Monday, February 26, 2018

One big happy family

Matt White remembers that day in September 2016 when a mystery began to unravel that would change his life.

It started when White read a news report that Dr. Donald Cline, a retired Indianapolis fertility specialist, faced charges for lying when he denied he'd inseminated unwitting patients with his own sperm decades earlier. He searched out Cline's address online, recognizing it as the location of his mother's former doctor. Then he Googled the doctor's name. When a photo popped up, he was stunned: He looked like Cline.

"It was just too similar to be coincidental," he says. White had long known he was a donor baby, but that day, he had an eerie feeling he was staring at the man who was likely his biological father…

These two women and White recently crowded into an Indianapolis courtroom to hear Cline receive a one-year suspended sentence for lying to investigators when he denied wrongdoing; DNA tests determined he is the biological father of Ballard and another woman whose mother was his patient. Cline apologized "for the pain my actions have caused" but didn't specify how often he used his own sperm in procedures — court documents say he told Ballard about 50 times….

Cline's sentencing, though, was not the end of this story. Instead, in an extraordinary epilogue, three one-time strangers — White, Harmon and Ballard — have forged a kinship as brother and sisters, even as they wrestle with the revelation about their identities. They've also reached out to 21 other men and women, all in their 30s, who've been identified through DNA tests as half-siblings — evidence, they say, that Cline is likely their father, as well. About a half-dozen of them live in central Indiana.

Many stay in touch through a private Facebook page, and several gathered last fall for a cookout with their spouses, children and three mothers who'd been Cline patients. Others have gone on social outings, shared childhood photos, taken note of similarities (most of the men are over 6 feet tall) and, at times, confided in one another private details of their lives.

"It's a very surreal experience," White says. "I've shared personal stories that I haven't shared with anyone but my wife. You have almost this instant bond with people who are not only part of this horrible situation, but you can relate to them on an intimate level in a way you can't with anyone else."…

Jacoba Ballard was angry when she sat in court in December, describing a three-year ordeal that determined Cline is her biological father.

"There has not been one part of my life that has not suffered," she told the judge. "I find myself mentally drained by thinking of this constantly. I now have anxiety, panic attacks. ... I isolate myself from family and friends."

Ballard, 37, says Cline told her mother he used donor sperm from medical residents. She'd known since she was 10 that she was a donor child, but in 2014, Ballard grew curious about her family history and thought she might be able to track down some brothers and sisters. She took a DNA test from, a biotech company that uses saliva samples to determine ancestry and identify distant and close relatives, health risks and physical traits.

Clients can choose whether to be identified in a "DNA relatives tool" that connects them to others. When Ballard's results came back, they listed seven half-siblings, all but one identified by name. Ballard and two others got together, assembled a family tree and realized one common thread: Their mothers had gone to Cline for fertility treatments…

Ballard and a half-sister arranged to meet with two of Cline's adult children. At first, she says, they denied their father had been a donor, then said he'd done so in a small number of cases. About a month later, Ballard and a group of the half-siblings met with Cline himself, and she says he told conflicting stories, finally saying he'd donated sperm about 50 times to help unknowing patients who desperately wanted children….

Ballard's DNA match to Cline was 99.9997, court records show.

The case wasn't the first of its kind. In Virginia, Dr. Cecil Jacobson was convicted in 1992 of fraud and perjury for using his sperm to impregnate patients without telling them. Cline was convicted of obstruction of justice for lying to investigators, but a measure pushed by Ballard and others was introduced in the Indiana Senate this year to make it a crime for doctors to treat patients for infertility by using their own sperm or egg without consent. The measure didn't receive a hearing, so it's dead for this session; its sponsor has not yet decided if he'll reintroduce it.

"I feel like our mothers were violated," Ballard says. "He has torn all of our lives apart."

If there is any comfort, she says, it's in the camaraderie that's developed among several half-siblings. They've gotten together for concerts, an occasional softball game for one of their kids and a few Christmas celebrations. White and Harmon attended the high school graduation ceremonies of Ballard's two children, and the two women speak every day. They laugh about their similar tastes; they even prefer the same order at McDonald's — no onions…

The connection, though, goes beyond appearances. White says he clicked instantly with another half-sister who was a 99.998 DNA match to Cline. At their first meeting, White says, they talked for five hours, developing an instant rapport.

White, a biologist, says he's been able to open up with his new half-siblings, even discussing his own infertility problems, something he's spoken about with very few people. White and his wife have two children conceived through in vitro fertilization.

"I've pretty much given up all my life's secrets," he says.

For a time, White says everywhere he'd go in the Indianapolis area, he'd be searching for anyone who resembled him, wondering: "Are they my brother? Are they my sister?"

With DNA tests becoming more popular, White believes their group will grow. As recently as a few weeks ago, he learned of another half-sibling. All were born between 1979 and 1987, and considering that's a long span, he says:

"To think we've found all of us in a two-year period? That's not likely. There's got to be many more children out there."

Gottesfeld on Gottesfeld

by Marty Gottesfeld
from jail

My name is Marty Gottesfeld and I defended Justina Pelletier and her parents’ rights when she was medically kidnapped by Harvard’s Boston Children’s Hospital (BCH) in 2014.

Shortly thereafter the FBI and U.S. Justice Department began systematically trying to destroy the lives that my lovely and courageous wife Dana and I had built for ourselves in nearby Somerville, Massachusetts.

They nearly succeeded. This month marks the beginning of my third year in jail awaiting trial for helping to save Justina’s life.

It also marks the beginning of the end of the 5-year federal criminal statute of limitations on the crimes perpetrated by the hospital and its staff, who accepted hundreds of thousands of Medicaid dollars to treat Justina for a condition that she never had in the first place.

I’ve been called Justina’s “Guardian Hacktivist.” Rolling Stone calls me “The Hacker Who Cared Too Much.” I’ve also been called a “political prisoner.”

As many victims of medical kidnapping are acutely aware, unfortunately political connections matter more than facts in these cases and the one common thread which weaves its way through nearly every party that chose to persecute the Pelletiers as well as my family and me is Harvard.

You see, not only is BCH a Harvard institution whose employees use Harvard email addresses, not only is it a local hotspot for medical kidnappings, but the former U.S. attorney who chose to indict me, as well as the acting U.S. attorney who replaced her before Trump was sworn in and the former governor of Massachusetts who ignored Justina’s plight until she was crippled and nearly dead are all closely-aligned with the Ivy League university.

In fact, federal Magistrate Judge Marianne Bowler, who signed off on the search warrant for my home and who ordered me detained without bail, worked at Harvard Medical School, she is married to a current Harvard medical school professor and she was the director of a foundation which still raises money for Justina’s torturers.

She didn’t recuse herself from my case, though this past summer she recused herself from another matter involving Harvard hospitals.

Throughout this whole ordeal, until recently, there was also Adam J. Bookbinder, the former top federal cybercrime prosecutor in Boston and – you guessed it – he’s a Harvard grad. It was Bookbinder who applied for a wiretap on my cable modem as well as for a search warrant for my home.

