Thursday, August 30, 2018

Nusinersen in type 1 SMA infants, children and young adults

Pane M, Palermo C, Messina S, Sansone VA, Bruno C, Catteruccia M, Sframeli M, Albamonte E, Pedemonte M, D'Amico A, Brigati G, de Sanctis R, Coratti G, Lucibello S, Bertini E, Vita G, Tiziano FD, Mercuri E; Italian EAP working group. Nusinersen in type 1 SMA infants, children and young adults: Preliminary results on motor function. Neuromuscul Disord. 2018 Jul;28(7):582-585.

We report preliminary data on the six month use of Nusinersen in 104 type 1 patients of age ranging from three months to 19 years, 9 months. Ten of the 104 were classified as 1.1, 58 as 1.5 and 36 as 1.9. Three patients had one SMN2 copy, 65 had two and 24 had three copies. In 12 the SMN2 copy number was not available. After six months an improvement of more than two points was found in 58 of the 104 (55.7%) on the CHOP INTEND and in 21 of the 104 (20.19%) on the Hammersmith Infant Neurological Examination (HINE). Changes more than two points were found in 26/71 patients older than two years, and in seven of the 20 older than 10 years. Changes ≥ four points were found in 20/71 older than two years, and in six of the 20 patients older than 10 years. The difference between baseline and six months on both CHOP INTEND and HINE was significant for the whole group (p < 0.001) as well as for the subgroups with two (p < 0.001), and three SMN2 copies (p < 0.001). Our preliminary results suggest that functional improvement can be observed in type 1 patients outside the range of the inclusion criteria used in the Endear study.

Courtesy of:

CELF4 mutations

Inspired by a patient

Barone R, Fichera M, De Grandi M, Battaglia M, Lo Faro V, Mattina T, Rizzo R. Familial 18q12.2 deletion supports the role of RNA-binding protein CELF4 in autism spectrum disorders. Am J Med Genet A. 2017 Jun;173(6):1649-1655.

Deletion of 18q12.2 is an increasingly recognized condition with a distinct neuropsychiatric phenotype. Twenty-two patients have been described with overlapping neurobehavioral disturbances including developmental delay, intellectual disability of variable degree, seizures, motor coordination disorder, behavioral/emotional disturbances, and autism spectrum disorders. The CUGBP Elav-like family member 4 (CELF4) gene at 18q12.2 encodes a RNA-binding protein that links to RNA subsets involved in pre- and postsynaptic neurotransmission including almost 30% of potential autism-related genes. Haploinsufficiency of CELF4 was associated with an autism or autistic behavior diagnosis in two adult patients with de novo 18q12.2 deletions. We report on a girl and her mildly affected mother with a 275 kb deletion at 18q12.2 involving CELF4 and KIAA1328 whose disruption is not associated with any known disease. The child was diagnosed with syndromic intellectual disability and autism at 6 years of age. Her mother had minor dysmorphisms, mild intellectual disability, and autistic behavior. The deleted region reported in this family is one of the smallest so far reported at 18q12.2. This is also the first full clinical description of maternally inherited CELF4 haploinsufficiency. The present study refines the molecular and neuropsychiatric phenotype associated with 18q12.2 deletion leading to CELF4 haploinsufficiency and provides evidence for a role for CELF4 in brain development and autism spectrum disorders.

Halgren C, Bache I, Bak M, Myatt MW, Anderson CM, Brøndum-Nielsen K, Tommerup N. Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity. Eur J Hum Genet.2012 Dec;20(12):1315-9
Only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability, behavioral problems, seizures, obesity, and eye manifestations. Here, we report a male patient with a de novo translocation involving chromosomes 12 and 18, with borderline IQ, developmental and behavioral disorders, myopia, obesity, and febrile seizures in childhood. We characterized the rearrangement with Affymetrix SNP 6.0 Array analysis and next-generation mate pair sequencing and found truncation of CELF4 at 18q12.2. This second report of a patient with a neurodevelopmental phenotype and a translocation involving CELF4 supports that CELF4 is responsible for the phenotype associated with deletion of 18q12.2. Our study illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental and neurobehavioral genes, and it adds to the growing evidence, including a transgenic mouse model, that CELF4 is important for human brain development.

Wednesday, August 29, 2018

Cyclodextrin for Niemann-Pick Type C

Chris and Hugh Hempel, parents of twin girls with an extremely rare and fatal genetic disease, are suing the rare disease therapy accelerator Cydan and the biotech companies Vtesse and Sucampo Pharmaceuticals for alleged breach of contract, unjust enrichment, and misappropriation of trade secrets.

The suit, filed in United States District Court in Nevada Friday, comes after Vtesse was purchased by Sucampo for $200 million in April, and Sucampo struck a December deal to be sold to Mallinckrodt Pharmaceuticals for $1.2 billion. It centers around cyclodextrin, which Vtesse calls VTX-270, and which is being tested as a treatment for Niemann-Pick Type C, a rare disease. “A massive fraud has been perpetrated not only against the twins and our family but our researchers, doctors, hospitals, donors and community,” Chris Hempel wrote on Facebook in August. “Cyclodextrin has been stolen and now sold for $200 million dollars!! It’s going to a billion++ dollars when approved. This was a drug funded and created by all of you who helped us.”

The Hempels are filing on behalf of their daughters Addison and Cassidy, who were diagnosed with Niemann-Pick Type C when they were toddlers. The girls had enlarged spleens, one of the many symptoms of Niemann-Pick Type C that also include movement problems, developmental delays, seizures, and hearing loss. Cells in the girls’ bodies don’t metabolize and transport cholesterol properly, which leads to buildup in the liver, spleen, and brain. The disease is an ultra-rare genetic condition with only an estimated 500 diagnosed cases worldwide. There is no cure.

Soon after getting the diagnosis, the Hempels started pursuing cyclodextrin, a sugary compound, as a potential treatment based on the research of scientist Benny Liu while he was at the University of Texas Southwestern Medical Center. Along the way, they’ve grabbed plenty of press attention. The early story of the Hempel’s pursuit of cyclodextrin and other efforts to develop drugs for Niemann-Pick Type C at the National Institutes of Health were previously reported in The Wall Street Journal by Amy Dockser Marcus after she followed the parents, scientists, and children for six years. In 2014, they were profiled on Dr. Sanjay Gupta’s CNN show Vital Signs. “We were willing to do anything and take that risk,” Chris Hempel said in the segment. “And, you know, without risk, there’s no reward.”

The Hempels say they bought cyclodextrin, which is an ingredient in household products like Febreze and used in the formulation of some drugs to make them useful in the body, from a distributor.  At first, they gave the girls cyclodextrin dissolved in water in their sippy cups. Later, the Hempels sought FDA permission to give the girls weekly IV infusions of the compound, then intrathecal injections through spinal taps every two weeks, then infusions through catheters that gave direct access to the brain. They convinced Johnson & Johnson to share safety research on cyclodextrin, which the company used in an antifungal medicine, and developed treatment protocols with the girls’ doctor, collecting safety data all the while.

As researchers associated with the National Center for Advancing Translational Sciences, a division of the NIH, began clinical trials of cyclodextrin in children with Niemann-Pick Type C, the Hempel’s lawsuit says they asked to reference data on the Hempel twins’ treatment, which their parents and doctor allowed. That data is at the center of the lawsuit. The Hempels allege that the data was provided to a doctor treating a patient in the NIH trial for one-time use, but instead was used to inform Vtesse’s clinical trials. The Hempels say they had intended to create a non-profit to develop cyclodextrin, and that they had conversations with Cydan, a biotech incubator, to do so. But they allege that Cydan instead used that information to help start Vtesse.

