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The proportion of people diagnosed with familial <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) among all cases is 8%, according to a pooled analysis of studies published worldwide.
Still, data show there was a wide variation of estimates across the studies based partly on geographical differences, study design, the definition of familial ALS, and the decade when assessed.
The researchers noted there were few studies outside of European populations, therefore, more population-based studies in non-European populations are needed.
In addition, the researchers suggested that increased genetic testing may address some of the limitations in estimating the proportion of familial ALS.
[recommended-reading id=88074]
The pooled analysis was published in the journal <a href="https://www.neurology.org/journal/nxg">Neurology Genetics</a>, in the study, “<a href="https://www.neurology.org/doi/10.1212/nxg.0000000000200109">Estimated Familial Amyotrophic Lateral Sclerosis Proportion</a>.”
Muscle weakness and atrophy (wasting) are hallmark features in all individuals with ALS, a neurological disorder <a href="https://alsnewstoday.com/causes-of-als/">caused</a> by the progressive death of nerve cells that control voluntary movements called motor neurons.
Estimates suggest about 5%-10% of ALS cases have a known family history, referred to as familial ALS (fALS). The remaining 90% are considered sporadic (sALS) due to a lack of family connections.
However, it has been a challenge to clearly determine the proportion of familial versus sporadic ALS cases due to variations in the design of studies examining their prevalence.
Suggested reasons for such variation include different definitions of familial ALS, geographical discrepancies, changes over time, misdiagnosis, or the early death of family members who would have developed ALS. A lack of family history also can result from low gene penetrance, meaning not all family members who inherit an ALS-linked gene develop ALS, an assessment further complicated by family size.
“These situations may result in erroneous labeling of patients as sporadic, when family inheritance occurred,” according to a team led by researchers at Emory University, in Georgia, in collaboration with Biogen.
<h3>Estimating the proportion of cases</h3>
Thus, the team conducted a pooled (meta) analysis, funded by Biogen, of published studies to estimate the proportion of familial ALS by geographic region and examine study characteristics that may have influenced these estimates.
Database searches yielded a final sample of 165 study estimates, of which 58 (35%) identified ALS cases using large population methods and 107 (65%) were based on case series with smaller groups of patients.
A clear definition of familial ALS was reported in 56 studies. Among them, 13 (23%) restricted the definition to first-degree relatives only (parent or offspring), 14 (25%) restricted to first or second-degree relatives (grandparent and grandchild, half-siblings, aunt/uncle or niece/nephew), and 8 eight (14%) allowed for more distant generations.
In addition, eight (14%) studies considered those with confirmed genetic mutations to be classified as familial ALS, one (2%) required an ALS family history in multiple relatives, while 12 (21%) allowed a family history that included other neurological diseases.
Across all 165 studies, the pooled proportion of familial ALS was 8%. Europe had the highest proportion of familial ALS at 9%, followed by the Middle East and North Africa at 9% and Australasia at 8%. The lowest proportion was found in Asia at 4% and Sub-Saharan Africa at 5%. “Few studies outside of European ancestral populations were available,” the team noted.
When divided by study design, the proportion of familial ALS was higher among case series compared with population-based studies (9% vs. 5%). The researchers noted this result was likely due to referral bias, a type of selection bias that occurs when individuals included in a study are not representative of the overall population.
<h3>Defining the disease matters</h3>
As expected, population-based studies with a broader definition of familial ALS (first- or second-degree or more distant family history) had a higher proportion at 11%. In comparison, in studies that restricted the definition to first- or second-degree, the proportion of familial ALS was 7%, and 5% among those including first-degree relatives only.
Population-based studies from the 2000s or earlier reported a lower proportion of familial ALS than those published in the 2010s or later (3% vs. 9%). According to researchers, these findings likely were due to changes in ALS case identification, diagnostic criteria, an understanding of the disease, familial ALS classification, environmental risk factors, and the average family size.
When cases considered sporadic due to missing/unknown family history were included, as well as studies that allowed for alternative motor neuron diseases, the results remained consistent.
Still, excluding the eight studies that classified familial ALS based on confirmed genetic mutations, the proportion of familial ALS was slightly lower in all studies (7% vs. 8%) and in case series (8% vs. 9%). European studies drove these changes. Population-based studies and other regional data remained unchanged.
“This study contributes to an improved understanding of factors that affect variability in reports of the proportion of ALS cases that are of familial vs sporadic origin in the epidemiologic literature,” the researchers wrote.
“Future identification of ALS cases, especially fALS cases, with an underlying genetic etiology may benefit from increased genetic testing to address limitations in estimating proportion fALS,” they added.

