Monday, July 31, 2017

Charlie Gard redux?

Another family in the UK is fighting to keep doctors from forcing their sick baby off of life support. From The Mirror story:

Charlie Gard supporters are rallying round the family of a seriously ill little boy as his parents face a battle with medics to keep him alive.

Tiny Alfie Evans in being treated at Alder Hey Children’s Hospital in Liverpool and suffers from a mystery condition staff are struggling to diagnose.

The 14-month-old family are hoping to find pioneering treatment for their little boy abroad.

 Alfie has been in in a coma in the hospital’s intensive care ward since last December, and suffers regular seizures.

As in the Charlie Gard case, doctors have warned they may have to take legal action as Tom will not let let them switch off Alfie’s life support.

That’s a twist: Unlike in Charlie Gard’s case, there is no firm diagnosis. Why would doctors try to force a baby off of life support when they haven’t been able to determine the cause of his cognitive disability?

But realize, as in all “futile care” cases, the treatment is unwanted by doctors because it is working. Hence, it isn’t the treatment but Alfie’s life that would be declared futile if the courts pulled another “Charlie Gard.”

Half a dozen US hospitals may be willing to offer alternative care for the Alfie:

Tom and Alfie’s mum, Kate James, have not yet faced a court battle like and are hopeful it will not come to that after more than a dozen American hospitals said they might be able to help.

Tom said: “I’m pleading for help from anywhere now. I’ve been getting in touch with lots of hospitals, and I’ve had a particularly positive response from one in Miami, which has received Alfie’s details.”

Hopefully, the international brouhaha over Charlie will make it more difficult in Alfie’s case for the authorities to impose another “futile patient” die-sooner-than-later outcome.

P.S. Alfie’s parents have established an “Alfie’s Army” Facebook Page for those who may be interested.

Identification of absence of fidgety movements

Støen R, Songstad NT, Silberg IE, Fjørtoft T, Jensenius AR, Adde L. Computer-based video analysis identifies infants with absence of fidgety movements. Pediatr Res. 2017 Jul 26. doi:10.1038/pr.2017.121. [Epub ahead of print]


Background Absence of fidgety movements (FMs) at 3 months' corrected age is a strong predictor of cerebral palsy (CP) in high-risk infants. This study evaluates the association between computer-based video analysis and the temporal organization of FMs assessed with the General Movement Assessment (GMA).

Methods Infants were eligible for this prospective cohort study if referred to a high-risk follow-up program in a participating hospital. Video recordings taken at 10-15 weeks post term age were used for GMA and computer-based analysis. The variation of the spatial center of motion, derived from differences between subsequent video frames, was used for quantitative analysis.

Results Of 241 recordings from 150 infants, 48 (24.1%) were classified with absence of FMs or sporadic FMs using the GMA. The variation of the spatial center of motion (CSD) during a recording was significantly lower in infants with normal (0.320; 95% confidence interval (CI) 0.309, 0.330) vs. absence of or sporadic (0.380; 95% CI 0.361, 0.398) FMs (P<0.001). A triage model with CSD thresholds chosen for sensitivity of 90% and specificity of 80% gave a 40% referral rate for GMA.

ConclusionQuantitative video analysis during the FMs' period can be used to triage infants at high risk of CP to early intervention or observational GMA.

Courtesy of


Medications worth considering when traditional antiepileptic drugs have failed

Turner AL, Perry MS. Outside the box: Medications worth considering when traditional antiepileptic drugs have failed. Seizure. 2017 Jun 27;50:173-185. doi: 10.1016/j.seizure.2017.06.022. [Epub ahead of print]

Review and discuss medications efficacious for seizure control, despite primary indications for other diseases, as treatment options in patients who have failed therapy with traditional antiepileptic drugs (AEDs).
Literature searches were conducted utilizing PubMed and MEDLINE databases employing combinations of search terms including, but not limited to, "epilepsy", "refractory", "seizure", and the following medications: acetazolamide, amantadine, bumetanide, imipramine, lidocaine, verapamil, and various stimulants.
Data from relevant case studies, retrospective reviews, and available clinical trials were gathered, analyzed, and reported. Experience with acetazolamide, amantadine, bumetanide, imipramine, lidocaine, verapamil, and various stimulants show promise for cases of refractory epilepsy in both adults and children. Many medications lack large scale, randomized clinical trials, but the available data is informative when choosing treatment for patients that have failed traditional epilepsy therapies.
All neurologists have encountered a patient that failed nearly every AED, diet, and surgical option. For these patients, we often seek fortuitous discoveries within small series and case reports, hoping to find a treatment that might help the patient. In the present review, we describe medications for which antiepileptic effect has been ascribed after they were introduced for other indications.

Courtesy of a colleague

Sunday, July 30, 2017

DNA as a medium for archiving data

Shipman SL, Nivala J, Macklis JD, Church GM. CRISPR-Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature. 2017 Jul 20;547(7663):345-349.


DNA is an excellent medium for archiving data. Recent efforts have illustrated the potential for information storage in DNA using synthesized oligonucleotides assembled in vitro. A relatively unexplored avenue of information storage in DNA is the ability to write information into the genome of a living cell by the addition of nucleotides over time. Using the Cas1-Cas2 integrase, the CRISPR-Cas microbial immune system stores the nucleotide content of invading viruses to confer adaptive immunity. When harnessed, this system has the potential to write arbitrary information into the genome. Here we use the CRISPR-Cas system to encode the pixel values of black and white images and a short movie into the genomes of a population of living bacteria. In doing so, we push the technical limits of this information storage system and optimize strategies to minimize those limitations. We also uncover underlying principles of the CRISPR-Cas adaptation system, including sequence determinants of spacer acquisition that are relevant for understanding both the basic biology of bacterial adaptation and its technological applications. This work demonstrates that this system can capture and stably store practical amounts of real data within the genomes of populations of living cells.

Friday, July 28, 2017

Fumarase deficiency

Fast-forward to 1990, a century after polygyny was abandoned, and the upshot was only just beginning to emerge. In an office several hundred miles from where Young gave his speech, a 10-year-old boy was presented to Theodore Tarby, a doctor specialising in rare childhood diseases.

The boy had unusual facial features, including a prominent forehead, low-set ears, widely spaced eyes and a small jaw. He was also severely physically and mentally disabled.

After performing all the usual tests, Tarby was stumped. He had never seen a case like it. Eventually he sent a urine sample to a lab that specialises in detecting rare diseases. They diagnosed “fumarase deficiency”, an inherited disorder of the metabolism. With just 13 cases known to medical science (translating into odds of one in 400 million), it was rare indeed. It looked like a case of plain bad luck.

