Thursday, February 29, 2024

A 60-second MRI test for shunt failure

A Children’s Hospital Los Angeles team has developed a 60-second MRI test that may help to more easily diagnose shunt failure in children with hydrocephalus—a condition in which cerebrospinal fluid (CSF) builds up in the brain.

The noninvasive test, which uses phase-contrast MRI, is the first to precisely measure a key factor: how much fluid is flowing through a child’s shunt. Flow through a shunt is the primary metric for how well a shunt is working, so when flow starts to decline, this indicates the shunt is beginning to fail. The test is already being incorporated into clinical use at CHLA.

Peter Chiarelli, MD, DPhil, a pediatric neurosurgeon in the Neurological Institute, led the groundbreaking study, which was published in the Journal of Neurosurgery- Opens in a new window and involved multiple collaborators, including Chief Emeritus of Neurosurgery J. Gordon McComb, MD, as well as investigators Stefan Bluml, PhD, and Matthew Borzage, PhD. Recently, he also presented results at the 2023 American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Pediatric Neurological Surgery conference—which earned him the Hydrocephalus Association Award.

Dr. Chiarelli shares how this test will improve patient care and accelerate opportunities for research.

Why is this test needed?

Shunts are lifesaving devices. But when your child has one, you live under the constant shadow of the possibility that that shunt will fail. Because if that happens, it can be life-threatening. And it does happen.

Unfortunately, we don’t have a test that can definitively diagnose shunt failure. We do a variety of tests, such as an MRI to see if the brain’s ventricles are enlarged. We’ll do a shunt tap. We may do a nuclear medicine study.

Many of these tests are invasive or painful or involve radiation. And yet, none of them tell us what we really want to know, which is: Exactly how much fluid is flowing through the shunt? That’s the Holy Grail. And that’s what this new MRI sequence does—it gives us that number.

How did this study come about?

We put together a research team called the CSF Flow Dynamics Group, which includes neurosurgeons, radiologists, biomedical engineers, and MRI physicists at CHLA. We work on different projects, but our initial idea was this one: Can we use MRI to measure how well a shunt is working?

Our goal is to find simple ways to solve major clinical problems right now, using technology that is available today. In this case, phase-contrast MRI is well established. We created a sequence that would work for this specific application, and then tested and validated it.

Has it changed your clinical practice?

We’ve been transitioning this test into routine clinical care at Children’s Hospital Los Angeles. Every child who comes in with a question of shunt failure gets this test. Our neurosurgeons are now looking for these numbers as we manage patients.

The nice thing is, it’s not an extra test. These children would already get an MRI anyway. It just makes that MRI one minute longer.

I see this as a valuable adjunct to standard care. We’re still doing things like shunt taps because that is the clinical standard, and we want to be as rigorous as possible. But I do see this MRI as potentially replacing a nuclear medicine test.

How will this impact patient care?

At CHLA, we see on average one to three patients each day where we’re evaluating for possible shunt failure. This same scenario is happening at centers across the country, which is one reason this test has the potential to be so impactful.

More accurately diagnosing shunt failure would give families peace of mind and prevent neurosurgeons from having to do nuclear medicine tests or unnecessary surgeries. It could also allow surgeons to diagnose shunt problems sooner—before they become emergencies for kids and their families.

What happens next?

We want to study this as part of a national, multicenter clinical trial. Our initial research was in 21 patients; we’ve since acquired data on over 200 children. We have received funding, and are applying for additional grants to support that trial, and we’re in the process of writing a paper on additional novel findings from our data.

Our team is also conducting clinical studies to help us better understand how certain factors—like eating or exercise—affect CSF production.

What does this mean for future research?

It’s exciting because this test gives us a new avenue for investigating basic shunt flow physiology.

So now we can study things like: What flow values are better for kids? Should we design a better shunt to optimize that flow? And even: Do certain patients not need their shunts anymore? Those are questions we haven’t been able to study in the past. But all of a sudden, we have a test. It opens up a whole new world.

Study authors were Joseph H. Ha, Matthew T. Borzage, Erik B. Vanstrum, Jacob K. Al-Husseini, Eamon K. Doyle, Meenakshi Upreti, Benita Tamrazi, Marvin Nelson, Stefan Blüml, Malkiat S. Johal, J. Gordon McComb, Jason Chu, Susan Durham, Mark Krieger, Rex A. Moats and Peter A. Chiarelli.

Quantitative noninvasive measurement of cerebrospinal fluid flow in shunted hydrocephalus
Joseph H. Ha, Matthew T. Borzage, Erik B. Vanstrum, Eamon K. Doyle, Meenakshi Upreti, Benita Tamrazi, Marvin Nelson, Stefan Blüml, Malkiat S. Johal, J. Gordon McComb, Jason Chu, Susan Durham, Mark D. Krieger, Rex A. Moats, and Peter A. Chiarelli

Research Fellowship Program (National Cancer Institute R25 grant: no. CA225513). Disclosures Dr. Borzage reported a patent for Provisional Patient Application (modest association with this paper) pending to Children’s Hospital Los Angeles. Dr. Chiarelli reported a patent for Professional Patent (somewhat related to this paper) pending to Children’s Hospital Los Angeles. Author Contributions Conception and design: Chiarelli, Ha, Borzage, Doyle, Johal, Krieger. Acquisition of data: Chiarelli, Ha, Borzage, Vanstrum, Doyle, Krieger. Analysis and

In Journal of Neurosurgery Publish Before Print

Wednesday, February 28, 2024

WDR62 primary microcephaly

Inspired by a patient

Verloes A, Ruaud L, Drunat S, Passemard S. WDR62 Primary Microcephaly. 2022 Feb 17. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 35188728.


Clinical characteristics: In WDR62 primary microcephaly (WDR62-MCPH), microcephaly (occipitofrontal circumference [OFC] ≥2 standard deviations below the mean) is usually present at birth, but in some instances becomes evident later in the first year of life. Growth is otherwise normal. Except for brain malformations in most affected individuals, no other congenital malformations are observed. Central nervous system involvement can include delayed motor development, mild-to-severe intellectual disability (ID), behavior problems, epilepsy, spasticity, and ataxia.

Diagnosis/testing: The diagnosis of WDR62-MCPH is established in a proband with suggestive clinical findings and biallelic pathogenic variants in WDR62 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic. Care by a multidisciplinary team (often including a pediatric neurologist, developmental pediatrician, speech-language pathologist, occupational and physical therapist, medical geneticist, and social worker) is recommended.

Surveillance: Follow up at each visit to assess: neurologic manifestations and response to medications for those with seizures; developmental progress and educational needs; speech-language development; behavior; physical therapy / occupational therapy needs; and social support.

Genetic counseling: WDR62-MCPH is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WDR62 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the WDR62 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing, and preimplantation genetic testing are possible.

Ruaud L, Drunat S, Elmaleh-Bergès M, Ernault A, Guilmin Crepon S; MCPH Consortium; El Ghouzzi V, Auvin S, Verloes A, Passemard S. Neurological outcome in WDR62 primary microcephaly. Dev Med Child Neurol. 2022 Apr;64(4):509-517. doi: 10.1111/dmcn.15060. Epub 2021 Sep 25. PMID: 35726608.


Aim: To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)-related primary microcephaly.

Method: In this observational study, we describe the developmental, neurological, cognitive, and brain imaging characteristics of 17 patients (six males, 11 females; mean age 12y 3mo standard deviation [SD] 5y 8mo, range 5y-24y 6mo) and identify 14 new variants of WDR62. We similarly analyse the phenotypes and genotypes of the 59 previously reported families.