He had the FBI hand-deliver me a target letter after they seized thousands of dollars of my computer equipment. And that was before the FBI went to see my in-laws in California to try to intimidate them as well. It was also Bookbinder who hand-picked magistrate Bowler and lied by omission about her conflicts of interest.

And when we started exposing all of this, it was Bookbinder who threatened my wife for posting things to YouTube. He’s now been lampooned by the left and emasculated by the right.

Then, at the last court hearing that I attended, I confronted Bookbinder while Dana held up before and after photos of Justina, showing how his alma mater had transformed her from vibrantly figure skating into barely being able to push her wheelchair.
For the record too, there are other things about Bookbinder that I look forward to exposing soon, but that will be another story.

Regardless, right after the hearing above a new prosecutor was assigned to my case. Then Bookbinder withdrew from it.

Fast forward a month or two, and we have just learned that Bookbinder – a career prosecutor and division chief – quit his job to go into private practice as a partner at the firm Holland and Knight LLP.

I wonder, do they really know who they just hired? And did Bookbinder leave his career as a prosecutor because of the facts that are already out there or was there more?

It’s no secret to the Boston U.S. attorney’s office that I’ve long been suspicious of Bookbinder and that we’ve been digging into his background…

A man facing prison time for the 2014 hacking of a Boston hospital's computer network says he is running for Senate as a Republican from behind bars.

Martin Gottesfeld's wife, Dana, said in an email Wednesday that volunteers are helping collect the 10,000 signatures required for Gottesfeld to run in the 2018 Massachusetts race to unseat incumbent Elizabeth Warren. The U.S. Constitution doesn't bar those accused or even convicted of crimes from serving in Congress.

Martin Gottesfeld said he's running because he feels "monied interests can just violate constitutional rights and take children away from their families."

He previously said he orchestrated the hospital computer attack to protest the treatment of Justina Pelletier, a Connecticut teenager at the center of a custody dispute based on conflicting medical diagnoses.


Saturday, February 24, 2018

Migraine and yawning

Güven B, Güven H, Çomoğlu SS. Migraine and Yawning. Headache. 2018 Feb;58(2):210-216.


Yawning is considered to be a symptom that reflects dopaminergic activity, although its pathophysiological mechanism is not yet fully understood. Interestingly, repetitive yawning is seen in some patients during migraine attacks. The aim of this cross-sectional study is to investigate the frequency of yawning during migraine attacks and its association with different characteristics of migraine.

Patients with migraine with or without aura were evaluated using questionnaires and diaries to determine the characteristics of headache and accompanying symptoms. Repetitive yawning in the premonitory phase and/or during headache were determined.

Three hundred and thirty-nine patients were included in the study. One hundred and fifty-four patients reported repetitive yawning (45.4%) during migraine attacks. Repetitive yawning was reported in the 11.2% of the patients in the premonitory phase, 24.2% during headaches, and 10% both in the premonitory phase and during headaches. Migraine with aura (46.8 vs 31.9%; P = .005), accompanying nausea (89.6 vs 75.1%; P = .001), vomiting (48.7 vs 37.8%; P = .044), osmophobia (66.7 vs 52.3%; P = .024), and cutaneous allodynia (58.2 vs 46%; P = .032) were more common in patients with yawning than without. Other dopaminergic-hypothalamic premonitory symptoms (41.6 vs 26.5%; P = .003), especially sleepiness (17.5 vs 5.9%; P = .001), irritability/anxiety (21.4% vs 11.4%; P = .019), nausea/vomiting (10.4 vs 4.3%; P = .03), and changes in appetite (18.2 vs 9.7%; P = .024), were also more frequent in patients with yawning than without. After being adjusted for all other relevant covariates, the odds of repetitive yawning were increased by the presence of nausea (OR 2.88; 95% CI 1.453-5.726; P = .002) and migraine with aura (OR 1.66; 95% CI 1.035-2.671; P = .036).

Our results demonstrated that yawning is a common self-reported symptom leading or accompanying migraine attacks and is associated with aura, nausea and/or vomiting, osmophobia, and cutaneous allodynia in patients with migraine. Although yawning is a rather frequently seen behavior, it is a unique and reliable symptom in patients with migraine that may offer an opportunity for early treatment of migraine attacks.
Migraine with aura, accompanying nausea, vomiting, osmophobia, and cutaneous allodynia and other symptoms were more common in migraine patients with yawning than without yawning. Other dopaminergic-hypothalamic premonitory symptoms, especially sleepiness, irritability/anxiety, nausea/vomiting, and changes in appetite, were also more frequent in patients with yawning…

"This is a valuable study in helping illustrate that migraine is more than just a headache disorder," Juliana H. VanderPluym, MD, Department of Neurology, Mayo Clinic, Phoenix, Arizona, told Medscape Medical News.

"There are a number of symptoms, including yawning, that may accompany and precede a migraine attack. Nonheadache symptoms in migraine, like yawning, may be subtle and/or overshadowed by the other symptoms.

"In addition, patients may misattribute symptoms like yawning to other causes, for example too little sleep or too little caffeine," said VanderPluym, who wasn't involved in the study.

"If patients can be educated about these symptoms it will help empower patients by providing a better understanding of what they are experiencing and perhaps can be used to identify an impending attack so that patients may take appropriate actions to treat their migraine early," VanderPluym said.

Commenting on the findings for Medscape Medical News, Noah Rosen, MD, director, Northwell Health's Headache Center in Great Neck, New York, said clinicians have known for some time that yawning can be a prodrome for migraine.

"It's commonly seen in association with other prodromal symptoms, oftentimes with changes in level of energy, levels of hunger, sometimes irritability. These are other subtle changes that some people can be attuned to that herald the start of a migraine.  Yawning does have utility, I think, because people are not always very good judges of when they are going to have a migraine attack," said Rosen.

His advice to patients: "If you find yourself tired at odd times, or yawning excessively, you should take note of that because it's possible that a headache is oncoming and you may want to be prepared with your medication or anticipate maybe changing your environment."

Mitochondria-lysosome contacts regulate mitochondrial fission

Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature. 2018 Feb 15;554(7692):382-386.

Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation. Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Mitochondria-lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.

For the first time, Northwestern Medicine scientists have discovered that two key cellular structures, mitochondria and lysosomes, come into direct contact with each other to regulate their respective functions. The findings were published in the journal Nature.

“In some ways, we assume that scientists have discovered all the major inner workings of our cells in the 21st century. And yet in this work, we made a new observation that these two organelles are directly talking to each other,” said principal investigator Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor and chair of The Ken and Ruth Davee Department of Neurology. “It’s a surprising finding that provides new insights into normal cell function and will likely have implications for a number of diseases across the board.”

Mitochondria and lysosomes are critical to every cell in the body, where they play distinct roles: mitochondria produce energy for the cell, while lysosomes recycle waste material. Dysfunction of these organelles has been implicated in many diseases, including neurodegenerative disorders and cancer.

Krainc’s laboratory had previously identified a functional link between mitochondrial and lysosomal dysfunction in Parkinson’s disease, in findings published in Science. This study, however, is the first to identify direct physical contact between the two organelles.

Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor and chair of The Ken and Ruth Davee Department of Neurology, was the lead author of the study, published in Nature.

By using video microscopy with fluorescent tagging of the two organelles, the scientists observed that the mitochondria and lysosomes formed stable contacts inside living human cells. The authors also employed other advanced imaging techniques — including electron microscopy and super-resolution imaging — to discover that the formation, and subsequent loosening, of these contacts is regulated by a lysosomal protein called RAB7.

“The discovery of these mitochondria-lysosome contacts is extremely exciting,” said first author Yvette Wong, PhD, a postdoctoral fellow in Krainc’s laboratory. “We now show that these contacts offer a potential site through which mitochondria and lysosomes can crosstalk, and it suggests that defects in the regulation of this contact site may drive the pathogenesis of various human diseases.”

In follow-up studies, the scientists are now investigating how dysfunction of the proteins that tether mitochondria and lysosomes together may affect the function of the organelles, as mutations in some of these proteins have already been implicated in neurological diseases.

“It’s very important that we now know that these organelles are talking to each other directly. How exactly these contacts are disrupted in various diseases, including Parkinson’s, and how to restore them therapeutically, will be the subject of in-depth investigations in the future,” said Krainc, also director of the Center for Neurogenetics, a professor of Neurological Surgery and Physiology at Feinberg, and a professor of Neurobiology at the Weinberg College of Arts and Sciences.

Courtesy of Doximity

Smaller head circumference in neonatal abstinence syndrome

Infants born with neonatal abstinence syndrome (NAS) had significantly smaller head circumference than infants with no fetal exposure to opioids, a researcher said here.

Mean head circumference was almost a full centimeter smaller in infants born with NAS compared to controls (33.04 cm versus 33.99 cm, respectively, P<0.001), reported Craig V. Towers, MD, of the University of Tennessee Medical Center in Knoxville. 

At a presentation at the Society for Maternal-Fetal Medicine's Annual Pregnancy Meeting, Towers said that there have only been a few retrospective studies examining the effect of NAS on head circumference, and very limited prospective data on the subject.

He added that recently, a few smaller studies reported smaller brain volumes and abnormal white matter development in older children ages 9 to 14 treated for neonatal abstinence syndrome at birth.

Researchers therefore performed a prospective cohort study, where cases were selected when a neonate ≥34 weeks was diagnosed and treated for neonatal abstinence syndrome in the NICU. This was defined through a Finnegan score (two consecutive scores of ≥10 or one ≥12). Controls were matched for race, parity, mode of delivery and gestational age at delivery, and control mothers did not have illicit substance use based on history and a urine drug screen. All pregnancies were well-dated.

Use of illicit drugs, tobacco, alcohol, gabapentin, anti-emetics and SSRIs were recorded in both cases and controls. Towers noted that the control group had a median of three drug screens, while the cases had a median of six drug screens.

Overall, 858 neonates were assessed -- 429 cases and controls apiece. In addition to the smaller mean head circumference, many more infants with NAS versus controls had head circumference at the 10th percentile or less (30.1% versus 11.9%, respectively, P<0.0001) and the 3rd percentile or less % (8.2% versus 1.9%, respectively, P<0.0001). In line with earlier data, NICU length of stay was significantly longer for infants with neonatal abstinence syndrome compared to controls (about 21 days versus around 3 days, P<0.0001). 

In most of the neonatal abstinence syndrome cases, mothers were on opioid agonist medication-assisted treatment, with three-quarters on buprenorphine, and 12% on methadone.
But in a multi-variate analysis, the authors found the only significant risk factor for a smaller head circumference was opioid use in pregnancy resulting in neonatal abstinence syndrome (adjusted OR 3.19, 95% CI 2.23-4.56) -- not any other drug or substance use.

At the presentation, Towers noted that recent guidelines from the American College of Obstetricians and Gynecologists (ACOG) do not recommend detoxification during pregnancy for managing opioid use disorder, and questioned whether this should be revisited.

"Analyses of newborns delivered of mothers that undergo opiate detoxification during pregnancy and deliver newborns without NAS are needed to determine if the current recommended management of [opioid use disorder] in pregnancy should be altered," he said.

Towers said further research is needed to determine if neonates born with neonatal abstinence syndrome are at increased risk for future neurologic dysfunction. He said his group is currently following a cohort of these infants to try to help shed some light on this question.

"Hopefully, I'll be able to come back with follow-up on these kids in 2 to 3 years to tell you how they're doing," he said.

Friday, February 23, 2018

To err Is homicide in Britain

The good that doctors do is oft interred by a single error. The case of Dr Hadiza Bawa-Garba, a trainee pediatrician in the NHS, convicted for homicide for the death of a child from sepsis, and hounded by the General Medical Council (GMC), is every junior doctor's primal fear…

Dr Bawa-Garba had just returned from a 13-month maternity break. She was the on-call pediatric registrar—the second in command for the care of sick children at Leicester Royal Infirmary. As a "registrar," she was both a master and an apprentice—a juxtaposition of roles necessary for the survival of acute care in the NHS. Because there aren't enough commanders, or consultants (attendings), in the NHS, trainees must fill their shoes, or else the NHS will collapse.

The captain of the ship and Dr Bawa-Garba's supervisor, Dr O'Riordan, was not in the hospital but teaching in a nearby city…

Normally, a registrar each is assigned to cover the wards, the emergency department, and the Children's Assessment Unit (CAU). On that day, Dr Bawa-Garba covered all three. She was new to the hospital but with no formal induction (ie, no explanation where things are and how stuff gets done in the hospital). She was expected to get along with the call and find her way around the hospital…

Triple booked, Dr Bawa-Garba was making critical decisions and also doing the scut work and teaching and supervising her team. To borrow an aviation analogy, she was flying the plane and serving food to the passengers.

At 10:30 am, she assessed Jack Adcock, a 6-year old boy with Down syndrome who was referred by the general practitioner (GP) for nausea, vomiting, and diarrhea….

Dr Bawa-Garba made a presumptive diagnosis of fluid depletion from gastroenteritis and administered an intravenous fluid bolus immediately and started him on maintenance fluids. She requested a chest radiograph; sent off bloods for blood count, renal function, and inflammatory markers; and drew blood gases, which showed that Jack was acidotic with a pH of 7 and a lactate of 11…

At 3 pm, she looked at the chest radiograph, which showed Jack had pneumonia. She prescribed Jack antibiotics, which were given at 4 pm. The radiograph had been exposed at 12:30 pm….

At 4:30 pm, she met Dr O'Riordan, her boss, in the hospital corridor. She showed him Jack's blood gas results and explained her plan of action. Her boss did not see Jack.

In the ward, Jack received enalapril. Dr Bawa-Garba had not prescribed enalapril, and she clearly stated in her plan that enalapril must be stopped—the drug lowers blood pressure and is absolutely contraindicated in shock. Nor was enalapril given by the nursing staff—they stick to the doctor's orders.

