Wednesday, December 22, 2021

Infantile neuroaxonal dystrophy

Courtesy of my daughter

The Frost Family consists of Whitney (mom), Jason (dad), Natalie (16), Riley (8) and Harrison (6).

Riley and Harrison have a rare, terminal disease called Infantile Neuroaxonal Dystrophy (INAD). They were born after easy pregnancies, no complications and no indication that anything was wrong. Riley was born in 2013 and was meeting her milestones (talking and starting to walk) but at 13 months, Riley started to lose the abilities she had gained. She started falling over a lot, having trouble holding her head up, swallowing and many other seemingly simple tasks. Then Harrison was born in July 2015 (right before Riley turned 2), also without complications. But in 2016, Riley was diagnosed with INAD after losing her ability to walk, talk, or crawl. Because INAD is genetic, Harrison was tested and had just turned 1 when we got his diagnosis, and he wasn't even showing symptoms yet. It was the worst day ever - finding out that the 2 youngest children had INAD.

Now, in 2021, both children are bed-bound, can't move, fragile and floppy as newborns, on feeding tubes, cannot talk and rely on parents or nursing staff to take care of all their basic human needs. Despite these circumstances, the children are extremely well-cared for and happy. The family is mostly in good spirits. Whitney and Jason are great parents, the nurses are wonderful people, Natalie and grandparents help out, and the community has rallied around this family - for which Jason & Whitney are extremely grateful.

Riley is almost 8 (her birthday is Halloween) and Harrison is 6. They both weigh over 50 pounds (25kg) and it is getting harder to carry them to bed at night and into the living room in the morning, to get them into the bathroom for showers and its harder to get them up the steep ramp & into the van for trips and doctor appointments. Although there life expectancy is 8-12 years of age, we still need to make modifications to our home and vehicle in order to make them more comfortable and to make caring for them easier and safer.

The Frosts need your help to raise enough money to:
put a track system in the house
modify the van with a wheelchair lift and change the seating for Natalie & nursing staff
pay bills (Whitney's parents are paying her mortgage)

The Frost Family would also like to collect money to be able to help other families. Whitney has helped other families in the past and would like to continue to do that.

Thank you for helping whether its by donating, sharing their story or following along. Thank you so much for being here.

https://www.gofundme.com/f/frostarmy


Riley

Slightly homicidal and obsessed with crime shows, Riley is a handful. She vocalizes when she's happy and heavy sighs when she isn't. She loves chaos and going out whenever she can. Her hair and nails always look amazing thanks to her nurse. 

Harrison

Harrison is the sweetest boy you'll ever meet. He's head over heels in love with his nurse and his favorite place is his bed. He doesn't like leaving the house but enjoys fart noises and cuddles. He is the most laid back kid in the world.

OUR JOURNEY

By the time Harrison was almost a year old, Riley and Harrison had been diagnosed with a very rare terminal disease called infantile Neuroaxonal dystrophy. Because of this they both received Make-A-Wish trips and both chose Disney, Riley going at Christmas in 2017 and Harrison going in Halloween of 2018.

https://dubfrost.com/meet-the-fam

Whitney Frost has always done her best to remain strong for her kids, but it certainly hasn't been easy. Two of her three children have been living with a rare genetic disorder known as infantile neuroaxonal dystrophy, or INAD, which she regularly chronicles on TikTok, where she's amassed more than 1.7 million followers. But Whitney has shared an unexpected and tragic update: her son Harrison quietly died at the age of 6 on New Year's Day...  

According to a GoFundMe page recently set up for the family, Riley was the first to be diagnosed with INAD in 2016 after losing the ability to walk, talk, or even crawl. Though Harrison was two years behind her and not showing any symptoms at the time, doctors encouraged Whitney and her husband to have him tested, since the condition is genetic. 

Sadly, Harrison was also diagnosed with INAD just shortly after his first birthday. 

"It was the worst day ever — finding out that the two youngest children had INAD," the GoFundMe page explains. 

In time, Whitney's reality as a mother of three would change dramatically. In addition to raising her now 17-year-old daughter Natalie (who does not have INAD), she suddenly became a special needs mom responsible for the increasing demands of her youngest children's care. 

Because INAD gradually impacts a person's motor skills and voluntary muscle function, both Harrison and Riley eventually became bedbound and reliant on oxygen machines. 

Still, the most heartbreaking part about INAD is what it does to a person's life expectancy. 

