The structural consequences of the mutation in Kennedy's Disease

The following was published in IRB Barcelona yesterday. It is further research on research performed a few years ago.  https://www.irbbarcelona.org/en/tags/kennedys-disease-0

Researchers at IRB Barcelona discover the structural consequences of the mutation that causes Kennedy disease

The androgen receptor helix of polyglutamine becomes increasingly stable as the number (n) of glutamine amino acid residues increases.

12 JUN 2019

Kennedy’s disease is an untreatable neuromuscular disorder considered a rare disease

A study led by Xavier Salvatella may pave the way for new lines of treatment for Kennedy’s disease

Kennedy’s disease is a rare neuromuscular disease caused by a mutation in the androgen receptor protein. The Laboratory of Molecular Biophysics led by Xavier Salvatella at the Institute for Research in Biomedicine (IRB Barcelona) has recently discovered new key structural features of the androgen receptor induced by the mutation. This finding has been published in the journal Nature Communications and could open up new therapeutic avenues for a family of incurable rare conditions called polyglutamine (polyQ) expansion diseases.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an untreatable neuromuscular disorder that causes a dramatic decrease in patients’ quality of life. It is classified as a rare disease, meaning that it affects less than 5 in 10,000 people. The mutation in the androgen receptor protein causing the disease is an expansion of a repetitive amino acid sequence containing only glutamine residues, called a polyQ tract. Interestingly, the length of this tract determines whether a person develops Kennedy’s disease.

A similar mutation can also be found in other polyQ expansion diseases, the most known of which is Huntington’s disease. Why an expansion of the polyQ tract leads to the development of polyQ expansion diseases in not understood. In the case of Kennedy’s disease, researchers believe that androgen receptor proteins containing a very long polyQ tend to oligomerize. These oligomers then generate toxic protein aggregates inside the cell, thereby impeding its proper functioning.

For a protein to function properly, it must fold into an ordered three-dimensional structure. Up to now, the part of the androgen receptor protein holding the polyQ expansion was thought to be disordered and therefore unable to fold into such a structure. In 2016, Salvatella’s group found that the polyQ tract of the androgen receptor could adopt a helical structure. “This was a very interesting result, as so far these tracts were thought not to adopt any specific structure,” explains Salvatella.

In the current study, the team went one step further and visualized the polyQ tract protein helix via advanced biophysical and computational methods. They now report that this specific region can form well-ordered helices and, crucially, that the polyQ expansion greatly increases the degree of order and stability of these helices. This information furthers our understanding of androgen receptor function.

Symptoms, Diagnosis, and Treatment for SBMA

This is a well written and easy to understand article in Well Written Health.
 

Symptoms, Diagnosis, and Treatment for SBMA

Kennedy disease, also known as spinal bulbar muscular atrophy or SBMA, is an inherited neurological disorder. Kennedy disease affects the specialized nerve cells that control muscle movement (specifically, the lower motor neurons), which are responsible for the movement of many muscles of the arms and legs. It also affects the nerves that control bulbar muscles, which control breathing, swallowing, and talking. Kennedy disease can also lead to androgen (male hormones) insensitivity which causes enlarged breasts in men, decreased fertility, and testicular atrophy.

Kennedy disease is caused by a genetic defect on the X (female) chromosome. Since males have only one X chromosome, they are most severely affected by the disorder. Females, who have two X chromosomes, may carry the defective gene on one X chromosome, but the other normal X chromosome lessens or hides the symptoms of the disorder. Kennedy disease is estimated to occur in 1 in 40,000 individuals worldwide. ... 

Diagnosis of the Condition

There are a number of neuromuscular disorders with symptoms similar to Kennedy disease, so misdiagnosis or under-diagnosis may be common.

Often, individuals with Kennedy disease are mistakenly thought to have amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). However, ALS, as well as the other similar disorders, does not include endocrine disorders or loss of sensation.

A genetic test can confirm if the Kennedy disease defect is present on the X chromosome. If genetic testing is positive, no other tests need to be done as diagnosis can be made from the genetic test alone. ...

Click on the header link to read the full article.

BVS857 Clinical Trial Yields Mixed Results

Below is another article reporting the results of the BVS857 Trial. Click on the link to read the article at SMA News Today.