Results: Brain malformations, including pachygyria, neuronal heterotopia, schizencephaly, and microlissencephaly, were present in 11 out of 15 patients. The mean full-scale IQ of the 11 assessed patients was 51.8 (standard deviation [SD] 12.6, range 40-70). Intellectual disability was severe in four patients, moderate in four, and mild in three. Scores on the Vineland Adaptive Behavior Scales obtained from 10 patients were low for communication and motor skills (mean 38.29, SD 7.74, and 37.71, SD 5.74 respectively). The socialization score was higher (mean 47.14, SD 12.39). We found a significant difference between scores for communication and daily living skills (mean 54.43, SD 11.6; p=0.001, one-way analysis of variance). One patient displayed progressive ataxia.

Interpretation: WDR62-related cognitive consequences may be less severe than expected because 3 out of 11 of the assessed patients had only mild intellectual disability and relatively preserved abilities of autonomy in daily life. We identified progressive ataxia in the second decade of life in one patient, which should encourage clinicians to follow up patients in the long term.

Zombor M, Kalmár T, Nagy N, Berényi M, Telcs B, Maróti Z, Brandau O, Sztriha L. A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature. J Appl Genet. 2019 May;60(2):151-162. doi: 10.1007/s13353-019-00486-y. Epub 2019 Feb 1. PMID: 30706430.


Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat-containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.

Monday, February 26, 2024

Ben and me

Dr. Vivien Thomas is a legend of cardiac care — here’s the pulse-pounding tale of the high school-educated heart surgeon

With his dreams of medical school dashed by the Great Depression, Tennessee carpenter Vivien Thomas became one of the world’s most influential cardiac surgeons.

Dr. Vivien Thomas was born with the skill to mend broken hearts.

Armed with the brain of a scientist and the hands of a craft carpenter, he stands today as one of the world’s most influential cardiac surgeons.

Thomas never attended medical school. He couldn’t even afford college.

But in 1944, he directed one of the landmark procedures in the history of heart medicine.

Thomas guided his mentor, Dr. Alfred Blalock, in the first successful operation to repair the heart of a baby suffering Tetralogy of Fallot – better known as blue-baby syndrome.

"Blalock knew what he had, and what he had was a Michael Jordan of surgery in his lab," said Dr. Koco Eaton, Thomas’ nephew, in a telephone interview with Fox News Digital.

Eaton is the team physician for the Tampa Bay Rays of Major League Baseball.

Dr. Blalock was the chief of surgery at Johns Hopkins University School of Medicine, one of the nation’s most renowned doctors.

Yet he entrusted his career, the future of cardiac surgery and the life of the 18-month-old baby to the direction of a former carpenter with a high-school diploma.

"What he had was a Michael Jordan of surgery in his lab."

Eaton said his "humble" uncle never discussed his career at the forefront of cardiac surgery.

He only learned of Thomas’ prestige when his uncle volunteered to drive him to his medical school interview at Johns Hopkins in the early 1980s.

Thomas’ portrait hung on the wall. He was greeted warmly, even reverently, by school staff.

Eaton grew up attending July 4th family cookouts at Thomas’ Baltimore, Maryland home.

Only after walking in the shadow of his uncle did Eaton realize there was something special about the man sweating over the grill on Independence Day.

"The tongs he used to flip the hot dogs and hamburgers were modified surgical clamps he designed himself," said Eaton.

Thomas had the audacity to build a better spatula.

He also had the talent to teach the world's best surgeons how to stitch new life into the dying hearts of infants.

Vivien Theodore Thomas was born on Aug. 29, 1910 to Willard Maceo and Mary Alice (Eaton) Thomas in Lake Providence or New Iberia, Louisiana.

He was raised in Nashville, Tennessee, graduating with honors from Pearl High School in 1929.

He worked as a carpenter and harbored dreams of attending college and then medical school.

The world had different ideas. The stock market crash of 1929 wiped out his college savings, Thomas wrote in his autobiography.

He instead found work as a research assistant for Dr. Blalock at Vanderbilt University School of Medicine.

He proved an intuitive scientist and surgeon.

"Thomas rapidly mastered complex surgical techniques and research methodology," the school writes in an online biography.

Because of "institutional racism," the institution admits today, "Thomas was classified, and paid, as a janitor, despite the fact that by the mid-1930s he was doing the work of a postdoctoral researcher in Blalock’s lab."

Still, Thomas’ genius could not be contained by title or numbers on a paystub.

Because of his mechanical aptitude, said Eaton, "he could take Blalock’s ideas and make them a reality."

German bombing raids over the United Kingdom in the early days of World War II, meanwhile, amplified the need to address a phenomenon known as Crush syndrome.

Crushing injuries to limbs set off a chain reaction in the body that caused heart failure.

Thomas "and Blalock did groundbreaking research into the causes of hemorrhagic and traumatic shock," Vanderbilt reports.

"This work later evolved into research on Crush syndrome and saved the lives of thousands of soldiers on the battlefields of World War II."

Blalock was offered the position of chief of surgery at his alma mater, Johns Hopkins, in 1941.

He insisted his gifted research partner make the move with him.

"Blalock and Thomas began experimental work in vascular and cardiac surgery, defying medical taboos against operating upon the heart," Vanderbilt adds.

Ellen Saxon was just 18 months old, suffering from a fatal heart defect commonly known as blue baby syndrome, when she was presented on a surgery table before Dr. Blalock.

It was Nov. 29, 1944, a landmark day in the history of heart surgery.

"Up to that day, most infants and children with Tetralogy of Fallot had in fact no hope for cure," Johns Hopkins writes in its online account of the event.

But Thomas had "perfected" the technique to repair the defective hearts, Eaton said, during hundreds of demonstrations and experiments he performed on dogs.

The exercises revealed that new devices were needed to make the surgery successful. Thomas conceived, designed and crafted them.

Among his innovations was a clamp of exact precision that allowed two tiny blood vessels to be sewn together.

"It was the first time you were sewing blood vessels together that are the size of angel pasta."

"The clamp had to stop the flow of blood, but not damage the delicate tissue," said Eaton.

The plan was for Dr. Blalock to practice on the animals using Thomas' techniques before operating on a human infant.

Baby Ellen’s condition quickly worsened. She was rushed into the operating room — Blalock leading the surgical team, Thomas observing from a gallery.

Eaton describes the dramatic events that followed.

"It’s a very complex surgery. It was the first time you were sewing blood vessels together that are the size of angel-hair pasta," the doctor said.

Dr. Blalock needed help from the top expert in the field.

"Blalock saw Thomas in the balcony and told him to come down and stand next to him. So Thomas comes down and stands behind and basically tells him, ‘Flip your hand this way, do the stitch the other way, come back with it this way.’"

Thomas had the skills and the knowledge they had yet to learn.

The research assistant, said Eaton, "literally walked Dr. Blalock through the entire surgery."

A Hall of Fame cast of heart doctors witnessed the medical miracle.

Dr. Helen Brooke Taussig, a pioneer of cardiac medicine, had brought the baby to Dr. Blalock's attention and assisted the procedure directed by the lab researcher. Chief resident Dr. William Longmire later helped found the UCLA School of Medicine.

And resident Dr. Denton Cooley entered medical history in 1969 with the first successful implant of an artifical heart in a human.

Thomas did not have the title and the pedigree of the others in the operating room.

But he had the skills and the knowledge they had yet to learn.

"Even if you’d never seen surgery before, you could do it because Vivien made it look so simple," Cooley said 45 years later in an interview with Washingtonian magazine.

The surgery caused an immediate sensation in the medical world and in popular media. But Blalock and Taussig got all the credit. The procedure was actually named the Blalock-Taussig Shunt.

