Stiff person syndrome

A little-known neurological disorder has been thrust into the spotlight after a documentary revealed singer Celine Dion’s struggle with stiff person syndrome (SPS).

The disease is rare, affecting only one or two people for every million. Yet for those who are diagnosed, it can have a devastating impact, causing muscle rigidity, pain and spasms.

Two people who are living with stiff person syndrome — Carrie Robinette, 45, from San Diego, California, and Corwyn Wilkey, 44, who lives in Anchorage, Alaska — shared with Fox News Digital the details of their experience. 

Path to diagnosis

Robinette, a Navy wife and mother who was working as a full-time defense consultant, had been dealing with multiple health issues — pain, neuropathy, fatigue, migraines, asthma, allergies, thyroid and endocrine issues, kidney issues, even cancer — for more than 15 years.

"I was honestly ‘always sick’ from the time I was born," she said in a phone interview with Fox News Digital.

"Also, even as far back as high school, I had incredibly tight muscles in my legs, and there were countless times that I woke up crying with charley horse cramps in my calves."

Then, in May 2023, Robinette began experiencing painful, full-body spasms.

That kicked off a year of testing and visits to specialists in rheumatology, nephrology, endocrinology and neurology.

"After learning more and going back through my medical history, we realized that symptoms we previously blamed on other causes were likely early signs of stiff person syndrome."

Over the last year, as Robinette’s "constellation of symptoms" intensified, the doctors finally narrowed it down.

"It is beyond frustrating to literally not know at the start of each day if it will be a good day or a bad day."

"There is not a consensus within the SPS community on exact diagnostic criteria, and some doctors seem hesitant to diagnose rare diseases, so the journey to diagnosis is complicated by how rare the illness is," Robinette said.

"Definitive testing is not readily available."

These days, Robinette’s biggest challenge is frequent pain. 

"Even if my body is not actively spasming, it feels like my muscles are sore, even bruised — all day, every day," she said. "I think eventually, we grow accustomed to our pain, so it just becomes the new normal."

Some days, Robinette can walk and move "almost like normal," while other days she can’t walk without a cane or walker.

She regularly uses a mobility chair when traveling any distance beyond 50 feet.

"It is beyond frustrating to literally not know at the start of each day if it will be a good day or a bad day."

'Initial symptoms'

Wilkey, a father of young children who works as an interpretive media publications specialist for Alaska State Park and is also a singer, first noticed muscle spasms in his larynx while performing with his band.

"Like Celine Dion, my initial symptoms were throat and facial spasms that have progressed into full-body seizures," he told Fox News Digital via email. 

Wilkey was officially diagnosed with stiff person syndrome in 2021 at the Mayo Clinic in Rochester, Minnesota.

"The most prominent physical challenges are muscle stiffness and rigidity, seizure-like muscle spasms, cognitive distortion and decline, chronic pain and fatigue, PTSD, loss of coordination and fine motor control, headaches, joint pain, back pain, and inability to coordinate my body the way I want to," he said.

Wilkey’s full-body spasms are sometimes strong enough to dislocate and even fracture bones, he said. 

James Chung, M.D., PhD, chief medical officer at Kyverna Therapeutics in Emeryville, California, noted that diagnosis of stiff person syndrome is a complex process. (He has not treated either of the patients mentioned in this article.)

"We start with a detailed clinical evaluation, looking for characteristic muscle rigidity and spasms," Chung, who focuses on drug development for autoimmune diseases, told Fox News Digital via email. 

Blood tests are also needed to detect the antibodies that are found in a majority of cases, he said.

"Given the rarity of SPS, patients often feel misunderstood, even by health care professionals."

"Electromyography (EMG) is essential, showing continuous motor unit activity in affected muscles," he said.

In many cases, doctors will perform a lumbar puncture (spinal tap) to analyze cerebrospinal fluid for elevated antibodies and to rule out other conditions, along with imaging scans. 

"SPS is often a diagnosis of exclusion due to its rarity," Chung said.

Limited treatments

While there is currently no cure for stiff person syndrome, therapies can help manage symptoms and improve patients’ quality of life.

Treatments are highly personalized for each patient, according to Chung.

In most cases, patients take medications like diazepam and baclofen to reduce muscle stiffness and spasms, and may take intravenous immunotherapies to help reduce autoantibodies. 

"Pain management often involves a combination of medications," Chung said. "Physical and occupational therapy are vital."

Some current medications can have intense side effects, however.

Robinette has experienced hallucinations, loss of muscle control, nausea, vomiting and brain fog.

"For now, unfortunately, I am currently battling my condition without any helpful medications, and it is nearly unbearable," she said.

Kyverna Therapeutics is currently developing a new CAR-T cell therapy, KYV-101, that aims to "reset" the immune systems of patients with autoimmune diseases, according to Chung.

"This approach could potentially offer a more targeted treatment that addresses the root cause of SPS rather than just managing symptoms," he said.

The drug has recently gotten FDA approval to enter phase 2 clinical trials.

"I can really see it being the life-changing treatment that so many people with SPS and other autoimmune conditions need," said Robinette. "I just wish science moved faster!"

Mental and emotional effects

Many patients with stiff person syndrome struggle with anxiety about experiencing spasms in public, which often leads to social isolation, according to Chung. 

"Depression is common, stemming from chronic pain, loss of independence and the disease's unpredictable nature," he told Fox News Digital.

"Patients also frequently experience frustration with the medical system due to misdiagnosis or dismissal of symptoms," he added.

"Given the rarity of SPS, patients often feel misunderstood, even by health care professionals."

When Wilkey received his diagnosis, he struggled with treatment-resistant depression, PTSD and complex regional pain syndrome, he told Fox News Digital.

"The difficulties associated with the disease destroyed my marriage and, for a time, turned me into a rage monster," he said. 

"It has felt very much like receiving a death sentence."

To treat his "incredible" pain, Wilkey was prescribed oxycodone and morphine, which ultimately led to addiction.

"I became unable to function and felt like a burden on my family, which led me to attempt suicide," he said.

Wilkey underwent a period of hospitalization, intensive therapy and pain rehabilitation programs.

"I lost everything — my marriage, all my money, my home and even my children for a time," he said. 

Today, Wilkey continues to participate in palliative care therapy — as SPS is considered a progressive and terminal disease — as well as psychedelic-assisted therapy for PTSD and depression.

Robinette has also experienced mental and emotional challenges stemming from her disease.

"This past year, on my journey with SPS, my family and I have really been put through the wringer," she told Fox News Digital.

"It takes a toll to feel like you are in a medical crisis and yet know that even if you go to the hospital, no one will help you."

"Seizing, in 10 out of 10 pain, losing control of muscles, and having the body twist and contort into a terrifying, seemingly endless episode — some of these events last 10 to 60 minutes, which feels like an eternity."

The hardest part, she said, is that some doctors have told her, "It could be in your head," or "We can't help you because we aren't sure what it is."

"It takes a toll to feel like you are in a medical crisis and yet know that even if you go to the hospital, no one will help you," Robinette said. 

"I think it would make a world of difference to SPS patients to not have the added stress of having to constantly have to advocate for care."

Stress management is crucial for SPS patients, Chung said, as emotional stress can trigger or worsen spasms. 

"Supporting mental health is a key component of comprehensive SPS care."

Who is most at risk?

Stiff person syndrome is a progressive and ultimately terminal neuromuscular autoimmune disease.

SPS shows certain demographic patterns, Chung said. 

"It is incredibly empowering to know that you are not alone."

"Women are more commonly affected, with a 2:1 ratio compared to men," he said.

The typical age of diagnosis is between 30 and 60 years of age. 

"There's a strong association with other autoimmune disorders," Chung said, which can complicate the diagnosis process.          

"About 30% to 40% of SPS patients have type 1 diabetes, and we see higher rates of thyroiditis, vitiligo and pernicious anemia," the doctor went on.

"This clustering suggests a genetic predisposition to autoimmunity, although we haven't identified specific genes for SPS."

Advice for handling a diagnosis

For those who are living with stiff person syndrome, Chung said the best course of action is to get education from reliable sources and to build a strong support network.

"Work closely with a multidisciplinary medical team, be proactive in your treatment and communicate openly with your health care providers," he advised.

The doctor also recommended practicing stress-reduction techniques and staying as physically active as safely possible under professional guidance.

Wilkey’s best advice: "Don't try and go it alone."

He said, "You will drive yourself insane and beat your head against the wall, trying to cope on your own. Connecting with other survivors and developing a solid support system of crucial allies is essential."

For Robinette, sharing her story has been a helpful coping mechanism.

"It is incredibly empowering to know that you are not alone," she said.

"I believe that the more our voices rise, the more chance we all have of being heard."