It doesn’t appear that the Hempels possessed any patents protecting this use of cyclodextrin. They are alleging breach of contract. They also appear to have had data from only their daughters, although this included information on how best to dose cyclodextrin, including how to inject the drug directly into the spinal column. Caroline Hastings, the doctor at UCSF Benioff Children’s Hospital who treated the Hempel twins, is not a party to the lawsuit and says she has no financial relationship with the Hempels or the company they were trying to form. But she says she found the way data she shared was used to be irregular.

“I have to say we all feel pretty shafted by what happened,” Hastings says. “And it’s divided the patient community. With rare diseases, you want people to come together. It’s been divisive having multiple groups.” She later added: “I’ve never personally had an experience like this in my 25 years of doing clinical trials.”

The press release announcing the Sucampo-Mallinckrodt deal says they expect to file a new drug application for VTS-270 in 2018 for anticipated approval in 2019. Its estimated peak net sales are greater than $150 million. Approval of the drug for a rare pediatric disease would also award Mallinckrodt a priority review voucher, which it could use for a drug application of its own or sell.
The Hempels say their plan was to direct half of the profits from commercializing cyclodextrin into more research on treatments for Niemann-Pick Type C and to help families affected by the disease. In the lawsuit they express concern about losing control of future cyclodextrin research and the drug’s price.

“In short,” the Hempels allege in the lawsuit, “Cydan, Vtesse, and Sucampo had not only misappropriated the Hempels’ Confidential Information and trade secrets, but also the [Niemann-Pick Type C] community’s autonomy.”

“While we cannot comment on active litigation, we will defend our position vigorously,” Peter Greenleaf, Sucampo’s Chairman and CEO, said in a statement. “We are pleased that Sucampo has been able to play an active role in advancing the science around this potential treatment for Niemann-Pick Disease Type C with the scientific rigor that a clinical trial demands – all in efforts to benefit the patients and families living with this devastating, fatal disease for which there is no approved therapy in the U.S.”

“We cannot provide specific comment on ongoing litigation, but believe their claims are without merit and plan to vigorously defend ourselves,” Cydan said in a statement. “Cydan is committed to improving the lives of patients living with rare monogenetic diseases, such as NPC. We are pleased we were able to play a role in advancing VTS- 270, a potentially meaningful new treatment for patients and families living with this devastating, fatal disease, for which there are no currently approved treatment options in the U.S.”

Courtesy of a colleague


Tuesday, August 28, 2018

Tide of lies

Sato's fraud was one of the biggest in scientific history. The impact of his fabricated reports—many of them on how to reduce the risk of bone fractures—rippled far and wide. Meta-analyses that included his trials came to the wrong conclusion; professional societies based medical guidelines on his papers. To follow up on studies they did not know were faked, researchers carried out new trials that enrolled thousands of real patients. Exposing Sato's lies and correcting the literature had been a bruising struggle for Avenell and her colleagues.

Yet they could not understand why Sato faked so many studies, or how he got away with it for so long. They puzzled over the role of his co-authors, some of whom had their names on dozens of his papers. (“Do we honestly believe they knew nothing at all about what was going on?” Avenell asked.) They wondered whether other doctors at his hospital read Sato's work—and whether the Japanese scientific community ever questioned how he managed to publish more than 200 papers, many of them ambitious studies that would have taken most researchers years to complete.

The tools of science that the group had used—analyzing studies, calculating statistics, writing papers—could reveal fraud. But they could not expose the personal and cultural factors that drove it, or assess its emotional toll. So I set off on a quest that would eventually lead me to the Mitate Hospital in Tagawa, a small town on the island of Kyushu, where Sato had worked in the last 13 years of his life…

Avenell's own quest began in 2006, when she was combing through dozens of papers for a review evaluating whether vitamin D reduces the risk of bone fractures. In two papers by Sato, she stumbled on a weird coincidence. They described different trials—one in stroke victims, the other in Parkinson's disease patients—but the control and study groups in both studies had the exact same mean body mass index. Looking further, she quickly found several other anomalies. She decided not to include Sato's studies in her analysis.

She wasn't the first to notice something was off. In a 2005 Neurology paper, Sato claimed that a drug named risedronate reduces the risk of hip fractures in women who have had a stroke by a stunning 86%. In a polite letter to the journal, three researchers from the University of Cambridge in the United Kingdom noted that the study was “potentially of great importance,” but marveled that the authors had managed to recruit 374 patients in just 4 months.

Two years later, a letter in what was then the Archives of Internal Medicine was less polite. A study of male stroke patients published by Sato had managed to enroll 280 patients in just 2 months; another one, of women with Alzheimer's disease, recruited a staggering 500 in an equally short period. Sato claimed to have diagnosed all of the Alzheimer's patients himself and done follow-up assessments of all 780 patients every 4 weeks for 18 months. Both studies had very few dropouts, and both showed risedronate, again, to be a resounding success. “We are deeply concerned whether the data provided by Sato et al are valid,” Jutta Halbekath of Arznei-Telegramm, a Berlin-based bulletin about the drug industry, and her co-authors wrote. Sato apologized in a published response and claimed the study had been conducted at three hospitals, not one. “The authors did not describe this fact, the reason being that these hospitals were reluctant to have their names in the article,” he wrote. He didn't name the other hospitals or explain why they wanted to remain anonymous. The journal apparently accepted the explanation.

The letter's authors also spotted a troubling pattern. In addition to the two papers in the Archives of Internal Medicine, they found 11 further studies by Sato, published elsewhere, that tested whether sunlight, vitamin D, vitamin K, folate, and other drugs could reduce the risk of hip fractures. All but two reported “extremely large effects with significant results,” they noted. But the Archives of Internal Medicine didn't want to point fingers at other journals. “You may allude to your concern that other papers have similar concerns,” its editors warned Halbekath, “but we cannot allow you to mention those other papers by journal name.”

By now, several researchers had raised red flags and waved them for everyone to see—and then everybody moved on. “The trail just went cold,” Avenell says.

Mark Bolland had never heard of Sato when Avenell first mentioned him in late 2012. She and Bolland, a clinical epidemiologist at the University of Auckland in New Zealand, have never met in person, but they joined forces to write meta-analyses on calcium supplements in 2008, together with Andrew Grey and Greg Gamble, both also at the University of Auckland. One topic the quartet discussed frequently was why meta-analyses on the same topic sometimes reach different conclusions. Avenell mentioned Sato's studies and noted that the effects they reported were so strong that they might swing meta-analyses if they were included.

Intrigued, Bolland looked up the papers. He, too, was stunned by the large cohorts, the low number of dropouts, and the big effects of almost any treatment tested. “There is nothing that I can think of that produces a 70% to 80% reduction in hip fractures, yet Sato was able to do it consistently in all his trials,” he says.

To follow up on his suspicions, Bolland turned to statistics. When scientists compare a treatment and a control group, they usually report “baseline characteristics” for each—things like age, weight, and sex, or, in osteoporosis studies, bone density and calcium intake. From these values, scientists can calculate p-values that are a measure of the similarity of two groups for a given characteristic; the closer to one the value is, the more the groups resemble each other. Because the groups are randomly selected, the p-values should normally be “equally distributed”; the value for age or weight is just as likely to be between 0 and 0.1 as between 0.9 and 1.0, for example.