But there was a twist. It turned out his sister, whom the couple believed was suffering from cerebral palsy, had it too. In fact, together with colleagues from the Barrow Neurological Institute, soon Tarby had diagnosed a total of eight new cases, in children ranging from 20 months to 12 years old.

In every case, the child had the same distinctive facial features, the same delayed development – most couldn’t sit up, let alone walk – and, crucially, they were from the same region on the Arizona-Utah border, known as Short Creek.

Even more intriguingly, this region is polygynous. In this small, isolated community of Fundamentalist Church of Jesus Christ of Latter-Day Saints (FLDS), the likelihood of being born with fumarase deficiency is over a million times above the global average…

Faith Bistline has five cousins with the disease, who she used to look after until she left the FLDS in 2011. “They are completely physically and mentally disabled,” she says. The oldest started learning to walk when he was two years old, but stopped after a long bout of seizures. Now that cousin is in his 30s and not even able to crawl.

Fumarase deficiency is rare because it’s recessive – it only develops if a person inherits two faulty copies of the gene

In fact, only one of her cousins can walk. “She can also make some vocalisations and sometimes you can understand a little bit of what she’s saying, but I wouldn’t call it speaking,” she says. They all have feeding tubes and need care 24 hours a day.

Fumarase deficiency is rare because it’s recessive – it only develops if a person inherits two faulty copies of the gene, one from each parent. To get to grips with why it’s plaguing Short Creek, first we need to back to the mid-19th Century…

Followers needed somewhere to go…

They settled on the remote ranching town of Short Creek, which formed part of the Arizona Strip. This was an area larger than Belgium (14,000 sq miles, or 36,000 sq km) with only a handful of inhabitants – the perfect place to hide from the prying eyes of federal marshals.

Today it’s home to the twin towns of Hildale and Colorado City – either side of the Utah-Arizona border – and some 7,700 people. It’s the headquarters of the FLDS, which is famous for its conservative way of life and polygyny. “Most families include at least three wives, because that’s the number you need to enter heaven,” says Bistline, who has three mothers and 27 siblings.

In the end, the link to fumarase deficiency is a numbers game. Take Brigham Young. In all, his children begat 204 grandchildren, who, in turn, begat 745 great-grandchildren. By 1982, it was reported that he had at least 5,000 direct descendants.

This sudden explosion is down to exponential growth. Even with just one wife and three children, if every subsequent generation follows suit a man can have 243 descendants after just five generations. In polygynous families this is supercharged. If every generation includes three wives and 30 children, a man can – theoretically – flood a community with over 24 million of his descendants in the space of five generations, or little over 100 years. Of course this isn’t what actually happens. Instead, lineages begin to fold in on themselves as distant (and in the FLDS, not so distant) cousins marry. In polygynous societies, it doesn’t take long before everyone is related.

This is thought to be how one-in-200 men (one in 12.5 in Asia) are descended directly from super-fertile Mongol warrior Genghis Khan, who died nearly eight centuries ago. As Brigham Young said himself: “It is obvious that I could not have been blessed with such a family, if I had been restricted to one wife…”

In Short Creek, just two surnames dominate the local records – Jessop and Barlow. According to local historian Benjamin Bistline, who spoke to news agency Reuters back in 2007, 75 to 80% of people in Short Creek are blood relatives of the community’s founding patriarchs, Joseph Jessop and John Barlow…

The fumarase deficiency gene has been traced to Joseph Jessop and his first wife, Martha Yeates (14 children). One of their daughters went on to marry co-founder John Barlow – and the rest is history. Today the number of people carrying the fumarase gene in Short Creek is thought to be in the thousands…

Which brings us to the good news. Since inbreeding tends to uncover “recessive” mutations that would normally remain in hiding, studying these communities has helped scientists to identify many disease-causing genes. That’s because genetic information is useless on its own. To be meaningful to medical research, it must be linked to information about disease. In fact, more human disease genes have been discovered in Utah – with its Mormon history – than any other place in the world.

It’s not the legacy Brigham Young expected, but in the end, it’s possible that the controversial practice might have some unintended positives.

Courtesy of a colleague

Cancer doesn't care If you're a fighter

It is very common when learning that someone has been newly diagnosed with a life-threatening cancer that well-meaning family and friends weigh in with encouragement to fight. It is also unfortunate.

Cancer could not care less whether you are a fighter or not. What evidence there is does not show that adopting a fighting stance helps in terms of survival. I have seen many fighters die of cancer, and some who chose not to be seen as fighters live longer than others who did.

And there is an implication that if you are not a fighter, then you must be a coward or worse. This suggests that the only option available to anyone who is courageous is to choose to fight—to utilize every surgery, complementary medicine, chemotherapy, and experimental option. This is unfortunate as well, because it takes courage to decide not to battle fatal cancers, but rather to enjoy a better quality of life in the time that remains.

The latest example of this "you must be a fighter" ethic is John McCain.

The senator from Arizona just found out he has a glioblastoma, a very nasty form of brain cancer. Upon announcing his diagnosis, McCain was greeted by a chorus of friends and admirers urging him to fight and calling on him to be courageous in taking on the cancer. This is advice McCain does not need.

Here is a sample from Twitter. Barack Obama said, "John McCain is an American hero, and one of the bravest fighters I've ever known. Cancer doesn't know what it's up against. Give it hell, John." Joe Biden: "He is strong, and he will beat this."

Gabrielle Giffords: "You're tough! You can beat this. Fight, fight, fight!" Mike Pence: "Cancer picked on the wrong guy. John McCain is a fighter, and he'll win this fight too." A bunch of editorials in many newspapers across the nation echoed similar thoughts.

This is advice McCain does not need.

The odds of beating this cancer are long. Whether he does or doesn't has nothing to do with his character or courage. That is not, despite some incredibly disrespectful comments President Trump made about him in the run-up to the presidential election, up for dispute.

McCain is a military hero. The genuine article. The former Navy pilot spent five and a half years in a notorious North Vietnamese prison known as the "Hanoi Hilton," where he spent 2 years in solitary confinement and was brutally tortured despite being severely injured when he bailed out of his plane. Concerned about his fellow prisoners, he would not accept an early release.

Whatever cancer does to John McCain and however he chooses to treat it or not, he is a brave man who is certainly a fighter. As with anyone, he will find his own best path to dealing with a grim diagnosis. Whatever that is, he will remain a hero and a fighter.

Gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

Veldhuijzen van Zanten SEM, El-Khouly FE, Jansen MHA, Bakker DP, Sanchez Aliaga E, Haasbeek CJA, Wolf NI, Zwaan CM, Vandertop WP, van Vuurden DG, Kaspers GJL. A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol. 2017 Jul 26. doi:10.1007/s11060-017-2575-9.

The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0-5.7) and 8.7 months (95% CI 7.0-10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4), showed a PFS and MOS of 6.4 and 12.4 months, respectively, versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n = 5). Gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, is safe and well tolerated in children with newly diagnosed DIPG. PFS and MOS were not significantly different from literature.

A phase I/II, open–label, single–arm trial was carried out with the goal to study the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). For this group of patients, gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, was found to be safe and well tolerated.


The clinicians administered six doses of weekly gemcitabine intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy.

Moreover, they gave increasing doses of 140, 175 and 200 mg/m2 gemcitabine to successive cohorts, following a 3+3 dose-escalation schedule without expansion cohort.

Monitoring was done for dose-limiting toxicities (DLT) during treatment period.

They used predefined case report forms to evaluate clinical response.

Radiological response was assessed using the modified RANO criteria.

PedsQL questionnaires were utilized to appraise quality of life (QoL).


This study incorporated nine patients, between June 2012 and December 2016.

Treatment was found to be well tolerated.

This study did not find DLTs up to the maximum dose of 200 mg/m2.

Reduction of tumor-related symptoms were observed in all patients.

Findings reported that QoL tended to improve during treatment.

4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4) were PFS and MOS.

By classifying patients according to the recently developed DIPG survival prediction model, this study noticed a PFS and MOS of 6.4 and 12.4 months in intermediate risk patients (n=4), versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n=5).

Thursday, July 27, 2017

Charlie Gard and Baby Bollinger

A baby is born with intense physical and developmental problems. Extensive treatment is necessary to preserve his life, but with an unsure likelihood of success. The doctors in charge refuse to treat him on the grounds that it will likely be unsuccessful and that the child is suffering. They remain inactive, despite pleas for the boy’s life.

At the last moment, one doctor steps forward to attempt a life-saving treatment, but by then it is too late. The baby dies and the watching world is left to make sense of tragedy.

You may be surprised to hear that this is not the story of Charlie Gard in 2017, but of a newborn known as “Baby Bollinger,” who died in Chicago in 1915. He was less than a week old.

The details of Baby Bollinger’s condition still aren’t completely clear. Sources say that he was born with some paralysis on one side of his body, was missing or had deformities in his ears, and his shoulder may have been connected directly to his head. His spine was unusually curved and he had a significant problem with his intestinal tract. All accounts agree that immediate surgery was necessary to save his life.

Dr. Harry Haiselden, the chief of hospital staff, refused to operate on the child. He believed that, though the child had a good chance of survival from surgery, “There is no doubt the child would be defective mentally and morally if allowed to live. It might be criminal. Certainly it would be dependent. It would be a burden to itself and to society.”

While there are great differences between Baby Bollinger and Charlie Gard, there are also eerie similarities. In both cases, there was disagreement on the child’s prognosis and level of suffering. In both cases, elites in medicine and government were allowed to run out the clock on critically ill children. For both children, their ultimate “usefulness” dictated how hard the world would fight for their survival.

As with Charlie, the fate of Baby Bollinger polarized the American public. Haiselden received hundreds of irate phone calls begging him to reconsider. Many press outlets lambasted him. However, Haiselden and his actions had a sinister but powerful advocate: the eugenics movement…

By 1915, America’s elites were convinced that the survival of humanity depended on eliminating the weak from the gene pool. Race and class-driven social Darwinism was fueled by “scientific” research from respected organizations like the Rockefeller Foundation and the Carnegie Institution. It had vocal support from folks like Margaret Sanger, Woodrow Wilson, Alexander Graham Bell, and Haiselden. From the halls of academia to high society, eugenics was considered scientific fact.

Armed with these “facts,” 33 states enacted laws for forced sterilization of the “feeble-minded,” the deaf, epileptics, the handicapped, and others whose lives eugenicists found to be unworthy. This led to the forced sterilization of more than 60,000 Americans. Not surprisingly, immigrants, African-Americans, and the poor were most often those deemed “unfit.”

So when Baby Bollinger’s case came into the public eye in 1915, many thought that allowing the “defective” newborn to die was for the good of both the child and society. Haiselden was doing the world “a favor.” Ironic proof of this can be found in one of Haiselden’s most ardent defenders: Helen Keller. She proposed that juries of medical experts should, “decide whether a man is fit to associate with his fellows, whether he is fit to live.”

While renowned eugenicist and birth control advocate Margaret Sanger did not specifically comment on the Bollinger case, one can only assume her sentiments. In Sanger’s 1922 book “The Pivot of Civilization,” her thoughts on biological frailty are quite clear: “Every single case of inherited defect, every malformed child, every congenitally tainted human being brought into this world is of infinite importance to that poor individual; but it is of scarcely less importance to the rest of us and to all of our children who must pay in one way or another for these biological and racial mistakes.”

Thankfully, these two tragedies are not identical. Charlie Gard has loving parents who have fought intensely for their son’s chance to survive. Baby Bollinger died with the tacit consent of his parents, who agreed to let Haiselden treat him as he saw fit.

And while Haiselden’s perverse belief in eugenics made him boast of the deaths of many weak, imperfect newborns in his care, Charlie’s death will be universally mourned. I am certain that nurses, doctors, courts, and the greater public who support the decision to end Charlie’s treatment do so out of love and sympathy for a sick, helpless child.

Still, there is a frightening similarity that cannot be ignored: Charlie Gard and Baby Bollinger were both deemed unworthy of survival. Doctors, courts and the public have weighed in and decided that death is superior to lives like theirs. In different nations, a century apart, the systems in place to protect human life have failed two of society’s most helpless members.

And while no one celebrates this little boy’s tragic passing, do not many think it’s “all for the best?” Would they not say in hushed tones to close friends, “Maybe it would have been better if he were never born at all?” Don’t many well-intentioned folks believe as twentieth-century eugenicists believed—that Charlie’s death is nature “righting itself?”

No one has made Haiselden’s evil, perverse argument that Charlie Gard should be allowed to die “for the good of humanity.” But the end result is the same: society’s medical and legal elites have gotten to decide that dying is for Charlie’s own good.

Tragically, Charlie Gard is neither the first nor the last vulnerable child to be let down by the system that is supposed to defend him. With medical technology and knowledge of genetics advancing every day, these moral dilemmas will only become more common.