The best surgeon in the room was in danger of being forgotten.

"He had a great mind and great hands and that is a rare combination," said Dr. Eaton of his uncle. "He was a genius."

Thomas finally received an honorary doctorate from Johns Hopkins in 1976, and joined the faculty as a surgery instructor that same year, before retiring in 1979.

"Today, in operating rooms all over the world, there are great surgeons performing life-saving surgical procedures who received their training from Vivien Thomas," Morehouse School of Medicine writes in an online testament.

Vivien Thomas suffered from pancreatic cancer and died on Nov. 26, 1985 in Baltimore. He was 75 years old.

In his later years, Dr. Thomas worked on his autobiography. "Partners of the Heart: Vivien Thomas and His Work with Alfred Blalock" was published soon after his death.

The acclaim he deserved has since come his way.

His book and dramatic story inspired HBO’s Emmy Award-winning film "Something the Lord Made" and the PBS documentary "Partners of the Heart."

"A lot of people say with pride today, ‘I was taught surgery by Vivien Thomas.’"

The lifesaving procedure he demonstrated under lifesaving pressure in 1944 has since been renamed the Blalock-Taussig-Thomas Shunt.

The operation has saved the lives of thousands of babies from what was once a death-sentence heart defect.

Thomas missed his chance to go to medical school; but fate apparently planned something more profound for him.

"He probably wouldn't have done all this work if he had attended medical school," said Dr. Eaton.

"Things worked out for him and for the betterment of mankind. We all benefited from his work."

The beaming nephew added, "A lot of people say with pride today ‘I was taught surgery by Vivien Thomas.’"

Sunday, February 25, 2024

Trisomy 18

The story of Kate Cox, a Texas mother of two, made national headlines in December when she was unable to obtain an abortion in her state after learning the baby she was carrying was diagnosed with what doctors said was a fatal genetic condition known as Trisomy 18 that occurs when there is an extra copy of the 18th chromosome, resulting in a range of potential abnormalities and difficulties. Doctors advised her that if she carried the baby to term, it could leave her infertile.

Despite the fact that the Texas law includes exceptions for a "life-threatening physical condition… or a serious risk of substantial impairment of a major bodily function," it does not include fetal anomalies. Cox's request for an abortion was denied by the Texas Supreme Court and she was forced to leave the state to have an abortion elsewhere.

Nebraska's legislature held a hearing on Thursday about a new bill that would add an exception for abortions in the state after 12 weeks in the case of a fatal fetal anomaly, a term used for babies considered "incompatible with life" outside the womb. The diagnosis and abortion, according to the proposal, would need to happen before 20 weeks of pregnancy, which is in line with Nebraska's previous 20-week abortion limit. 

Nebraska Senator Merv Riepe, who introduced the bill to the state legislature, told Fox News Digital that the aim of the legislation is "to fix" the current 12-week limit on elective abortions in Nebraska. 

"The legislation is allowing women who want-to-be-mothers and it is only after the 12-week limit that they discover they do not have a viable fetus," he said. "The determination the fetus is not viable recognizes the opinion of two physicians; with the diagnosis of the nonviable fetus, the mother has two choices- carry the nonviable fetus to full term or seek a medical abortion to terminate the nonviable pregnancy."

"The loss of a much-wanted pregnancy is heart-wrenching but may be necessary to preserve the health and life of the want-to-be-mother," he added. 

Lawmakers in Tennessee, which currently has a life at conception law, are also working to create a similar exception to the one proposed in Nebraska's that would allow abortions when it is believed the mother could become "sterile and unable to bear children" in the future if she carried the baby to term. 

Critics argue such bills would remove protections for babies with disabilities and allow children with fetal anomalies to be discriminated against and aborted even in late-term pregnancies. 

Beverly Jacobson, the mother of a 7-year-old girl with Trisomy 18 and Founder and President of Verity's Village, a nonprofit aimed at providing practical support for families who receive a life-limiting prenatal diagnosis for their babies, told Fox News Digital that oftentimes terms to describe fatal fetal anomalies, such as "incompatible with life," can be misleading. 

"My daughter Verity is nearly seven-years-old and there are hundreds - maybe even thousands - of babies, children, teens and adults in the United States like her who are living with Trisomy 18," she said. "These sons and daughters are in no way ‘incompatible with life’ as the medical community often labels them, and families and communities are stronger and better because of these children." 

"It's the unfortunate truth that many doctors push abortion to parents whose unborn children are diagnosed with a life-limiting condition," she added. "I hope lawmakers will do the compassionate thing by taking a stand for Verity and those like her who have Trisomy 18 or other disabilities so they will not be targeted to an even greater extent for painful, late-term abortion."

Kelsey Pritchard, the director of state public affairs at SBA Pro-Life America, told Fox News Digital that they feel for any mother who receives a difficult diagnosis for her unborn child, but criticized what she called the "abortion industry’s spin doctors" who "manipulate these stories to justify unlimited abortion and attack babies with disabilities."

"The abortion lobby is zealously trying to confuse the issue by conflating fetal anomaly diagnoses with life-threatening emergencies experienced by pregnant women," she said. "The truth is that most fetal anomaly conditions do not put mothers at greater risk, and in the instances when a woman is in danger, every pro-life law in the country allows doctors to act."

Dr. Tara Sander Lee, the vice president and director of life sciences at the Charlotte Lozier Institute, echoed this sentiment, arguing that many babies with a prenatal diagnosis die not because of their medical condition, but because of the "discrimination and denial of treatment from the medical establishment."

"Before birth, as many as 60% of babies diagnosed with trisomy 13 or 18 are aborted," she said. "When given the proper care, survival rates are much higher. A Japanese study shows that when babies with trisomy 18 received appropriate care and surgical interventions, 81.5% survived until discharge."

"Some babies with T13 or T18 who receive surgery to treat their heart problem have an even longer median survival of 15 and 16 years," she added. "Too often in America, we fail to accept every child as a gift, regardless of ability. The obvious truth is that abortion is not a cure or treatment for the child’s condition."

Nebraska Family Alliance Policy Director Nate Grasz said discriminating against people with disabilities is wrong and that "those with different abilities are worthy of life and should always receive proper medical care."

"The Nebraska Pro-Life Coalition urges lawmakers to take a stand for babies in the womb who are believed to have a life-limiting condition and their families," he said. "We urge senators to stop LB 1109 to protect these precious children – the most vulnerable among us – from abortion at the point when they can feel pain."

Jacobson detailed the experience she had when she received the Trisomy 18 diagnosis for her daughter in an interview with Fox News Digital. 

"I remember the doctor saying that I had an elevated risk for this baby I was carrying, to have a condition known as Trisomy 18 and I was floored," she said.

As a military wife and mother to eight children, when Jacobson found out she was pregnant, she said she was just trying to get her mind wrapped around the fact that she was going to have a ninth child when she got a phone call she said she would never forget. 

"I had never heard of this before... so I was trying to process this information," she added. "I kept pressing her [the doctor], ‘Well, what does this mean? What if our baby does have this?’ And I just remember it getting quiet on the other end of the phone, and then she said, ‘Well, if your baby does have this condition, most likely, most babies will pass in utero and, if they do make it to birth, they live maybe 5 to 15 days with pretty severe defects and difficulties.’" 

"We just immediately said, 'Okay, whatever happens, we really don't know what's going on, but we do know that we love this baby, whether there are complications or not, for us, abortion is simply not an option, and we just want information to know how we can be prepared," she said. "We made that pretty clear when we spoke to professionals, so we did not experience something that many families do."

But, Jacobson said conversations with two different professionals stuck out to her and while they didn't tell her she needed to abort her baby, they did tell her that "if she survives to birth, she will live a futile life." 