Those seeking more information and resources for stiff person syndrome can visit The Stiff Person Syndrome Research Foundation at www.stiffperson.org.

https://www.foxnews.com/health/stiff-person-syndrome-patients-share-like-live-disease

MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects

Inspired by a patient

AlAbdi L, Desbois M, Rusnac DV, Sulaiman RA, Rosenfeld JA, Lalani S, Murdock DR, Burrage LC; Undiagnosed Diseases Network; Billie Au PY, Towner S, Wilson WG, Wong L, Brunet T, Strobl-Wildemann G, Burton JE, Hoganson G, McWalter K, Begtrup A, Zarate YA, Christensen EL, Opperman KJ, Giles AC, Helaby R, Kania A, Zheng N, Grill B, Alkuraya FS. Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects. Brain. 2023 Apr 19;146(4):1373-1387. doi: 10.1093/brain/awac364. PMID: 36200388; PMCID: PMC10319777.

Abstract

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

A treatment for SPG50

When his infant son was diagnosed with a rare, fatal disease, a Canadian father was dismayed to discover there was no treatment or cure. So he set out to make one himself.

Terry Pirovolakis, an IT director in Toronto, Ontario, welcomed his third son in Dec. 2017. It was a "normal, healthy birth," he told Fox News Digital — but within six months, he and his wife, Georgia Pirovolakis, noticed their baby, Michael, was not lifting his head.

"He just didn’t seem like he was meeting his milestones," Pirovolakis said.

After months of doctors’ appointments, physiotherapy and genetic testing — what Pirovolakis describes as an "18-month diagnostic odyssey" — a neurologist diagnosed baby Michael with spastic paraplegia 50 (SPG50), a neurological disorder that affects fewer than 100 people in the world.

"They told us to just go home and love him — and said he would be paralyzed from the waist down by age 10, and quadriplegic by age 20," Pirovolakis said.

"They said he’d never walk or talk, and would need support for the rest of his life."

What is SPG50?

Spastic paraplegia 50 (SPG50) is a neurological disorder that affects a child’s development, gradually leading to cognitive impairment, muscle weakness, speech impairment and paralysis, according to the National Organization for Rare Disorders.

Most people with the disease will die by the time they reach their 20s.

"Children with SPG50 may experience early developmental delays, muscle weakness and spasticity, but they continue to strive and adapt," Dr. Eve Elizabeth Penney, an epidemiologist at the Texas Department of State Health Services and medical contributor for Drugwatch, told Fox News Digital. 

"Over time, these symptoms can worsen, making it hard for affected individuals to walk and perform daily activities," added Penney, who was not involved in Michael Pirovolakis’ care.

"The prognosis varies from person to person, but it’s generally a progressive condition, meaning symptoms can become more severe over time," she also said. 

In the absence of a cure, most families can only manage symptoms through physical therapy, occupational therapy, speech therapy and medications to help control spasticity or seizures, Penney said. 

"Managing SPG50 requires a comprehensive, multidisciplinary approach to address its various symptoms and challenges," she added.

A father’s mission

There is no treatment currently approved by the U.S. Food and Drug Administration (FDA) for SPG50.

After the shock of the diagnosis, Pirovolakis immediately started researching, with a focus on finding a gene therapy that could help his son.

"They said he would be paralyzed from the waist down by age 10, and quadriplegic by age 20."

A month after his baby’s diagnosis, Pirovolakis flew to Washington, D.C., for a gene therapy conference, where he met with several experts. He also visited Sheffield, England, and the National Institutes of Health at the University of Cambridge, where scientists had been studying the disease. 

"We then liquidated our life savings, refinanced our home and paid a team at the University of Texas Southwestern Medical Center to create a proof of concept to start Michael's gene therapy," Pirovolakis said.

After successful tests showed the gene therapy was effective at stopping the disease’s progression in mice and in human cells, Pirovolakis worked with a small drug company in Spain to manufacture the drug.

On Dec. 30, 2021, Health Canada granted approval to move forward with the gene therapy for Michael Pirovolakis. 

"On March 24, 2022, my son was the first person to ever get treated with gene therapy at SickKids in Toronto," Pirovolakis said.

The procedure, which involves injecting cerebral spinal fluid through a lumbar puncture, does come with risks — but the potential benefits are life-saving.

‘I couldn’t let them die’

After Michael Pirovolakis received the one-time treatment, there were three more doses left.

"We decided that we had to help other kids," Pirovolakis said.

"When I heard that no one was going to do anything about it, I had to — I couldn't let them die."

Pirovolakis opened up a Phase 2 study in the U.S., which treated three children two years ago. 

One of those was 6-month-old Jack Lockard, the youngest child to ever receive the treatment.

"Jack has thrived since then," Rebekah Lockard, the boy’s mother, told Fox News Digital.

"He is sitting independently, banging toys together, drinking from a straw cup and working really hard on crawling."

She added, "Doctors and therapists share the same sentiment: The treatment works!"

Other children who participated in the trial have experienced similar results, Lockard said.

"They've all shown that their disease has stopped progressing and their cognition has improved."

There are more children who still need the treatment — including Lockard’s first child, 3-year-old Naomi, who also has SPG50 — but are unable to access it because the clinical trial has now run out of money, as Fox News Digital previously reported. 

‘Time is of the essence'

It costs about $1 million to make the drug for each child, Pirovolakis said, and another $300,000 or so to treat the patient in the U.S. at the hospital. 

Pirovolakis has approached pharmaceutical companies, but all of them have declined to manufacture the drug.

"We want to make sure the trial moves on and these kids get treated."

"No investor is going to give you money to treat a disease that is not going to make money," he said. "That's the dilemma we're in."

While Pirovolakis and his team are actively working to secure grants and investors, it’s largely up to the parents to raise funds for the next phase of the clinical trial.

So far, Lockard has raised more than $90,000 via GoFundMe (called "Naomi and Jack Battle SPG50") to get her daughter’s treatment, but that is only a fraction of what is needed.

Penney noted that treatment for SPG50 is challenging and expensive to develop — "mainly because it’s a sporadic disease."

The doctor told Fox News Digital, "Pharmaceutical companies often prioritize conditions that affect larger populations, with a more significant potential for recouping research and development costs."

"The market is much smaller for rare diseases like SPG50, making it financially less viable for companies to invest in creating a treatment."

To devote himself to the cause, Pirovolakis quit his job and started a nonprofit in California, which now has five employees and 20 consultants.

The company — called Elpida Therapeutics, after the Greek word for "hope" — will run a Phase 3 study for SPG50 at the NIH in November.

Without the backing of major drug companies, however, there isn’t funding available to get the therapies to the children who need them. 

Eight doses of the drug for SPG50 were produced in Spain and have been flown to the U.S.

"The treatment is here, just literally sitting in a refrigerator, ready to go," Lockard said. "Doctors are ready. There just isn't enough money to make it happen."

There are currently four families in the U.S. who are trying to raise the money that's needed, according to Pirovolakis.

"Time is of the essence," he said. "We want to make sure the trial moves on and these kids get treated."

The end goal

Looking ahead to the Phase 3 clinical trial at the NIH, Pirovolakis’ goal is to treat eight children with SPG50.

"If we can show that it works in all eight children — and we can prove to the FDA that it is making a difference — then the drug will get approved and every child can get it," he said.

Ideally, after the drug is approved — which could take three to five years, Pirovolakis estimates — SPG50 will be added to hospitals’ newborn screening programs and every child with the disease will be able to get the therapy.

Elpida Therapeutics has partnered with the Columbus Children’s Foundation (Fundación Columbus in Spain) and CureSPG50 to help save children with the disease.

"Our partnership with Elpida is driven by an unwavering commitment to leaving no child behind," Sheila Mikhail, co-founder of the CCF, said in a statement to Fox News Digital.

"At the Columbus Children's Foundation and Fundacion Columbus, as a global organization, we believe that every child deserves a chance for a healthy future. Together, we're making groundbreaking strides in treating ultra-rare genetic disorders, ensuring that no child is left to face these challenges alone."

"The biggest challenge in providing treatment for children with rare diseases often comes down to a lack of funding and vision."

Pirovolakis said he gets several calls each week from families around the world, asking for help saving their children.

"Unfortunately, the biggest challenge in providing treatment for children with rare diseases often comes down to a lack of funding and vision," he told Fox News Digital. 

"The technology to cure our children is already here. I hope that someone with immense wealth — and more importantly, the vision and influence — will step in," he said. 

"Their support could not only impact a handful of diseases and children, but extend hope to thousands of rare diseases and millions of children, both this generation and the next."

Currently, 40 million Americans are living with a rare disease, and one in 10 will be afflicted by a potentially treatable rare condition.

Pirovolakis added, "Someone you know or love will likely be affected by a rare disease."

https://www.foxnews.com/health/father-created-drug-save-his-son-from-rare-disease-now-other-families-desperate-get

A rare, fatal disease called SPG50 affects fewer than 100 people in the world — and one of them is Naomi Lockard, a 3-year-old in Colorado.

An experimental genetic therapy has shown promise in stopping the disease’s progression — but it is far too expensive for most families to afford.

Rebekah Lockard, the girl’s mother, is on a mission to raise the funds needed to save her daughter’s life.

Spastic paraplegia 50 (SPG50) is a neurological disorder that affects a child’s development, gradually leading to cognitive impairment, muscle weakness, speech impairment and paralysis, according to the National Organization for Rare Disorders.

Most people with the disease will die by the time they reach their 20s.