 

BVS857 Clinical Trial Yields Mixed Results

BY ALICE MELÃO

Novartis Pharmaceuticals‘ investigational compound BVS857 significantly improved muscle volume in patients with X-linked type spinal muscular atrophy (SMA) over a short period of time, Phase 2 clinical results show. However, the compound failed to improve muscle strength and function.

These findings were reported in the study, “Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial,” published in The Lancet Neurology.

X-linked type SMA, also known as spinal and bulbar muscular atrophy (SBMD), or Kennedy’s disease, is caused by a faulty androgen receptor (AR) gene and is characterized by degeneration of muscle and lower motor neurons of the brain stem and spinal cord.

Previous studies have shown that patients with this disease have low amounts (less than 170 ng/mL) of insulin-like growth factor-1 (IGF-1) in the blood. Also, cellular and mouse studies have suggested that by increasing the amount of this signaling molecule it may be possible to ease the features of AR gene mutations.

IGF-1 is a growth factor with different roles in many aspects of childhood growth. It also plays an important role in adult metabolism.

Novartis developed the artificial compound BVS857 specifically to mimic the natural activity of the IGF-1 hormone, while holding enhanced efficiency. This molecule is capable of IGF-1 receptor activation, but has a longer half-life — the time it takes for the body to eliminate half of the substance — than IGF-1.

The safety and effectiveness of BVS857 was evaluated in a Phase 2 trial (NCT02024932) in adult patients with genetically confirmed Kennedy’s disease recruited at six clinical sites in Denmark, Germany, Italy, and the United States. Patients were at least 18 years old, were ambulatory, had muscle weakness and IGF-1 blood serum levels below 170 ng/mL.

The study was divided into two parts. The first part included eight patients who received increasing doses of the investigational compound or a placebo. In the second part, 27 patients received weekly intravenous injections of 0.06 mg/kg BVS857 or placebo for up to 12 weeks.

During the study 89% and 94% of the patients in the placebo and BVS857 groups, respectively, experienced at least one adverse side effect, with the proportion of moderate adverse side effects being higher in the BVS857-treated group.

The most common treatment-related side effects were inflammation of the nose and pharynx, and headache. In general the treatment was found to be safe without inducing any serious problems.

Repeated treatment with BVS857 induced a significant increase in IGF-1 levels up to a mean value of 788 ng/mL.

Evaluation by magnetic resonance imaging (MRI) scans revealed that BVS857 could induce a significant, but mild, improvement of thigh muscle volume (TMV) — a marker of muscle wasting — compared to initial values. Also, TMV in BVS857-treated patients remained stable during the trial, while it decreased in the placebo group.

However, new assessment of TMV approximately 21 and 48 days after completion of the treatment showed no significant differences between the two groups.

BVS857 also failed to induce significant improvements on disease symptoms, as determined by the Adult Myopathy Assessment Tool score, and lean body mass when compared to placebo after 12 weeks.

“Overall, no significant differences were found in any of the motor functional measures between the BVS857 and placebo groups,” researchers wrote.

During the trial, about 72% of the patients on the BVS857 treatment group developed antibodies against both the investigational compound and natural IGF-1, which in 46% of the cases had a neutralizing effect. This enhanced immunoreactivity was fully resolved upon treatment discontinuation.

Collectively, these results demonstrated that IGF-1 pathway activation over a short period of time can significantly improve muscle volume in patients with Kennedy’s disease. Still, it failed to improve muscle strength and function.

“The evidence of preliminary efficacy over the short timeframe of 12 weeks in this study is encouraging and not previously described,” researchers wrote. “Activation of the IGF-1 pathway by other means, perhaps in combination with an anti-androgen drug, might be worth pursuing in future clinical trials.”

“We believe this result has implications for other clinical proof-of-concept studies in patients with muscle atrophy or wasting,” researchers concluded.

Trial Shows Positive Initial Results for IGF-1

This is a follow-up article written by Lucy Piper on the IGF-1 trials that is written more for the layperson. It was published in Medwire News. Click on the link below to read the article at Medwire.

Positive initial results for IGF-1 pathway as treatment target in spinal and bulbar muscular atrophy

medwireNews: The insulin-like growth factor-1 (IGF-1) pathway may be a suitable treatment target for patients with spinal and bulbar muscular atrophy, suggest preliminary findings.