The first words out of one of her doctor's mouth at a consultation were: "So you're here to talk about your retarded daughter," which Beverly said left her stunned. 

"The head of the department at the university hospital opened the conversation talking about my unborn daughter in this manner and went on to say that if she were to survive, she would live a futile life," she said. "That's a direct quote, a futile life. Those words still ring, I can still hear that, my body still reacts, I have a visceral reaction when I think about that meeting with him." 

"He said that she would be a drain on the family mentally, emotionally and financially," she added. "None of that has come to pass. I didn't know that was coming. I wasn't prepared to have to advocate for my daughter in that moment, because I was just not expecting a medical professional to speak to me in those terms when I was there to get information about what our daughter might need if she were to be born alive, if she were to overcome the statistics."

After receiving the diagnosis, Beverly said that for the first 4 to 6 weeks she and her husband were "actually preparing to bury" their daughter.  

"We were making plans for what we would do for a memorial service, where we would take her little body, just conversations that you do not expect to be having as parents when you are expecting a little baby," she said. "My heart was crushed, I was dealing with depression, severe anxiety, and I had these other children to care for," but "about a month and a half after receiving the diagnosis, when we started to get connected with online support groups, and I began to see that actually there are some babies living, not just babies, children, even teenagers, even some young adults," living with Trisomy 18. 

Beverly said the medical professionals she spoke with continually made insinuations that she and her family would not have a quality of life if they chose to go to term with their disabled child.  

"I've known many people with disabilities and I can't imagine not having known them and having had their influence in my life and just their perspective," she said. "So as much as it was a fearful experience and alarming to think that I would have a child with significant needs, I began to have hope that we could meet her alive."

Beverly and her husband have since started Verity's Village, named after their daughter, which serves hundreds of families with children who have Trisomy 18 and other similar genetic conditions.

"Now that we have a nonprofit serving families in our position, we know we hear from almost all of them that abortion is presented as the logical next step once you get a diagnosis, I'm very grateful that was not brought up," she said.

"It's a sensitive topic. I understand that," Beverly said. "I know it's so controversial."

"Obviously she was born alive, we did get to bring her home from the hospital," she said. "In a sense, we were a success story because she lived and people didn't expect her to live, but really, bringing her home was the beginning of a journey."

"When we realized how difficult that journey was and I was in the community talking to families, my heart was drawn to these mamas that were given a diagnosis and they were so scared and so overwhelmed, hearing nothing but dire predictions of what would happen to their baby," she said. "Would they live, would they not live, I was stunned. I even heard of a mom who, her doctor scheduled her abortion before she even knew about the diagnosis."

"For me, the pregnancy part was so hard," she added. "I'm a planner, I like to know what's coming ahead of time and not knowing whether she would be born alive, what our family dynamics would look like if we brought her home, that was a very anxious time for me. So I found myself wanting to support these moms."

Beverly said that for those reasons, Verity's Village was born and has been operating for almost three years, helping moms understand that they have other options besides terminating their pregnancy. 

She also said she would like to see the term "incompatible with life" erased altogether and instead replaced with "life limiting diagnosis because there are some limitations for these children, these babies, and yes, it is true that many do pass away in utero," but "we certainly didn't expect to have almost seven years with her."

"Verity has given us so much," Beverly said. "She is non-verbal. She's non-ambulatory. She doesn't do for the family like my other kids can cook and clean and help… But you know what? She doesn't have to do a thing. She is her own self and brings us joy and delight and my kids love her fiercely."

"They are growing hearts of compassion, they're learning to serve others in a way that I don't know how we would have given them that opportunity, to put others before self, and to look for others' needs if they hadn't lived it day in and day out with their little sister."

Coprolalia and job discrimination

 Courtesy of Dt. Louis Offen

Thursday, February 22, 2024

Alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease

Dornelles AD, Junges APP, Krug B, Gonçalves C, de Oliveira Junior HA and Schwartz IVD (2024) Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis. Front. Pediatr. 12:1310317. doi: 10.3389/fped.2024.1310317

Introduction: Pompe disease (PD) is a glycogen disorder caused by the deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for infantile-onset PD (IOPD).

Methods: We systematically searched the MEDLINE (via PubMed) and Embase databases for prospective clinical studies evaluating ERT for IOPD on pre-specified outcomes. Meta-analysis was also performed.

Results: Of 1,722 articles identified, 16 were included, evaluating 316 patients. Studies were heterogeneous and with very low certainty of evidence for most outcomes. A moderate/high risk of bias was present for most included articles. The following outcomes showed improvements associated with alglucosidase alfa, over natural history of PD/placebo, for a mean follow-up of 48.3 months: left ventricular (LV) mass {mean change 131.3 g/m2 [95% confidence interval (CI) 81.02, 181.59]}, time to start ventilation (TSV) [HR 0.21 (95% CI: 0.12, 0.36)], and survival [HR 0.10 (95% CI: 0.05, 0.19)]. There were no differences between the pre- and post-ERT period for myocardial function and psychomotor development. Adverse events (AEs) after ERT were mild in most cases.

Conclusion: Our data suggest that alglucosidase alfa potentially improves LV mass, TSV, and survival in IOPD patients, with no important safety issues.

Wednesday, February 21, 2024


Deep brain stimulation for depression

Emily Hollenbeck lived with a deep, recurring depression she likened to a black hole, where gravity felt so strong and her limbs so heavy she could barely move. She knew the illness could kill her. Both of her parents had taken their lives.

She was willing to try something extreme: Having electrodes implanted in her brain as part of an experimental therapy.

Researchers say the treatment —- called deep brain stimulation, or DBS — could eventually help many of the nearly 3 million Americans like her with depression that resists other treatments. It’s approved for conditions such as Parkinson’s disease and epilepsy, and many doctors and patients hope it will become more widely available for depression soon.

The treatment gives patients targeted electrical impulses, much like a pacemaker for the brain. A growing body of recent research is promising, with more underway — although two large studies that showed no advantage to using DBS for depression temporarily halted progress, and some scientists continue to raise concerns.

Meanwhile, the Food and Drug Administration has agreed to speed up its review of Abbott Laboratories’ request to use its DBS devices for treatment-resistant depression.

“At first I was blown away because the concept of it seems so intense. Like, it’s brain surgery. You have wires embedded in your brain,” said Hollenbeck, who is part of ongoing research at Mount Sinai West. “But I also felt like at that point I tried everything, and I was desperate for an answer.”

Hollenbeck suffered from depression symptoms as a child growing up in poverty and occasional homelessness. But her first major bout happened in college, after her father’s suicide in 2009. Another hit during a Teach for America stint, leaving her almost immobilized and worried she’d lose her classroom job and sink into poverty again. She landed in the hospital.

“I ended up having sort of an on-and-off pattern,” she said. After responding to medication for a while, she’d relapse.

She managed to earn a doctorate in psychology, even after losing her mom in her last year of grad school. But the black hole always returned to pull her in. At times, she said, she thought about ending her life.

She said she’d exhausted all options, including electroconvulsive therapy, when a doctor told her about DBS three years ago.

“Nothing else was working,” she said.

She became one of only a few hundred treated with DBS for depression.

Hollenbeck had the brain surgery while sedated but awake. Dr. Brian Kopell, who directs Mount Sinai’s Center for Neuromodulation, placed thin metal electrodes in a region of her brain called the subcallosal cingulate cortex, which regulates emotional behavior and is involved in feelings of sadness.

The electrodes are connected by an internal wire to a device placed under the skin in her chest, which controls the amount of electrical stimulation and delivers constant low-voltage pulses. Hollenbeck calls it “continuous Prozac.”