An hour after receiving enalapril, Jack had a cardiac arrest. After vigorous attempts at resuscitation, interrupted for a minute by Dr Bawa-Garba mistaking Jack for another child who was not for resuscitation, Jack was pronounced dead.

Jack died from streptococcal sepsis…

After Jack's death, Dr Bawa-Garba was distraught, and her consultant encouraged her to record her failings in her electronic portfolio. Trainees are encouraged to record their mistakes, predominantly for pedagogy. She could have, if she wanted, written about the system failures of that day. But that would have been making excuses, and you don't stick around in a field like pediatrics if you're the sort who points fingers at others.

Though the details of her reflections are not public, she is likely to have been merciless on herself. She likely admonished herself for not thinking about sepsis instantly, for not insisting that the chest radiograph be done immediately, for not reviewing the film sooner, for not starting the antibiotics immediately, and, most of all, for not being clear that under no circumstances was Jack to be given enalapril. It is likely she omitted that she was doing the work of three registrars that day, that she had a long hiatus from clinical medicine, that she was new to the hospital, that her consultant did not help out. In a cruel twist, her reflections, instead of purging her of guilt and delivering her from purgatory, would later deliver her to purgatory…

The first police inquiries did not find enough grounds for a prosecution. However, the Adcocks persisted—understandably, given their circumstances. And it's important to acknowledge that many people would have done exactly what the Adcocks did. You don't lose a 6-year-old child to sepsis and just shrug your shoulders.

Dr Bawa-Garba, and the two nurses who were caring for Jack, were charged with manslaughter. The case against the pediatric trainee was simple—she wasn't just clueless but grossly negligent. With the power of hindsight, Jack's case was dissected to the hilt. Sepsis, the deadly deceiver, became a diagnosis that any half-competent pediatrician should casually be able to detect…

Expert witnesses opined that had Jack received antibiotics within 30 minutes, rather than 6 hours, his chances of survival would have increased dramatically. There was tremendous certainty in the counterfactual. Diagnostic medicine is a fog of uncertainty until you know what the patient had. Dr Bawa-Garba was found guilty of manslaughter; the jury returned the verdict 10:2…

The problem with the law isn't that the law is an ass, it is that the law is an inconsistent ass. Jack's blood gases were deemed characteristic of sepsis. If they were so characteristic, why did Dr O'Riordan, the peripatetic consultant of the day and Dr Bawa-Garba's supervisor, not instantly diagnose sepsis when he saw the blood gases? It was Friday, 4:30 pm—the weekend was nigh. Why did he not immediately see Jack and transfer him to the intensive care unit?

If a trainee, an apprentice, who was doing the work of three registrars, can be found guilty of homicide for not understanding acid-base physiology, what does it say about the competence of her supervisor? How can she be criminally negligent and not he? This is neither scientific nor logical. Dr O'Riordan was either incompetent or lazy. Or there's another explanation: Perhaps sepsis in a child is difficult to diagnose, even for a seasoned consultant pediatrician.

Dr O'Riordan was not on trial, it was Dr Bawa-Garba. When asked why he did not see Jack, Dr O'Riordan said that Dr Bawa-Garba had not asked him to; she had not impressed upon him Jack's clinical urgency. This is deeply disingenuous. Every consultant must recall being a junior doctor—recall that trainees don't not ask for help because of their pride but because they're hesitant to ask for help, and they're hesitant not because they're afraid but because there's a culture of hesitancy, and that culture of hesitancy is a corollary to a culture in which apprentices are expected to make decisions independently, without which hospital medicine would abruptly halt. The onus is on the consultant to sniff out trouble…

Had Dr Bawa-Garba prescribed the fatal dose of enalapril, she ought to have been found guilty of manslaughter—that error is egregious. But she did not. And here, too, a failing, a mysterious failing, was internalized by the apprentice. It was deemed her fault for not anticipating that Jack would receive enalapril, even though it was not on his drug chart. She was guilty for not thinking about all the contingencies…

She was not surfing on the web whilst, unbeknownst to her, Jack's organs were being attacked by Streptococcus. She was performing lumbar punctures, attending to codes, taking referrals from GPs, managing several wards, all by herself…

I don't know how long it had been since his last meal when the Justice opined. But, with a bit of thoughtfulness, he might have arrived at an alternative interpretation—that Dr Bawa-Garba, hungry, exhausted, and overwhelmed, was at the end of her tethers. That doing the work of three registrars, which is difficult on any day, was particularly challenging in a new hospital after a year's break for a young mother who probably got little respite at home…

Like hyenas drawn to a carcass, the GMC began circling Dr Bawa-Garba. It was not enough that she was wrongly convicted of manslaughter. It was not enough that Health Education England withdrew her training number (ie, annulled her residency position). They wanted to make sure she could never practice medicine again. They wanted to erase her name from the medical register. Instead of rescuing the wounded soldier, they wanted to stab her whilst she was exsanguinating…

The GMC wasn't happy with mere suspension of Dr Bawa-Garba's medical license. They wanted her removed from their register. The GMC continued to pursue Dr Bawa-Garba's expulsion with extraordinary zeal. Finally, the high court sided with them, which opened the flood gates of the national angst of doctors in Britain.

The tribunal believed that Dr Bawa-Garba was remediable. The GMC did not. How was the GMC able to reason away the compelling evidence attesting to her competence? How did the GMC convince itself that she was a perennial threat to the public? What goes on behind the scenes at the GMC? I ask these questions not rhetorically but with incredulity. Is the prime regulatory body of doctors in Britain no longer fit to regulate? Who regulates the regulator?...

In the short term, junior doctors must, without compromise, be protected from manslaughter charges. This has to be built into the employment contract. The principle of respondeat superior must be installed. The hospital must assume complete responsibility for the actions of junior doctors, contractually. This'll put more skin in the game for the trusts, who will apply downward pressures on consultants.

The British public can't have it both ways. They can't simultaneously enjoy the thrift of a healthcare system with a tab of only 9% of the GDP, yet demand a structure needed to catch outliers. Such a structure costs. It'd have taken a village to save Jack. Jack died not because the village failed him but because the village did not exist….

If the British public insists on thrift, they must also accept the errors that come with thrift.

Thursday, February 22, 2018

Stephen A Smith, MD 1941-2018

Stephen A. Smith, M.D. was born on May 25, 1941 and passed away peacefully on February 18, 2018.

Born in Portland, Oregon, to Esther and Addison Smith. Preceded in death by his parents and younger sister, Johanna. Survived by his loving wife, Teresa Maki; Children, Christine Spangler, Stephen Smith, Bradley Smith and stepsons, Mathew and Luke Jacobsen; and 12 grandchildren.
Dr. Smith was Medical Director, Neuromuscular Program, Gillette Children's Specialty Clinic in St. Paul, Minnesota. He was also Neuropathologist at Hennepin County Medical Center, Minneapolis, Minnesota; Senior Clinical Instructor, Neuromuscular Neurology, Children's Hospital Colorado Springs, Colorado; Consultant Child and Adult Neuromuscular Diseases, Parkview Medical Center, Pueblo, Colorado; and Neuromuscular Pathologist, Department of Pathology, Parkview Hospital, Pueblo, Colorado. His medical education and experiences span decades. Dr. Smith will be cremated per his wishes and a memorial service will take place in Pueblo, Colorado and Minnesota at a future date. In lieu of flowers; please send donations in memory of Dr. Stephen A. Smith to Teresa Maki at 150 W. Mangrum Ct., Pueblo West, CO., 81007.