When Naomi Lockard was born in 2021, her parents immediately noticed some developmental delays.

By around six months, when she still "wasn't really moving," Lockard said, they started the baby in physical therapy, which didn’t help.

Eventually, an MRI and full genetic testing panel revealed the shocking diagnosis of SPG50.

At the time, Lockard was just a month away from giving birth to her second child — which added another element of fear given that the condition is genetic.

"My husband and I each have one healthy copy of this gene, but we each have one mutated copy," she told Fox News Digital in a phone interview. 

"Naomi got both mutated copies, and there was a 25% chance that Jack (the second baby) would also get both mutated copies."

"It was a lot of panic at first, a lot of tears, because it's a horrible condition," Lockard said.

A few weeks later, after Lockard gave birth, another round of genetic testing revealed the family’s worst fear: Baby Jack also had SPG50.

"Children with SPG50 may experience early developmental delays, muscle weakness, and spasticity, but they continue to strive and adapt," Dr. Eve Elizabeth Penney, an epidemiologist at the Texas Department of State Health Services and medical contributor for Drugwatch, told Fox News Digital. 

Fewer than 100 people in the world are known to have SPG50.

"Over time, these symptoms can worsen, making it hard for affected individuals to walk and perform daily activities," added Penney, who was not involved in the Lockard children's care.

"The prognosis varies from person to person, but it’s generally a progressive condition, meaning symptoms can become more severe over time."

A glimmer of hope

There is currently no FDA-approved treatment for SPG50, but the Lockards found hope when they enrolled in a clinical trial for an experimental gene therapy that was started by another parent, Terry Pirovolakis.

"It’s kind of like a transplant for genes," Lockard told Fox News Digital. "It functions like a treatment, or maybe even a cure."

The procedure, which involves injecting cerebral spinal fluid through a lumbar puncture, does come with risks.

"But it's worth the risk, because it's the only thing that could possibly help prevent the condition from getting worse," Lockard said.

Her newly diagnosed baby — who was just shy of six months old — received the gene therapy treatment first, as there was a better chance of stopping the disease at a younger age.

He was the youngest child ever to receive an intrathecal (spinal) gene therapy treatment.

"Jack has thrived since then," Lockard said. "He is sitting independently, banging toys together, drinking from a straw cup, and working really hard on crawling."

She added, "Doctors and therapists share the same sentiment: The treatment works!"

Other children who participated in the trial have experienced similar results, Lockard said.

"They've all shown that their disease has stopped progressing and their cognition has improved," she said.

Lockard’s daughter, Naomi, has not yet received the therapy.

"We can’t help but compare Jack and Naomi, and we see how he's meeting these milestones. He's caught up to her developmentally, and he’ll probably surpass her within the next few months, even though they're two years apart," Lockard said.

"Naomi just turned 3, and she only learned to crawl about six months ago. She can't walk or talk, and her cognitive level is probably that of a 9-month-old."

"Kids develop paralysis in elementary school, become quadriplegic in high school and pass away in their 20s."

Although her daughter will likely always have deficiencies, as she’s missed the "critical window" of development, the gene therapy could still stop further progression.

"If they can treat her before she gets the paralysis, the hope is that she'll never develop that," Lockard said.

If her daughter doesn’t receive the therapy, she will likely experience the typical trajectory of the disease, Lockard said.

"Kids develop paralysis in elementary school, become quadriplegic in high school and pass away in their 20s — never learning to talk, and losing any ability to move over the course of their short lives."

The problem is that the clinical trial has run out of funding.

Cost and complexity

Dr. Penney noted that treatment for SPG50 is challenging and expensive to develop — "mainly because it’s a sporadic disease."

The doctor told Fox News Digital, "Pharmaceutical companies often prioritize conditions that affect larger populations, with a more significant potential for recouping research and development costs."

"The market is much smaller for rare diseases like SPG50, making it financially less viable for companies to invest in creating a treatment."

Developing treatments for genetic disorders requires significant research, time and specialized technology, Penney added, all of which add to the cost and complexity.

In the absence of a cure, most families can only manage symptoms through physical therapy, occupational therapy, speech therapy and medications to help control spasticity or seizures, Penney said. 

"Managing SPG50 requires a comprehensive, multidisciplinary approach to address its various symptoms and challenges," Penney said.

Fighting to keep hope alive

The experimental trial that potentially saved Jack Lockard’s life was started by another parent, Terry Pirovolakis.

Pirovolakis, based in Canada, found out in 2017 that his youngest son, Michael, had SPG50.

"They told us he would be paralyzed from the waist down by the age of 10, and a quadriplegic by the age of 20," Pirovolakis told Fox News Digital in an interview. "They said he would need support for the rest of his life."

Pirovolakis refused to accept that. He immediately started doing research and traveling around the world to gene therapy conferences, speaking with medical experts about his son’s disease.

Eventually, he liquidated his life savings, refinanced his home and paid a team of scientists at the University of Texas Southwester Medical Center to create a "proof of concept" for a genetic treatment for his son.

"I couldn't just let these kids die. I had to do something."

After seeing positive results in mice studies, as well as in cells from his son and a few other children with SPG50, Pirovolakis partnered with a small company in Spain to manufacture the drug. 

In Dec. 2021, Health Canada granted Pirovolakis permission to move forward with the gene therapy for his son.

"After that, we had three more doses, and we decided that we had to help other kids," Pirovolakis said.

"I couldn't just let these kids die. I had to do something."

He opened a Phase 2 study in the U.S., in which three more children with SPG50 were treated — including Jack Lockard.

"I tried to give the therapy to pharmaceutical companies, but no one wanted to make it, so I quit my job and started a nonprofit, Elpida Therapeutics, in California," Pirovolakis said.

"We now have five employees and 20 consultants, and our goal is to save kids with five diseases, almost all of them fatal."

Next, Pirovolakis will start a Phase 3 study at the National Institute of Health for SPG50, with future trials planned for other diseases.

"Doctors are ready. There just isn't enough money to make it happen."

The problem is that without the backing of major drug companies, there isn’t funding available to dose the therapies to the children who need it.

"They have eight doses that were produced in Spain and have been flown to the U.S.," Lockard said. 

"It’s here, just literally sitting in a refrigerator, ready to go. Doctors are ready. There just isn't enough money to make it happen."

It costs about $1 million to make the drug for each child, Pirovolakis said, and another $300,000 or so to treat each patient in the U.S. at the hospital. 

While Pirovolakis and his team are actively working to secure grants and investors, it’s largely up to the parents to raise funds for the next phase of the clinical trial.

So far, Lockard has raised $50,000 via a GoFundMe fundraiser (called "Naomi and Jack Battle SPG50"), but that is only a fraction of what is needed to get her daughter treated.

"Right now, there are four families in the U.S. who are trying really hard to fundraise the money that's needed, because time is of the essence," he said.

"We want to make sure the trial moves on and these kids get treated."

The end goal

Looking ahead to the Phase 3 clinical trial at the NIH, Pirovolakis’ goal is to treat eight children with SPG50.

"If we can show that it works in all eight children — and we can prove to the FDA that it is making a difference — then the drug will get approved and every child can get it," he said.

"I get calls at least five times a week from families around the world, asking to help me save their kids."

Ideally, after the drug is approved — which could take three to five years, Pirovolakis estimates — SPG50 will be added to hospitals’ newborn screening programs and every child with the disease will be able to get the therapy.

"I get calls at least five times a week from families around the world, asking to help me save their kids," he said.

"It’s tough — there's only so much you can do, and unfortunately, this is a money problem. It's just heartbreaking."

https://www.foxnews.com/health/mother-frantic-save-clinical-trial-could-cure-daughter-treatment-sitting-fridge

If I have a heart attack tomorrow, why should I stay dead?

Can we come back from the dead? It depends, says a leading expert. Dr. Sam Parnia’s blockbuster book Lucid Dying chronicles decades of research that has led him and other experts to believe that our current methods of reviving those considered clinically dead are antiquated.

“Although for decades scientists believed the brain dies within 10 minutes of oxygen deprivation, recent scientific advances have proven this incorrect,” Parnia tells Newsmax. “Instead, after death, the oxygen-deprived brain and body go through a hibernation-like state for many hours longer. This means that for people who are otherwise healthy, such as those who are victims of accidents, shootings, or sudden cardiac arrests, death should be understood as a medically treatable event ─ like a stroke — for many hours after it has taken place.”

Parnia, associate professor of medicine at New York University’s Langone Medical Center, has been studying end-of-life phenomena for over 30 years and reveals his eye-opening research in his new book.

He questions when life ends, and when death begins, adding that while we’ve made major breakthroughs in the fields of treatment for cancer, cardiovascular disease and other ailments, our progress in treating death has been stagnant.

“What we believe about death is fundamentally wrong,” says Parina. It is not the end, he says, but a “reversible state.”

According to Yahoo.com, Parnia says that seeing a flatline on an electrocardiogram (EKG) ─ a measure of the electrical impulses of the heart ─ is not necessarily a death sentence. Recent evidence backs this up.