Bolland extracted the baseline characteristics from the 33 clinical trials Sato had published at the time, more than 500 variables all in all, and calculated their p-values. More than half were above 0.8, he found. “That just shouldn't happen,” he says. “The randomized groups were incredibly similar.” There was just one plausible explanation, he says: Sato had fabricated data for both groups and had made them more similar than they would ever be in real life.

The team felt it had a damning indictment. “I thought: ‘This is so convincing. Everybody is going to believe this,’” Avenell says. Still, “It needed detailed statistical refereeing, and it needed to be published by a journal so that other affected journals would take note,” she adds. So they wrote their accusation as a scientific paper. All they had to do was publish it and wait for researchers, journals, and institutions to react, investigate, and retract. Or so they thought.

In March 2013, the team submitted the manuscript to The Journal of the American Medical Association (JAMA), the highest profile journal Sato had published in, and one it felt might have the resources for an in-depth investigation. After reviewing the evidence, JAMA Editor-in-Chief Howard Bauchner told the team the editors would ask Sato and, if necessary, his institution to respond.

Two years later, in April 2015, JAMA told the researchers the hospital had not responded, and it would publish an “expression of concern”—a short note to flag Sato's JAMA paper as suspicious. It would not publish the whistleblowers' paper, however; if the team had concerns about other papers, it should contact the journals that had published them, Bauchner said.

The four researchers were shocked. “To find out after waiting 2 years that in fact nothing much had really happened and, other than an expression of concern, was going to happen in JAMA, was quite frustrating,” Bolland says. (Bauchner declined to answer Science's questions about the case.)…

Next, the paper was rejected by JAMA Internal Medicine, which had also published Sato's work. The Journal of Bone and Mineral Research, a highly rated journal in the osteoporosis field, said it would investigate Sato's papers, but would not publish the manuscript either. The editors of Trials, which had not published Sato's work, said it would not be appropriate to get involved.

Bolland became demoralized. The other three persuaded him not to give up. “If you ever embark on something like this, make sure you have a good support team,” he says now. Avenell, too, was sometimes despondent. Whereas the other three researchers at least saw each other in Auckland, she was on her own, frustrated, in the dreary, gray town of Aberdeen. Sometimes, she says, she would just sit in a corner of her open floor plan office and cry.

Then, in June 2015, came a small success: The Journal of Bone and Mineral Research retracted one of the 33 trials the team had analyzed. A few other journals followed suit in the months after. But some seemed irritated by the group's persistence. “It is apparent that the responses to the JAMA investigation by Dr. Sato and his institution have been either inadequate or not forthcoming,” Grey wrote to Bauchner in December 2015. “At what point will JAMA consider more decisive action, such as retraction?” “We will consider your opinion about how you think it best we should conduct the investigation,” Bauchner responded. “We often hear from people how they think we should perform our responsibilities as editors.”

In what Bolland calls “really just the last throw of the dice,” that same month the group submitted the paper to Neurology, where Sato had published three papers about bone fractures in patients with neurological disease. When it was accepted 8 months later, Avenell cried again. “I'm not one usually given to showing such emotion, especially when all I have is a computer screen and emails to look at,” she says…

By the time Neurology published the investigation in December 2016, 10 of the 33 trials had been retracted, all but one by journals the team had contacted. Three months later, Avenell received an email from an editor with troubling news. Sato was dead…

Today, 21 of Sato's 33 trials have been retracted by the journals or Sato himself; Avenell has crossed them off a list taped next to her computer with a red marker. But now the team is following the ripples that the studies caused, focusing, for the time being, on a dozen papers published in the journals with the highest impact factors. Together, these studies reported results for 3182 participants. They have been referenced more than 1000 times, and 23 systematic reviews or meta-analyses have included one or more of the 12 trials…

The letter does not mention fraud, however. “I couldn't force him to confess,” Ogawa says. “I think he had a mental illness.” His emails were not logical, he says. “To tell the truth, I predicted that he would commit suicide.”

Suicide. Is he sure that's what happened?

“I received the information from the lawyer of Mr. Sato,” Ogawa says. Sato also left a note, he says, and he paraphrases it: “I am very sorry for Mr. Iwamoto. I decided to commit suicide.”

When I call Avenell after my return from Japan and tell her what I have learned, there is stunned silence at first. “That's what we were dreading,” she says. “That's horrible, really horrible.” Exposing the misconduct was important, she says. “Could we have done it without Sato committing suicide? So that he felt less guilty? I just don't know.”

Later she follows up with an email, still astonished at “how such a small piece of data analysis a long time ago can end up with someone dying.” As a clinician and a researcher, Avenell wrote, she knows her work can eventually make the difference between life and death. “But seldom is the connection between a clinician and another human being's death so obvious.”

Courtesy of a colleague

Saturday, August 25, 2018

An enormous study of the genes related to staying in school

An Enormous Study of the Genes Related to Staying in School

When scientists publish their research, it’s rare for them to write an accompanying FAQ that explains what they found and what it means. It’s especially rare for that FAQ to be three times longer than the research paper itself. But Daniel Benjamin and his colleagues felt the need to do so, because they work on a topic that is frequently and easily misunderstood: the genetics of education…
Now, after scanning the genomes of 1,100,000 people of European descent—one of the largest studies of this kind—they have a much bigger list of 1,271 education-associated genetic variants. The team—which includes Peter Visscher, David Cesarini, James Lee, Robbee Wedow, and Aysu Okbay—also identified hundreds of variants that are associated with math skills and performance on tests of mental abilities.

The team hasn’t discovered “genes for education.” Instead, many of these variants affect genes that are active in the brains of fetuses and newborns. These genes influence the creation of neurons and other brain cells, the chemicals these cells secrete, the way they react to new information, and the way they connect with each other. This biology affects our psychology, which in turn affects how we move through the education system.

This isn’t to say that staying in school is “in the genes.” Each genetic variant has a tiny effect on its own, and even together, they don’t control people’s fates. The team showed this by creating a “polygenic score”—a tool that accounts for variants across a person’s entire genome to predict how much formal education they’re likely to receive. It does a lousy job of predicting the outcome for any specific individual, but it can explain 11 percent of the population-wide variation in years of schooling.

That’s terrible when compared with, say, weather forecasts, which can correctly predict about 95 percent of the variation in day-to-day temperatures. But when it comes to predicting education, it’s comparable to classic factors such as household income or how educated your parents are. “Within social science, that’s basically unheard of,” says Benjamin, who works at the University of Southern California, Los Angeles. “We can explain education as well with saliva samples as with demographics.”…

On the flip side, there are fears that this kind of research could lead to discrimination against, or stigmatization of, people with certain genetic variants. Such fears aren’t unreasonable: Many forefathers of genetics were also proponents of eugenics, advocating that people with supposedly inferior genes should be discouraged from reproducing.

Paige Harden, a clinical psychologist at the University of Texas at Austin, thinks that neither these dystopian perils nor the more beneficent applications around personalized education are realistic. “I don’t think that’s where we are,” she says, because one still cannot use a person’s DNA to accurately predict their scholastic fates.

Benjamin and his colleagues agree. Look at the graph below, which plots years of schooling against subjects’ polygenic scores. Each dot is a person. Sure, on average, those with higher scores got more education than those with the lowest. But for any given score, there are huge variations in years of schooling. “Should we use the score to put some people into more advanced classes and others into more remedial classes?” says Benjamin. “That’s a total nonstarter because of the low predictive power for any given individual.” The same applies to mathematical prowess, or overall cognitive ability…

“It’s actually quite reassuring in showing that you could not accurately predict educational outcome from DNA,” says Dorothy Bishop, a neuroscientist and geneticist at the University of Oxford. “The disturbing scenario of people screening babies in the hope of selecting the brightest does not seem supported by this study.”