Steve Smith was a perfectionist.  He performed and interpreted muscle and nerve biopsies and performed and interpreted electron microscopy on the specimens obtained with consummate skill and exactitude.  He was my faculty mentor during my pediatric neurology fellowship at the University of Minnesota 1981-1984.  Steve taught me these skills.  Unfortunately, his perfection could apparently not be taught.

Steve was a superlative clinician.  His focus of interest was in neuromuscular disease.  He was an astute observer and analyst.  Steve was quite easy going and personable.  Many neuromuscular patients and their families attest to how he addressed their anxieties and was able to give them strength to persevere. Steve had a ready smile and he was very affable with his colleagues.

Steve was active in his practice until he was taken from us by surprise.  In the realm of neuromuscular disease, he stood very tall in Minnesota.

Neonatal screening for SMA

Minnesota Newborn Screening: The Addition of SMA

Posted on February 6, 2018

Maggie Dreon, MS, CGC, Sondra Rosendahl, MS, CGC, and Bridget Busacker, MA, Minnesota Department of Health

Minnesota continues to be a leader in the country for timely and well-executed newborn screening. In 2017, Minnesota’s program added three new disorders (X-ALD, MPS I, and Pompe disease) to the newborn screening panel. In 2018, Minnesota will be one of the first states to start screening for spinal muscular atrophy (SMA).

SMA is the leading genetic cause of early childhood death, affecting as many as one in every 6,000 live births. SMA is a neurodegenerative disease, characterized by muscle weakness and atrophy resulting from the deterioration and loss of the lower motor neurons.

SMA is caused by mutations in the SMN1 gene. A second gene, SMN2, often called the “back-up gene,” informs which type a child has. There are four types of SMA based on age of onset and highest motor milestone reached.

While onset of symptoms range from birth to adolescence, the symptoms tend to be nonspecific. Type I is the most common and most severe with death occurring within the first two years of life.
Until recently, families often had little hope given treatments focused on symptom management, rather than symptom mitigation. A year ago, that changed when the drug Spinraza (nusinersen) was approved by the FDA to treat all ages and types of SMA.

Newborn screening seeks to identify children with rare, hidden disorders before the onset of symptoms in order to prevent serious health complications. Given the recent FDA approval of Spinraza, SMA became a relevant disorder for consideration of newborn screening. Over the past year, Minnesota’s Newborn Screening Program worked closely with the CDC to develop and refine a test method for population-wide screening of SMA.

In parallel, Minnesota was equipping the program’s Advisory Committee on Heritable and Congenital Disorders with information about SMA to help them evaluate its candidacy for newborn screening.

In October 2017, Minnesota advisory committee members voted to recommend to the Commissioner of Health the addition of SMA to the newborn screening panel. The addition of SMA was approved in December 2017 and Minnesota will begin screening for SMA early in 2018.

Minnesota’s Newborn Screening Program expects to identify approximately 6-14 newborns with SMA each year.

In Minnesota, SMA screening will target the specific genetic change that is responsible for about 95 percent of cases. This specific change is the loss of exon 7 in both SMN1 genes. Minnesota will not be screening to determine the number of SMN2 genes. This means that children identified to have exon 7 absent will very likely have SMA, though the type will be unknown.

Upon the identification of an abnormal result, the program’s genetic counselors will contact the primary care clinic to discuss the result. They will provide the clinician with the result, a provider fact sheet, a family fact sheet, and a resource list of treatment centers available for consultation. These treatment centers will perform a comprehensive diagnostic evaluation on the child, including the determination of SMA type.

It is important to point out that while the program expects to identify all cases of SMA resulting from the loss of exon 7 in both SMN1 genes, there are about 5 percent of cases caused by different, rarer genetic changes. Minnesota’s current method will not screen newborns for these other changes, and therefore, false negative results are likely.

As with all disorders on the newborn screening panel, if you have clinical suspicion, diagnostic testing should be pursued regardless of a child’s newborn screening result.

Wednesday, February 21, 2018

Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome

Sarah Camargos, Rita Guerreiro, Jose Bras and Luis Sergio Mageste. Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome in a Brazilian family.  Neurol Genet. 2018 Feb 1.

Riboflavin transporter deficiency (formerly known as Brown-Vialetto-Van Laere [BVVL] or Fazio-Londe syndrome) is a neurodegenerative disorder characterized by progressive bulbar palsy with sensorineural deafness or bulbar hereditary neuropathy. It is caused by mutations in the riboflavin transporter genes SLC52A2 (RFVT2) or SLC52A3 (RFVT3). It is a rare syndrome with approximately 70 cases reported worldwide, with molecular diagnoses of RFVT2 or RFVT3.1,4 We have previously described the first Brazilian family with a clinical diagnosis of BVVL.

In this report, we extend the clinical spectrum associated with this family and describe a new mutation related to the metabolism of riboflavin.

The proband was a previously healthy woman aged 34 years, who presented with hearing and vision loss in the last 6 months. She was disturbed by facial pain, numbness in the left hemiface, difficulty moving her tongue, dysphagia, weight loss, and bilateral foot drop.

Examination demonstrated bilateral optic atrophy, normal ocular movements, bilateral facial paresis, atrophic tongue, and flaccid dysarthria. Reflexes were brisk except for ankle reflexes that were absent. Plantar responses were indifferent. All sensory modalities were normal. Strength was globally diminished with important distal impairment and foot drop. As dysphagia and dyspnea progressed, a feeding tube was placed and noninvasive ventilation support was initiated. At that time, she was quadriplegic and could not walk.

Electroneuromyography demonstrated cervical and acute lumbar denervation, with chronic neurogenic changes. Audiologic evaluation demonstrated neurosensorial loss.

The patient was the eldest sibling of a consanguineous marriage. She had 3 maternal aunts, also sisters from a consanguineous marriage, with a probable diagnosis of BVVL syndrome.

The patient was started on empiric treatment with riboflavin (1,800 mg per day), and within 6 months of therapy, she could walk with a cane; the feeding tube and noninvasive ventilation were withdrawn. Electroneuromyography was performed after B2 treatment and demonstrated low CMAP amplitudes and persistence of recent denervation.

By analyzing the variability identified by WES in genes previously known to cause riboflavin transporter deficiency, we identified a novel homozygous insertion in SLC52A3….