What’s more, as Western society is increasingly detached from a Judeo-Christian foundation, human dignity is no longer self-evident, endowed by a Creator. As a result, our society lacks the moral vocabulary to explain why a human life that is not “useful” is still sacred. I imagine this struggle will only worsen with time.

The brief but meaningful life of Charlie Gard forces us to confront how we view our society’s weakest members. Sanger saw babies like Charlie as “biological and racial mistakes” and sought the power of the state to enforce their limitation. Charlie’s parents see him as “an absolute warrior” and are grateful “for the joy he has brought to our lives.” In a just society, whose legacy will endure longer: Sanger’s or Charlie’s?

See :

Wednesday, July 26, 2017

CSF delivery of AAV9-mediated gene therapy for SMA

Kathrin Meyer, Laura Ferraiuolo, Sukumar Nagendran, James L’Italien, Douglas M. Sproule, Minna Du, Jessica Cardenas, Arthur Burghes, Kevin D. Foust, Allan A. Kaspar, Shibi Likhite, Jerry Mendell and Brian Kaspar.  CSF delivery of AAV9-mediated gene therapy for SMA, a lethal neuromuscular disease in children: a dose-response study in mice and nonhuman primates.  Neurology April 18, 2017 vol. 88 no. 16 Supplement P3.133


Objective: Spinal muscular atrophy Type-1 (SMA1) is the most frequent lethal genetic neurodegenerative disorder in infants caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration, progressive paralysis, and death. SMA1 symptoms are thought to be caused by death of motor neurons within the central nervous system. However, other non-central nervous system tissues may contribute to systemic disease symptoms in SMA1 patients that may not contribute to the milder phenotypes (SMA2-3). We previously demonstrated that a single intravenous injection (IV) of a gene therapy (AVχS-101) resulted in complete rescue of the disease phenotype in the SMA1 mouse model. Here, we evaluate the dosing and efficacy of AVχS-101 delivered directly to the cerebral spinal fluid (CSF) via single injection.

Background: AVχS-101 delivers the SMN gene in a single-dose via the AAV9 viral vector (crosses blood-brain-barrier), utilizing self-complementary DNA technology for rapid onset transgene expression, and exploiting a chicken b-actin promoter for continuous and sustained transgene expression.

Design/Methods: AVχS-101 was delivered via Intracerebroventricular (ICV) injection in the mouse model for SMA (SMND7 mouse) to evaluate phenotypic rescue. The scAAV9-Green Fluorescent Protein (scAAV9-GFP) was used to evaluate transgene/AAV9-biodistribution and was delivered via ICV injection in mice and intrathecal sacral infusion in cynomolgus macaques.

Results: We found transgene expression throughout the spinal cord in mice and nonhuman primates. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate vector distribution.

Conclusions: CSF delivery of gene therapy utilizing the AAV9 viral vector combined with tilting (Trendelenburg position) allows widespread transgene transduction in the brain and all regions of the spinal cord of nonhuman primates. These findings support the use of IT delivery of gene therapy for neurological diseases, such as SMA 2 and 3 where there is minimal systemic involvement.


Tuesday, July 25, 2017


Doumlele K, Friedman D, Buchhalter J, Donner EJ, Louik J, Devinsky O. Sudden Unexpected Death in Epilepsy Among Patients With Benign Childhood Epilepsy With Centrotemporal Spikes. JAMA Neurol. 2017 Jun 1;74(6):645-649.

Children with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP).
To determine if cases of BECTS are present in the North American SUDEP Registry (NASR).
The NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists.
Cases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR.
Three boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures.

Sudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.

Safety of antiepileptic drugs for fetus and nursing child

Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D'Souza J, MacDonald H, Tricco AC. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open. 2017 Jul 20;7(7):e017248.

Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding.
Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers.
29 cohort studies including 5100 infants/children.
Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group.
Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes.
The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control.
Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen.

This systematic review aimed to compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. Compared with control, valproate alone or combined with another AED was associated with the greatest odds of adverse neurodevelopmental outcomes. Oxcarbazepine and lamotrigine were correlated with increased occurrence of autism. The physicians advised counselling for women considering pregnancy to tailor the safest regimen.


The physicians conducted a systematic review and Bayesian random-effects network meta-analysis (NMA).

Until 27 April 2017, they searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials.

By independent reviewers, screening, data abstraction, and quality appraisal were completed in duplicate.

This systematic review involved 29 cohort studies including 5100 infants/children.

The primary outcomes were cognitive developmental delay and autism/dyspraxia.

The secondary outcomes were attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment.


On cognitive developmental delay (11 cohort studies, 933 children, 18 treatments), the NMA proposed that among all AEDs only valproate was statistically significantly correlated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46).

On autism (5 cohort studies, 2551 children, 12 treatments), the NMA proposed that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were correlated with significantly greater odds of developing autism compared with control.

On psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments), the NMA found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were correlated with significantly greater odds of psychomotor delay compared with control.

Monday, July 24, 2017

Predominant area of brain lesions in neonates with herpes simplex encephalitis

Kidokoro H, de Vries LS, Ogawa C, Ito Y, Ohno A, Groenendaal F, Saitoh S, Okumura A, Ito Y, Natsume J. Predominant area of brain lesions in neonates with herpes simplex encephalitis. J Perinatol. 2017 Jul 20. doi: 10.1038/jp.2017.114.[Epub ahead of print]

Nonspecific manifestations and a varied distribution of brain lesions can delay the diagnosis of herpes simplex encephalitis (HSE) in neonates. The aim of this study was to report predominant brain lesions in neonatal HSE, and then to investigate the association between pattern of predominant brain lesions, clinical variables and neurodevelopmental outcome.
A multicenter retrospective study was performed in neonates diagnosed with HSE between 2009 and 2014. Magnetic resonance (MR) images, including diffusion-weighted images, were obtained in the acute and chronic phase.
Three predominant areas of brain injury could be defined based on characteristic MRI findings in 10 of the 13 infants (77%). The inferior frontal/temporal pole area was involved in five (38%) patients. The watershed distribution was present in six (46%) patients. Four (31%) infants involved the corticospinal tract area. No significant association was found between any predominant distribution of brain lesion pattern and sex, country, viral type or viral load. However, the corticospinal tract involvement was significantly associated with motor impairment (P=0.045).
Three predominant areas of brain lesion could be recognized in neonatal HSE. Recognition of those areas can improve prediction of neurodevelopmental outcome.