Doctors say the stimulation helps because electricity speaks the brain’s language. Neurons communicate using electrical and chemical signals.

In normal brains, Kopell said, electrical activity reverberates unimpeded in all areas, in a sort of dance. In depression, the dancers get stuck within the brain’s emotional circuitry. DBS seems to “unstick the circuit,” he said, allowing the brain to do what it normally would.

Hollenbeck said the effect was almost immediate.

“The first day after surgery, she started feeling a lifting of that negative mood, of the heaviness,” said her psychiatrist, Dr. Martijn Figee. “I remember her telling me that she was able to enjoy Vietnamese takeout for the first time in years and really taste the food. She started to decorate her home, which had been completely empty since she moved to New York.”

For Hollenbeck, the most profound change was finding pleasure in music again.

“When I was depressed, I couldn’t listen to music. It sounded and felt like I was listening to radio static,” she said. “Then on a sunny day in the summer, I was walking down the street listening to a song. I just felt this buoyancy, this, ‘Oh, I want to walk more, I want to go and do things!’ And I realized I’m getting better.”

She only wishes the therapy had been there for her parents.

The road to this treatment stretches back two decades, when neurologist Dr. Helen Mayberg led promising early research.

But setbacks followed. Large studies launched more than a dozen years ago showed no significant difference in response rates for treated and untreated groups. Dr. Katherine Scangos, a psychiatrist at the University of California, San Francisco, also researching DBS and depression, cited a couple of reasons: The treatment wasn’t personalized, and researchers looked at outcomes over a matter of weeks.

Some later research showed depression patients had stable, long-term relief from DBS when observed over years. Overall, across different brain targets, DBS for depression is associated with average response rates of 60%, one 2022 study said.

Treatments being tested by various teams are much more tailored to individuals today. Mount Sinai’s team is one of the most prominent researching DBS for depression in the U.S. There, a neuroimaging expert uses brain images to locate the exact spot for Kopell to place electrodes.

“We have a template, a blueprint of exactly where we’re going to go,” said Mayberg, a pioneer in DBS research and founding director of The Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai. “Everybody’s brain is a little different, just like people’s eyes are a little further apart or a nose is a little bigger or smaller.”

Other research teams also tailor treatment to patients, although their methods are slightly different. Scangos and her colleagues are studying various targets in the brain and delivering stimulation only when needed for severe symptoms. She said the best therapy may end up being a combination of approaches.

As teams keep working, Abbott is launching a big clinical trial this year, ahead of a potential FDA decision.

“The field is advancing quite quickly,” Scangos said. “I’m hoping we will have approval within a short time.”

But some doctors are skeptical, pointing to potential complications such as bleeding, stroke or infection after surgery.

Dr. Stanley Caroff, an emeritus professor of psychiatry at the University of Pennsylvania, said scientists still don’t know the exact pathways or mechanisms in the brain that produce depression, which is why it’s hard to pick a site to stimulate. It’s also tough to select the right patients for DBS, he said, and approved, successful treatments for depression are available.

“I believe from a psychiatric point of view, the science is not there,” he said of DBS for depression.

Hollenbeck acknowledges DBS hasn’t been a cure-all; she still takes medicines for depression and needs ongoing care.

She recently visited Mayberg in her office and discussed recovery. “It’s not about being happy all the time,” the doctor told her. “It’s about making progress.”

That’s what researchers are studying now — how to track progress.

Recent research by Mayberg and others in the journal Nature showed it’s possible to provide a “readout” of how someone is doing at any given time. Analyzing the brain activity of DBS patients, researchers found a unique pattern that reflects the recovery process. This gives them an objective way to observe how people get better and distinguish between impending depression and typical mood fluctuations.

Scientists are confirming those findings using newer DBS devices in a group of patients that includes Hollenbeck.

She and other participants do their part largely at home. She gives researchers regular brain recordings by logging onto a tablet, putting a remote above the pacemaker-like device in her chest and sending the data. She answers questions that pop up about how she feels. Then she records a video that will be analyzed for things such as facial expression and speech.

Occasionally, she goes into Mount Sinai’s “Q-Lab,” an immersive environment where scientists do quantitative research collecting all sorts of data, including how she moves in a virtual forest or makes circles in the air with her arms. Like many other patients, she moves her arms faster now that she’s doing better.

Data from recordings and visits are combined with other information, such as life events, to chart how she’s doing. This helps guide doctors’ decisions, such as whether to increase her dose of electricity – which they did once.

On a recent morning, Hollenbeck moved her collar and brushed her hair aside to reveal scars on her chest and head from her DBS surgery. To her, they’re signs of how far she’s come.

She makes her way around the city, taking walks in the park and going to libraries, which were a refuge in childhood. She no longer worries that normal life challenges will trigger a crushing depression.

“The stress is pretty extreme at times, but I’m able to see and remember, even on a bodily level, that I’m going to be OK,” she said.

“If I hadn’t had DBS, I’m pretty sure I would not be alive today.”

Monday, February 19, 2024

Sudden death syndrome

Sudden death syndrome (SDS) is a broad term that can describe any sudden, unexpected death from natural causes. It is not a formal condition or diagnosis and does not necessarily indicate a specific medical condition.

Sudden death syndrome (SDS) is an umbrella term for many biological scenarios leading to quick-onset and unforeseen mortality. The person involved often has little to no warning signs of illness. Even after death, an autopsy may not reveal obvious abnormalities.

This article explores what SDS is, its causes, and whether a person can prevent it. It also looks at commonly asked questions about SDS-related conditions.

How do doctors define SDS?

SDS is not a formal diagnosis: no set criteria universally define sudden death.

However, a 2023 article suggests that many experts have adopted the World Health Organization’s (WHO) definition.

It states that SDS is sudden, unexpected death from natural causes witnessed within one hour of symptom onset. If not witnessed, death occurring within 24 hours of someone seen alive and symptom-free is considered SDS.

Vs. sudden cardiac death (SCD)

People may use SDS interchangeably with sudden cardiac death (SCD), also known as sudden cardiac arrest (SCA).

SCD describes death caused by loss of heart function, occurring within one hour of any cardiovascular cause.

SDS and SCD have become synonymous. While many different diseases can result in a fatal chain reaction in the body, SCD is a common cause.

According to a 2022 comprehensive review, cardiovascular causes account for up to 73% of sudden deaths. This is compared with other conditions such as asthma, epilepsy, and intracerebral hemorrhage.

Are there symptoms or warning signs of SDS?

There is no standardized list of symptoms in SDS. Since SDS is not a single illness or disease, symptoms, if any, can vary significantly depending on the underlying cause.

For example, in the case of SCD, warning signs may be similar to any heart complication. Almost half of people report no symptoms of SCD. However, if symptoms are present, they may include:

chest discomfort
shortness of breath

Warning signs of other conditions that can lead to SDS may be subtle. For example, a person could mistake cerebral aneurysm symptoms for ordinary discomfort, such as a stiff neck or strong headache.

What causes SDS?

Numerous known and unknown processes in the body can contribute to SDS. However, cardiovascular disease plays a major role overall.

Sudden cardiac death (SCD) is the most common cause of SDS. It is a widely inclusive term that can describe a variety of cardiovascular events, such as:

sudden arrhythmia death syndromes (SADS), genetic heart conditions that alter the heart’s electrical activity, potentially causing sudden cardiac arrest
heart attack
coronary spasm
anomalous coronary origin, a coronary artery that has an abnormality
Brugada syndrome, a rare, inherited condition that can lead to irregular heartbeats
long or short QT syndrome, a condition that affects the heartbeat
myocarditis, inflammation of the heart
aortic stenosis, narrowed aortic valves

Coronary artery disease and SADS are among the most common underlying causes. Coronary artery disease may be responsible for as many as 80% of SCD deaths. According to a large-scale cohort study, SADS accounted for 53% of reviewed SCD cases.