The mutation was confirmed to be present in homozygosity in the index and was found in heterozygosity in both parents using Sanger sequencing. In addition, WGG revealed a large (1.5 Mb) homozygous region encompassing the SLC52A3 locus (chromosome 20: 643,919–2,146,580 Mb) that was not present in either parent. Consequently, we tested the phenotypically affected aunt, and she presented the mutation in homozygosity…

Here, we report a Brazilian patient with late-onset and uncharacteristic acute and severe presentation, demonstrating some phenotypic heterogeneity within a family.  The mutation, a homozygous insertion of 60 bp in SCL52A3, has not been previously described as the cause of riboflavin transporter deficiency. So far, response to riboflavin therapy was documented in 11 patients harboring mutations in RFVT3. Of them, 9 patients demonstrated some response and 2 remained stable. Some authors argue that response tends to be better and more rapid when earlier treatment is started. Riboflavin dose reposition is unknown, and treatment, although generally efficient, is empirical. In addition, there is still no evidence to reassure that treatment would prevent the occurrence of symptoms indefinitely. Despite all this, clinicians might be aware of this potentially treatable condition and initiate riboflavin supplementation as soon as diagnosis is suspected.

The High Court as arbiter of human life 2

Doctors treating a sick British toddler can shut off the child’s life support despite his parents’ wishes to seek alternative treatment, London’s High Court ruled on Tuesday.

The decision on Alfie Evans’ condition renewed the contentious debate about who should make life-and-death health care decisions for children.

Evans, a 21-month-old child who has been in a coma for a year, is expected to be taken off life support on Friday, the BBC reported. Alfie’s parents, Tom Evans and Kate James, lost a legal battle after Justice Hayden said the child need “peace, quiet and privacy.”

The parents began their case against Alder Hey Children’s Hospital when they said they wanted to take their son to a medical center in Rome for treatment. Alfie suffers from a mystery degenerative brain condition that has left him hospitalized. The parents maintained that the doctors in Rome could give their son a diagnosis and proper treatment. 

Doctors at the Liverpool hospital, however, believed it was “unkind, unfair and inhumane” to keep the child alive. The toddler was determined to be in a “semi-vegetative state.”

"Alfie's need now is for good quality palliative care,” the judge said during Tuesday’s ruling.

The Evans family is considering an appeal.

"Unfortunately there are sometimes rare situations such as this where agreement cannot be reached and the treating team believe that continued active treatment is not in a child's best interests,” the hospital said in a statement.

Alfie's father said outside the courthouse: "I'm not giving up, my son isn't giving up. No one -- I repeat, no one -- is taking my boy away from me, and they're not violating his rights or mine."
The case follows at least two more similar sagas that have gripped Britain in recent months.
The parents of 11-month-old Isaiah Haastrup lost their court battle earlier this year to continue his care despite the child having brain damage that doctors categorized as “catastrophic.”

Charlie Gard, who suffered from a rare genetic disorder called mitochondrial depletion syndrome, was embroiled in a heated court battle until his death in late July. Gard’s parents wanted to bring their son to the United States for an experimental treatment they believed could help him.

But the doctors at the Great Ormond Street Hospital argued that the treatment would be ineffective and only cause more suffering.

British courts and the European Court of Human Rights all sided with the hospital in its bid to remove life support and allow Charlie Gard to die naturally.     video at link

Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

Haskell GT, Adams MC, Fan Z, Amin K, Guzman Badillo RJ, Zhou L, Bizon C, Chahin N, Greenwood RS, Milko LV, Shiloh-Malawsky Y, Crooks KR, Strande N, Tennison M, Tilley CR, Brandt A, Wilhelmsen KC, Weck K, Evans JP, Berg JS. Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurol Genet. 2018 Feb 1;4(1):e212.


To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).

We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.

The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.

Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

From the article 

Retrospective analysis of the NMD patient cohort revealed that most individuals had undergone an extensive prior workup, often over a period of many years. Almost half (43%) of patients had undergone a muscle biopsy before enrollment in this study, and almost 10% had undergone a nerve biopsy. A majority (86%) had prior electrodiagnostic testing. Furthermore, most patients (67.7%) had previously had negative single gene testing, with an average of roughly 2 genes tested per patient, and 20.4% of patients had prior multigene panel testing, all with negative results (since not having received a molecular diagnosis was necessary for participation in the study). All prior diagnostic workup is summarized in figure 1, illustrating the challenging nature of obtaining an accurate diagnosis in such patients…

In at least 2 cases, WES identified molecular diagnoses that directly impacted medical treatment. In case H this patient was thought to have a chronic inflammatory demyelinating polyneuropathy; WES identified 2 frameshifting indels in SACS, consistent with Spastic Ataxia of Charlevoix-Saguenay, and consequently, this individual was not started on immunotherapy. In 1 patient previously thought to have hereditary spastic paraplegia, WES identified a nonsense variant in GCH1, indicating dopa-responsive dystonia (MIM 128230). This patient demonstrates the dramatic utility that can stem from making a correct diagnosis, as she was started on dopa therapy and regained the ability to walk without assistance…

Only 62.5% of prior muscle biopsy or electrodiagnostic testing suggested the type of NMD in patients later found to have a pathogenic mutation in an NMD gene. Often, the prior testing could identify no specific myopathy/neuropathy or did not identify the same type of myopathy/neuropathy indicated by the genetic testing result. Uninformative muscle biopsies were often apparently normal, or consisting mainly of fat tissue, which while possibly consistent with mild myopathies, or later stage myopathy or muscular dystrophy, are not informative toward a specific diagnosis. Nerve conduction studies that were informative often delineated the affected region (proximal vs distal) and those that were uninformative often were due to being normal or limited due to the patient being uncomfortable with the procedure. One limitation of our analysis is that patients in this study were often enrolled on the basis of being undiagnosed, despite extensive prior testing, potentially biasing the present analysis in a way that makes invasive or prior testing appear to be less informative than in an unselected cohort. Nevertheless, we propose the use of sequencing early in the diagnostic workup of patients with NMD, particularly in complex cases in which additional testing may be likely to be uninformative in pointing to a specific diagnosis.

The decreasing cost of massively parallel sequencing, coupled with clear diagnostic utility, raises the question of the precise role that genomic analysis should have in a diagnostic workup for NMDs. A thorough physical examination, clinical history, and common laboratory test results should always be obtained first to identify more common, nonheritable causes of NMD. WES cannot reliably detect some major causes of several more common NMDs, including large deletions, duplications, and repeat expansions such as those causative of Duchenne muscular dystrophy, type 2 myotonic dystrophy facioscapulohumeral muscular dystrophy, or CMT1A. If a heritable condition amenable to sequencing is considered most likely, it is reasonable to consider a “sequence-early” approach, consisting of a dedicated gene panel or exome sequencing with targeted analysis.

Given the potential costs, invasiveness and incomplete yield from muscle biopsy, as well as the cost of testing for a broad array of hereditary conditions using traditional Sanger single gene testing, we suggest that genome-scale sequencing or multigene panel testing be considered early in the diagnostic process in patients likely to have a monogenic neuromuscular disorder, particularly in complex or challenging cases. Early genome-scale sequencing may shorten the diagnostic odyssey, minimize invasive testing, and provide potential opportunities for clinical and investigational therapeutics for patients with NMD.

Tuesday, February 20, 2018

Tetra-amelia syndrome

Nick Vujicic is one of the seven known surviving individuals planet-wide who live with the tetra-amelia syndrome.

