptors confer neuroprotective properties, and that research mice lacking the sigma R1 gene exhibit symptoms of motor deficiency.
Amr Al-Saif, Futwan Al-Mohanna and Saeed Bohlega, all at King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia, reported their findings online Aug. 12, 2011, in the Annals of Neurology.
The sigma R1 protein is found throughout the body, including in the brainstem and spinal cord. In addition to conferring neuroprotective benefits, it’s known to oppose stress-triggered programmed cell death called apoptosis. Mutations in the sigma R1 gene also are known to affect localization of the TDP43 and FUS proteins, both associated with ALS.
The only other gene so far identified with juvenile ALS is senataxin (SETX).
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D11Y mutation causes mild form of ALS
A mutation called D11Y in the superoxide dismutase 1 (SOD1) gene appears to cause a mild form of ALS, a team of researchers in Rome has reported.
The research team, including corresponding author Mario Sabatelli at the Institute of Neurology, Catholic University of Sacred Heart, Rome, described its findings online Aug. 11, 2011, in the Journal of the Neurological Sciences.
More than 150 ALS-causing mutations in the SOD1 gene have been identified to date, but robust associations between particular mutations and specific disease characteristics are not always apparent.
The investigators found that the D11Y mutation causes a form of ALS characterized by “predominant involvement of the distal muscles [those of the lower arms, hands, lower legs and feet] and a very slow progression of the disease.”
Such an association between a particular genetic mutation (genotype) and the resulting manifestation in a person (phenotype) is called a genotype-phenotype correlation.
Known correlations can help physicians speed diagnosis and predict disease course.
“The most important implication of our findings is diagnostic,” Sabatelli confirmed, noting that testing for the mutation can now be used to help make a diagnosis in people with an atypically slow form of ALS. The unusually slow clinical course of the disease, he added, is “fundamental information for patients.”
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NeuRx Diaphragm Pacing System approved for ALS
|Respiratory problems are one of the most serious medical complications in ALS. The NeuRx DPS is designed to supplement breathing efforts and help preserve diaphragm muscle function. Illustration courtesy of Synapse Biomedical.
Synapse Biomedical announced Sept. 29, 2011, that the U.S. Food and Drug Administration has approved its NeuRx Diaphragm Pacing System (DPS) for treatment of hypoventilation (inadequate breathing) in ALS.
The pacing system, which is surgically implanted, assists breathing by stimulating the diaphragm muscle. It is intended to improve quality of life by improving respiration, and it’s hoped it may forestall or negate the need for invasive ventilation (via tracheostomy). However, it does not treat the underlying molecular mechanisms that cause ALS, so it is unable to slow, stop or reverse the disease course.
The DPS received FDA approval as a “humanitarian use device” (HUD), a designation given to medical devices intended for use in rare diseases. The FDA requires sufficient evidence that such devices do not pose “an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use.”
FDA approval of the DPS reflects the agency’s judgment that adequate safety in ALS was demonstrated. The effectiveness of the device for this use has not yet been demonstrated. The HUD designation clears the way for physicians to prescribe the device for people with ALS and for potential insurance coverage.
The DPS is not appropriate for everyone. In order to benefit from the pacing system, people with ALS must have adequate function both of the diaphragm (one of the main muscles involved in breathing) and the phrenic nerves (which connect the diaphragm and spinal cord).
To determine eligibility, respiratory function is tested, and the right and left diaphragm must be shown to be stimulatable by the pacing system.
To place the pacing system, electrodes must be surgically implanted in the diaphragm. Although the surgery is minimally invasive (laparoscopic), it does entail risks for infection, or anesthesia and respiratory complications.
Preliminary data suggest that some individuals with ALS who are using noninvasive ventilation (such as a BiPAP-type device) may show some benefit with the DPS. However, more studies will be needed to evaluate who is likely to benefit. To learn more, contact your MDA clinic team.
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Astrocytes and SOD1 link familial, sporadic ALS
|Motor neuron killers? Star-shaped cells called astrocytes appear to play a role in both inherited and noninherited forms of ALS.
Astrocytes — cells that normally support and protect nerve cells (neurons) — have been found to cause motor neuron degeneration in human cellular models of both familial (inherited) and sporadic (noninherited) ALS.
Scientists tied the astrocytes’ effects, in both forms of the disease, to the superoxide dismutase 1 (SOD1) protein.
Previous studies in the SOD1 research mouse model of familial ALS have shown that astrocytes affected by mutated SOD1 are toxic to motor neurons. Until now, however, it remained undetermined whether astrocytes may be similarly toxic in the sporadic forms of the disease.
The research team involved in the new National Institutes of Health-supported study published its findings online Aug. 10, 2011, in Nature Biotechnology.
The investigators first created a new research model of ALS, generating astrocytes from cells retrieved from postmortem spinal cord tissue.
Samples were taken from one person with SOD1-related familial ALS and seven people with the sporadic form of the disease. The team then cultured the astrocytes in combination with mouse motor neurons.
Degeneration was observed both in motor neurons cultured with familial ALS-affected and sporadic ALS astrocytes. The researchers noted that the motor neuron damage caused by astrocytes derived both from the person with familial ALS and those with sporadic ALS was “indistinguishable.” This, they suggested, indicates — at least under described conditions — a “shared mechanism for motor neuron death” in the two forms of the disease.
The team then demonstrated that toxic effects could be reversed by “knocking down,” or causing a decrease in, SOD1 protein levels in astrocytes derived from either the familial or sporadic ALS cells. Suppression of SOD1 by approximately 50 percent in the sporadic ALS astrocytes was enough to protect motor neurons.
Results from this study indicate that potential benefits gained by knocking down SOD1 may be applicable to a far greater number of people with the disease than previously thought.
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FUS and TDP43 collaborate on critical processes
In a fruit fly research model of inherited ALS, human FUS and TDP43 proteins work together on some processes necessary for the long-term survival of muscle-controlling motor neurons (nerve cells), a research team at Columbia University Medical Center in New York has reported.
Investigators found that when the genes for either of these proteins are mutated, interaction between the two proteins is impaired, causing disruption of the critical molecular processes that require their collaboration.
The researchers, led by Brian McCabe at Columbia University’s Center for Motor Neuron Biology and Disease, published their findings online Sept. 1, 2011, in the Journal of Clinical Investigation.
Initially, the research team created a fruit fly model with a FUS-associated ALS-like disease, and found that the flies had impaired mobility and reduced life span. A model with a TDP43-associated ALS-like disease showed similar deficits in survival and motor function.
In a series of experiments, the team found that:
- flies with abnormal FUS genes could be “rescued” (returned to normal) via insertion of normal human FUS genes, but not with human FUS genes carrying an ALS-causing mutation;
- flies with mutated TDP43 genes could be rescued with insertion of normal human TDP43 genes (and not with mutated human TDP43 genes); and
- increased activity of normal FUS protein rescued flies with TDP43 mutations, but overproduction of normal TDP43 protein did not rescue flies with FUS mutations.
“Our results show that these two genes work together in a familial ALS model,” McCabe said, noting that it’s important to discover how ALS-related genes and proteins cause the disease, and if and how they work together in humans.
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