Indeed, Benjamin suspects that there’s a ceiling of accuracy that his team has almost hit. Even if they study millions more people, he believes they won’t be able to predict the educational fate of a single person with much more reliability than they can now. For that reason, the team have this to say in their FAQ:

What policy lessons or practical advice do you draw from this study?

None whatsoever. Any practical response—individual or policy-level—to this or similar research would be extremely premature and unsupported by the science…

Perhaps counterintuitively, Benjamin thinks that his team’s research “is really important for research on improving educational systems.” To understand how, forget genes for a moment, and think about wealth.

It’s uncontroversial to say that people who are born into rich families are more likely to fare better in school than those from poorer backgrounds. Of course, poor kids can still soar in school, and rich ones can flunk out, but few would deny that money is a powerful influence on people’s futures. Now, consider that household income explains just 7 percent of the variation in educational attainment, which is less than what genes can now account for. “Most social scientists wouldn’t do a study without accounting for socioeconomic status, even if that’s not what they’re interested in,” says Harden. The same ought to be true of our genes.

Imagine that authorities are planning to provide free preschool to kids from disadvantaged backgrounds. To see if such a policy actually helps children stay in school for longer, scientists would randomly assign the free classes to some kids but not others. Then, they would look at how the two groups fared. In doing so, they’d always try to account for factors like wealth that might also vary between the two groups. Similarly, “you can now wash away the genetic effects so you don’t have to worry about them,” says Benjamin. And in doing so, researchers could more precisely work out whether a policy change has any benefits—and they could do it through smaller, cheaper studies.

This, he argues, is the most powerful reason to study the genetics of education or cognitive ability—and ironically, it has very little to do with genes. Instead, it’s a way of making social science more powerful.

The team is essentially studying genes so they can more thoroughly ignore them.

Courtesy of  Doximity

J. Lee, Robbee Wedow, Aysu Okbay, Edward Kong, Omeed Maghzian, Meghan Zacher, Tuan Anh Nguyen-Viet, Peter Bowers, Julia Sidorenko, Richard Karlsson Linnér, Mark Alan Fontana, Tushar Kundu, Chanwook Lee, Hui L, Ruoxi Li, Rebecca Royer,  Pascal N. Timshel1, Raymond K. Walters, Emily A. Willoughby, Loïc Yengo, 23andMe Research Team, COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, Maris Alver, Yanchun Bao, David W. Clark, Felix R. Day, Nicholas A. Furlotte, Peter K. Joshi, Kathryn E. Kemper, Aaron Kleinman, Claudia Langenberg, Reedik Mägi, Joey W. Trampush, Shefali Setia Verma, Yang Wu, Max Lam, Jing Hua Zhao,  Zhili Zheng, Jason D. Boardman, Harry Campbell, Jeremy Freese, Kathleen Mullan Harris, Caroline Hayward, Pamela Herd, Meena Kumari, Todd Lencz, Jian’an Luan,  Anil K. Malhotra, Andres Metspalu11, Lili Milani, Ken K. Ong, John R. B. Perry,  David J. Porteous, Marylyn D. Ritchie, Melissa C. Smart, Blair H. Smith, Joyce Y. Tung, Nicholas J. Wareham, James F. Wilson, Jonathan P. Beauchamp, Dalton C. Conley,  Tõnu Esko, Steven F. Lehrer, Patrik K. E. Magnusson,  Sven Oskarsson, Tune H. Pers,  Matthew R. Robinson, Kevin Thom, Chelsea Watson, Christopher F. Chabris,  Michelle N. Meyer, David I. Laibson, Jian Yang, Magnus Johannesson, Philipp D. Koellinger,  Patrick Turley, Peter M. Visscher, Daniel J. Benjamin and David Cesarini.  Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.  Nature Genetics| Vol 50 | August 2018 | 1112–1121 |

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This predic-tion accuracy substantially increases the utility of polygenic scores as tools in research.

Friday, August 24, 2018

Treatment for Friedreich's ataxia

A dozen years ago, Joel Gottesfeld became intrigued with the conclusion of a paper he was editing for the Journal of Biological Chemistry.

The article that the Scripps Research Institute scientist was reviewing dealt with the gene that codes for frataxin, an essential protein that’s missing in Friedreich’s ataxia.

The authors, frataxin experts Bob Wells and Marek Napierala, offered an explanation for frataxin’s absence: A mutation in the FXN gene, which other scientists had identified, causes the gene to adopt an unusual DNA structure. And that structure silences the gene, preventing frataxin production. The paper’s conclusion “basically said something like, wouldn’t it be neat if you could find a pharmacological agent, a small molecule, to turn the frataxin gene back on,” Gottesfeld said in an interview with Friedreich’s Ataxia News…

The first step, Gottesfeld said, was basic science.

“What my lab and a number of other labs did a decade or so ago was to figure out just what the genetic mutation does to cause the loss of this protein,” he said.

The reason the FXN gene is abnormal in FA is that it contains too many repeats of one of the DNA sequences that make up the gene.

At the heart of frataxin silencing, scientists discovered, was a characteristic of another type of protein that is packaged with the FXN gene.

These proteins, called histones, “can have chemical tags put on them, and these tags either tell the gene whether it’s going to be active or inactive,” Gottesfeld said. “It turns out that the repeats cause the chemical tags to be inactive,” which means they don’t produce frataxin.

“So the idea that we had was to identify small molecules [chemical compounds] that would reverse the tags that say ‘I’m an inactive gene,’ and cause the tags to say ‘I’m an active gene,’” he said.

His team found a commercially available molecule that prompted the gene to become active — but not active enough.

So a chemist in his laboratory, Ann-Kristen Jenssen, tweaked the compound to “show us the path forward to make a molecule that would fully reactivate the silent gene,” Gottesfeld said.

The next step was to test the refined molecule in cell cultures of FA and in mice with the disease. Gottesfeld’s team collaborated on the mouse research with Massimo Pandolfo, who discovered the FXN gene mutation that causes FA and who developed a mouse model of the disease to help study it.

The cell and mouse research showed that the molecule could turn on frataxin production. This meant that it was time to find a corporate partner to work toward a therapy, Gottesfeld said.

A small Boston-area biopharmaceutical company called Repligen became that partner. It improved on the molecule, which it named RG2833, and brought it to a Phase 1 crossover clinical trial in 20 FA patients that concluded in 2013.

The results, published in Annals of Neurology in 2014, “showed that, at least in circulating white blood cells in Friedreich’s ataxia patients, that we could turn the gene back on,” Gottesfeld said.

As the study’s authors put it, results provided “proof of principal for orally administered class I HDAC inhibitor as potential therapeutics for Friedreich’s ataxia.”

“So this was very encouraging,” Gottesfeld said. “But the problem was — and in drug discovery this is very common — there were problems with the molecule. So this was Round One.”

At that point, Repligen decided to get out of drug development and sell its FA therapy development technology to BioMarin, the nation’s ninth-largest pharmaceutical.

Since then, Gottesfeld’s team has been collaborating with the California-based company “on screening a large collection of derivatives of the original compound class.”

After BioMarin decides on a final compound and tests it in cell cultures and in animals, the next step will be to request a clinical trial.

A decision by BioMarin on a final version of the compound is on the horizon, Gottesfeld said…
Gottesfeld has been at the Scripps institute for 40 years, he said. Regulatory approval of a small-molecule therapy that helps people with FA would be a fitting cap to his career.