Imagine getting through your busy day without hands or legs. Picture your life without the ability to walk, care for your basic needs, or even embrace those you love. Meet Nicholas Vujicic (pronounced VOO-yee-cheech). Without any medical explanation or warning, Nick was born in 1982 in Melbourne, Australia, without arms and legs. Three sonograms failed to reveal complications. And yet, the Vujicic family was destined to cope with both the challenge and blessing of raising a son who refused to allow his physical condition to limit his lifestyle.

The early days were difficult. Throughout his childhood, Nick not only dealt with the typical challenges of school and adolescence, but he also struggled with depression and loneliness. Nick constantly wondered why he was different than all the other kids. He questioned the purpose of life, or if he even had a purpose.

According to Nick, the victory over his struggles, as well as his strength and passion for life today, can be credited to his faith in God. His family, friends and the many people he has encountered along the journey have inspired him to carry on, as well.

Since his first speaking engagement at age 19, Nick has traveled around the world, sharing his story with millions, sometimes in stadiums filled to capacity, speaking to a range of diverse groups such as students, teachers, young people, business professionals and church congregations of all sizes. Today this dynamic young evangelist has accomplished more than most people achieve in a lifetime. He’s an author, musician, actor, and his hobbies include fishing, painting and swimming. In 2007, Nick made the long journey from Australia to southern California where he is the president of the international non-profit ministry, Life Without Limbs, which was established in 2005.

Nick says, “If God can use a man without arms and legs to be His hands and feet, then He will certainly use any willing heart!”

Nick Vujicic was born in Melbourne, Australia, in 1982 to Dušanka and Borislav Vujičić, Serbian immigrants from Yugoslavia.

He was born with tetra-amelia without fully formed limbs. According to his autobiography, his mother refused to see or hold him while the nurse held him in front of her, but she and her husband eventually accepted their son's condition and understood it as "God's plan for their son".

Vujicic has two small and deformed feet, one of which he calls his "chicken drumstick" because of its shape.

Originally, he was born with the toes of that foot fused. So an operation was performed to separate the toes so that he could use them as fingers to grab, turn a page, or perform other functions. He has been able to use his foot to operate an electric wheelchair, a computer and a mobile phone. Vujicic attempted suicide but notes that he had an "amazingly normal childhood".

Vujicic thrived in his teenage and young adult years despite being bullied. After his mother showed him a newspaper article about a man dealing with a severe disability when he was seventeen, he started to give talks at his prayer group. Vujicic graduated from Griffith University at the age of 21 with a Bachelor of Commerce degree, with a double major in accountancy and financial planning….

In 2006, he moved to California. In 2008 in McKinney, Texas, near Dallas, he met Kanae Miyahara, the Mexican-born, Texas-based younger daughter of a Japanese agricultural engineer and a Mexican mother. She had come to hear him give a motivational speech. They married on 12 February 2012. The couple have four children: sons Kiyoshi James (b. 13 February 2013) and Dejan Levi (b. 7 August 2015), and identical twin daughters Olivia Mei and Ellie Laurel (b. 20 December 2017),  who were born on Kanae's birthday. The family lives in southern California.

Joanne O'Riordan (born 24 April 1996) is one of seven currently living people born with the condition Tetra-amelia syndrome, and is from Millstreet, County Cork, Ireland. She has addressed the United Nations and discussed technology with Massachusetts Institute of Technology (MIT) and Apple…

An invitation to appear on The Late Late Show, the world's longest running chat show, followed. This brought her even further to public attention. Not many knew of her before this but, ahead of her second appearance on the programme in June 2012, The Irish Times described O'Riordan as "one of the guests on the show in recent years who has made the most impact on viewers".

In April 2012, O'Riordan spoke before the United Nations in New York City, giving an address on the use of technology and challenging those present to build a robot for her to use.  A standing ovation followed.

Her brother Steven made a film of her life, titled No Limbs No Limits.

Prince Randian (sometimes misspelled Rardion or Randion; October 12, 1871 – December 19, 1934), also nicknamed as The Snake Man, The Human Torso, The Human Caterpillar and a variety of other names, was a Guyanese-born American performer with tetra-amelia syndrome and a famous limbless sideshow performer of the early 1900s, best known for his ability to roll cigarettes with his lips. He was reportedly brought to the United States by P.T. Barnum in 1889, age 18 and was a popular Coney Island carnival and circus attraction for 45 years. Prince Randian (credited "Rardion") was featured in the 1932 film Freaks, his only film appearance, in which he is seen lighting up a cigarette with a match.

Randian (whose birth name is unknown) was born with no arms and legs in Demerara, British Guyana. He was a Hindu and spoke Hindi, English, French, and German. According to a passenger manifest of SS Parima from April 14, 1917 he had lived previously at Charlotte Amalie, Saint Thomas, U.S. Virgin Islands. With his wife, known as Princess Sarah (apparently a Hindu woman, born circa 1872), he fathered three daughters and a son. Their children were Mary Randian (born circa 1893), Richard Randian (born circa 1901), Elizabeth Randian (born circa 1904), and Wilhelmina Randian (born circa 1904).[2] In the 1920s he was working for Krause Amusement Company and lived in Plainfield, New Jersey. He and his wife lived at 174 Water Street, Paterson, New Jersey, until his death.

For his act, Randian wore a one-piece wool garment that fit tightly over his body, giving him the appearance of a caterpillar, snake or potato, and would move himself around the stage by wiggling his hips and shoulders. His best-known ability was rolling and lighting cigarettes using only his lips, but he was also capable of painting and writing by holding a brush or stylus with his lips and of shaving himself by securing a razor in a wooden block. He kept all of the props and materials used in his act in a wooden box that he reportedly constructed, painted and affixed a lock to by himself. His cigarette-lighting ability was featured in the MGM film Freaks.

Nick Vujicic

Joanne O'Riordan

Prince Randian


Lab-grown human cerebellar cells yield clues to autism

Sundberg M, Tochitsky I, Buchholz DE, Winden K, Kujala V, Kapur K, Cataltepe D, Turner D, Han MJ, Woolf CJ, Hatten ME, Sahin M. Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Mol Psychiatry. 2018 Feb 15. doi:10.1038/s41380-018-0018-4. [Epub ahead of print] 

Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.


Increasing evidence has linked autism spectrum disorder (ASD) with dysfunction of the brain's cerebellum, but the details have been unclear. In a new study, researchers at Boston Children's Hospital used stem cell technology to create cerebellar cells known as Purkinje cells from patients with tuberous sclerosis complex (TSC), a genetic syndrome that often includes ASD-like features. In the lab, the cells showed several characteristics that may help explain how ASD develops at the molecular level…

TSC, a rare condition in which benign tumors grow in multiple organs of the body, is associated with ASD in about half of all cases. Previous brain autopsies have shown that patients with TSC, as well as patients with ASD, have reduced numbers of Purkinje cells, the main type of neuron that communicates out of the cerebellum. In a 2012 mouse study, Sahin and colleagues knocked out a TSC gene (Tsc1) in Purkinje cells and found social deficits and repetitive behaviors in the mice, together with abnormalities in the cells.