Familial ALS accounts for 8% of all cases, analysis suggests

People with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) due to mutations in the FUS gene may benefit from interferon-gamma treatment to delay disease onset and/or progression, an early preclinical study suggests.
Researchers found that an immune signaling protein called interferon (INF)-gamma protected patient-derived motor neurons from oxidative stress.
INF-gamma also restored the activity of genes that normally respond to oxidative stress, a type of cellular damage implicated in the disease, and improved overall protein production within motor neurons, which is compromised in FUS-related ALS.
The cell-based study, “<a href="https://onlinelibrary.wiley.com/doi/10.1111/bpa.13206">IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis</a>,” was published in the journal <a href="https://onlinelibrary.wiley.com/journal/17503639">Brain Pathology</a>.
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<h3>FUS gene mutations account for 5% of familial ALS, 1% of sporadic cases</h3>
<a href="https://alsnewstoday.com/als-and-genetics/">Mutations in the FUS gene</a>, which encodes a protein of the same name, cause about 5% of <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and about 1% of <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> cases. FUS mutations have been associated with the most aggressive forms of ALS, including a type that occurs in adolescents and young adults.
FUS protein is typically found in the cell nucleus and plays various roles in protein production. However, exactly how these mutations cause the death of motor neurons, the nerve cells that control voluntary movements, which lead to <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a>, is still unclear.
To reveal biological defects caused by FUS mutations, scientists in the Netherlands and Brazil generated motor neurons derived from ALS patients who carried FUS-R521H, a prominent ALS mutation. Control cells were derived from family members who did not have ALS.
Results showed that cell viability, or the proportion of healthy cells, was similar between the control and FUS-ALS motor neurons. However, when exposed to sodium arsenite, a well-known inducer of oxidative stress, mutant cells were significantly less viable than controls.
<h3>FUS-ALS motor neurons more sensitive to oxidative stress</h3>
FUS-ALS motor neurons were “more sensitive to oxidative stress,” the scientists noted.
Gene activity experiments revealed oxidative stress sensitivity of motor neurons might be explained by changes in genes related to the immune system and two major signaling pathways: TGF-beta and mTORC, both essential for proper cell function.
Consistent with TGF-beta’s role in the production of immune signaling proteins called cytokines, FUS-ALS motor neurons, when exposed to sodium arsenite, produced more interleukin-8 and CCL2 cytokines and less INF-gamma and interleukin-15. In control cells, INF-gamma increased with sodium arsenite exposure, something that FUS-ALS cells failed to do, the team noted.
Because mTORC and FUS both have known roles in protein production, the researchers also measured the rates of protein synthesis. Overall, FUS-ALS motor neurons had lower rates than control cells, but no differences were noticeable in gene activity, which was “in agreement with findings of others.”
Significantly decreased protein production rates were also found in healthy cells engineered to overproduce FUS-R521H. This suggested that the FUS mutation resulted in an overly-active FUS protein in ALS motor neurons, rather than in reduced levels of FUS.
[quote=&#8221;center&#8221;]Our findings suggest that early-diagnosed [FUS-ALS] patients might benefit from [INF-gamma] treatment to slow down disease progression.[/quote]
<h3>ALS motor neurons more susceptible to cell death</h3>
ALS motor neurons are “more susceptible to apoptosis [cell death] due to decreased protein synthesis rates caused by an R521H gain-of-function [overactive] mutation in the FUS gene,” the researchers wrote.
In healthy cells, FUS is known to move between the cell nucleus and the cytoplasm (the gelatinous liquid that fills the inside of a cell). In ALS, however, FUS is mainly found in the cytoplasm of motor neurons, which ultimately leads to FUS clumping.
Consistently, in FUS-ALS motor neurons, FUS levels were reduced in the nucleus and increased in the cytoplasm. Protein interaction studies showed that, when in the cytoplasm, FUS-R521H binds to various proteins that initiate protein synthesis.
The abnormal localization of FUS-R521H was also found in cells harboring mutations that cause other forms of ALS.
“These findings suggest that aberrant cytoplasmic localization of FUS is common among ALS subtypes,” the scientists wrote, and “leads to promiscuous binding of FUS to cytoplasmic proteins with a role in [protein production].”
[recommended-reading id=21684]
<h3>INF-gamma treatment decreased cell death to control levels</h3>
Finally, treatment with INF-gamma, which was reduced in FUS-ALS motor neurons, increased mutant cell viability after sodium arsenite exposure and decreased cell death to control levels. INF-gamma treatment also rescued the impaired gene activity seen in response to oxidative stress.
Although the treatment did not affect protein synthesis rates in control cells, it significantly increased them in FUS-ALS motor neurons, with or without sodium arsenite exposure.
INF-gamma treatment also increased FUS levels in the nucleus, almost to those in control cells. In agreement, suppressing levels of FUS improved protein synthesis rates in FUS-R521H cells and reduced cell death, similar to INF-gamma.
“While further work is required to understand how [INF-gamma] restores FUS localization and impaired translation rates, our findings suggest that early-diagnosed [FUS-ALS] patients might benefit from [INF-gamma] treatment to slow down disease progression,” the researchers concluded.