Meanwhile, his lab will continue working with BioMarin until it makes a final decision on a compound for possible human trials.

“They send us molecules that they have synthesized, and we have this cell model — actually human neurons from patients’ cells — that we test them on,” he said.

His team has put a good deal of work into developing a way to treat FA since he reviewed that journal article 12 years ago.

But if you were to ask him about it, he would likely say it’s been a lot of fun.

Soragni E, Miao W, Iudicello M, Jacoby D, De Mercanti S, Clerico M, Longo F, Piga A, Ku S, Campau E, Du J, Penalver P, Rai M, Madara JC, Nazor K, O'Connor M, Maximov A, Loring JF, Pandolfo M, Durelli L, Gottesfeld JM, Rusche JR. Epigenetic therapy for Friedreich ataxia. Ann Neurol. 2014 Oct;76(4):489-508.


To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients.

We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells.

In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered.

Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.

High-dose prednisolone for infantile spasms

John R. Mytinger.  High-Dose Prednisolone as a First-line Treatment for Infantile Spasms.  Pediatric Neurology, in press.

Infantile spasms (IS) are seizures associated with a severe infantile epileptic encephalopathy called West syndrome. Both clinical remission of IS and electrographic remission of the epileptic encephalopathy are necessary for the best possible patient-specific epilepsy and neurodevelopmental outcomes. Corticosteroids and adrenocorticotropic hormone (ACTH) are hormone therapies that have been used for the treatment of IS since the late 1950s.  By the early 1990s, the preference for ACTH for the treatment of IS was relatively uniform among US child neurologists.The superiority of ACTH over corticosteroids seemed to be confirmed with a small 1996 study reporting electroclinical remission in 13 of 15 (86.6%) children treated with high-dose natural ACTH (150 IU/m 2 /day) and only 4 of 14 (28.6%) children treated with low-dose prednisone (2 mg/kg/day).  We later learned that the rate of IS remission with corticosteroids could be improved by increasing the dose. 

The 2004 study by Lux and colleagues (United Kingdom Infantile Spasms Study [UKISS]) reported a 70% rate of clinical IS remission using high-dose prednisolone (40-60 mg/day).  This result led some members of the IS community to question the superiority of ACTH over corticosteroids. Then, in 2007, the price of a single vial of natural ACTH (H.P. Acthar Gel) in the US suddenly increased from $2,063 to $23,000.  In the years since, the cost of H.P. Acthar Gel has soared to approximately $40,000 per vial, resulting in a minimum cost of $80,000 to $120,000 for a typical one-month treatment course. These factors, as well as prednisolone's low cost (less than $40 for a one-month course), widespread availability, and ease of administration, have led to an increase in the use of high-dose prednisolone (40-60 mg/day or 4-8 mg/kg/day) for IS.

High-dose prednisolone was included as one of three recommended treatments (in addition to ACTH and vigabatrin) in the 2017 Quality Measure Set from the American Academy of Neurology and Child Neurology Society.  This measure states that ACTH, high-dose prednisolone, or vigabatrin should be used for the initial treatment of IS unless refused, contraindicated, enrolled in research, or better treated with surgery.  Consistent use of these standard treatments over nonstandard treatments (e.g. topiramate) significantly improves the rate of electroclinical remission.   ACTH, high-dose prednisolone, and vigabatrin are also tnd vice versa). Thus, even when high-dose prednisolone is the preferred initial treatment for IS, ACTH and vigabatrin are the best next treatment options.

Physicians from the Johns Hopkins Hospital took an early position in the debate about ACTH versus high-dose prednisolone. This group chose to use high-dose prednisolone or the ketogenic diet as the initial treatment of IS beginning in 2007, and they no longer offered ACTH.  In this issue of Pediatric Neurology , Gonzalez-Giraldo and colleagues from John Hopkins report their experience treating IS with high-dose prednisolone from 2006 to 2016.  In this retrospective analysis, the authors identified 87 children treated with high-dose prednisolone as the first or second treatment. The main outcome measure was clinical remission of IS by two weeks and resolution of hypsarhythmia or similar pattern between two to four weeks on a 30 minute electroencephalogram (EEG). Electroclinical remission occurred in nearly two thirds (56/87, 64.4%) of children. However, a relapse of IS occurred in 26 of 56 (46.4%) children indicating an early sustained remission rate of 34.5%.

Although the study by Gonzalez-Giraldo and colleagues gives additional support for the use of high-dose prednisolone as a first-line treatment for IS, we have yet to definitively answer the fundamental question about the relative effectiveness of ACTH versus prednisolone. Two recent randomized controlled trials, both reporting electroclinical remission as a secondary outcome measure, advance our understanding of hormone therapy but provide differing results. In 2015, Wanigasinghe and colleagues (Shri Lankan study) reported that electroclinical remission starting within two weeks and sustained for 28 days was significantly higher in children receiving high-dose prednisolone (15/48, 31.3%) compared to children receiving synthetic ACTH (6/49, 12.2%; P=0.008).  In 2017, O'Callaghan and colleagues (International Collaboration Infantile Spasms Study: ICISS) reported that electroclinical remission beginning within two weeks and sustained to day 42 was significantly higher in children receiving synthetic ACTH (76/111, 68.5%) compared to children receiving high-dose prednisolone (151/263, 57.4%; P=0.04).  The reasons for these incongruous results are unknown but considerations include differences in enrollment and study design.

In contrast to the US, where natural ACTH is used for the treatment of IS, the synthetic depot form of ACTH was used in both the Shri Lankan study and ICISS. A US clinical trial of synthetic depot ACTH (as monotherapy or dual therapy with vigabatrin) is underway (NCT03347526). This raises the possibility that we would ultimately have access to a synthetic depot ACTH in the US. However, recent history justifies some apprehension about the potential price of an FDA approved IS treatment with an orphan drug status.

Even if the US acquires access to a synthetic depot ACTH, the cost of this product is likely to be much higher than the cost of prednisolone. In addition, questions will persist about the relative effectiveness of ACTH versus high-dose prednisolone as well as synthetic versus natural ACTH. While there has been an interest within the IS community of a US randomized control trial of natural ACTH versus high-dose prednisolone essentially since the 2004 UKISS publication, the cost of H.P. Acthar Gel has made this nearly impossible. There is no incentive for an owner of H.P. Acthar Gel to support a clinical trial that may fail to show ACTH superiority over high-dose prednisolone. The approval of a lower cost synthetic depot ACTH in the US may revive interest in a US study of ACTH versus high-dose prednisolone, but drug cost may remain a barrier. Yet, a well done clinical trial has the potential to change clinical practice, whether it results in an increase in the use of ACTH for superiority or in the consistent initial use of high-dose prednisolone prior to ACTH if efficacy is similar. In an effort to confirm electroclinical remission, a future clinical trial should utilize multiple EEG reviewers (given the lack of inter-rater agreement in the determination of hypsarhythmia) and longer duration EEGs that include sleep. 

Ernesto Gonzalez-Giraldo, Carl E. Stafstrom, Anthony C. Stanfield and Eric H. Kossoff.  Treating Infantile Spasms with High-Dose Oral Corticosteroids: A Retrospective Review of 87 Children. Pediatric Neurology, in press. 


Hormonal therapy is the treatment of choice in most cases of infantile spasms (IS), but the optimal way to provide this is unclear. Intramuscular adrenocorticotropic hormone (ACTH) is historically used first-line; however, there are significant logistical and financial issues. Our institution has used high-dose prednisolone as the first-line hormonal treatment of IS since 2006 and published our early experience with 15 infants in 2009. This study updates our institutional experience over more than 10 years of continuous use.