In the new paper, Sahin and colleagues took their observations to humans, studying Purkinje cells derived from three patients with TSC (two also had ASD symptoms, and all three also had epilepsy).
To make the cells, Sundberg first created induced pluripotent stem cells from patients' blood cells or skin cells, then differentiated these into neural progenitor cells and finally Purkinje cells. The team then compared them with Purkinje cells derived from unaffected people (parents or gender-matched controls) and with cells whose TSC mutation was corrected using CRISPR-Cas9 gene editing.

"We saw changes," says Sahin. "The cells are bigger and fire less than control cells - exactly what we see in the mouse model." 

Purkinje cells with the TSC genetic defect were harder to differentiate from neural progenitor cells, suggesting that TSC may impair the early development of cerebellar tissue. On examination, the patient-derived Purkinje cells showed structural abnormalities in dendrites (the projections neurons use to take in signals) and signs of impaired development of synapses (junctions with other neurons)…
The study was the first to create human Purkinje cells using TSC patients' own stem cells. In future studies, Sahin and colleagues hope to generate larger numbers of patient-derived cells to investigate differences between patients with TSC alone and those who also have ASD. Additionally, they hope to use the Purkinje cell platform to study other ASD-related genetic disorders, including Fragile X and SHANK3 mutation, and to test potential drugs. Sundberg also plans to create other types of neurons for modeling ASD.

Nusinersen in later-onset spinal muscular atrophy

Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K, Shieh PB, Tulinius M, Mazzone ES, Montes J, Bishop KM, Yang Q, Foster R, Gheuens S, Bennett CF, Farwell W, Schneider E, De Vivo DC, Finkel RS; CHERISH Study Group. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018 Feb 15;378(7):625-635.


Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).

We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.

In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).

Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group.

Beta-propeller protein-associated neurodegeneration

Stige KE, Gjerde IO, Houge G, Knappskog PM, Tzoulis C. Beta-propeller protein-associated neurodegeneration: a case report and review of the literature. Clin Case Rep. 2018 Jan 4;6(2):353-362.

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next-generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.
All patients had delayed psychomotor development and intellectual disability manifesting from infancy or early childhood characterized by pronounced loss of expressive language skills. In addition, 44 of 59 patients (74.6%) developed progressive cognitive decline upon reaching adolescence or early adulthood. The majority had epileptic seizures (42/62, 67.7%) and movement disorders including dystonia (44/60, 73.3%) and parkinsonism (35/58, 60.3%). Epileptic seizures started in early childhood and showed a spectrum ranging from focal to generalized seizures and epileptic spasms. Multiple seizure types were commonly seen in the same individuals. The epilepsy was generally most severe in childhood and improved with advancing age. Dystonia and parkinsonism developed in adolescence or early adulthood when the motor function started deteriorating and caused severe motor disability with many patients becoming wheelchair-dependent or bedridden.

From the article

Rett-like features, including developmental regression, loss of purposeful hand skills, stereotypic hand movements, and bruxism, were seen in 14 patients (14/50, 28%). All but one of these had atypical Rett syndrome or Rett-like features, meaning that they did not fulfill all formal diagnostic criteria for Rett syndrome.

Spasticity, sleep disturbances, and ocular/visual defects have been variably reported to be a part of the phenotype. A systematic statistical evaluation of these was not possible due to inconsistent reporting and incomplete descriptions in the literature. Limb spasticity of highly variable severity has been described in both children and adults. A wide range of sleep disturbances has been reported including REM sleep disorder, excessive movement during sleep, circadian rhythm sleep disorder, hypersomnolence with choreiform movements at onset of sleep, parasomnia with nocturnal screaming, and unspecified sleep disorders. Ocular/visual involvement has been reported in 17 patients and comprises myopia, astigmatism, strabismus, abnormal pupillary shade, spontaneous retinal detachment, bilateral partial retinal coloboma, patchy loss of pupillary ruff, difficulties with eyesight with intermittent double-vision, bilateral optic disk pallor, bilateral optic atrophy, increased visual evoked potential (VEP) latency, cortical blindness, and retinitis pigmentosa.

Dysmorphic features have not been systematically characterized in BPAN. Definite data were only available for 16 of 64 patients (25%) of whom 11 (68.8%) were reported to have dysmorphic features. These included microcephaly, abnormal nasal bridge (depressed, high, wide, and flat), a small mouth [, tented upper lip, hypertelorism, epicanthal folds, downslanting palpebral fissures, large ears, bilateral low-set ears, low hanging columella, short philtrum, high palate, downturned mouth and micrognathia , narrow face , narrow nose, thin upper lip, kyphosis, flat and almost rocker bottom feet, fingers tapered  with fifth finger clinodactyly, partial synophrys, and congenital talipes varus. Small cold hands and feet were also reported. It was not possible to identify any common dysmorphic features from this analysis.

Other clinical features of BPAN include neuropsychiatric symptoms, “happy demeanor”, and excessive drooling. Chorea has been reported in one patient. Bilateral sensory neural hearing loss has also been reported as well as auditory agnosia.

The vast majority of patients with BPAN (55/61, 90.2%) had MRI findings consistent with iron deposition in the basal ganglia. The two most typical findings were as follows:

Hypointense signal in the substantia nigra and globus pallidus on T2-weighted or iron-sensitive sequences such as SWI. This finding was more prominent in older individuals. The T2 hypointensity was generally more pronounced in the substantia nigra compared to the globus pallidus, a feature that may help distinguish BPAN from other forms of NBIA.

Hyperintense “halo” surrounding a band of central hypointensity in the substantia nigra and cerebral peduncles on T1-weighted images. This finding is generally regarded as pathognomonic for BPAN.

MRI findings in BPAN. Brain MRI of the Norwegian patient at the age of 33 years, showing typical findings for BPAN. (A) Axial T1-weighted image at the level of the midbrain shows symmetric hyperintense “halos” surrounding a band of central hypointensity in the substantia nigra (arrows). Axial T2-weighted and SWI image of the same area shows prominent hypointensities in the substantia nigra and cerebral peduncles (arrows). (B) Axial images at the level of the striatum show high T1 signal and low T2 and SWI signal in the globus pallidus. The low SWI signal corresponds to areas of increased iron deposition (arrowheads).

Takano K, Goto K, Motobayashi M, Wakui K, Kawamura R, Yamaguchi T, Fukushima Y, Kosho T. Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. Eur J Med Genet. 2017 Oct;60(10):521-526.

Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN.

Hattingen E, Handke N, Cremer K, Hoffjan S, Kukuk GM. Clinical and Imaging Presentation of a Patient with Beta-Propeller Protein-Associated Neurodegeneration, a Rare and Sporadic form of Neurodegeneration with Brain Iron Accumulation (NBIA). Clin Neuroradiol. 2017 Dec;27(4):481-483.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye-of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity.

Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron
accumulation. Handb Clin Neurol. 2018;147:293-305.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.

Inspired by a colleague's patient