“By targeting the IGF-1 pathway in spinal and bulbar muscular atrophy, we aimed to replenish the reduced IGF-1 concentrations found in this disease, to stimulate downstream Akt activity to reduce the toxicity of the mutant androgen receptors, and to increase anabolic activity to prevent muscle loss”, the researchers explain.

They examined the tolerability and preliminary efficacy of the IGF-1 mimetic BVS857 in 27 patients, of whom 18 who were randomly assigned to receive the drug while nine were assigned to placebo.

The patients, aged at least 18 years, were ambulatory, had symptomatic weakness and had serum IGF-1 levels of 170 ng/mL or below.

The patients given BVS857 0.06 mg/kg intravenously once a week for 12 weeks showed a significant improvement from baseline in thigh muscle volume – a marker of muscle wasting and denervation – on magnetic resonance imaging scans, compared with placebo, with a geometric mean ratio of 1.04 in favour of the treatment.

Specifically, thigh muscle volume remained stable in the patients taking BVS857, whereas it declined in the placebo group over the course of treatment.

Improvements in the Adult Myopathy Assessment Tool score were seen in both groups, at 7.0% in the placebo group and 4.9% in those taking BVS857, but there was no significant difference between the two. There was also no change in lean body mass in either group.

There was a similar positive change in EQ-5D score for the two groups and a significant improvement with BVS857 over placebo in SF-36 Mental Component Score.

The researchers, led by Christopher Grunseich (National Institutes of Health, Bethesda, Maryland, USA), note in The Lancet Neurology that there was no treatment effect on muscle function, which may be “a consequence of the small effect on muscle volume.” And there was no increase in Akt signalling in monocytes or muscle biopsy samples possibly as a consequence of “the short duration of the increase in total IGF-1 equivalency”, they propose.

In a related commentary, Atsushi Hashizume and Masahisa Katsuno, both from Nagoya University Graduate School of Medicine in Japan, say that the discrepancy between a positive drug effect on thigh muscle volume and clinical outcomes “suggests a need for identification of novel biomarkers that reflect both biological and clinical effects of IGF-1 mimetics and related drugs.”

They add that “extension of the half-life of IGF-1 is key to improving the biological effects of this therapy in patients with spinal and bulbar muscular atrophy.”

BVS857 was otherwise generally well tolerated, with no cases of hypoglycaemia, Bell’s palsy or serious adverse events. However, immunogenicity was detected in 72% of patients taking BVS857, which “limits its use as a therapeutic drug”, note Grunseich and team.

They conclude that the findings are “encouraging” and call for further trials with sufficient power and longer duration to better assess the effects of IGF-1 targeting on muscle strength and function.

“Activation of the IGF-1 pathway by other means, perhaps in combination with anti-androgen drug[s], might be worth pursuing in future trials,” they suggest.

By Lucy Piper

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

Image:  https://www.alpco.com/role-igf-1-growth-hormoneigf-axis

IGF-1 Clinical Trial for Kennedy's Disease

The Lancet – Neurology published the following article yesterday on the IGF-1 clinical trial for Kennedy’s Disease (SBMA). Below are excerpts of the Summary. The full Summary can be read at the link below and the article can also be purchased on the website.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Summary

Background

“Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. …”

Methods

“In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). …”

Findings

“31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. …”

Interpretation

“TMV (thigh muscle volume) remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. …”

Note:  There is an accompanying article also noted:

IGF-1for spinal and bulbar muscular atrophy: hope and challenges

Image:  http://www.hgh-pro.com/igf-1.html

Symptoms of Kennedy's Disease (SBMA)

Any time I list the potential symptoms of Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy (SBMA), there is a tendency for someone to comment, “I have that. Do you think it’s Kennedy’s Disease?”

My answer is always the same. “I don’t know. You need to see your primary care doctor and discuss your symptoms with her/him.”

When my symptoms started, there was no DNA test for Kennedy’s Disease (SBMA). Most doctors and many neurologists did not know about SBMA. Neurologists put you through a series of tests, some not very pleasant, to help determine the cause of the symptoms. Most often, it was an educated guess based upon available evidence. In my case, I was diagnosed with ALS.