SDS is not limited to cardiovascular events. Examples of non-cardiac conditions that can also lead to sudden death include:

pulmonary embolism, a blockage in the pulmonary arteries
brain hemorrhage
sudden infant death syndrome (SIDS)
brain aneurysm
anaphylaxis, a severe allergic reaction
hypertensive crisis, a sudden and severe increase in blood pressure
cerebral abscesses, an abscess in the brain
meningitis, inflammation of the lining that surrounds the brain and spinal cord

In many cases, the causes of SDS can never be explained. When this happens in adults, it may be referred to as sudden adult death syndrome. Similarly, unexplained infant mortality is referred to as sudden infant death syndrome.

What are the risk factors for SDS?

Due to the number of conditions that can lead to SDS, individual risk factors vary significantly.

Because SCD is the most common cause of SDS, its risk factors are among the most well-known. These include the general risk factors for adverse cardiac events, such as:

heavy alcohol consumption
tobacco use
physical inactivity
high blood pressure
living with a chronic disease, such as diabetes or kidney disease
a family history of SCD
substance misuse

Some causes of SDS can be heritable, or passed down through families. SADS, for example, are conditions passed down from parent to child. If a parent lives with a SADS condition, each child has a 50% chance of inheriting that condition.

Is prevention possible?

It may be possible to prevent SDS through chronic disease management and lifestyle changes.

For example, people at high risk of cardiovascular events can reduce their risk with lifestyle modifications and medical treatments.

Proactive disease management can also be important in preventing SDS.

For someone living with a life-threatening allergy, carrying an emergency epi-pen is one way to prevent sudden death. Similarly, for certain asthma conditions, an emergency inhaler may save a person’s life.

Not all sudden deaths can be prevented, however. Some conditions in SDS might not have modifiable risk factors, such as those influenced by genetics.

Frequently asked questions

Below are commonly asked questions about sudden death syndrome (SDS) and SCD.

How common is SDS?

Sudden deaths in the United States may account for between 150,000 and 450,000Trusted Source deaths annually.

Is SDC painful?

SDC may be accompanied by pain or discomfort immediately before heart function stops.

What is the most common underlying condition of SCD?

Coronary artery disease is one of the most common underlying conditions in SCD. It accounts for approximately 80%Trusted Source of sudden cardiac arrests.


SDS is not a formal diagnosis. It is an umbrella term that describes unexpected, sudden, natural causes of death.

SCD is the most common cause of SDS. However, other conditions can also cause SDS, such as epilepsy, cerebral hemorrhage, and asthma.

It may be possible to reduce a person’s chances of experiencing SDS with certain methods. These include making lifestyle modifications and treating underlying chronic diseases.

Thursday, February 15, 2024

SORD neuropathy

Inspired by a patient (the article is about me)

Furuta Y, Nelson ET, Neumann SM, Phillips JA 3rd, Hamid R, Tinker RJ, Cogan JD, Rives L, Newman JH; Undiagnosed Diseases Network. A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency. Am J Med Genet A. 2023 Dec;191(12):2873-2877. doi: 10.1002/ajmg.a.63383. Epub 2023 Aug 25. PMID: 37622199.


A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN.


ARX: a gene for all seasons

Inspired by a patient

Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev. 2006 Jun;16(3):308-16. doi: 10.1016/j.gde.2006.04.003. Epub 2006 May 2. PMID: 16650978.


The Aristaless-related homeobox gene, ARX, is an important transcription factor with a crucial role in forebrain, pancreas and testes development. At least fifty-nine mutations have been described in the ARX gene in seven X-chromosome linked disorders involving mental retardation. Recent studies with ARX screening suggest that the gene is mutated in 9.5% of X-linked families with these disorders. Two different polyalanine expansion mutations represent 46% of all currently known mutations and show considerable pleiotropy. The ARX gene is emerging as one of the more important disease-causing genes on the X chromosome and ought to be considered for routine screening. Although the normal Arx protein is known to be a bifunctional transcriptional activator and repressor, the complete biochemical characterization of the normal and mutated ARX awaits further investigation. Pax4 was identified as one of the ARX target genes, and both proteins have crucial functions in endocrine mouse pancreas alpha-cell and beta-cell lineage specification.

Lisik M, Sieroń AL. ARX--jeden gen--wiele postaci niepełnosprawności intelektualnej [ARX--one gene--many phenotypes]. Neurol Neurochir Pol. 2008 Jul-Aug;42(4):338-44. Polish. PMID: 18975239.


Mental retardation is a serious social problem. It affects 2-3% of the population. It is estimated that mutations in the ARX gene can be found in 1 in 12,000 live male births. This is the second most common cause of X-linked mental retardation after fragile X syndrome. The ARX gene belongs to transcription factors involved in differentiation of specific neuronal cells in the central nervous system. The most common mutation in the ARX gene is c. 428_451dup24, duplication of 24 bp in exon 2 of the gene, causing elongation of the second alanine tract (polyA12_II). Described disorders caused by mutations in the ARX gene include: hydrocephaly with abnormal genitalia (HYD-AG), lissencephaly with abnormal genitalia (XLAG), agenesis of corpus callosum with abnormal genitalia (ACC-AG), Partington syndrome (PRTS), X-linked infantile spasms (ISSX), myoclonic epilepsy with spasticity and mental retardation (XMESID), and nonspecific mental retardation (NS-XLMR).

Takeshita Y, Ohto T, Enokizono T, Tanaka M, Suzuki H, Fukushima H, Uehara T, Takenouchi T, Kosaki K, Takada H. Novel ARX mutation identified in infantile spasm syndrome patient. Hum Genome Var. 2020 Mar 31;7:9. doi: 10.1038/s41439-020-0094-2. PMID: 32257294; PMCID: PMC7109071.


We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.

SATB2-associated syndrome

Inspired by a patient

Zarate YA, Bosanko KA, Caffrey AR, Bernstein JA, Martin DM, Williams MS, Berry-Kravis EM, Mark PR, Manning MA, Bhambhani V, Vargas M, Seeley AH, Estrada-Veras JI, van Dooren MF, Schwab M, Vanderver A, Melis D, Alsadah A, Sadler L, Van Esch H, Callewaert B, Oostra A, Maclean J, Dentici ML, Orlando V, Lipson M, Sparagana SP, Maarup TJ, Alsters SI, Brautbar A, Kovitch E, Naidu S, Lees M, Smith DM, Turner L, Raggio V, Spangenberg L, Garcia-Miñaúr S, Roeder ER, Littlejohn RO, Grange D, Pfotenhauer J, Jones MC, Balasubramanian M, Martinez-Monseny A, Blok LS, Gavrilova R, Fish JL. Mutation update for the SATB2 gene. Hum Mutat. 2019 Aug;40(8):1013-1029. doi: 10.1002/humu.23771. Epub 2019 Jun 18. PMID: 31021519.


SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Döcker D, Schubach M, Menzel M, Munz M, Spaich C, Biskup S, Bartholdi D. Further delineation of the SATB2 phenotype. Eur J Hum Genet. 2014 Aug;22(8):1034-9. doi: 10.1038/ejhg.2013.280. Epub 2013 Dec 4. PMID: 24301056; PMCID: PMC4350596.