Characteristic distribution of brain lesions. The inferior frontal and temporal pole distribution (upper panels: a–c). The inferior frontal and anterior temporal lobes are symmetrically involved, as shown on a diffusion-weighted image taken 3 days after disease onset (a). T2-weighted MR images exhibit high signal intensity at 2 weeks (b) and cystic evolution of the anterior temporal lesions at 2 months after onset (c) (Supplementary Table S1 online, patient 10). The watershed distribution (middle panels: d–f). Scattered, punctate cortical lesions (termed 'stardust appearance') in the watershed areas on diffusion-weighted imaging (DWI) taken at 5 days after disease onset (a and b) and on T2-weighted MR images taken at 58 months (c) (Supplementary Table S1 online, patient 1). The corticospinal tract (CST) distribution (lower panels: g–i). Bilateral CST involvement, including posterior limbs of internal capsule, is evident on DWI at 6 days after disease onset (g and h). Note that the posterior watershed area is also present (i). Cystic evolution is seen in the occipital watershed regions on a T2-weighted MR image taken 20 days after disease onset (Supplementary Table S1 online, patient 7).

Sunday, July 23, 2017

Neu-Laxova syndrome

[2014 seems to have been a good year for Neu-Laxova syndrome]

Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong Y, Almoisheer A, Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh MA, Alkuraya FS. Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. Am J Hum Genet. 2014 Jun 5;94(6):898-904.

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.

El-Hattab AW, Shaheen R, Hertecant J, Galadari HI, Albaqawi BS, Nabil A, Alkuraya FS. On the phenotypic spectrum of serine biosynthesis defects. J Inherit Metab Dis. 2016 May;39(3):373-81.

L-serine is a non-essential amino acid that is de novo synthesized via the enzymes phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). Besides its role in protein synthesis, L-serine is a precursor of a number of important compounds. Serine biosynthesis defects result from deficiencies in PGDH, PSAT, or PSP and have a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal multiple congenital anomaly disease at the severe end to a childhood disease with intellectual disability at the mild end, with infantile growth deficiency, and severe neurological manifestations as an intermediate phenotype. In this report, we present three subjects with serine biosynthesis effects. The first was a stillbirth with Neu-Laxova syndrome and a homozygous mutation in PHGDH. The second was a neonate with growth deficiency, microcephaly, ichthyotic skin lesions, seizures, contractures, hypertonia, distinctive facial features, and a homozygous mutation in PSAT1. The third subject was an infant with growth deficiency, microcephaly, ichthyotic skin lesions, anemia, hypertonia, distinctive facial features, low serine and glycine in plasma and CSF, and a novel homozygous mutation in PHGDH gene. Herein, we also review previous reports of serine biosynthesis defects and mutations in the PHGDH, PSAT1, and PSPH genes, discuss the variability in the phenotypes associated with serine biosynthesis defects, and elaborate on the vital roles of serine and the potential consequences of its deficiency.

Saturday, July 22, 2017

The future of SMA therapy

Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Jul 23. doi: 10.1038/gt.2017.52. [Epub ahead of print]

Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.

From the article


The children treated in the recent nusinersen trial showed acceptable tolerance to the intrathecal procedure and the vast majority of serious adverse events reported were disease related. However, it is important to note that these children showed progress but did not achieve completely normal motor function in the timescale reported in the trial, and face an uncertain future as they grow and develop from a baseline of established neuromuscular weakness. Therefore, despite the promise provided by nusinersen, it should be seen as the first step in a transformative environment for SMA therapy. There is still much progress to be made and a number of other approaches are under investigation, including modified ASOs to increase cell penetration, oral small molecule approaches aimed at increasing SMN levels, and virally delivered gene replacement therapy (a list of ongoing clinical trials in SMA is available at It will be difficult to recruit any drug naïve patients in which these agents can be tried, making it challenging to identify the clinical effectiveness of newer agents, except perhaps as adjunctive therapy. Clinical trial methodology in SMA will have to accommodate this complexity, as it will not be ethically acceptable to prevent subjects in new trials taking an established therapy, if available. Trials and protocols of combinatorial therapies aiming for synergies and complementation are envisaged. It remains possible that SMN restoration might not be a sufficient therapy for all patients with SMA, either because it functions in a time-dependent window in early development and will never prevent the slow progressive decline seen in older children and adults, or because the typical insidious clinical presentation of milder forms of SMA does not allow early treatment in the absence of post-natal screening. For these reasons, a whole range of other, non-SMN, pathways are under investigation, including those based on modifiers of the pathobiology and phenotype. The future of SMA therapy covering the whole period from infancy to late life may well require a range of therapies in combination. Even if SMA can be treated pre-clinically, it is well established that in the most severely affected children, the pathological process begins in utero.15Even with the best approaches to SMN replacement, there may be late effects in neuromuscular weakness due to a reduced functional reserve.

Friday, July 21, 2017

Maternal antidepressant use during pregnancy does not cause intellectual disability in offspring

Viktorin A, Uher R, Kolevzon A, Reichenberg A, Levine SZ, Sandin S. Association of  Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring. JAMA Psychiatry. 2017 Jul 12. doi:10.1001/jamapsychiatry.2017.1727. [Epub ahead of print]

Maternal antidepressant medication use during pregnancy has previously been associated with adverse outcomes in offspring, but to our knowledge, the association with intellectual disability (ID) has not been investigated.
To examine the association of maternal antidepressant medication use during pregnancy with ID in offspring and investigate the importance of parental mental illness for such an association.
A population-based cohort study of 179 007 children born from January 1, 2006, through December 31, 2007, with complete parental information from national registers who were followed up from birth throughout 2014.
We estimated relative risks (RRs) and 95% CIs of ID in children exposed during pregnancy to any antidepressant medication or specifically to selective serotonin reuptake inhibitor (SSRI) antidepressants, all other non-SSRI antidepressants, or other nonantidepressant psychotropic medications. Analyses were adjusted for potential confounders. In addition to full population analyses, we used a subsample to compare mothers who used antidepressants during pregnancy with mothers who had at least one diagnosis of depression or anxiety before childbirth but did not use antidepressants during pregnancy.
Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. With adjustment for potential confounders, the RR of ID after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Results from analyses of SSRI antidepressants, non-SSRI antidepressants, and nonantidepressant psychotropic medications and analyses in the clinically relevant subsample did not deviate from the full-sample results.
The unadjusted RR of ID was increased in offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to a mechanism integral to other factors, such as parental age and mother's psychiatric disorder.

A team of researchers from the Icahn School of Medicine at Mount Sinai, in New York City, found that intellectual disability (ID) was diagnosed in 37 children (0.9%) who had been exposed to antidepressants vs 819 (0.5%) who had not been exposed.

Although there was a higher estimate of relative risk (RR) for intellectual disability, once confounding factors such as parental age and psychiatric history were accounted for, the risk was no longer deemed statistically significant.