Charts of infants who presented to the Johns Hopkins Hospital with IS and were treated with high-dose oral prednisolone (40-60 mg/day) from 1/2006-12/2016 were reviewed. Electroclinical response was defined as clinical spasm-freedom and resolution of hypsarrhythmia within two weeks of initiation of therapy. Presence of IS at 3 months and adverse effects throughout treatment were evaluated.

Over the 10-year time period, 87 infants with new-onset IS were treated. Electroclinical response was seen in 64% infants within 2 weeks; 62% were spasm-free at 3 months. Fifty two percent had side effects, primarily irritability, weight gain, and gastroesophageal reflux. Five percent had major adverse events, including gastrointestinal bleed (n=2), herpes simplex virus reactivation (n=1), and necrotizing enterocolitis (n=1).

Our results continue to demonstrate that high-dose oral prednisolone is very effective for the treatment of new-onset IS, with few major adverse effects. Oral prednisolone represents a less expensive, readily available alternative to ACTH injections.


Paroxysmal dyskinesia

The toddler zipped across the room on her hands and knees. She had only recently started crawling and clearly loved the sense of speed and independence that her newfound mobility gave her. Go, baby, go, her mother called out encouragingly. Suddenly the child stopped; her head dipped toward the floor. Her arms bent, lowering her upper body to the floor. Kamiyah? Her mother called out. Baby? She hurried toward where her daughter knelt, head on the floor, eyes closed. But before she got there, the child’s eyes popped open; she lifted her head, straightened her arms and immediately raced across the floor, as if nothing had happened.

What was that? the young mother asked her husband. Is that normal? The baby, their first, now seemed fine. Maybe it was O.K., the father suggested. Then it happened again, and again. A total of 10, maybe 20 times in the hours she played on the floor. The mother had never seen anything like it before. Neither had the father. Maybe this was just something that babies did? She had an appointment with her pediatrician in Sioux Falls, S.D., in a couple of weeks. She could ask him then.

After that day, the little girl’s mother began to see the strange spells all the time. Sometimes it was so quick that it was almost as if she imagined it. Her beautiful daughter’s eyes would flutter shut, and she would seem to be asleep — but just for a second or two. Then her eyes would open and she would be back in the room, back with them, as if she had never been away. Was is something that just started? Or was it that they had never really noticed it until she was moving. The baby had some developmental delay — they had been told that — but was this part of whatever it was that caused her delay? [video at link]

The strangest part of these little spells was that she was most likely to have them when she was happy. That first time, the delight in her own speed had been so clear on the little girl’s face. Other times, she would be smiling, even laughing, when suddenly she would draw her arms close to her body stiffly. Then she would blink, once, twice, and her eyes would close. Sometimes you could hear her breathing change, becoming raspy and slowed, before she drew her arms in and her eyelids fell. If she was sitting up, her head would drift forward until her chin was resting on her chest. And then her torso would take up the movement, sinking forward, almost in slow motion. Sometimes her mother would catch her before her forehead made contact with the floor, but often enough before she even got close, the child would wake up and sit back up as if the past 10 to 15 seconds had never happened….

The pediatrician sent Kamiyah for an EEG and referred them to a pediatric neurologist.

When the day of the appointment with the neurologist finally came, the child’s mother brought all Kamiyah’s favorite toys. She knew that if she could make her laugh, she would trigger one of these spells and the doctor could see what was happening. The neurologist did see. It looked to her like an absence seizure, a type of epilepsy usually seen in children and characterized by brief episodes of a loss of awareness, without a loss of consciousness.

She ordered an EEG to look for seizure activity. It was completely normal. Thinking that they had missed the episodes, she ordered a longer EEG and then a video EEG. None showed any seizure activity in the brain. A CT scan was also normal. Despite the normal EEGs, the neurologist continued to think that what she was seeing in her office and on the videos were most likely some type of seizure. She prescribed an anti-seizure medication called Keppra, but Kamiyah’s parents weren’t ready to drug their child. Instead they sought a second opinion from a pediatric neurosurgeon in nearby Omaha. That doctor agreed with the first neurologist: Despite the normal EEG, it was still possible that these were seizures. They would get an M.R.I., but if it was normal, she still should try the medication…

They started the little girl on Keppra. Nothing. The seizures kept coming, and the medicine made the child sleepy. They tried a second drug, which seemed to make the spells a little less frequent, but she still had them. What about sending her to the Mayo Clinic in Rochester, Minn., the first neurologist suggested. They would try anything, the parents told him. So when Kamiyah was 2 years old, she and her mother went to the Mayo Clinic. The pediatric neurologist there saw several of Kamiyah’s spells. Her first thought was also that these were some sort of seizures, and she ordered still another EEG with video monitoring. Other possibilities on her list was some sort of movement disorder — either a type of dystonia, a transient stiffening of the muscles, or dyskinesia, a loss of voluntary muscle control…

 The following year, Kamiyah’s neurologist suggested that the child be referred to the National Institutes of Health’s Undiagnosed Diseases Network. This is a program developed by three branches of the N.I.H. — the National Human Genome Research Institute, the Genetic and Rare Diseases office of the National Center for Advancing Translational Sciences and the N.I.H. Clinical Center — to help provide a diagnosis for patients with mysterious symptoms who have remained without one even after a thorough evaluation…

And so mother and child returned to South Dakota, hopeful, but trying to remain realistic. Kamiyah’s mother waited, and waited, for an answer, but none came. She had practically given up when she finally heard from the U.D.N. just six weeks ago. The email said they had an answer for Kamiyah, now 6 years old. The whole team wanted to be there to discuss the results. When would she be available the following week? The young mother almost exploded. When she recovered herself, she emailed back, How about now? I mean, I’ve waited more than two years, and you call me with an answer that I have to wait another week for? The team couldn’t get together before then, the reply said…

Finally, the call came. It was good to hear the voices of the doctors she and Kamiyah had gotten to know during their trip to Bethesda. Dr. Cynthia Tifft, the pediatric geneticist who led the team, broke the news. Kamiyah had a genetic defect that was causing these strange spells. It was not something she inherited from either of her parents but was what is called a de novo, or new, mutation. This particular mutation caused a slowdown of one of the mechanisms controlling activity in the brain and spinal cord, and that, in turn, caused her episodes of slowing down, or what the U.D.N. team called paroxysmal dyskinesia.

There are a number of types of paroxysmal dyskinesia, triggered by a variety of problems. Although many of those with this kind of rare disorder experienced unexpected movement, Kamiyah’s mutation actually causes a suppression of movement leading to her transient episodes of weakness. And while Kamiyah was the first to receive this diagnosis at the U.D.N., a handful of patients around the world were known to have the same abnormality. Most of these young people had, in additional to the paroxysmal dyskinesia, some combination of seizure disorder, intellectual disability or developmental delay.

So Kamiyah was something of an outlier, even here. They were certain that Kamiyah did not have a seizure disorder or intellectual disability, and Tifft thought that much, perhaps all of Kamiyah’s very mild developmental delay was caused by these frequent episodes of dyskinesia, which stole developmental time from her. Treating these episodes — probably with some type of anti-seizure medication — so that they became less frequent, could allow Kamiyah to catch up to her normal developmental age. She doesn’t have epileptiform seizures, but those medicines can affect brain activity, and that’s what she needs — a medication that can affect her brain in a way that lets it work more normally…

And that’s where you may be able to help. There have been 21 patients with this exact genetic abnormality published in the scientific literature. But there are probably many more than that here in the real world. Does your child, nephew, granddaughter, patient have a disorder that looks like Kamiyah’s? Let us know. If possible, send us a video, with the patient’s consent, naturally. Let’s help Kamiyah and her mother build their village and, with luck, find a treatment that works well for Kamiyah.