In fact, most patients don't get to live past the age 12 — and that's if they're lucky. 

In Harrison's case, he died at home before he could even live to see his seventh birthday. 

In a TikTok shared on Saturday, Whitney revealed that her boy was surrounded by family when he died, and assured her followers that he "went quickly" and "did not suffer." 

"We are devastated," Whitney admitted in the video captions. "But glad he's no longer in pain." 

The 6-year-old had recently battled sepsis following a urinary tract infection. 

According to People, his mom had previously shared a positive update about his health status, reporting that he was doing well despite his recent setback. But on Saturday, it appears that the 6-year-old's health took a turn for the worse. 

Over the past few days, hundreds of comments have flooded the grieving mom's post. 

“From all of us … I think it’s safe to say we are collectively crying with you," wrote one TikToker. "Never doubt what a wonderful life you gave him. It was full of love." 

“I am so sorry," added another. "I’m a silent viewer, but my heart is with you in these heavy times. No words can life the burden. 

“I’m picturing Harrison running and playing in Heaven," said someone else. "No more pain and sickness.” 

“Be free, Harrison!" wrote yet another follower. 

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Before her son's death, Whitney checked in to thank everyone for their love and support. 

But sadly, she had some more upsetting news to share: Riley isn't doing well now, either. 

Struggling through tears, Whitney explained that her 8-year-old is currently suffering from a gastrointestinal bleed, a fever, and other complications tied to her illness, and that at the moment, things don't look good. 

"Her stomach contents are almost black, so that's something that we're worried about," the mother said. "She also has crackling sounds in her lungs so she's had to sleep on her side all day so that she can breathe better." 

Whitney has continued to update her followers, who are constantly checking in to make sure she's doing OK. 

In one update, she said that friends and family have come over to help watch Riley in the wake of Harrison's death, so the exhausted mother can get some much-needed rest. She also shared that Riley seems to be doing "OK" though her health still seems touch-and-go. 

The rest of the family, however, is struggling. 

“I don’t know what to say … We’re not doing OK, we’re just coping," said Whitney. "And we’re not all coping in a very healthy way right now, which is fine." 

As for Harrison, Whitney says she expects his funeral to take place on January 15. She also shared that the family donated his brain to a research hospital in hopes that it will help doctors better understand the debilitating genetic disorder. 

In the meantime, friends, family, and followers are continuing to leave messages of encouragement on her page, and donate to the Frost family's GoFundMe campaign, which has raised more than $25,000 toward their $50,000 goal. 


https://cafemom.com/news/tiktok-whitney-frost-son-harrison-genetic-disorder-death/on-monday-frost-checked-in-to-thank-everyone-for-their-love-and-support 
 

 

 

 
 

 

Monday, December 20, 2021

A key mechanism that causes ALS

Israeli researchers announced on Tuesday that they uncovered a key mechanism that causes the neurodegenerative disease ALS, in a study published in the journal Nature Communications. 

This breakthrough could unlock a way to delay or reverse the condition which affects hundreds of thousands of people worldwide, The Times of Israel (ToI) reported. 


The team consisted of researchers from Tel Aviv University and Sheba Medical Center in central Israel, as well as from institutes in Germany, France, Britain and the United States. 


They found that a buildup of a protein called TDP-43 near neuromuscular junctions — which translates neural signals into motor activity — causes neurons to degenerate and die. 


As a result, this leads to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease, which causes the loss of the ability to walk, talk, or even breathe. 


“The paralysis caused by the disease results from damage to the motor neurons, which leads to the degeneration of nerve endings and to the loss of muscle innervation,” said Prof. Eran Perlson, ToI reported. 


Perlson led the study with doctoral students Topaz Altman and Ariel Ionescu. 


“Until now, we could not understand the basic biological mechanism causing the initial damage behind this vicious cascade,” he added. 


The scientists were able to restore motor neuron activity using an experimental molecule to break down TDP-43 in animals, according to ToI. 


Perlson explained that the discovery could “lead to the development of new therapies… and thereby heal the nerve cells before the irreversible damage that occurs in the spinal cord.” 


https://www.i24news.tv/en/news/israel/society/1639549833-israel-university-breakthrough-touted-as-key-for-als-reversal 


Researchers at Tel Aviv University's Schools of Medicine and Neuroscience uncovered, for the first time, the biological mechanism causing nerve destruction in the most common type of neurodegenerative disease, Amyotrophic lateral sclerosis (ALS).  