Researchers at Yale University successfully revived decapitated pig brains up to 14 hours post-mortem in 2019. In 2022, Yale scientists showed how a modified heart and lung machine combined with drugs restored organs in pigs. “It is just a matter of time,” suggests Parnia, that these results can be translated to humans.

There are also stories about how people have been revived after their hearts stopped for hours because they were in freezing temperatures that somehow preserved the organ. Thanks to a machine called an ECMO (extracorporeal membrane oxygenation), which serves as an artificial heart and lung, these patients survived. Parnia says that cooling the body is highly protective.

In a study published last year, researchers found that in patients who survived cardiac arrest, nearly 40% had brain activity that returned to normal, or nearly normal, even an hour into CPR. An electroencephalogram (EEG) captured the brain activity with electrodes, according to NYU Langone Health. These patients later had clear memories of experiencing death and while unconscious, had brain patterns linked to thought and memory.

“This is the first large study to show that these recollections and brain wave changes may be signs of universal, shared elements of so-called near-death experiences,” said Parnia, who was senior author of that study.

The expert says that we need to revise our thinking and methods of reviving patients. CPR, introduced in 1959, has a paltry 10% success rate and many hospitals now have ECMO machines that are far superior. He acknowledges that not every patient can be brought back from the dead. People with multiple organ failure are unlikely candidates. But others, like himself at age 52, do not have to stay dead.

“I tell everyone, look, I’m going to have a cardiac arrest soon. And I am appalled at the treatment I’m going to get. If I have a heart attack tomorrow, why should I stay dead? That’s not necessary anymore. I have little doubt that, in the future, people who would be declared dead today will routinely be brought back to life.”

https://www.newsmax.com/health/health-news/death-reversible-revive/2024/08/28/id/1178199/

Parnia S. Death and consciousness--an overview of the mental and cognitive experience of death. Ann N Y Acad Sci. 2014 Nov;1330:75-93. doi: 10.1111/nyas.12582. PMID: 25418460.

Abstract

Advances in resuscitation science have indicated that, contrary to perception, death by cardiorespiratory criteria can no longer be considered a specific moment but rather a potentially reversible process that occurs after any severe illness or accident causes the heart, lungs, and brain to stop functioning. The resultant loss of vital signs of life (and life processes) is used to declare a specific time of death by physicians globally. When medical attempts are made to reverse this process, it is commonly referred to as cardiac arrest; however, when these attempts do not succeed or when attempts are not made, it is called death by cardiorespiratory criteria. Thus, biologically speaking, cardiac arrest and death by cardiorespiratory criteria are synonymous. While resuscitation science has provided novel opportunities to reverse death by cardiorespiratory criteria and treat the potentially devastating consequences of the resultant postresuscitation syndrome, it has also inadvertently provided intriguing insights into the likely mental and cognitive experience of death. Recollections reported by millions of people in relation to death, so-called out-of-body experiences (OBEs) or near-death experiences (NDEs), are often-discussed phenomena that are frequently considered hallucinatory or illusory in nature; however, objective studies on these experiences are limited. To date, many consistent themes corresponding to the likely experience of death have emerged, and studies have indicated that the scientifically imprecise terms of NDE and OBE may not be sufficient to describe the actual experience of death. While much remains to be discovered, the recalled experience surrounding death merits a genuine scientific investigation without prejudice.

Parnia S, Keshavarz Shirazi T, Patel J, Tran L, Sinha N, O'Neill C, Roellke E, Mengotto A, Findlay S, McBrine M, Spiegel R, Tarpey T, Huppert E, Jaffe I, Gonzales AM, Xu J, Koopman E, Perkins GD, Vuylsteke A, Bloom BM, Jarman H, Nam Tong H, Chan L, Lyaker M, Thomas M, Velchev V, Cairns CB, Sharma R, Kulstad E, Scherer E, O'Keeffe T, Foroozesh M, Abe O, Ogedegbe C, Girgis A, Pradhan D, Deakin CD. AWAreness during REsuscitation - II: A multi-center study of consciousness and awareness in cardiac arrest. Resuscitation. 2023 Oct;191:109903. doi: 10.1016/j.resuscitation.2023.109903. Epub 2023 Jul 7. PMID: 37423492.

Abstract

Introduction: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR).

Methods: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO2) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences.

Results: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO2 = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR.

Conclusions: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences).

West RL, Otto Q, Drennan IR, Rudd S, Böttiger BW, Parnia S, Soar J. CPR-related cognitive activity, consciousness, awareness and recall, and its management: A scoping review. Resusc Plus. 2022 May 9;10:100241. doi: 10.1016/j.resplu.2022.100241. PMID: 35586308; PMCID: PMC9108988.

Abstract

Background: There are increasing numbers of reports of cognitive activity, consciousness, awareness and recall related to cardiopulmonary resuscitation (CPR) and interventions such as the use of sedative and analgesic drugs during CPR.

Objectives: This scoping review aims to describe the available evidence concerning CPR-related cognitive activity, consciousness, awareness and recall and interventions such as the use of sedative and analgesic drugs during CPR.

Methods: A literature search was conducted of Medline, Embase and CINAHL from inception to 21 October 2021. We included case studies, observational studies, review studies and grey literature.

Results: We identified 8 observational studies including 40,317 patients and 464 rescuers, and 26 case reports including 33 patients. The reported prevalence of CPR-induced consciousness was between 0.23% to 0.9% of resuscitation attempts, with 48-59% of experienced professional rescuers surveyed estimated to have observed CPR-induced consciousness. CPR-induced consciousness is associated with professional rescuer CPR, witnessed arrest, a shockable rhythm, increased return of spontaneous circulation (ROSC), and survival to hospital discharge when compared to patients without CPR-induced consciousness. Few studies of sedation for CPR-induced consciousness were identified. Although local protocols for treating CPR-induced consciousness exist, there is no widely accepted guidance.

Conclusions: CPR-related cognitive activity, consciousness, awareness and recall is uncommon but increasingly reported by professional rescuers. The data available was heterogeneous in nature and not suitable for progression to a systematic review process. Although local treatment protocols exist for management of CPR-induced consciousness, there are no widely accepted treatment guidelines. More studies are required to investigate the management of CPR-induced consciousness.

Keywords: ALS, Advanced life support; Awareness; CPR, Cardiorespiratory resuscitation; Cardiac arrest; Cardiopulmonary resuscitation; Consciousness; ED, Emergency Department; EMS, Emergency medical service; GCS, Glasgow coma scale; ICU, Intensive care unit; IHCA, In-hospital cardiac arrest; ILCOR, International Liaison Committee on Resuscitation; Near death experience; OHCA, Out-of-hospital cardiac arrest; OR, Odds Ratio; PTSD, Post-traumatic stress disorder; Post-traumatic stress disorder; ROSC, Return of spontaneous circulation; VF, Ventricular fibrillation; VT, Ventricular tachycardia; pVT, pulseless ventricular tachycardia.

Parnia S, Post SG, Lee MT, Lyubomirsky S, Aufderheide TP, Deakin CD, Greyson B, Long J, Gonzales AM, Huppert EL, Dickinson A, Mayer S, Locicero B, Levin J, Bossis A, Worthington E, Fenwick P, Shirazi TK. Guidelines and standards for the study of death and recalled experiences of death--a multidisciplinary consensus statement and proposed future directions. Ann N Y Acad Sci. 2022 May;1511(1):5-21. doi: 10.1111/nyas.14740. Epub 2022 Feb 18. PMID: 35181885.

Abstract

An inadvertent consequence of advances in stem cell research, neuroscience, and resuscitation science has been to enable scientific insights regarding what happens to the human brain in relation to death. The scientific exploration of death is in large part possible due to the recognition that brain cells are more resilient to the effects of anoxia than assumed. Hence, brain cells become irreversibly damaged and "die" over hours to days postmortem. Resuscitation science has enabled life to be restored to millions of people after their hearts had stopped. These survivors have described a unique set of recollections in relation to death that appear universal. We review the literature, with a focus on death, the recalled experiences in relation to cardiac arrest, post-intensive care syndrome, and related phenomena that provide insights into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We also identify issues and controversies related to the study of consciousness and the recalled experience of cardiac arrest and death in subjects who have been in a coma, with a view to standardize and facilitate future research.

Keywords: cardiac arrest; cardiopulmonary resuscitation-induced consciousness (CPRIC); death; death by brain death criteria; external visual awareness (EVA); near-death experiences (NDEs); out-of-body experiences (OBEs); post-intensive care syndrome (PICS); recalled experience of death (RED) coma; resuscitation.