Interferon-gamma therapy may help delay familial ALS: Cell study

Magnetic stimulation restored the health of lab-grown motor neurons — the muscle-controlling nerve cells that die in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — derived from people with familial ALS, according to a proof-of-concept study.
The approach improved several biological processes in motor neurons, including the movement of cellular components along nerve fibers, or axons, and the growth of new axons.
“In the numerous series of experiments, we were able to demonstrate that the motor neurons from ALS patients respond to the magnetic fields,” Arun Pal, a cell biologist at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) research center, in Germany, who served as the study&#8217;s co-senior author, said in a <a href="https://www.hzdr.de/db/Cms?pNid=99&amp;pOid=69393">university press release</a>.
Thomas Herrmannsdörfer, PhD, another study author from the HZDR, noted that “detailed follow-up studies are required to corroborate [these] findings,” but added, “We regard these … results as an encouraging approach on the path to a potential novel therapy for ALS as well as other neurogenerative diseases.”
The study, “<a href="https://www.mdpi.com/2073-4409/12/11/1502">Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach</a>,” was published in the journal <a href="https://www.mdpi.com/journal/cells">Cells</a>.
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<h3>Magnetic stimulation applied to lab-grown motor neurons</h3>
Motor neurons are nerve cells in the brain and spinal cord that send signals to muscles to perform various bodily functions, including movement, speaking, swallowing, and breathing. Their <a href="https://qbi.uq.edu.au/brain/brain-anatomy/axons-cable-transmission-neurons">axons</a> — the cable-like part that snakes away from the main part of the cell — are the longest in the body and can stretch from the spinal cord to the toes.
Most cases of ALS are characterized by the sporadic and progressive loss of motor neurons. In about 10% of cases, however, inherited genetic mutations are responsible for motor neuron death.
Magnetic stimulation is a non-invasive procedure that uses magnetic fields to stimulate nerve cells. It&#8217;s been approved for use in psychiatric disorders, such as depression.
A small clinical trial recently showed that <a href="https://www.nature.com/articles/s41598-019-39313-z">magnetic stimulation slowed muscle function decline</a> in ALS patients.
To investigate its impact at the cellular level, researchers in Germany now applied magnetic stimulation directly to lab-grown motor neurons derived from three ALS patients carrying inherited <a href="https://alsnewstoday.com/causes-of-als/">disease-causing mutations in the FUS gene</a>.
Motor neurons were grown from patient-derived induced pluripotent stem cells, called iPSCs. Such iPSCs are generated from fully matured cells that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell.