Courtesy of a colleague

Wednesday, August 22, 2018

Disorders of consciousness update

Giacino JT, Katz DI, Schiff ND, Whyte J, Ashman EJ, Ashwal S, Barbano R, Hammond FM, Laureys S, Ling GSF, Nakase-Richardson R, Seel RT, Yablon S, Getchius TSD, Gronseth GS, Armstrong MJ. Comprehensive systematic review update summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018 Aug 8. pii: 10.1212/WNL.0000000000005928. doi: 10.1212/WNL.0000000000005928. [Epub
ahead of print]


To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.

Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.

No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.

Tuesday, August 21, 2018

Stiripentol for seizures with Dravet syndrome

The US Food and Drug Administration (FDA) has approved the anticonvulsant drug stiripentol (Diacomit, Biocodex) for the treatment of seizures associated with Dravet syndrome, the agency has announced.

Stiripentol is indicated for patients aged 2 or older who are taking clobazam. No clinical data support its use as monotherapy in Dravet syndrome, the FDA said. 

The most common side effects reported with stiripentol are somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, and insomnia.

Stiripentol must be dispensed with a patient Medication Guide that describes important information about the drug's uses and risks. As is true for many other antiepileptic agents, the most serious risks include suicidality, agitation, new or worsening depression, aggression, and panic attacks, the FDA said.

The dosage of stiripentol is 50 mg/kg/day, administered by mouth in two or three divided doses. Full prescribing information for stiripentol is available online.  

In June, as reported by Medscape Medical News, the FDA approved the first cannabis drug for Dravet syndrome and another rare form of epilepsy, Lennox-Gastaut syndrome.

Dravet syndrome is a rare genetic condition that usually appears in the first year of life with prolonged febrile seizures, followed often by other types of seizures, including myoclonic seizures. Patients with Dravet syndrome may also develop status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care.


Monday, August 20, 2018

Distinct origin of ADHD in children with a history of brain injury

Stojanovski S, Felsky D, Viviano JD, Shahab S, Bangali R, Burton CL, Devenyi GA, O'Donnell LJ, Szatmari P, Chakravarty MM, Ameis S, Schachar R, Voineskos AN, Wheeler AL. Polygenic Risk and Neural Substrates of  Attention-Deficit/Hyperactivity Disorder Symptoms in Youths With a History of Mild Traumatic Brain Injury. Biol Psychiatry. 2018 Jul 12. pii:
S0006-3223(18)31669-X. doi: 10.1016/j.biopsych.2018.06.024. [Epub ahead of print]


Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI.

Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata.

Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI.

The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.

Courtesy of Doximity

Diagnosing GH deficiency as a late effect of radiotherapy in childhood cancer survivors

Sfeir JG, Kittah NEN, Tamhane SU, Jasim S, Chemaitilly W, Cohen LE, Murad MH. Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2785-2793.


Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs).

We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing.

We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours).

The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.


Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus were searched for studies evaluating GHD.

Studies using IGF-1 or IGFBP-3 measurements compared with GH dynamic testing were identified.


Fifteen studies (IGF-1 [8 studies] and IGFBP-3 [7 studies]) enrolling 477 patients were included.
Wide variation in comparator tests was noted.

Although strongly correlated, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy, and simultaneous use of both tests in the same cohort did not improve the diagnostic accuracy.
For appropriately identifying patients with GHD, dynamic tests remained the most accurate despite high variability in the testing protocols.

Outcomes suggest the insulin tolerance test (ITT) to be the most accepted reference test when used alone or in combination with arginine; however, among practice groups, there were no standardized testing strategies.

GHRH and arginine stimulation were almost similar to ITT regarding their performance; however, one study displayed 66% sensitivity and 88% specificity for GHRH with arginine stimulation compared with the ITT.

They identified no sufficient data assessing the accuracy of serial GH testing (nocturnal or over 24 hours).

A kiss for brain tumor treatment

The family of a Philadelphia girl who was declared tumor-free three years after receiving a kiss from the pope has donated $50,000 to the hospital that helped save her.

Gianna Masciantonio, who was kissed from Pope Francis while battling an inoperable brain tumor that landed her in hospice for the first six months of her life, is now gearing up for preschool.

Masciantonio’s story first went viral in 2015, when she was hoisted up by a member of the Swiss Guard during the papal visit so that he could kiss her. Pope Francis did not know that Masciantonio was diagnosed with histiocytosis, which was causing a potentially fatal brain tumor to grow on her brain stem. But scans after the visit showed that her tumor was almost undetectable.

“She’s blown our expectations out of the water in terms of how she’s doing,” Dr. Amish Shah, a pediatric neuro-oncologist at Children’s Hospital of Philadelphia, told CBS Philly. “She’s resilient and she’s tough and instead of taking all this as something to be fearful of, she’s really taking this in stride.”

The family’s foundation, “For the Love of Grace,” shared on Aug. 17 that they were making a $50,000 donation to CHOP for pediatric brain tumor research. Masciantonio’s father, Joey, said the hospital is special to them, and that while no money could ever repay their gratitude, “we just want to help the kids.”

“Seeing your kid run around and seeing her doing the things she’s doing with what they told us from the beginning is amazing,” Joey Masciantonio told the news outlet….

One of the most touching stories centered on little Gianna Masciantonio and her family.
Little Gianna was diagnosed with an inoperable brain tumor when she was just one month old. According to her father, Joey Masciantonio, she spent the first six months of her life in hospice care.

Her parents were told by medical professionals that she had “days to months to live.” 

But Gianna has since defied those odds, and just celebrated her first birthday on September 17.
And when her family learned that Pope Francis was coming to town, they wanted him to bless their family, and especially their little girl. 

But the family of four had no idea that they would even be able to get as close to the pope as they did. 

“There are no words,” Kristen Masciantonio said on Good Day Philadelphia. “A gift from God.”
Kristen explained that one of her friends, Lori, is friends with someone who works for the FBI. Lori emailed the FBI connect months again, sharing Gianna’s story, but unfortunately there was nothing he could do at that point.

But the night before the family was planning on making their way into the city to see the pope, Lori received an email back. Kristen says that the email was sent late, so Lori didn’t see it until the next day.

Joey explained that they walked to the federal building where they got a sneak peek of the Popemobile before the pope’s took his ride around the city.

But at that point they still didn’t know they were going to see the Pope. 

“We just thought we’d see him drive by. We never thought in a million years that he would bless our daughter,” Joey said. 

A member of the Swiss Guard picked little Gianna up so that the Pope could bless her. Also, other marshals and FBI agents stood around the family, pointing and yelling towards the family so they would be noticed. 

The blessing proved to be a significant improvement for baby Gianna’s health.  Kristen tells FOX 29 that Gianna’s story has turned to truly be a miraculous one.

“We feel blessed for her incredible medical care and for God's grace. So, Gianna had her first scan since her kiss from Pope Francis. We are ecstatic to announce that her tumor is almost undetectable in a lot of the MRI cuts,” Kristen said.

A pediatric review of facioscapulohumeral muscular dystrophy

Jean K. Mah, Yi-Wen Chen.  A Pediatric Review of Facioscapulohumeral Muscular Dystrophy.   J Pediatr Neurol 2018; 16(04): 222-231.  