SPTAN1 monoallelic variant associated disorders

Inspired by a patient

Morsy H, Benkirane M, Cali E, Rocca C, Zhelcheska K, Cipriani V, Galanaki E, Maroofian R, Efthymiou S, Murphy D, O'Driscoll M, Suri M, Banka S, Clayton-Smith J, Wright T, Redman M, Bassetti JA, Nizon M, Cogne B, Jamra RA, Bartolomaeus T, Heruth M, Krey I, Gburek-Augustat J, Wieczorek D, Gattermann F, Mcentagart M, Goldenberg A, Guyant-Marechal L, Garcia-Moreno H, Giunti P, Chabrol B, Bacrot S, Buissonnière R, Magry V, Gowda VK, Srinivasan VM, Melegh B, Szabó A, Sümegi K, Cossée M, Ziff M, Butterfield R, Hunt D, Bird-Lieberman G, Hanna M, Koenig M, Stankewich M, Vandrovcova J, Houlden H; Genomics England Research Consortium. Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia. Genet Med. 2023 Jan;25(1):76-89. doi: 10.1016/j.gim.2022.09.013. Epub 2022 Nov 4. PMID: 36331550; PMCID: PMC10620943.

Abstract

Purpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.

Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.

Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.

Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

Syrbe S, Harms FL, Parrini E, Montomoli M, Mütze U, Helbig KL, Polster T, Albrecht B, Bernbeck U, van Binsbergen E, Biskup S, Burglen L, Denecke J, Heron B, Heyne HO, Hoffmann GF, Hornemann F, Matsushige T, Matsuura R, Kato M, Korenke GC, Kuechler A, Lämmer C, Merkenschlager A, Mignot C, Ruf S, Nakashima M, Saitsu H, Stamberger H, Pisano T, Tohyama J, Weckhuysen S, Werckx W, Wickert J, Mari F, Verbeek NE, Møller RS, Koeleman B, Matsumoto N, Dobyns WB, Battaglia D, Lemke JR, Kutsche K, Guerrini R. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain. 2017 Sep 1;140(9):2322-2336. doi: 10.1093/brain/awx195. PMID: 29050398; PMCID: PMC6248409.

Abstract

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium; Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. Mov Disord. 2022 Jun;37(6):1175-1186. doi: 10.1002/mds.28959. Epub 2022 Feb 12. PMID: 35150594; PMCID: PMC9232883.

Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism.

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium; Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. Mov Disord. 2022 Jun;37(6):1175-1186. doi: 10.1002/mds.28959. Epub 2022 Feb 12. PMID: 35150594; PMCID: PMC9232883.

Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

BCAP31 mutations

Inspired by a patient

Whalen S, Shaw M, Mignot C, Héron D, Bastaraud SC, Walti CC, Liebelt J, Elmslie F, Yap P, Hurst J, Forsythe E, Kirmse B, Ozmore J, Spinelli AM, Calabrese O, de Villemeur TB, Tabet AC, Levy J, Guet A, Kossorotoff M, Kamien B, Morton J, McCabe A, Brischoux-Boucher E, Raas-Rothschild A, Pini A, Carroll R, Hartley JN; Care4Rare Canada Consortium; Frosk P, Slavotinek A, Truxal K, Jennifer C, Dheedene A, Cui H, Kumar V, Thomson G, Riccardi F, Gecz J, Villard L. Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants. Eur J Hum Genet. 2021 Sep;29(9):1405-1417. doi: 10.1038/s41431-021-00821-0. Epub 2021 Feb 18. PMID: 33603160; PMCID: PMC8440520.

Abstract

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.

Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Lévy N, Girard N, Sarda P, Boespflug-Tanguy O, Villard L. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet. 2013 Sep 5;93(3):579-86. doi: 10.1016/j.ajhg.2013.07.023. PMID: 24011989; PMCID: PMC3769969.

Abstract

BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.

Louie RJ, Collins DL, Friez MJ, Skinner C, Schwartz CE, Stevenson RE. Schimke XLID syndrome results from a deletion in BCAP31. Am J Med Genet A. 2020 Sep;182(9):2168-2174. doi: 10.1002/ajmg.a.61755. Epub 2020 Jul 18. PMID: 32681719.

Abstract

A family with three affected males and a second family with a single affected male with intellectual disability, microcephaly, ophthalmoplegia, deafness, and Involuntary limb movements were reported by Schimke and Associates in 1984. The affected males with Schimke X-linked intellectual disability (XLID) syndrome (OMIM# 312840) had a similar facial appearance with deep-set eyes, downslanting palpebral fissures, hypotelorism, narrow nose and alae nasi, cupped ears and spacing of the teeth. Two mothers had mild hearing loss but no other manifestations of the disorder. The authors considered the disorder to be distinctive and likely X-linked. Whole genome sequencing in the single affected male available and the three carrier females from one of the families with Schimke XLID syndrome identified a 2 bp deletion in the BCAP31 gene. During the past decade, pathogenic alterations of the BCAP31 gene have been associated with deafness, dystonia, and central hypomyelination, an XLID condition given the eponym DDCH syndrome. A comparison of clinical findings in Schimke XLID syndrome and DDCH syndrome shows them to be the same clinical entity. The BCAP31 protein functions in endoplasmic reticulum-associated degradation to promote ubiquitination and destruction of misfolded proteins.

Rinaldi B, Van Hoof E, Corveleyn A, Van Cauter A, de Ravel T. BCAP31-related syndrome: The first de novo report. Eur J Med Genet. 2020 Feb;63(2):103732. doi: 10.1016/j.ejmg.2019.103732. Epub 2019 Jul 19. PMID: 31330203.

Abstract

Pathogenic variants in the BCAP31 gene have recently been associated with a severe congenital neurological phenotype, named DDCH after its key features: deafness, dystonia and central hypomyelination. BCAP31 is located at the Xq28 chromosomal region and only male individuals are currently known to be affected, the pathogenic variant being usually transmitted by healthy mothers. Here, we describe a three-year-old male child referred for severe developmental delay, failure to thrive, hearing loss and dyskinetic movements. After a conventional diagnostic workflow, including a normal array-CGH, a tentative diagnosis of dyskinetic cerebral palsy was retained. Clinical exome sequencing in the trio identified a small intragenic deletion in exon 8 of BCAP31, c.709_721del (p.Val237Trpfs*69), originated de novo and not previously reported. Based on the ACMG variant classification, this variant is predicted to be 'likely pathogenic'. Given the consistent phenotypical overlap with the subjects already ascertained with DDCH, we considered this variant to be clinically relevant for this child and causative of his condition.

Frontal horn cysts in normal neonates

Inspired by a patient

Nakamura N, Miyazaki C, Hasegawa Y, Onodera M, Sugiura M, Kubo K, Nakajima T, Hattori S, Terae S. [Neonatal cystic structure adjacent to frontal horn--MRI features]. Nihon Igaku Hoshasen Gakkai Zasshi. 2005 Oct;65(4):368-72. Japanese. PMID: 16334388.

Abstract

Purpose: To evaluate the incidence and features of cystic structures adjacent to the frontal horns of neonates using MRI, and to assess the clinical features of the neonates.

Materials and methods: Between April 2001 and January 2005, MRI examinations were performed at our hospital in 352 neonates and infants whose postconceptional age was less than 48 weeks. We retrospectively evaluated the MRI findings and the clinical records.

Results: Seventeen babies (8 males and 9 females) showed cystic structures adjacent to frontal horns, hemilaterally or bilaterally. The incidence of the cysts was 4.8% in total, and was 1.4% (1/74), 9.2% (6/65), and 4.7% (10/213)in term infants, preterm infants born at 33-36 weeks of gestational age, and at less than 32 weeks, respectively. The cysts ranged from 1 to 8 mm in diameter, and were located in the white matter adjacent to ventricular walls and in the portion cephalad to the frontal horns. The cysts resolved in 5 cases (with follow-up ranging from 3 months to 2 years of age), causing slight dilatation of the frontal horn. Developmental disturbances were not observed in patients without other abnormalities.

Conclusion: Cystic structures near the frontal horns in neonates are detected by MRI at a rate of 4.8%. They will resolve spontaneously without causing developmental abnormalities.

Chang CL, Chiu NC, Ho CS, Li ST. Frontal horn cysts in normal neonates. Brain Dev. 2006 Aug;28(7):426-30. doi: 10.1016/j.braindev.2006.01.002. Epub 2006 Feb 28. PMID: 16503391; PMCID: PMC7125929.

Abstract

Frontal horn cysts (FHCs) are elliptical, smooth, thin-walled cysts adjacent to the tip of the anterior horns of the lateral ventricles. Among 3,545 terms or near term healthy babies who underwent cranial ultrasound examination in our hospital over a 2-year 5-month period, 18 were found to have FHCs (17 typical and one atypical; seven bilateral and 11 unilateral, of which seven were on the left and four on the right). The female to male ratio was 2:1. The incidence of FHCs in normal term babies was thus 0.5%. Six children had resolution of the cyst within 1 month, and 6 more had resolution on repeat scan from 2 to 11 months of age. Four children did not have subsequent ultrasonography to document resolution, but they had normal growth and development. Two were lost to follow up. The infant with an atypical FHC had an enlarged left frontal horn cyst with a midline shift on follow up, but he had normal development. Our study suggests that FHC may be a normal physiologic variant or a benign pathologic condition that can be expected to resolve spontaneously within a few months. It is reasonable to follow typical FHC by cranial ultrasound examinations at 1 or 2 and 6 months of age. In the case of an atypical cyst, more frequent follow up and further image studies like CT or MRI are necessary.

Dr. Ann Tilton

I also received my MD from the University of Texas Medical Branch in Galveston.