SATB2 is an evolutionarily highly conserved chromatin remodeling gene located on chromosome 2q33.1. Vertebrate animal models have shown that Satb2 has a crucial role in craniofacial patterning and osteoblast differentiation, as well as in determining the fates of neuronal projections in the developing neocortex. In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID). A single patient carrying a nonsense mutation in SATB2 has been described to date. In this study, we performed trio-exome sequencing in a 3-year-old girl with CP and severely delayed speech development, and her unaffected parents. Previously, the girl had undergone conventional and molecular karyotyping (microarray analysis), as well as targeted analysis for different diseases associated with developmental delay, including Angelman syndrome, Rett syndrome and Fragile X syndrome. No diagnosis could be established. Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene (c.715C>T; p.R239*). The identification of a second patient carrying a de novo nonsense mutation in SATB2 confirms that this gene is essential for normal craniofacial patterning and cognitive development. Based on our data and the literature published so far, we propose a new clinically recognizable syndrome - the SATB2-associated syndrome (SAS). SAS is likely to be underdiagnosed and should be considered in children with ID, severe speech delay, cleft or high-arched palate and abnormal dentition with crowded and irregularly shaped teeth.

Zarate YA, Fish JL. SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am J Med Genet A. 2017 Feb;173(2):327-337. doi: 10.1002/ajmg.a.38022. Epub 2016 Oct 24. PMID: 27774744; PMCID: PMC5297989.


The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations.

Monday, February 12, 2024

Even in death, we won't part

 Former Dutch Prime Minister Dries van Agt and his wife committed legally assisted suicide by simultaneous euthanasia this week, the non-profit organisation founded by the ex-Dutch leader has revealed.

Public broadcaster Nederlandse Omroep Stichting (NOS) reported on Friday that former Dutch Prime Minister Dries van Agt (93), who led the Netherlands from 1977 to 1982, and his wife Eugenie van Agt (93) opted on Monday to take their lives in a joint act of euthanasia, which is legally permitted under medical supervision in the Western European nation.

Gerard Jonkman, the director of The Rights Forum non-profit founded by Van Agt in 2009, said that the former prime minister had discussed the option of assisted suicide after suffering a brain haemorrhage in 2019, saying that he said it was an “option if life and suffering became unbearable.”

Since then, Van Agt’s health, as well as his wife’s, steadily declined, according to Jonkman, who said: “His health became more and more fragile, and he wanted to focus his attention on his wife, children and grandchildren.” He said that their decision to commit assisted suicide hand in hand came from a feeling that they “couldn’t live without each other”.

The couple, who were married for seven decades, were buried together on Thursday. The Dutch public broadcaster noted that assisted suicide was a curious decision by Van Agt, given that he was a lifelong Roman Catholic — a faith which preaches against suicide — and a former member of the socially conservative Christian Democratic Appeal (CDA).

However, Jonkman noted that the former prime minister was always “idiosyncratic” and that Van Agt “never checked whether his own views are completely in line with those of a party or institution.”

Saturday, February 10, 2024

Arteriovenous malformation

A Texas family's trip to the Big Apple for their 10-year-old son's birthday turned into a nightmare, after their son became violently ill and was induced into a coma at a New York City ICU.

Riker Stippick's family surprised him with a birthday vacation to New York City to experience the popular Broadway musical, Hamilton, and to eat his first slice of New York City pizza.

"Bless his sweet little heart," David Stippick, Riker’s dad, told FOX 7.

"He wanted to go to the Weehawken dueling ground where Aaron Burr and Hamilton had their duel," he said.

Stippick said that on his son's tenth birthday, the last thing on his mind was that his son could become violently ill.

"Your kid is happy and healthy and 10, you kind of assume they're going to stay that way," said Stippick.

On the way to the World Trade Center, Riker's health took a turn, and he shared with his parents that he was experiencing the "worst headache" he had ever had.

"There's a building over there that we walked through and as soon as we walked through that building he said, 'Oh, I have a really bad headache. This is the worst headache I've ever had,’" Stippick told the local outlet.

Moments later, the birthday boy vomited and laid down near a bench to rest.

"It was like a shriek of pain," said Stippick.

They took him to the hospital, where doctors put him in a medically induced coma.

"It's as awful as it sounds, you know what I mean?" said Stippick.

New York City doctors told Riker's parents that they believe that he may have experienced an arteriovenous malformation, which is an abnormal connection between his arteries and veins and can cause bleeding into the brain or spinal cord.

Doctors said that the 10-year-old experienced an aneurysm inside his arteries and veins-- leading to his excruciating pain.

Surgeons had to drill a hole into Riker's skull to drain blood and fluid and to remove clotting.

"We don't know the genuine hope of if and when he does come out of this, what kind of therapies or treatments are going to be needed down the line," said Stippick.

Doctors still need to do an MRI on the boy before they can give his family an official diagnosis.

They told Riker's parents that he must become stable and get off of his tubes and machines before they can fully diagnose him.

Now the Stippicks are praying that their son will wake up from the coma and that they will receive answers to their many questions about their son's health.

"We never expected it to be our reality, but it is," said Stippick.

The family's support system, including their church in Texas, has rallied around the family during their nightmare.

Their church's lead pastor at Peace of Christ Church opened a GoFundMe account that reached more than $78,000 in just a few days.

"I don't have the words to say thank you to everybody outside the words thank you," said Stippick.

Sunday, February 4, 2024

Progress in assisted suicide in Canada

Canada has delayed the extension of its assisted suicide program to people suffering solely from mental illness, health officials announced Monday.

Canada offers medically assisted death to terminally and chronically ill people, but the plan to extend the program to people with mental illnesses has divided Canadians, the New York Times reported. Some critics attribute the problem to a lack of adequate psychiatric care in the country.

The controversial policy would allow anyone in Canada with an incurable medical condition to apply for assisted suicide, even if the disease is not terminal, which makes the law one of the most liberal assisted suicide programs in the world.

Canada introduced medically assisted dying after its Supreme Court ruled in 2015 that requiring people to cope with intolerable suffering infringed on fundamental rights to liberty and security. The law was expanded in 2021 to include people experiencing "grievous and irremediable" conditions, such as depression and other mental health issues.

Over 13,000 Canadians were euthanized as part of the program in 2022, the Daily Mail reported.

When the program was announced last year, one conservative lawmaker "charged that the Liberal government of Prime Minister Justin Trudeau is promoting a ‘culture of death.’"

"Have we gone too far and too fast with Canada’s assisted suicide program?" Conservative MP Ed Fast said. "Will we evolve into a culture of death as the preferred option for those who suffer from mental illness or will we choose life?"

But now, health officials are slow-walking plans to expand the program, stating there are not enough doctors, specifically psychiatrists, in Canada to evaluate mentally ill people who wish to die, according to the announcement made by Health Minister Mark Holland and Justice Minister Arif Virani. This followed a meeting of the special parliamentary committee looking into the plan, the Times reported.

"The system needs to be ready, and we need to get it right," Holland told reporters. "It's clear from the conversations we've had that the system is not ready, and we need more time."

"Although the curriculum is present, although the guidelines are set, there has not been enough time for people to be trained on them, and provinces and territories are saying their systems are not ready and need more time," he added.

The officials did not provide a timeline for the changes, although the expansion had been previously scheduled to go into effect on March 17.

One group in favor of medical assistance in dying, "Dying with Dignity Canada," issued a statement in reaction to the news, urging the Canadian government to provide clarity on their plan of action.

"For the people across the country who live with treatment-resistant mental disorders who have patiently waited for this change in Canada’s MAID law, Dying With Dignity Canada is disheartened and shares the frustration of the continued exclusion, stigmatization and discrimination based on diagnosis," the group said.

Canada’s Special Joint Committee on Medical Assistance in Dying (MAID) recommended assisted suicide for minors without parental consent in mid-February.