The team previously showed the movement of cellular components, or organelles, along axons was <a href="https://alsnewstoday.com/news/neurodegenratioals-patients-linnked-faulty-dna-repair/">impaired in spinal motoneurons</a> derived from FUS-ALS patients. These <a href="https://www.nature.com/articles/s41467-017-02299-1#:~:text=we%20observed%20the%20appearance%20of%20an%20axonal%20phenotype%20in%20FUS%2DALS%20with%20a%20virtual%20arrest%20of%20mitochondria%20and%20lysosomes%20distally%20as%20opposed%20to%20normal%20motility%20proximally">organelles included</a> mitochondria, the cell’s energy producers, and lysosomes, the cell’s recycling centers.
Now the researchers found that magnetic stimulation restored the movement of these organelles in lab-grown patient-derived motor neurons without affecting cells derived from three healthy people. Restoration depended on the frequency of the magnetic field, with a combination of 2 and 10 Hz (cycles per second) generating the best results.
“The axonal transport of mitochondria (the power stations of the cell) and other organelles that are impaired in ALS cells is reactivated by stimulation with magnetic fields,” Pal said.
[recommended-reading id=82060]
<h3>Scientists now planning clinical pilot studies</h3>
In FUS-ALS mouse models, the growth, branching, and distribution of axons — which go on to form connections to other nerve cells as well as muscle cells — have been shown to be impaired.
Consistently, untreated patient-derived motor neurons showed slower outgrowth than those derived from healthy controls.
With the 10 Hz treatment, axons of patient-derived motor neurons grew as fast as control cells, while the 2 Hz and 2/10 Hz combination did not show significant changes. No evidence of magnetic stimulation-related adverse effects on patient and control motor neurons was observed.
These findings showed that, with magnetic stimulation treatment, “axonal regeneration — which is the ability to regrow and reconnect — can be restored,” Pal said.
The shape of nerve cells is unique, with axons extending from the cell body. This shape is dictated by the cytoskeleton, a complex network of interlinking proteins called microtubules that helps cells maintain their shape and internal organization.
The levels of a microtubule stabilization marker were significantly lower in FUS-ALS motor neurons relative to controls. With magnetic stimulation, marker levels in patient cells rose back to control levels, pointing to “an improvement of microtubule stability that is feasibly beneficial for deficient axonal organelle trafficking and regeneration,” the researchers wrote.
“This work provides proof of concept demonstrating that magnetic field treatments are powerful in restoring several hallmarks of ALS [development] recapitulated in our cultured disease model of human iPSC-derived spinal [motor neurons],” the team concluded.
“Long-term and [living organism] studies are required to further substantiate the therapeutic potential of magnetic field treatments,” they added.
The scientists are now planning clinical pilot studies to assess the therapeutic potential of magnetic simulation, applied with specialized equipment.