"The take-home message to clinicians from our study is that although there is an association between antidepressant use in pregnancy — especially SSRIs [selective serotonin reuptake inhibitors] —and intellectual disability in offspring, it is probably not due to the medication," study author Abraham Reichenberg, PhD, professor of psychiatry, Icahn School of Medicine, told Medscape Medical News.

"Based on results of this study, the association is due to other characteristics in parents that we know are related to intellectual disability, including history of psychiatric disorders, older age of mothers or fathers, and psychiatric disorders in the mother before pregnancy," he said…

Conventional medications used in pregnancy, including certain antiepileptic and mood stabilizing medications, "have been associated with poor cognitive development and lower IQ in exposed offspring," the authors write.

Antidepressants in general and SSRIs in particular are increasingly being used by pregnant women. These agents, which pass the placenta, have been implicated in abnormalities of offspring in animal models and in some human observational studies…

Of the cohort, 3982 children (2.2%) were born to mothers with two or more dispensations of antidepressant medication that overlapped the pregnancy; 172,646 children (96.4%) were born to mothers who had no antidepressant medication dispensations that overlapped the pregnancy. The unadjusted RR of ID in exposed children was estimated at 1.97 (95% confidence interval [CI], 1.42 - 2.74)…

"We observed a higher RR of ID among offspring born to mothers treated with antidepressants during pregnancy (0.9% of children affected), compared with offspring of mothers not treated with antidepressants during pregnancy (0.5% of children affected) before adjustment for confounding factors.

"However, with incremental adjustment for maternal and paternal confounding factors, this association was gradually attenuated to a statistically nonsignificant RR estimated at 1.33 (95% CI, 0.90 - 1.98)," the researchers write.

They note several study limitations. The use of registry data captured only the number of medications prescribed and collected; it did not capture adherence to these medications.

"The evidence we have so far regarding autism and intellectual disability in mothers who used antidepressants during pregnancy is that the medications per se are not what increase the risk but rather it is what the mother may carry genetically or other confounding factors that may increase the risk. And even the increased risk is very small," said Dr Reichenberg.

Thursday, July 20, 2017

The consequence of a reversal sign 2

A male neonate was delivered by emergency cesarean section at 35 weeks gestation due to placental abruption.  Apgar scores were 0, 1, 0 and 4 at 1, 5, 10 and 15 minutes. An initial blood gas was 6.58/139/26/12.  An MRI at 3 days of age shows a reversal sign. See

                   A repeat MRI at 30 days of age shows destruction of the supratentorial brain

The war on parents

There has been a lot of talk in the media lately about little Charlie Gard, and how the courts and bureaucracy of the United Kingdom have prevented his parents from spending their own money to try to treat him in another hospital.

Many are asking, how did we get here? How did many of our brightest minds in law and government arrive at a conclusion that so callously disregards parental rights, parental love, and his parents’ right to fight for his life? How did we get to a place where the state has a higher authority than the boy’s parents? How are the rights of parents to choose a course of treatment completely disregarded? Why does the government think this is O.K.? Where does that authority come from?

Here in Massachusetts, it’s easy to see the roots of the Charlie Gard controversy in recent actions of the state legislature. This past July 8 marked the one-year anniversary of the passage of the Massachusetts Transgender special rights bill. Even as the rights of families and parents erode, leftist advocates are quick to note the “sky hasn’t fallen,” despite such radical pieces of legislation.
But the transgender laws currently on the books, along with guidelines promulgated by the state department of education, grant students (i.e., minor children) the ability to be free from parental involvement in their gender identity choices. If a student in our public schools wants to live as the opposite gender during school hours, and use the school as a conduit to referral to transgender-affirming counselors and networks, the school cannot even tell the parents. A school nurse’s office that can’t even give an aspirin without parental permission can connect a child with medical professionals who will explain the ins and outs of sex-transition surgery and hormone therapy, implying such a transition is good and normal regardless of parental wishes.

The progressive Left marches on, never satisfied with the special rights they’ve won, always determined to force others to accept and affirm their world-view. Several bills currently up for hearings on Beacon Hill pick up where the bathroom law leaves off, in the continuing slippery slope of eroding the rights of parents.              

Over the past several sessions, there have been pieces of legislation on Beacon Hill to usurp parental rights when it comes to sex education and abortion. The progressives readily admit they want our tax dollars to be used to teach 10-year-olds to affirm extra-marital sex, abortion, and the fluidity of gender identity, regardless of what their parents believe. Parental rights are neutered, but parents can still make their views on these subjects known to their kids, even though their public schools will use their tax dollars to teach that parents are “bigots” and “haters.”

The latest pieces of legislation filed this year take the war on families and parents one step further.
House Bill 1190, the Counseling Ban dictates a “gag rule” to prohibit licensed psychiatrists from counseling children in the way that such professionals assess to be in the best interest of the child. Instead, the gag rule mandates that professionals follow a “one size fits all” directive that favors feelings of homosexuality or gender identity disorder, regardless of any child’s history, or personal background, or past trauma.

This chilling legislation puts a gag order on a whole profession, stripping away the best interests of both parents and children. It prevents counselors from allowing and encouraging children to mature into their own biological selves, despite the fact that huge majorities of young gender-confused children eventually grow out of their identity problems and lead normal lives. The majority of parents and families across our nation still believe that the affirmation of these feelings of gender confusion in young impressionable kids is often abusive to the children, putting them on a difficult and unnecessarily troubled path in the name of political correctness.

This legislation goes even beyond simply freeing kids from parental authority, to condemn as child abusers parents who tap the brakes on a gender transition for not affirming the child’s true self. Despite all the medical evidence that suggests the child is likely to outgrow these feelings and never transition, the legislation enables the Department of Children and Families to remove kids from their parents for not affirming gender confusion and embracing a child’s chosen gender profile.
It’s completely contrary to common sense, but it’s typical of legislation being pushed by the Left. 

Another such proposal is House Bill 3249 (Senate Bill 1186) which would end parental consent and involvement for their underage kids seeking preventative treatments for sexually transmitted diseases.
Parents want and need to know about their children’s life choices. When it comes to questions about intimacy in particular, the guidance of parents is all-important. Why does their underage teen-ager feel he needs HIV or STD prevention drugs now? Has he begun engaging in risky behavior? With whom? And what people or associations have brought him to this point? HB 3249 would allow underage children to get HIV prevention drugs without even notifying parents; but ultimately, parents are responsible for their children’s health and actions, and cutting them out of the picture can only break down communication and have damaging life-altering consequences.