Ann Tilton, MD, FAAN, received the AAN President's Award at this year's AAN Annual Meeting in April. Here, she discusses the events and people who shaped her career—and what mentorship means to her.

As a child growing up in Texas, Ann Tilton, MD, FAAN, recalls precisely the moment when her friend asked her what she wanted to be when she grew up. She responded without hesitation from the top of a tree they had climbed: I want to be a doctor.

Dr. Tilton has more than achieved her childhood aspirations in her more than 40 years of work as a successful child neurologist conducting groundbreaking research and running a rehabilitation unit. She received the AAN President's Award this past April at the AAN Annual Meeting in Denver for her exemplary career and volunteer work on behalf of the field of neurology.

A former president of the Child Neurology Foundation and the Child Neurology Society and former vice president of the AAN Board of Directors, Dr. Tilton said she was “floored” when AAN President Carlayne E. Jackson, MD, FAAN, called her over the winter to inform her of the award.

“I walked up and told my husband, ‘This isn't real,’” said Dr. Tilton, a professor of neurology and pediatrics and chief of the child neurology section at Louisiana State University Health Sciences Center and member of the Neurology Today editorial board, adding, “It was just the most wonderful experience.”

One could say the same of her career. After graduating early from her undergraduate program at Texas A&M University—Kingsville with a degree in biology/chemistry and before starting medical school, Dr. Tilton spent time doing environmental impact studies as well as benchtop research, something she continued during residency. This gave her some more insight into what she might want to do—and not do—with her career.

“It became apparent even early on [while] I was talking to my rabbits and mung beans that I needed to talk to people,” she said with a laugh.

Dr. Tilton stayed in the Lonestar State for medical school, graduating from the University of Texas Medical Branch in Galveston, and then headed to the University of Texas Southwestern in Dallas for her residency.

Neurology wasn't Dr. Tilton's initial choice, though. “I flipped a coin—medicine or pediatrics—and went for best two out of three, and pediatrics won,” she said.

She enjoyed pediatrics, but a visit to a neurology clinic at a Dallas hospital grabbed her more and changed the course of her career.

“Behind every door was a diagnosis I'd never seen,” Dr. Tilton recalled. “I said, ‘I'm home. This is what I need to do.’ ... And I loved neuroscience. The unknown, the diagnostic—all of those things were fun.”

She combined her newfound fascination of the brain with her interest in treating children to become a child neurologist. After finishing residency, Dr. Tilton stayed on at the school for a couple years as a faculty member, an experience she described as “the ultimate super fellowship.”

“When you start out, you're the low person on the totem pole, and whatever they needed, I did,” she said. “I did all kind of things, [and] it was absolutely remarkable. ... I did neuromuscular clinics, set up the EEG lab, all of these things.”

Eventually, Dr. Tilton moved to Louisiana, where her husband, a cardiologist, grew up. They settled in New Orleans and raised two daughters and two sons as Dr. Tilton embraced her work at Louisiana State University.

Finding Mentors

“Mentors can come from many places, some unexpected,” she said, which for her included an orthopedist, who she said was “always looking to the future of care” and encouraged her to explore the use of botulinum toxins to treat patients.

“This was very early in its use, and there were few injectors, no guidebooks, and the beginning of clinical studies,” Dr. Tilton said. “I saw it as a challenge with great potential, so I accepted the challenge and decided to develop the program. That discussion and interest went on to define my research and clinical practice.”

As a mentor herself today, Dr. Tilton believes it is important for leaders to recommend junior members for positions. But they also must do their job well and enjoy it, she added.

Asked to run the Rehabilitation Center at Children's Hospital of New Orleans, Dr. Tilton said her career began to evolve as she ended up caring for lots of children with cerebral palsy. That condition and disabilities became her focus, and she's watched treatments bound forward, from botulinum toxin injections to intrathecal baclofen pumps and other interventions.

“It was just a wonderful ride,” she said. “The families, they have joy in things that people from the outside have no idea.”

Dr. Tilton also found time to give back to her field, serving as a member and vice chair of the ACGME Neurology Residency Review Committee and past chair of the American Board of Psychiatry and Neurology. She also held numerous roles with the AAN, including secretary/treasurer of the AAN Institute, vice president of the AAN Board of Directors, chair of the Meeting Management Committee, and mentor in AAN leadership programs, earning the academy's Leading in Excellence Through Mentorship award in 2022.

She has seen more women enter medicine since she graduated from medical school, and she tries hard to mentor them. This can be as simple as taking a walk with them and being available to listen and chat, encouraging them to “be authentic and truthful to yourself,” she said, adding that she makes sure to include, promote, encourage, and advocate for other women.

“It's incredibly important that women support women and people recognize the difficulties of being the primary caregiver and nurturer and nurturing in different places,” Dr. Tilton said.

Finding Challenges and Opportunities

Working with wonderful colleagues has been a highlight of her career, she said, but the job also has had its challenges, like knowing she can't change the course of disease for some patients and the extreme costs of the new treatments for neuromuscular diseases.

Dr. Tilton also continues to conduct clinical research—she has some work in movement disorders ready to begin—in addition to seeing patients and running the rehabilitation unit.

One patient whose story has stuck with her had an unusual disorder, dopa-responsive dystonia, which left him non-verbal and using a wheelchair but cognitively normal. Thanks to an available medicine, however, he soon was walking and talking and eventually went to college.

During elementary school, a classmate died of myasthenia gravis, a devastating incident that left Dr. Tilton questioning how such a thing could happen. Thanks to advances in treatment, however, such a death would not occur today, she noted. Mandatory newborn screenings for diseases like Duchenne muscular dystrophy and gene therapy for spinal muscular atrophy also have changed the game for child neurology—and transformed the lives of those patients.

While Dr. Tilton has no plans to retire just yet, the grandmother of two toddlers has some ideas for how she may spend her career after medicine.

“So much of your career is what's next, what's next?’” said Dr. Tilton. “I've taken some coaching courses. I hope to do career coaching and follow up on things I have postponed and have not done. I'm exploring art, sculpture, new travel, and of course always hunting for a long-lost talent.”

https://journals.lww.com/neurotodayonline/fulltext/2024/08150/aan_president_awardee_ann_tilton_on_career.9.aspx/?cid=eTOC+Issues.2024-neurotodayonline

AI reliably diagnoses Marfan syndrome from a simple facial photograph.

AI Accurately Diagnoses a Genetic Condition From Facial Photographs

August 12, 2024

by Sean McCabe

A Yale School of Medicine team reports in a new study, published in the journal Heliyon, that an artificial intelligence (AI) model was able to reliably diagnose people living with Marfan syndrome from a simple facial photograph.

Marfan syndrome is a genetic disorder, affecting about 1 in 3,000 people, which impacts the body's connective tissues. "Patients living with Marfan Syndrome are usually very tall and thin," said John Elefteriades, MD, professor of surgery at Yale School of Medicine and senior author of the study. "They have long faces and are prone to spine and joint issues. However, many are not diagnosed."

Marfan syndrome increases the risk for aortic dissection, where the aorta splits suddenly after becoming enlarged. "It is often lethal, and when the patient survives, urgent surgery is needed," Elefteriades said. "Being able to identify individuals from a photograph with AI will enhance diagnosis and enable protective therapies."

In their pilot study, researchers assembled 672 facial photographs of people with and without Marfan syndrome. A Convolutional Neural Network was trained on 80% of the photographs, then asked to identify the other 20% as Marfan or non-Marfan faces. The model successfully distinguished between Marfan and non-Marfan faces with 98.5% accuracy.

Researchers say they plan to make the tool available online in the future. "We are planning to extend this work beyond this initial pilot project," said Elefteriades. "We anticipate that many individuals may self-test once we put the test online."

"Yale School of Medicine faculty and students are leading the way in developing novel applications of AI to recognize and diagnose diseases, including rare diseases, earlier when we can have the greatest impact," said Nancy J. Brown, MD, dean of Yale School of Medicine.

Sandip Mukherjee, Mohammad A. Zafar, and Bulat Ziganshin were also authors on the study. Danny Saksenberg of Emerge, who also has an appointment at Yale, conducted the AI analysis.

https://medicine.yale.edu/news-article/ai-accurately-diagnoses-a-genetic-condition-from-facial-photographs/#:

Saksenberg D, Mukherjee S, Zafar MA, Ziganshin B, Elefteriades JA. Pilot study exploring artificial intelligence for facial-image-based diagnosis of Marfan syndrome. Heliyon. 2024 Jun 28;10(13):e33858. doi: 10.1016/j.heliyon.2024.e33858. PMID: 39055814; PMCID: PMC11269824.

Highlights
•
We explore Artificial Intelligence for detection of Marfan Disease (MFS) from simple facial images.
•
AI proves extremely effective at detection of MFS.
•
Overall accuracy is 98.5 % (0 false positives, 2 % false negatives).
•
Clinical usefulness is anticipated.