Magnetic stimulation seen to restore ALS motor neurons in cell study

A potential new genetic risk factor for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has been discovered by researchers at the University of Washington.
The scientists say a mutation in which a region of the WDR7 gene is repeated more times than usual may increase the risk of ALS.
“We believe that this expansion acts as a genetic modifier to disease susceptibility, as in the repeat on its own doesn’t cause disease, but it functions in conjunction with other genetic risk factors,” Samuel Smukowski, a graduate student at the University of Washington, said in a talk at the Muscular Dystrophy Association&#8217;s MDA Clinical &amp; Scientific Conference, held in Texas and virtually March 19 through 22.
Smukowski’s talk was titled “<a href="https://www.mdaconference.org/abstract-library/functional-consequences-of-a-human-specific-tandem-repeat-in-wdr7-associated-with-als/">Functional consequences of a human-specific tandem repeat in WDR7 associated with ALS</a>.”
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<h3>More than 50 VNTR expansions have been linked to neurological diseases</h3>
The human genome contains instructions for making all of the proteins needed for the body to function. Within the genome, there are many areas called variable number tandem repeats, or VNTRs, where a particular sequence of nucleotides (the building blocks of DNA) gets repeated over and over.
A VNTR expansion is a type of mutation where a VNTR sequence has many more repeats than normal. More than 50 VNTR expansions have been linked to neurological diseases, and a mutation of this type in the gene C9ORF72 is the most common <a href="https://alsnewstoday.com/als-and-genetics/">ALS-associated mutation</a>.
Smukowski and his colleagues initially assessed data from a family affected by <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a>. Using cutting-edge genetic sequencing technology, the team discovered a previously unreported 69-nucleotide-long VNTR sequence in the gene WDR7.
A VNTR expansion in this gene, which provides instructions for making a protein that’s involved in the function of synapses (the connections between nerve cells), appeared to be associated with ALS in the family.
Analyses of data from more than 900 people in three groups of <a href="https://alsnewstoday.com/forms-of-als-2/sporadic-als/">sporadic ALS</a> patients — one from the Answer ALS program, one from Quebec, and a third from the Coriell Institute for Medical Research — showed that ALS patients more commonly had an expanded VNTR region in the WDR7 gene compared with people who did not have ALS.
&#8220;ALS patients disproportionately have longer repeat expansions,&#8221; Smukowski said.
[quote=&#8221;center&#8221;]We believe that this expansion acts as a genetic modifier to disease susceptibility, as in the repeat on its own doesn’t cause disease, but it functions in conjunction with other genetic risk factors.[/quote]
When WDR7 and other protein-coding genes are &#8220;read&#8221; to produce a protein, the genetic code is copied over into a temporary molecule called messenger RNA (mRNA). Some ALS-associated mutations are known to cause mRNA and proteins to clump up inside cells, which is thought to be toxic and contribute to the nerve cell degeneration that drives ALS.
The researchers showed that mRNA from the WDR7 gene harboring an expansion in the VNTR region was found in clumps alongside the ALS-linked protein TDP-43.
The team also showed that the repeat region could be used by cells to produce microRNAs, which are regulatory RNA molecules that bind to the mRNAs of certain proteins to reduce their levels. The larger the expansion in the WDR7 VNTR region, the more microRNAs were produced, the research showed.
In theory, this could mean that the VNTR expansion could change the levels of specific proteins in cells, ultimately dysregulating cellular activity.
[recommended-reading id=82220]
Smukowski noted that several of the genes known to be regulated by these microRNAs have important roles in neurological function, with mutations in one gene, called VPS53, having been shown to spontaneously lead to ALS in mice.
&#8220;Therefore it’s possible that a high copy number of this repeat expansion is interfering with these target genes’ normal expression,&#8221; he said.
“Our findings underscore the biological impact of tandem repeat expansions in modulating susceptibility to ALS,” the scientists wrote in their abstract.
They are continuing work to understand how this WDR7 mutation, and other VNTR expansions, may affect the development and progression of ALS.

Tag: familial ALS

Familial ALS accounts for 8% of all cases, analysis suggests

Interferon-gamma therapy may help delay familial ALS: Cell study

Magnetic stimulation seen to restore ALS motor neurons in cell study

MDA 2023: Expansion in WDR7 gene linked to increased ALS risk