A 138-page Canadian Parliament document was shared online called, "Medical Assistance In Dying In Canada: Choices or Canadians." One part of the report addressed assisted suicide options for "mature" minors in Canada. They considered two tracks, one for whom there is "reasonably foreseeable" death, the second track for those for whom "mental disorder is the sole underlying medical condition."

The government document explained the debate among government witnesses about expanding assisted suicide to those who are not yet legal adults.

"For MAID and mature minors, the committee heard a mix of views about whether MAID should be available to those under the age of 18. Many witnesses believed that age alone does not determine whether someone is capable of consenting to MAID," the document’s authors wrote. "At the same time, a cautious approach was recommended, especially since there is little evidence from youth themselves on this topic."

While the paper ultimately did not recommend MAID for children who are mentally ill, "The committee agrees with the many witnesses who opined that MAID for mature minors should be limited to track one [reasonably foreseeable natural death] at this stage, especially given the lack of youth perspectives on the topic."

Among a list of recommendations was a suggestion that "That the Government of Canada restrict MAID for mature minors to those whose natural death is reasonably foreseeable."

One critical aspect was that while the government committee supported the concept of consulting parents about administering euthanasia, children would have the final say: "The committee agrees with those witnesses who supported a requirement for parental consultation, but not consent, in the context of MAID for mature minors."

One recommendation the committee gave was to formalize this idea into law.

"That the Government of Canada establish a requirement that, where appropriate, the parents or guardians of a mature minor be consulted in the course of the assessment process for MAID, but that the will of a minor who is found to have the requisite decision-making capacity ultimately take priority," the committee advised.

The Daily Mail, after noting children would be "joining the roughly 10,000 adults who end their lives each year by state-sanctioned euthanasia in Canada, quoted multiple critics of the proposal.

"I think it's horrible," Amy Hasbrouck, of the anti-MAID group, Not Dead Yet, told the outlet. "Teenagers are not in a good position to judge whether to commit suicide or not. Any teenagers with a disability, who's constantly told their life is useless and pitiful, will be depressed, and of course they're going to want to die."

Executive director of the Euthanasia Prevention Coalition Alex Schadenberg told the Daily Mail, "We said we were going to have safeguards and guardrails, but the next government can simply open it up further by making a decision — and that's exactly what's happening."

More than a quarter of Canadians said in a new poll that homelessness and poverty are legitimate reasons to give people access to assisted suicide services.

Assisted suicide was legalized in Canada in 2021 for those with a "grievous and irremediable medical condition," but a sizable portion of Canadian respondents in a May poll conducted by Research Co. want expanded access for those with in less fortunate economic conditions. Homelessness, 28% of respondents said, is enough reason for assisted suicide access, and another 27% of respondents said poverty is a justifiable reason.

An inability to receive medical treatment in the country, which has a socialized system, should qualify those for assisted suicide, according to 51% of respondents. Half of respondents said those with disabilities should have access to assisted suicide. Another 43% said mental illness is reason for access.

Nearly three quarters of the Canadian respondents approved of their country's guidelines for assisted suicide, which requires the person to be at least 18-years-old, have a grievous and irremediable medical condition, make a voluntary request, and give informed consent.

Legalized assisted suicide and euthanasia has grown in popularity in recent decades, with the most notable countries with access being Canada, Australia, Belgium, Spain and the Netherlands.

Canada's Veterans Affairs office offered to assist a Paralympian and veteran to commit suicide when she sought to have a wheelchair lift installed in her home, the woman told lawmakers last week.

Christine Gauthier, a 52-year-old retired corporal who competed in the 2016 Paralympics at Rio De Janeiro, testified to lawmakers that a VA official had offered — in writing — to provide her with a medically-assisted suicide kit. The case officer remains unnamed but reportedly made similar offers to at least three other veterans, according to the Independent.

"I have a letter saying that if you’re so desperate, madam, we can offer you MAID, medical assistance in dying," Gauthier said in a hearing before the House of Commons veterans affairs committee.

Prime Minister Justin Trudeau condemned the incident in a public statement on Friday after Gauthier said she personally wrote him a letter on the issue.

"We are following up with investigations and we are changing protocols to ensure what should seem obvious to all of us: that it is not the place of Veterans Affairs Canada, who are supposed to be there to support those people who stepped up to serve their country, to offer them medical assistance in dying," Trudeau said.

Canada first approved medically-assisted suicide in 2016, and the parameters around allowing it have since loosened. The law originally legalized assisted suicide only for those facing imminent death, but it now also includes those who suffered severe pain or disabilities, according to the Independent.

Gauthier's story comes just weeks after a Canadian fashion company glorified assisted suicide in a commercial.

Canadian fashion company La Maison Simons promoted the "beauty" in voluntary euthanasia in a promotional video titled "All is Beauty." The ad includes a voiceover from Jennyfer Hatch, a 37-year-old Canadian woman who voluntarily euthanized herself after suffering from Ehlers-Danlos syndrome.

"Last breaths are sacred. Even though as I seek help to end my life, with all the pain and in these final moments, there is still so much beauty," Hatch says in the Simons video.

Simons says that the ad aimed to "help people to reconnect to each other and to this hope and optimism," which he says "is going to be needed if we're going to build the sort of communities and spaces where we want to live and that are enjoyable to live in."

"The ‘All is Beauty’ campaign has come to an end this week. Simons is now entering their annual holiday sprint," a spokesperson for Simons told Fox News Digital. "In this context, all of their teams' efforts are focused on in-store and web holiday activities."

A Canadian armed forces veteran suffering from post-traumatic stress disorder and a traumatic brain injury was offered medical assistance in dying by an employee of Veterans Affairs Canada.

The VAC released a statement last week admitting to an incident "where medical assistance in dying was discussed inappropriately" with the veteran. The department pledged that "appropriate administrative action will be taken" after the veteran expressed outrage at the suggestion, according to a report in Global News.

According to the report, the veteran called VAC seeking support for PTSD when the employee brought up medical assistance in dying, or euthanasia, unprompted. The veteran was reportedly shocked by the suggestion. His family told Global News that the soldier had been making positive progress in his physical and mental rehabilitation and that he felt betrayed by an agency that is tasked with assisting veterans.

The veteran's ordeal has since raised fears that the exchange may not have been an isolated incident, leading to questions about how often the agency has offered or discussed MAID with those suffering from PTSD.

The agency has since apologized to the veteran in follow-up call after the incident resulted in several complaints, with the VAC saying it "deeply regrets what transpired."

Canada legalized MAID in 2016, with 2021 amendments broadening eligibility for those requesting the procedure. People suffering from mental disorders will also be allowed access to MAID starting in 2023.

But discussing MAID with veterans is not within the scope of the VAC, an agency in charge of the care of a population already at higher risk of suicide.

In 2017, the Canadian government introduced a new suicide-prevention strategy for military personnel and veterans which promised improved care and services. The plan also provided training to medical staff on how to respond to the warning signs of suicide.

Reached for comment by Fox News, a VAC spokesperson said "advice pertaining to Medical assistance in dying is not a VAC service."

"VAC’s Case Managers, Veteran Service Agents, and Veteran Service Team Managers have no mandate or role to recommend medical assistance in dying to Veteran clients," the spokesperson said. "Considerations for medical assistance in dying are the subject of discussions between a patient and their primary care providers to determine appropriateness in each individual context. It is covered through the provincial and territorial health authorities and is administered by a physician or nurse practitioner directly to the individual.

"We are investigating what occurred. We have not found any other similar incidents," the spokesperson continued. "This isolated incident is not indicative of a pattern of behaviour or a systemic issue."