Several years later, another doctor diagnosed it as SBMA and sent me to see Dr. Fischbeck for a second opinion. I still remember walking into Dr. Fischbeck’s office that morning. He saw my gate, nodded his head, and said, “You have the walk.” He performed a DNA test and confirmed Kennedy’s Disease.

Today, because of the DNA test, a doctor can draw a little blood and send it off to a lab. Within a few weeks you will have an answer as to if you have Kennedy’s Disease. If not, you will still have to go through more testing, but at least SBMA is ruled out.

In regards to the list of symptoms below, those of us living with Kennedy’s Disease normally do not have all of them. We will have several and some might not appear until later in the progression. The most common early symptoms are severe cramping, hand tremors, unexplained fasciculations, and gynecomastia.

Please note there is a wealth of information available on the Kennedy’s Disease Association website (http://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease).

SYMPTOMS (I apologize for the formatting problem below)

Neurological:
Bulbar Signs	The Bulbar muscles are those supplied by the motor nerves coming off the brain stem. They control breathing, swallowing, talking and other functions of the throat. Bulbar signs are problems with these functions.
Dysphagia	Trouble swallowing. (One of the Bulbar signs.)
Intention Tremor	Hand tremors when trying to do something.
Normal Babinski	Normal plantar response, ie., when the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward bending of the toes indicating a problem in the brain itself.
Lower Motor Neuropathy	The lower motor nerves are those that run from the spinal cord to the muscles that they stimulate to move. Loss of that nerve leads to weakness and wasting of the muscle.
Primary Sensory  Neuropathy	Numbness over certain areas. Loss of sensation.
Decreased or Absent Deep Tendon Reflexes	When a doctor taps the knee with his hammer there is no response.
Muscular:
Fasciculations	Twitching of small muscles without purposeful movement. These can be seen through the skin.
Cramps	Large muscle spasms.
Postural Tremor	Shaky muscles with certain positions.
Muscular Atrophy	Wasting and shrinkage of muscles that occurs when the lower motor nerve does not stimulate the muscle adequately.
Hypertrophied Calves	Calf muscles that become thicker because of cramps.
Thoracic:
Gynecomastia	Enlarged breasts.
Endrocrine
Androgen Deficiency	Loss of masculinizing effect (qualities that are perceived as masculine).
Estrogen Excess	More of an apparent estrogen effect because of the lost of masulinizing effect.
Genito-Urinary:
Impotence	Erectile dysfunction.
Reduced Fertility	Low sperm count.
Testicular Atrophy	Testicles become smaller and less functional.
Miscellaneous Characteristics:
Late Apparent Onset	Symptoms could become apparent in 20's or 30's, but might not appear until the 60's or 70's.
Slow Progression	Near-normal lifespan.
Asymmetry of Clinical Signs	Muscles of one side may be more affected than the same muscles on the other side.
Laboratory:
Elevated Serum Creatine Kinase	Elevation of CPK enzyme in the blood test.  Can be confused with the enzyme released during a heart attack.

Long-Term Care Options

Below is a guest post from Hazel Bridges. I consider it an excellent primer for an important subject facing most everyone at sometime in their life, not just those of us living with Kennedy's Disease. Thanks, Hazel, for sharing this information.

Living with a Chronic Disease

Long-Term Care Options

When you wake up in pain every morning, can’t handle daily living tasks, or have difficulty with cognitive functions, you need help. Often, that help comes in the form of loving friends and family who want to lend a hand. However, the reality is that you must also plan for long-term care needs that can’t be handled by your loved ones.

Planning for Long-Term Care

Barriers to Self-Care

Chronic illnesses present specific barriers to long-term self-care. The Lippincott Nursing Center categorizes these as psychological, physical, cognitive, economic, and social and cultural. Regardless of the reason care is required, the decision to choose at-home or residential/nursing care is deeply personal and requires planning and preparation.

Care at Home

Home is the most comfortable place for the vast majority of people with chronic illnesses. And with a little help, it can be a safe haven for recovery or just to enjoy life on your own terms. HomeAdvisor explains there are numerous forms of at-home services. These include:

●     Home health aides. A home health aide is an individual who helps with daily tasks such as hygiene and bathing. They may also assist with cooking, laundry, and grocery shopping. Home health aides are not licensed for offer medical services.