Abstract

Background

Marfan Syndrome (MFS), a genetic disorder impacting connective tissue, manifests in a wide array of phenotypes which can affect numerous bodily systems, especially the thoracic aorta. The syndrome often presents distinct facial features that potentially allow for diagnostic clinical recognition. Herein, we explore the potential of Artificial Intelligence (AI) in diagnosing Marfan syndrome from ordinary facial images, as assessed by overall accuracy, F1 score, and area under the ROC curve.

Methods

This study explores the utilization of Convolutional Neural Networks (CNN) for MFS identification through facial images, offering a novel, non-invasive, automated, and computerized diagnostic approach. The research examines the accuracy of Neural Networks in the diagnosis of Marfan Disease from ordinary on-line facial images. The model was trained on 80 % of 672 facial images (182 Marfan and 490 control). The other 20 % of images were used as the test set.

Results

Overall accuracy was 98.5 % (0 % false positive, 2 % false negative). F1 score was 97 % for Marfan facies and 99 % for non-Marfan facies. Area under the ROC curve was 100 %.

Conclusion

An Artificial Intelligence (AI) program was able to distinguish Marfan from non-Marfan facial images (from ordinary on-line photographs) with an extremely high degree of accuracy. Clinical usefulness of this program is anticipated. However, due to the limited and preliminary nature of this work, this should be viewed as only a pilot study.

Chiropractic for crying

A newborn in Columbus, Ohio, has a brand new demeanor ever since being treated by a chiropractor, her parents say.

Lily Freeman, just 2 months old, wasn’t a happy baby, her father, Joseph Freeman, told Fox News Digital.

When his daughter was born, her umbilical cord was wrapped around her neck twice.

About a week after the birth, Freeman and his wife, Stephanie Murdock, noticed that the baby exhibited extreme fussiness, grimacing, clenched fists, and stiff arms and legs.

Murdock, who was breastfeeding, went on a strict diet, cutting out all dairy and eggs, hoping to spark some change.

"When she was placed on her back, she would cry uncontrollably," Freeman said. "The only thing that worked was holding her upright. We knew something was wrong."

The couple took their baby to four different doctors, who concluded that since she was gaining weight and was healthy, she probably had colic — which would improve in three to four months.

"As her parents, we could not just sit back and wait it out," Freeman said. "We knew she had invisible pain."

The couple posted on social media, searching for answers from fellow parents. Many recommended they see a chiropractor.

"We had no previous knowledge that chiropractors treated children," Freeman said. "We were extremely skeptical because Lily was only 2 weeks old."

Freeman and Murdock took their baby to see Dr. Josh Russell at Ability Chiropractic in Hillard, Ohio. The doctor explained to them that the birthing process can be "traumatic" for mother and child.

In an interview with Fox News Digital, Russell said that he and his colleague, Dr. Tyler Morman, often treat babies with colicky behavior.

They typically perform a "thorough exam" and investigate the child’s history, including the details of the pregnancy, labor and delivery.

"The whole premise of chiropractics is to help the nervous system function the way that it should," he said.

"When you have a lack of mobility within the spine and tightness in musculature … that interferes with the nervous system's communication to send signals to the rest of the body."

When evaluating a baby, the movements of the spinal joints will help determine where adjustments are needed, Russell said.

When adjusting, the doctor said the appropriate pressure is what might be used to check "a peach or a tomato for ripeness."

"It’s a sustained pressure, holding a specific area that needs to move better," he said. "Once that nervous system interference is gone, we see huge changes."

Freeman, the baby's mom, told Fox News Digital after the second chiropractic visit, he and Murdock noticed a "huge change" in their little one's mobility and demeanor.

"She started smiling for the first time since she was born," he said. "We could place her on her back without her uncontrollably crying."

He added, "She was able to sleep without waking up every 20 minutes in pain. It was a beautiful thing to witness Lily transform into a totally different baby."

Some claim practice is ‘overwhelmingly safe'

Russell said he sees family members ranging in age from one day old to 99 years old.

Babies, toddlers and kids who may be having trouble with eating, sleeping or bowel movements could find great benefit from an adjustment, according to the chiropractor.

For toddlers, Russell claims that chiropractic care can also help with hyperactivity.

Regarding parents’ worries that an adjustment could hurt their baby, he stated that the practice is "overwhelmingly safe."

"I haven't had any adverse reactions to chiropractic care," he said.

"Our protocol … is a thorough exam, very light adjustments. It's really nothing crazy."

Freeman encouraged other parents to "do their research" and consult with a chiropractor before undergoing treatment.

"Knowledge is power, and we had to advocate for Lily," he said. "You have to be the voice for the voiceless."

Dr. Lora Tanis, a New Jersey chiropractor who is also the president of the Council on Chiropractic Pediatrics, also weighed in, telling Fox News Digital that she "definitely recommends" chiropractic care for babies.

"Often there are mechanical forces or circumstances that would warrant a spinal evaluation for a baby, and therefore, having a baby evaluated early can potentially avoid future problems," she said in an email.

Chiropractors are trained to perform "age-appropriate exams prior to determining if the child is a candidate for chiropractic care," Tanis added.

Babies who suffer from neuromusculoskeletal conditions will show signs of "greater comfort" following a visit to the chiropractor, she said.

"Many parents report that their baby cries less and sleeps more soundly after chiropractic care."

"Adjustments performed on children are very gentle, precise and appropriate for their age," Tanis said.

She encouraged parents to seek chiropractic help for children if they notice abnormal posture or head position, decreased motion of extremities, irritability with movement, or trauma.

Experts warn of risks

Not all experts agree that chiropractic adjustments are safe for newborns.

An observational study published in Pediatrics, the journal of the American Academy of Pediatrics (AAP), concluded that "serious adverse events may be associated with pediatric spinal manipulation."

Beth C. Natt, M.D., system medical director of pediatrics at Atlantic Health System in New Jersey, echoed those concerns.

"I do not recommend chiropractic care for babies," she told Fox News Digital.

"Although watching a newborn baby get ‘adjusted’ might be a popular video clip on TikTok, the reality is that the American Academy of Pediatrics (AAP) and other reputable medical organizations do not recommend chiropractic care for infants due to safety and efficacy concerns."

"Infants are wired to adapt to their environment without external interventions like chiropractic care."

Claims that chiropractic care can treat conditions like colic, reflux and sleep disturbances are "not supported by rigorous scientific studies," according to Natt.

Although some believe that infants need to be "realigned" after childbirth, Natt disagreed.

"The infant’s body undergoes these natural adjustments and development after birth, and infants are wired to adapt to their environment without external interventions like chiropractic care," she said.

Infants have "delicate and developing bones and joints," the doctor noted, which makes them "more s

"There have been documented cases of serious injuries, including fractures and spinal cord injuries, after chiropractic care in infants," Natt warned.

The doctor recommended parents speak with their pediatricians about their concerns before seeing a chiropractor.

The pediatrician can perform an assessment of the infant and determine whether other, less risky therapies are better for the infant, she said.

Natt added, "At the end of the day, we are all aligned — we want to ensure that we care for the health, safety and comfort of our patients."

Fox News Digital reached out to the AAP requesting comment.

https://www.foxnews.com/health/ohio-baby-smiling-chiropractic-adjustments-parents-say-safe

Vohra S, Johnston BC, Cramer K, Humphreys K. Adverse events associated with pediatric spinal manipulation: a systematic review. Pediatrics. 2007 Jan;119(1):e275-83. doi: 10.1542/peds.2006-1392. Epub 2006 Dec 18. Erratum in: Pediatrics. 2007 Apr;119(4):867. Erratum in: Pediatrics. 2007 Jul;120(1):251. PMID: 17178922.

ABSTRACT

BACKGROUND. Spinal manipulation is a noninvasive manual procedure applied to specific body tissues with therapeutic intent. Although spinal manipulation is commonly used in children, there is limited understanding of the pediatric risk estimates.

OBJECTIVE. Our goal was to systematically identify and synthesize available data on adverse events associated with pediatric spinal manipulation.

METHODS. A comprehensive search was performed of 8 major electronic databases (eg, Medline, AMED, MANTIS) from inception to June 2004 irrespective of language. Reports were included if they (1) were a primary investigation of spinal manipulation (eg, observation studies, controlled trials, surveys), (2) included a study population of children who were aged 18 years or younger, and (3) reported data on adverse events. Data were summarized to demonstrate the nature and severity of adverse events that may result rather than their incidence.

RESULTS. Thirteen studies (2 randomized trials, 11 observational reports) were identified for inclusion. We identified 14 cases of direct adverse events involving neurologic or musculoskeletal events. Nine cases involved serious adverse events (eg, subarachnoidal hemorrhage, paraplegia), 2 involved moderately adverse events that required medical attention (eg, severe headache), and 3 involved minor adverse events (eg, midback soreness). Another 20 cases of indirect adverse events involved delayed diagnosis (eg, diabetes, neuroblastoma) and/or inappropriate provision of spinal manipulation for serious medical conditions (ie, meningitis, rhabdomyosarcoma).

CONCLUSIONS. Serious adverse events may be associated with pediatric spinal manipulation; neither causation nor incidence rates can be inferred from observational data. Conduct of a prospective population-based active surveillance study is required to properly assess the possibility of rare, yet serious, adverse events as a result of spinal manipulation on pediatric patients.