These pieces of legislation push our government and our courts to minimize the role of parents in children’s lives in regard to extremely sensitive decisions related to their values and their health.
We can see the path we’re on at the state level already in Massachusetts, one that not only seeks to remove parents from the equation, but even to usurp their role in the name of political correctness. One could surmise that legislators in the UK have followed a similar path, and one can see the road to a Bay State Charlie Gard right here in one of our hospitals — as we saw with Children’s Hospital and Justina Pelletier.

The war on parents is under way not just across the pond, but here as well.

Nasal encephalocele

Four years later and after a major surgery, little Jayden is happy and loved.

When Australian couple Thembe and Sipho Moyo went for their 21-week ultrasound, they were full of anxious hope and excitement — just like most parents. However, as doctors looked more closely at the scan they noticed a problem. The little boy was growing with a very rare deformity called nasal Encephalocele, which occurs when the the brain develops outside of the skull. In the case of Baby Moyo, a hole in his forehead had not closed up during a key stage in fetal development, which allowed the brain to protrude and continue growing externally.

The doctors’ immediately advised the Moyos to end the pregnancy, explaining “he wasn’t going to be human. He wasn’t going to be a human being.” The distraught father-to-be said: “It was confronting. We were scared. We were shattered. Lots of tears.” However, despite their shock, the Moyos decided to reject the advice of the doctors and persevere with the pregnancy, believing and holding onto hope. One week after his birth, little baby Jayden underwent a very risky and complicated surgery, involving a team of surgeons, to literally relocate his tiny brain.

The delicate six-hour operation was a huge success, with little Jayden surprising the medical staff with how quickly he recovered. The doctors said the operation would have no long-lasting effects on the baby, and he would only require some plastic surgery on his nose in the future. And now, four years later, the young boy is thriving and is a picture of happiness. His parents, looking at him smile today, said “considering everything he’s gone through, he’s an amazing boy.”

Amazing is right. He defied the doctors prognosis and is able to lead a normal life. His parents, clinging to a little hope, have been rewarded with much joy and love. The grateful couple have set up a charity called Face Up to help support people with facial differences. As Mrs. Moyo explained: We live in a world now where everything has to be perfect, but life is not perfect. Jayden, according to world standards, is not perfect even now, but what’s perfect?”

It takes great courage and strength to be able to cope with this sort of situation. We can marvel not only at the Moyos’ devotion to their unborn child, but also the God-given talents of the entire medical team who enabled Jayden to become the happy and loving boy he is today. Now that is perfection.

MRI for brain imaging in newborns

The US Food and Drug Administration (FDA) has granted 510(k) clearance for the first MRI device designed specifically for brain and head imaging of newborns in the neonatal intensive care unit (NICU).

The Embrace Neonatal MRI System (Aspect Imaging Ltd) can be used on neonates with a head circumference up to 38 cm and weighing between 1 and 4.5 kg.

The system has a temperature-controlled incubator placed directly into the MRI system, minimizing movement of the infant. If urgent access to the newborn is required during imaging, the baby can typically be removed from the system in less than 30 seconds, the FDA explains in a news release.
"Although we can use traditional MRI scanners to image neonates, taking babies outside of the neonatal intensive care unit to MRI suites presents great challenges. Having a system in the neonatal intensive care [unit] enables safer imaging for this vulnerable patient population," Vasum Peiris, MD, MPH, chief medical officer for pediatrics and special populations at the FDA's Center for Devices and Radiological Health, said in the release.

The Embrace Neonatal MRI System can be placed inside the NICU because the system does not require a safety zone or a radiofrequency shielded room. The system is fully enclosed, so medical device implants near the system are not required to be "MR Conditional" or "MR Safe."

"To avoid putting vulnerable patients at risk, the efficacy of the Embrace Neonatal MRI System was demonstrated primarily based on non-clinical testing including images of phantoms simulating an infant brain that were determined to be of sufficient quality for diagnostic use by an independent board-certified radiologist," the FDA says. The safety of the system was demonstrated through performance testing, including a review of electrical and mechanical safety measures.

The Embrace Neonatal MRI System should not be used in patients weighing more than 4.5 kg or with a head circumference greater than 38 cm.  The system is also contraindicated for all infants with metallic or electronically active implants because the MRI may cause tissue near the implant to heat or the implant to malfunction, the FDA said.

TRAK mutations

Barel O, Christine V Malicdan M, Ben-Zeev B, Kandel J, Pri-Chen H, Stephen J, Castro IG, Metz J, Atawa O, Moshkovitz S, Ganelin E, Barshack I, Polak-Charcon S, Nass D, Marek-Yagel D, Amariglio N, Shalva N, Vilboux T, Ferreira C, Pode-Shakked B, Heimer G, Hoffmann C, Yardeni T, Nissenkorn A, Avivi C, Eyal E, Kol N, Glick Saar E, Wallace DC, Gahl WA, Rechavi G, Schrader M, Eckmann DM, Anikster Y. Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain. 2017 Mar 1;140(3):568-581.

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.

Loss O, Stephenson FA. Developmental changes in trak-mediated mitochondrial transport in neurons. Mol Cell Neurosci. 2017 Apr;80:134-147.

Previous studies established that the kinesin adaptor proteins, TRAK1 and TRAK2, play an important role in mitochondrial transport in neurons. They link mitochondria to kinesin motor proteins via a TRAK acceptor protein in the mitochondrial outer membrane, the Rho GTPase, Miro. TRAKs also associate with enzyme, O-linked N-acetylglucosamine transferase (OGT), to form a quaternary, mitochondrial trafficking complex. A recent report suggested that TRAK1 preferentially controls mitochondrial transport in axons of hippocampal neurons whereas TRAK2 controls mitochondrial transport in dendrites. However, it is not clear whether the function of any of these proteins is exclusive to axons or dendrites and if their mechanisms of action are conserved between different neuronal populations and also, during maturation. Here, a comparative study was carried out into TRAK-mediated mitochondrial mobility in axons and dendrites of hippocampal and cortical neurons during maturation in vitro using a shRNA gene knockdown approach. It was found that in mature hippocampal and cortical neurons, TRAK1 predominantly mediates axonal mitochondrial transport whereas dendritic transport is mediated via TRAK2. In young, maturing neurons, TRAK1 and TRAK2 contribute similarly in mitochondrial transport in both axons and dendrites in both neuronal types. These findings demonstrate maturation regulation of mitochondrial transport which is conserved between at least two distinct neuronal subtypes.