●     Adult day care. These facilities are designed to cater to older adults or those with physical and cognitive disabilities. They offer supervision and assist with dispensing medications and hygiene as needed.

●     Skilled nursing. For individuals with health needs beyond the capabilities of themselves, friends, and family, a licensed nurse can provide more in-depth and involved medical services. This may include administering injected medications and assisting with physical therapy activities.

Residential/Nursing Facilities

If home health care is no longer feasible, an assisted living or skilled nursing care facility is an option. While typically associated with seniors, these housing programs may also be available to adults, teens, and children with severe disabilities.

●     Assisted living. An assisted living campus is one where individuals and couples (typically seniors) live in their own apartment, home, or condominium. They have access to a central campus area that provides recreational activities. Assisted living often includes housekeeping, meals, and help taking medication.

●     Skilled nursing. A skilled nursing care facility is different from assisted living in that people who live here are not able to care for themselves without direct medical intervention. Those who reside in a skilled nursing care facility may have the option of living in a private room or sharing accommodations with another patient in order to receive a discounted fee and enjoying constant companionship.

Paying for Long-Term Care

Covering Costs

One of the main concerns of receiving paid care is the question of financing it. Elmcroft Senior Living estimates that long-term nursing care averages between $225 and $253 per day. À la carte home services may be less expensive with an at-home caregiver charging an average of between $10 and $35 per hour. Medicare does not cover the cost of assisted living or skilled nursing care for the long-term. Paying for these accommodations and services often falls to private health insurance, Medicaid, individual savings, or SSI disability.

Lifestyle Factors That Affect the Need for Care

Those living with a chronic disease may have no choice other than to receive care the vast majority of their lives. Others, however, may find that small lifestyle changes reduce reliance on others. People who smoke are more likely to need intense medical supervision later in life than those that don’t. Exercise can also help preserve independence by keeping muscles strong and improving balance, which will lower the possibility of sustaining a falling injury. Excessive drinking, drug use, and engaging in risk-taking behaviors can also increase the chances that you or a loved one will need medical care. Minor home modifications, such as added lighting and a wheelchair ramp, may also extend your ability to remain independent.

For more information on making the decision to enter or put a loved one into nursing care, visit the AARP online.

Image via Pixabay

Don’t Give Up The Ship

"Don't give up the ship" was the dying command of James Lawrence in 1813 aboard the USS Chesapeake. Those words should be the battle cry for all of us living with Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy.

At times, it is easy to feel defeated. This is especially true after a ‘slide’. When we experience them, the first thought is will I bounce back. The next thought is usually laced with fear. What happens if I do not bounce back?

In my 40+ years of living with Kennedy’s Disease, I have experienced my share of slides. When I was a little younger and more resilient, my slides were steep and my bounces just as dramatic. These last few years, my bounces are not as dramatic and sometimes there is no bounce at all.

A few months back my choking became a daily issue. Almost everything I tried to eat would not go down without a fight. It took me thirty to sixty minutes to eat a meal. Many times, I could not finish a meal because of the choking. I lost more weight and began to research other options for receiving the required nutrition.

These choking episodes went on for a couple of months. It got to a point where I did not want it to be mealtime. Yet, something inside kept telling me to practice my swallowing exercises. Then, during the first week of August, I noticed an improvement. Food was going down easier. I found myself eating more and enjoying my meals again. The last few weeks I discovered I am putting on weight again.

During the ‘bounce back’, I continued to practice what I learned during the choking period. I drink water to help wash food down. I use more gravy and other juices to make it easier to swallow. I limit ‘sticky’ foods like bread that have crumbs and are more difficult to swallow. And, most importantly, I now practice my swallowing exercises at least three times a day.

Once again I learned no to give up the ship without a fight!

 

P.S. Want to learn more about the Captain Lawrence and the battle? [Click on this link]

"...During the War of 1812, Captain James Lawrence, commanding the 49-gun frigate U.S.S. Chesapeake, was attacked off Boston Harbor by the British ship H.M.S. Shannon.

In less than 15 minutes, Lawrence's crew was overwhelmed. Mortally wounded, Lawrence shouted, "Tell the men to fire faster and not to give up the ship; fight her till she sinks!" ..."