The novel study, which was published in Nature Communication journal, indicates that the course of this fatal disease, also known as Lou Gehrig's disease, can be delayed and even reversed in its early stages. 


One out of every 400 people will be diagnosed with ALS and given a life expectancy of about three years. Over those years, ALS patients will lose ability to control muscle movement, leading to paralysis. Currently, there is no cure.


Prof. Eran Perlson, who led the study with assistance from TAU doctoral students and Sheba Medical Center, noted that it remains unclear what causes the debilitating illness.  


 An illustration showing the TDP-43 protein destructively accumulating in motor nerve extensions, specifically in the neuromuscular junctions of ALS patients, where it traps messenger RNA molecules and prevents the synthesis of proteins essential to mitochondrial function. TEL AVIV UNIVERSITY


An illustration showing the TDP-43 protein destructively accumulating in motor nerve extensions, specifically in the neuromuscular junctions of ALS patients, where it traps messenger RNA molecules and prevents the synthesis of proteins essential to mitochondrial function. TEL AVIV UNIVERSITY 


"Only about 10% of the patients carry a familial background with known genetic mutations, but the remaining 90% are a mystery. The paralysis caused by the disease results from damage to the motor neurons, which leads to the degeneration of nerve endings and to the loss of muscle innervation. This consequently leads to the degeneration of the nerve and the death of motor neurons in the spinal cord, however until now we could not understand the basic biological mechanism causing the initial damage behind this vicious cascade," he said. 


To address the mystery, the researchers analyzed a protein called TDP-43, which had been shown in earlier studies to accumulate in unusual amounts and localization in the brains of about 95% of all ALS patients. 


The team revealed a novel biological link between the protein's accumulation and the degeneration of the synapses between the motor neuron endings and the muscles, called neuromuscular junctions, which translate neural commands into physical movements. In muscle biopsies taken from ALS patients the researchers found that the toxic protein accumulates also in high proximity to these neuromuscular junctions during the early stages of the disease and before patients develop any serious symptoms. In a series of experiments performed by the researchers, both in cells of ALS patients and in genetically modified model animals, they discovered that the accumulation of the TDP-43 protein in the neuromuscular junction inhibits the ability to locally synthesize proteins that are essential to mitochondrial activity, which provides the power of fundamental cellular processes. The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and ultimately to the death of the motor neurons. "It’s important first to understand the spatial complexity of motor neurons," Perlson said.  


"The motor neurons are found in the spinal cord and need to reach every muscle in the body in order to operate it. One can imagine, for example, an extension cable coming out of the spinal cord and reaching the muscles in the little toe in our foot. These extensions can be as long as one meter in adults and are called axons. In earlier studies, we have shown that to maintain this complex organization motor neuron axons require an increased amount of energy, particularly in the most remote parts, the neuromuscular junctions. In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions. In a normal motor neuron, this protein is mainly found in the nucleus. We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. As the function of motor neurons depends on these neuromuscular junctions located on the remote end of the 'extension cable', we realized that this finding could be of critical importance. We discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of essential proteins to mitochondrial function. Mitochondria are organelles found in cells and are the main energy providers for numerous cellular processes, including neural transmission. The condensation of TDP-43 protein in neuromuscular junctions results in a severe energy depletion, prevents mitochondrial repair, and consequently leads to the disruption of these junctions, degeneration of the entire ‘extension cable’ and to the death of motor neurons in the spinal cord," he continued. 


Perlson concluded that in the future if doctors could diagnose and intervene early enough, maybe it will be possible to inhibit the destructive degeneration in ALS patients' muscles. 


https://www.jpost.com/health-and-wellness/is-als-reversible-tau-study-688762  

 

Altman T, Ionescu A, Ibraheem A, Priesmann D, Gradus-Pery T, Farberov L, Alexandra G, Shelestovich N, Dafinca R, Shomron N, Rage F, Talbot K, Ward ME, Dori A, Kr├╝ger M, Perlson E. Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins. Nat Commun. 2021 Nov 25;12(1):6914. doi: 10.1038/s41467-021-27221-8. PMID: 34824257; PMCID: PMC8617040. 


Abstract 


Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development. 



https://www.eurekalert.org/news-releases/756815
https://deargen.me/en/updates/als-lou-gehrig-a-challenge-to-radical-cure/