Facioscapulohumeral dystrophy is one of the most common forms of muscular dystrophies worldwide. It is a complex and heterogeneous disease secondary to insufficient epigenetic repression of D4Z4 repeats and aberrant expression of DUX4 in skeletal muscles. Type 1 facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of D4Z4 repeats on 4q35, whereas type 2 FSHD is associated with mutations of the SMCHD1 or DNMT3B gene in the presence of a disease-permissive 4qA haplotype. Classical FSHD is a slowly progressive disorder with gradual-onset of muscle atrophy and a descending pattern of muscle weakness. In contrast, early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement. However, the correlation between D4Z4 repeats and disease severity remains imprecise. The current standard of care guidelines offers comprehensive assessment and symptomatic management of secondary complications. Several clinical trials are currently underway for FSHD. New and emerging treatments focus on correcting the transcriptional misregulation of D4Z4 and reversing the cytotoxic effects of DUX4. Other potential therapeutic targets include reduction of inflammation, improving muscle mass, and activating compensatory molecular pathways. The utility of disease-modifying treatments will depend on selection of sensitive clinical endpoints as well as validation of muscle magnetic resonance imaging (MRI) and other biomarkers to detect meaningful changes in disease progression. Correction of the epigenetic defects using new gene editing as well as other DUX4 silencing technologies offers potential treatment options for many individuals with FSHD.

Saturday, August 18, 2018

Long-term retention rates of antiepileptic drugs used in acute seizures.

Toledo M, Fonseca E, Olivé M, Requena M, Quintana M, Abraira-Del-Fresno L, Salas-Puig X,  Santamarina E. Long-term retention rates of antiepileptic drugs used in acute seizures. Seizure. 2018 Aug 11;61:78-82. doi:10.1016/j.seizure.2018.08.007. [Epub ahead of print]


A number of antiepileptic drugs (AEDs) are currently available for treating acute seizures. It is recommended to select the initial treatment option according to the type of epileptic syndrome and the patient's clinical characteristics, but little is known about the long-term retention rates of AEDs started in the emergency department.

We recruited patients admitted with seizures over a two-year period. All patients underwent early neurological assessment, EEG testing, and neuroimaging. The treatments received at baseline and at one year of follow-up were compared.

In total, 225 patients were included. Overall, monotherapy with levetiracetam was the regimen most often used in patients with new-onset seizures, whereas other AEDs were mainly used in patients previously treated with other drugs. Lacosamide use was most likely associated with the presence of lesion related seizures in elderly patients, and carboxamides with focal onset seizures of unknown cause. The mean retention rate of the total of AED treatments was nearly 70%. The main cause leading to discontinuation was the development of intolerable adverse events. Levetiracetam use decreased as lacosamide use increased in the overall group of patients.

Our study shows that there is a trend to use newer AEDs, particularly levetiracetam, as the first option in new-onset seizures in the emergency room. However, levetiracetam use significantly decreased over follow-up, mainly because of the development of adverse events. The use of other, better-tolerated AEDs, such lacosamide predominated in elderly patients and patients with lesion related seizures, or carboxamides in epilepsies of unknown etiology.

•Levetiracetam was the most common antiepileptic drug used in acute seizures.
•At long-term follow-up, 60%–80% of antiepileptic drugs remained as chronic treatment.
•Antiepileptic drugs used as monotherapy were more likely changed than those added to the patients’ active baseline treatment.
•At long-term follow-up, the number of patients treated with lacosamide increased.
•The development of adverse events was the most common reason for discontinuation of any antiepileptic drug.

Courtesy of:

Friday, August 17, 2018

To err is homicide in Britain update

As the dust settles around the latest decision in the case of UK physician Hadiza Bawa-Garba, MBChB — who yesterday won her appeal against a ruling by the physician's regulatory body, the General Medical Council (GMC), that she should lose her medical license (known in the UK as being "struck off" the medical register) over the death of a 6-year-old boy in her care 7 years ago — Medscape Medical News summarizes reaction in the UK to the judgment.

The ruling means that Bawa-Garba should soon be able to return to work.

Bawa-Garba was a trainee pediatrician in the National Health Service (NHS) who was convicted in a British court of law of "manslaughter by gross negligence" in 2015 and was ultimately prevented from practicing medicine by the subsequent GMC decision in the High Court in January of this year. 

The case centered on a catalog of errors in 2011 that led to the death of Jack Adcock, a 6-year-old boy with Down syndrome who died from sepsis at Leicester Royal Infirmary. At the time of the tragedy, Bawa-Garba had recently returned from maternity leave and was solely in charge of three separate units on an evening no senior physician was available and there was a delay in obtaining test results.

Giving judgment yesterday, Sir Terence Etherton, Master of the Rolls (of the Court of Appeal), said the court accepted that "no concerns have ever been raised about the clinical competency of Bawa-Garba, other than in relation to Jack's death," and that "the risk of her clinical practice suddenly and without explanation falling below the standards expected on any given day is no higher than for any other reasonably competent doctor."

A much more detailed account of the events in this tragic case was described in a commentary by Saurabh Jha, MBBS — To Err Is Homicide in Britain: The Case of Hadiza Bawa-Garba — published in Medscape Medical News in February, just after the GMC ruling meant she could no longer practice medicine.

Following that decision, physicians all over the world rallied behind Bawa-Garba, citing the undue pressures she was under, that she was only partially supervised, and that she was ultimately punished for being too honest about her own failings.

A crowd-funding initiative raised enough money for her to launch an appeal.

Following yesterday's decision, Bawa-Garba gave an interview to the BBC Panorama program. "I want to let the parents know that I'm sorry for my role in what has happened to Jack. I want to pay tribute [to him]," she said.

"My hope is that the lessons learned from this case will translate into better working conditions for junior doctors, better recognition of sepsis, and [will ensure] factors [are] in place that improve patient safety."

She also said she wants to "acknowledge and give gratitude to people around the world from the public to the medical community who have supported me."

Her ultimate emotion is of relief: "I can't see myself being anybody else but a practicing doctor, so of course when I got the news that I could work again, I was very pleased."

But the mother of the boy who died while in Bawa-Garba's care, Nicky Adcock, told the BBC she was "devastated" by yesterday's verdict.

"What she did that day, I will never ever, ever, ever forgive her for. And I don't know how she can go back into this profession; she has shown no remorse, she has no guilt. I don't know how she can live with herself."

"I'm disgusted. I cannot understand how someone can be charged with gross negligence manslaughter, struck off the [medical] register by the GMC, and then be reinstated."

She is now considering whether to take the decision to the Supreme Court….

The GMC has been greatly criticized by the medical profession for its handling of the case of Bawa-Garba, in which it was deemed to have overreacted, perhaps because of the criminal prosecution that followed the case….

Charlie Massey, chief executive of the GMC, said the organization will "carefully examine" the issues surrounding the case "to see what lessons can be learned."

"Doctors have rightly challenged us to speak out more forcefully to support those practicing in pressured environments, and that is what we are increasing our efforts to do," said Massey.

The Doctors' Association UK said the GMC had shown it could not be trusted to take a balanced and nonpunitive approach in situations in which a healthcare professional's abilities might be compromised by shortcomings of the system.

The case, it noted, has "united the medical profession in fear and outrage," whereby "a pediatrician in training...a highly regarded doctor, with a previously unblemished record, [was] convicted of [the criminal offence of] gross negligence manslaughter for judgments made whilst doing the jobs of several doctors at once, covering six wards across four floors, responding to numerous pediatric emergencies, without a functioning IT system, and in the absence of a consultant [senior physician], all when just returning from 14 months of maternity leave."