Study: Systemic Delivery of MicroRNA

István Reinhardt emailed me a link to a recent Kennedy’s Disease (SBMA) study. The video is also interesting. Clink on the link below to go to the site or download a PDF copy of the study with this link:  https://www.jove.com/pdf/55724

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 toTreat Neuromuscular Diseases in Rodents

ABSTRACT

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. In recent years, miRNA-mediated gene regulation has shown potential for treatment of neurological disorders caused by a toxic gain of function mechanism. However, efficient delivery to target tissues has limited its application. Here we used a transgenic mouse model for spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR), to test gene silencing by a newly identified AR-targeting miRNA, miR-298. We overexpressed miR-298 using a recombinant adeno-associated virus (rAAV) serotype 9 vector to facilitate transduction of non-dividing cells. A single tail-vein injection in SBMA mice induced sustained and widespread overexpression of miR-298 in skeletal muscle and motor neurons and resulted in amelioration of the neuromuscular phenotype in the mice.

In a 2011 post, Ed Meyerthoen explained the defective AR gene. You can read his post by following this link:  https://kennedysdisease.blogspot.com/2011/05/what-is-ar-and-why-is-it-important.html

When Should I Tell My Employer About My Condition?

One of the most difficult decisions I ever made was to advise my boss that I had Kennedy’s Disease. Pride, fear and the other unknowns kept me from disclosing my condition for far too long. Yet, after I told him, I discovered he was understanding and supportive of my condition and situation. Several accommodations were made that allowed me to work safely productively for several more years.

I don’t believe there is ever the “right time” to have the discussion because there are too many unknowns. But, when you begin to see possible job performance or safety issues involved, it is probably time to step up. As the article states, disclosing your condition is a matter of personal choice.

The MDA’s QuestMagazine has an article written by Karen Henry about disclosing your disability to your employer. A portion of the article is shown below. To read the entire article, click on the MDA Quest link above.

“…Talking with employers about neuromuscular disease can be challenging. Given the broad spectrum of neuromuscular diseases and their often unpredictable nature, some may find it difficult to navigate exactly when and how much to disclose. 

“The very first thing a person needs to consider is why you want to disclose,” says Sharon Rennert, senior attorney advisor at the U.S. Equal Employment Opportunity Commission (EEOC). Doing so for the right reason at the right time keeps the focus on your performance as an employee, rather than on your disability…”

“…Ultimately, disclosing information about your disability to your employer is a personal choice. Choosing not to disclose your disability might be the most appropriate choice if you are able to perform all your essential job functions without extra assistance. However, if your disability begins to impact your job performance, you could be held accountable for performance issues if you have not disclosed your disability and asked for reasonable accommodations.

“Even if you’re not quite sure what accommodations might help you, it is better to get the ball rolling,” Rennert says. “The last thing anybody wants is for there to be disciplinary action based on poor performance.”

Miller agrees. “It’s OK to let people around you know what you’re going through. It’s OK to take accommodations that are necessary for your disability…”

“…Title I of the Americans with Disabilities Act (ADA) of 1990 prohibits private employers, state and local governments, employment agencies and labor unions from discriminating against qualified employees with disabilities. They also must make reasonable accommodations employees with disabilities need to perform their jobs.

According to the U.S. Equal Employment Opportunity Commission (EEOC), a reasonable accommodation is any change in the workplace or the way things are customarily done that provides an equal employment opportunity to an individual with a disability. “The types of accommodations an employer could provide are quite broad,” says Sharon Rennert, senior attorney advisor at the EEOC…”

If air travel is in your future, check this out ...

The MDA Advocacy group published the results of their survey on air travel. Below is the email the MDA sent out with a link to the full article. I have also included a link to the DOT’s annual report on disability-related complaints for air travel. It shows a 224% increase in complaints over the last ten years. That's huge, but when you consider the actual number of complaints it is staggering. 

2007 Report =13,766                               2016 Report = 30,830

And, we all know that a vast majority of problems experienced are never formally submitted to the DOT.

___________________

MDA Advocacy Newsletter

“In an effort to understand the scale and scope of challenges faced by the neuromuscular disease community when traveling by air, at the end of 2016 we surveyed the MDA community about their flying experiences. We received more than 2,000 responses, and we thank everyone who took the time to participate in the survey. We hope you'll take a moment to review the results to see how challenges with and access to air travel impact our community.