Serial biomarker measurements to predict recovery in concussion

A study of 81 Australian football players with sports-related concussion suggests that serial biomarker measurements could help identify cases with heightened and prolonged increases in serum glial fibrillary acidic protein and neurofilament light levels, guiding return-to-play decisions based on patients' recovery. Researchers say that the next important step is demonstrating how and when the two proteins should be measured as return-to-play biomarkers.

How long does it take adult athletes' brains to fully recover after a concussion? Can blood biomarkers better estimate return-to-play readiness? A new study published online June 7 in JAMA Network Open provides some insight on these questions and others, as it found that biomarkers of neurobiological recovery could be detected after a sports-related concussion (SRC) and that they persisted over time in subsets of individuals—inviting important consideration for many sports neurologists and their patients.

Looking at 81 Australian football players who had experienced SRC, as well as 56 controls who had not, the study aimed to evaluate levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) at eight time points after injury—24 hours and one, two, four, six, eight, 12, and 26 weeks—as well as to measure cognitive performance, symptoms, and return-to-training times.

“In this cohort study, a subset of SRC cases, particularly those with loss of consciousness, showed heightened and prolonged increases in GFAP and NfL levels that persisted for at least four weeks,” wrote lead author Stuart McDonald, PhD, a senior research fellow in the department of neuroscience at the faculty of medicine at Monash University in Melbourne, Australia, and his colleagues. “These findings suggest that serial biomarker measurement could identify such cases, guiding return-to-play decisions based on neurobiologic recovery.”

Key Findings

The average age of participants was about 23 years for those with concussion and 25 for those without. A majority of both groups were male and White.

The SRC group exhibited higher GFAP levels at 24 hours and four weeks, and higher levels of NfL from one to 12 weeks, compared with the controls. Importantly, participants with SRC who also had loss of consciousness (comprising one-third of all SRC cases) showed higher GFAP at 24 hours, one week, two weeks, and four weeks, as well as higher NfL from one week to 12 weeks compared with SRC participants without loss of consciousness.

The investigators also found that participants in the subgroup with extreme and prolonged increases in GFAP and those with extreme/moderate NfL increases took longer to return to training than those in the moderate GFAP and minimal or no change NfL subgroups. Participants who took longer to return to training also showed higher rates of loss of consciousness; and after stratification by this factor, those with loss of consciousness exhibited larger and more persistent differences in GFAP and NfL.

“The unique thing about this study is not the measure but how many times and how consistently we did it—eight times over six months for 137 athletes,” Dr. McDonald said in a news release accompanying the study. “We demonstrated that blood levels of GFAP are elevated in the vast majority of athletes with concussion at 24 hours, and we are working to have this much-needed diagnostic test approved for use in the next few years.”

However, the authors acknowledged several key limitations—including the disproportionate percentage of men in the analysis as well as the younger ages of participants, meaning these data cannot provide insights into biological sex and age. The sample size was also relatively small, they wrote.

In the future, “our vision is for serial measures of these proteins to be integrated into clinical care, guiding return-to-play decisions based on both symptom and neurobiological recovery,” said Dr. McDonald. “The next important step is demonstrating how and when we should measure these two proteins as return-to-play biomarkers. Our findings take us closer to this becoming a reality.”

Expert Commentary

The current study design was both straightforward and thorough, said Joshua Kamins, MD, associate clinical professor of neurology and associate director of the Steve Tisch BrainSPORT Program at David Geffen School of Medicine at UCLA. Notably, “the authors were able to analyze very acute levels (within 24 hours) and also to track these values out to distant time points, weeks from the initial injury,” and these measures were able to both identify concussive injuries as well as predict subjects with delayed recovery.

Just a few years ago, Dr. Kamins said he would not have believed blood-based biomarkers had a function beyond determining if an injury is more severe than a concussion. Now, “we are seeing that these biomarkers may serve an important function in the near future, by diagnosing and prognosing mild traumatic brain injury/concussion.”

Biomarkers for concussion could achieve two potential goals, he explained: improving the diagnosis of concussion and improving prognosis of concussion, which has a “relatively heterogeneous rate of recovery.”

This first goal can be difficult, he said, “because although imperfect, our history and examination tools—if used in combination—can achieve a sensitivity of greater than 80 percent (JE Resch, et al, 2016). Moreover, taking a history and exam is both quick and free.”

However, for the second goal, “although most adults are symptom-free in fewer than 14 days, 20 to 30 percent of patients have symptoms beyond one month, often lasting months to years. If easy-to-perform tests are able to predict prolonged recovery at day one, or at various time points during the acute window, we would know to whom to direct more aggressive treatment and how to guide our patients.”

The present study adds to a growing body of biomarker literature that should offer hope that we are moving toward the reality of “reliable and useful blood-based biomarkers,” he said.

Still, these tests must be considered experimental at this time. “In particular, caution should be used when interpreting elevated biomarkers outside of the acute window,” Dr. Kamins said. The study's main limitations were well addressed by the authors—”most significantly, the smaller sample size limited the amount of statistical inference that could be made.”

“The challenge with mild traumatic brain injury is that it currently has no established biomarker. If this study is reproducible and well validated, there is the potential for it to offer us a blood biomarker that could help with return-to-play decisions,” said Teena Shetty, MD, MPhil, FAAN, a neurologist and the founder and director of the concussion program in neurology at the Hospital for Special Surgery in New York City.

One main point of interest from this paper, she said, is that some patients who pass currently established post-concussion assessments of full recovery may still be neurobiologically vulnerable even if clinicians are not able to detect this on provocative vestibular, balance, or exertion testing. “This paper suggests that neurobiologic effects may persist even after we clear individuals who are asymptomatic and otherwise pass tests of physical therapy and exertion,” Dr. Shetty said.

The interpretation of loss of consciousness for neurologists who treat concussion already has had a historic evolution, she continued. “Twenty years ago, neurologists believed that loss of consciousness represented a more severe concussion, but that theory has since been reconsidered, with loss of consciousness considered less of a prognostic indicator than initially thought.”

If validated, these findings “may see some providers return to the more conservative return-to-play guidelines that we have moved away from,” Dr. Shetty said. While this paper doesn't disagree with previous research, it may suggest a role for tracking these biomarkers along with the loss of consciousness.

“As someone who sees concussion patients, this paper leads me to want to strengthen the basis for my own return-to-play decisions and also to consider this phenomenon of neurobiologic recovery and how we can better understand and stratify this,” Dr. Shetty said. “At what point can we measure GFAP and NfL? What levels should we concerned about? How do we correlate this to recovery?”

It also points to the fact that we need to better define what neurobiologic recovery means for these patients and if this correlates with patients having a longer recovery time, she said.

This idea of neurobiologic recovery is germane “in part because we know these individuals are more susceptible to a second injury,” Dr. Shetty said. “If that's the concern, how do we determine that the brain has returned to normal using these biomarkers? How do we know that this is enough of a measure and these individuals won't still be at elevated risk?”

Mild traumatic brain injury is challenging because it is a functional injury rather than a structural one, so it can be difficult to validate biomarkers, she explained, adding that returning to exercise continues to offer clear advantages, notwithstanding their potential risks. Given this study, “it's really important to look at increased return-to-play time and cognitive performance and that trajectory and to understand this better,” she added.

Future studies of these biomarkers also would need to look a broader range of ages, different types of athletes, and more women, Dr. Shetty said.

“These biomarkers could theoretically challenge current decisions and influence clinical management if they are validated, but further study must be pursued,” Dr. Shetty told Neurology Today. Generally, she said, “looking at a combination of neurophysiologic imaging and blood markers would be more valuable and more accurate.”

It is not yet clear how to interpret persistently elevated biomarker levels, and these findings should not alter decision-making at this time, Dr. Kamins said. “However, I look forward to a future when we can utilize blood tests to aid in the objective diagnosis of brain injury and provide reliable information to our patients about the expected duration of their recovery.”

https://journals.lww.com/neurotodayonline/fulltext/2024/07180/elevated_blood_biomarkers_may_predict_recovery.3.aspx

O’Brien WT, Spitz G, Xie B, et al. Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion. JAMA Netw Open. 2024;7(6):e2415983. doi:10.1001/jamanetworkopen.2024.15983

Key Points

Question Do distinct trajectory subgroups exist in the serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) following sport-related concussion?

Findings In this cohort study of 81 individuals with sport-related concussion, in a subset of cases, increases in GFAP and NfL levels were substantial and persisted for at least 4 weeks. Individuals in these extreme biomarker subgroups were more likely to have experienced loss of consciousness (LOC) and longer to return to training times.

Meaning The findings of this study suggest the utility of serial measurements of GFAP and NfL to track neurobiologic recovery, with the association between LOC and extended biomarker elevations supporting the use of LOC for informing more conservative return-to-play timelines.

Abstract

Importance Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC.

Objective To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC.

Design, Setting, and Participants A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024.

Exposure Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms.

Main Outcomes and Measures Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times.

Results Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]).

Conclusions and Relevance In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.