Loss O, Stephenson FA. Localization of the kinesin adaptor proteins trafficking kinesin proteins 1 and 2 in primary cultures of hippocampal pyramidal and cortical neurons. J Neurosci Res. 2015 Jul;93(7):1056-66.

Neuronal function requires regulated anterograde and retrograde trafficking of mitochondria along microtubules by using the molecular motors kinesin and dynein. Previous work has established that trafficking kinesin proteins (TRAKs),TRAK1 and TRAK2, are kinesin adaptor proteins that link mitochondria to kinesin motor proteins via an acceptor protein in the mitochondrial outer membrane, etc. the Rho GTPase Miro. Recent studies have shown that TRAK1 preferentially controls mitochondrial transport in axons of hippocampal neurons by virtue of its binding to both kinesin and dynein motor proteins, whereas TRAK2 controls mitochondrial transport in dendrites resulting from its binding to dynein. This study further investigates the subcellular localization of TRAK1 and TRAK2 in primary cultures of hippocampal and cortical neurons by using both commercial antibodies and anti-TRAK1 and anti-TRAK2 antibodies raised in our own laboratory (in-house). Whereas TRAK1 was prevalently localized in axons of hippocampal and cortical neurons, TRAK2 was more prevalent in dendrites of hippocampal neurons. In cortical neurons, TRAK2 was equally distributed between axons and dendrites. Some qualitative differences were observed between commercial and in-house-generated antibody immunostaining.

Schwarz TL. Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol. 2013 Jun 1;5(6).

Neurons, perhaps more than any other cell type, depend on mitochondrial trafficking for their survival. Recent studies have elucidated a motor/adaptor complex on the mitochondrial surface that is shared between neurons and other animal cells. In addition to kinesin and dynein, this complex contains the proteins Miro (also called RhoT1/2) and milton (also called TRAK1/2) and is responsible for much, although not necessarily all, mitochondrial movement. Elucidation of the complex has permitted inroads for understanding how this movement is regulated by a variety of intracellular signals, although many mysteries remain. Regulating mitochondrial movement can match energy demand to energy supply throughout the extraordinary architecture of these cells and can control the clearance and replenishing of mitochondria in the periphery. Because the extended axons of neurons contain uniformly polarized microtubules, they have been useful for studying mitochondrial motility in conjunction with biochemical assays in many cell types.

Hyperbaric oxygen

She's a survivor.

Eden Carlson's near-fatal fall into her family pool left her brain damaged in February 2016 — but doctors have now significantly reversed the trauma in the tenacious toddler.

Physicians used a series of oxygen treatments, like hyperbaric oxygen therapy, to significantly reverse the 2-year-old's brain damage after she was in the water for 15 minutes.

To "wake up" her brain, doctors gave Carlson oxygen at a pressure higher than the general atmospheric pressure — increasing the amount of oxygen in her blood and repairing her damaged tissue in a sealed, pressurized hyperbaric chamber.

"The startling regrowth of tissue in this case occurred because we were able to intervene early in a growing child, before long-term tissue degeneration," hyperbaric specialist Paul Harch from LSU Health New Orleans said in the case report published by Medical Gas Research.

On the day of the near-drowning, the child's mother found her, pulled her out and performed CPR until doctors at her local hospital in Fayetteville, Ark., were ultimately able to revive her two hours later after she also suffered cardiac arrest. Her lack of oxygen resulted in a severe brain injury, leaving the child unable to speak, walk or respond to verbal cues.

She was at the hospital for 48 days receiving critical care before being discharged, but Harch wanted to try a course of oxygen therapies to try and help heal Carlson's brain.

First, she was administered oxygen treatments at "normobaric level" (sea level), 55 days after the accident, for 45 minutes at a time, two times per day which helped her regain movement of her arms and hands, her partial ability to eat and speak in short spurts.

Three weeks later, she was moved to New Orleans — at a hospital in possession of the closest hyperbaric chamber — where the hyperbaric oxygen therapy began.

In just 10 sessions, the toddler's mother said she was back to "near normal." Carlson was able to walk and speak even better than before the accident happened. She was markedly improved in all of her neurological, motor function and cognition tests.

An MRI scan 162 days after the incident showed that the child still has mild residual brain injury but the cortical and white matter atrophy she suffered was nearly completely reversed. The doctors cannot say for certain how exactly the oxygen treatments helped such a dramatic reversal of severe brain damage but said that the treatments helped to reduce swelling and encouraged brain cells to survive.

Note: (A) T2 coronal images at the level of the thalami from left to right at 3, 31, and 162 days post-drowning, showing reversal of white matter and cortical atrophy. Corpus callosum white matter and temporal lobe gray matter calculations embedded: 3.17, 2.00, 3.57 mm, and 8.10, 6.31, and 7.75 mm, at 3, 31, and 162 days respectively. (B) Axial FLAIR image at the level of the basal ganglia 162 days post-drowning, showing scattered residual signal change in the white matter (yellow arrows) despite apparent global return to normal tissue volumes. MRI: Magnetic resonance imaging.

"Although it's impossible to conclude from this single case if the (combined oxygen therapies) would be more effective than HBOT alone," Harch said. "In the absence of hyperbaric oxygen therapy, short duration, repetitive normobaric oxygen therapy may be an option until hyperbaric oxygen therapy is available."

Harch PG, Fogarty EF. Subacute normobaric oxygen and hyperbaric oxygen therapy in drowning, reversal of brain volume loss: a case report. Med Gas Res [serial online] 2017 [cited 2017 Jul 20];7:144-9. Available from:;year=2017;volume=7;issue=2;spage=144;epage=149;aulast=Harch;type=2

A 2-year-old girl experienced cardiac arrest after cold water drowning. Magnetic resonance imaging (MRI) showed deep gray matter injury on day 4 and cerebral atrophy with gray and white matter loss on day 32. Patient had no speech, gait, or responsiveness to commands on day 48 at hospital discharge. She received normobaric 100% oxygen treatment (2 L/minute for 45 minutes by nasal cannula, twice/day) since day 56 and then hyperbaric oxygen treatment (HBOT) at 1.3 atmosphere absolute (131.7 kPa) air/45 minutes, 5 days/week for 40 sessions since day 79; visually apparent and/or physical examination-documented neurological improvement occurred upon initiating each therapy. After HBOT, the patient had normal speech and cognition, assisted gait, residual fine motor and temperament deficits. MRI at 5 months after injury and 27 days after HBOT showed near-normalization of ventricles and reversal of atrophy. Subacute normobaric oxygen and HBOT were able to restore drowning-induced cortical gray matter and white matter loss, as documented by sequential MRI, and simultaneous neurological function, as documented by video and physical examinations.