Over the past two years, MDA has made accessible air travel one of our policy priorities. We're working closely with policy makers, federal agencies, industry and other advocacy and disability rights organizations to help improve access to air travel for MDA families. For more information about traveling with limited mobility, visit MDA's Accessible Air Travel Resource Center.”

Click here to read the full article on the MDA website.

___________________

A few months ago, I called upon my readers to contact their representatives regarding this important issue. The bill introduced in the Senate recently would go a long way in helping this ongoing issue.

“While there are efforts in place to increase access to air travel, there is still much to be done to improve the rights of passengers with disabilities during air travel. Recently, the U.S. Senate introduced a bill that strengthens the rights of disabled passengers under the Air Carrier Access Act. Included in the bill are provisions to:

1. Strengthen enforcement to include specific protections of the rights of passengers with disabilities and recourse when those rights are violated;

2. Ensure airplanes are designed to accommodate people with disabilities and airlines meet accessibility standards, including safe and effective boarding and deplaning;

3. Provide better stowage options for assistive devices;

4. Improve access to seating accommodations;

5. Close service gaps in air travel for passengers with disabilities; and

6. Require that the U.S. Access board conduct a study to determine the ways in which individuals who use assistive devices can be accommodated through cabin wheelchair restraint systems.”

All of the above would help, but I especially like #6.

If interested, click here to access the annual DOT Reports on Disability-Related Air Travel Complaints.

Photo:  http://www.disabledgo.com

New Research Paper Published on Kennedy's Disease

The World Journal of Biological Chemistry published another interesting Kennedy’s Disease study this week. Below is a portion of the abstract. The entire paper can be read by following the link below. This is preliminary research and more study is required to determine the potential benefits and possible side effects.

Background - The AR gene contains CAG repeats which affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity.

Identification of neuron selective androgen receptor inhibitors

World J Biol Chem. May 26, 2017; 8(2): 138-150

AIM

To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness.

METHODS

Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuron-selective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-qPCR of AR-regulated genes and immunohistochemistry.

RESULTS

We identified the thiazole class of antibiotics as compounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that shRNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles.

CONCLUSION

Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms.

Drawing and Background of CAG-AR - Wikipedia

Neuromuscular junctions are pathological but not

This abstract was published in PubMed ahead of the printed version of the study. No additional information is available at this time, but it sounds interesting.

Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy

Poort JE1, Rheuben MB1, Marc Breedlove S1, Jordan CL2.

Abstract

Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected in neuromuscular disease, whether the NMJs in SBMA are similarly affected by disease is not known.”

Follow this link to read the rest of the abstract.  NeuromuscularJunctions

Accessible Air Travel; Let members of Congress know it's important

Back in May I posted an article on Accessible Air Travel and what is being done to improve our travel experiences.

The MDA Advocacy Group has posted the following message asking for everyone's support to help push this through..

Take Action for Accessible Air Travel

Thank you to everyone who has joined us in advocating for increased access to air travel.  Many of you contacted your Senators previously, encouraging them to include provisions to increase air travel accessibility in the FAA reauthorization.  All four of those provisions were included in the final version that passed the Senate by an overwhelming vote of 95-3, thanks in part to the actions of many advocates.  

As you will recall, the accessible travel provisions in the Senate bill call for:
1) studying the use of in-cabin wheelchair restraint systems, 
2) identifying best practices in airport accessibility, 
3) examining training policies regarding assistance for disabled air travelers and 
4) creating an advisory committee with diverse stakeholders to investigate and report to Congress on the needs of passengers with disabilities. 

The same provisions that would increase access to air travel for passengers with disabilities, however, are not included in the current version of the FAA reauthorization in the House of Representatives.  The House and Senate are now considering how to move forward and an extension may be the first step.

Please TAKE ACTION TODAY to let your members of Congress know that accessible travel provisions are important to passengers with disabilities, and that as they work out an agreement, we urge them to include the provisions in any final FAA reauthorization or in any action that would extend the FAA’s current operating authority.

If you would like to help by contacting your representatives, please follow this link:  TAKE ACTION NOW