Wednesday, August 31, 2016

Ketogenic diet cognitive and behavioral impact

IJff DM, Postulart D, Lambrechts DA, Majoie MH, de Kinderen RJ, Hendriksen JG,
Evers SM, Aldenkamp AP. Cognitive and behavioral impact of the ketogenic diet in
children and adolescents with refractory epilepsy: A randomized controlled trial.
Epilepsy Behav. 2016 Jul;60:153-7.

The ketogenic diet (KD) is increasingly used for the treatment of refractory epilepsy in childhood because of the beneficial effect on seizure reduction. The aim of the current study was to objectively assess cognition and aspects of behavior during the first 4months of a randomized controlled study in children and adolescents.
Participants from a tertiary epilepsy center were randomized to a KD group (intervention) or a care-as-usual (CAU) group (control). Follow-up assessments on cognition and behavior were performed approximately 4months after initiation of the KD with a combination of parent report questionnaires and individually administered psychological tests for the children.
A total of 50 patients were enrolled in this study, 28 patients from the KD group and 22 patients from the CAU group. The KD group showed lower levels of anxious and mood-disturbed behavior and was rated as more productive. Cognitive test results showed an improvement of activation in the KD group.
This study showed a positive impact of the KD on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, an activated mood and cognitive activation were observed in patients treated with the KD.

Courtesy of:

Zhu D, Wang M, Wang J, Yuan J, Niu G, Zhang G, Sun L, Xiong H, Xie M, Zhao Y.
Ketogenic diet effects on neurobehavioral development of children with
intractable epilepsy: A prospective study. Epilepsy Behav. 2016 Feb;55:87-91.

This study aimed to determine the impact of a ketogenic diet (KD) on neurobehavioral development when used to treat children with intractable epilepsy, confirming the efficacy of the KD, as well as the correlation between early electroencephalography (EEG) changes in the early stage with treatment efficacy.
We enrolled 42 children who were starting treatment for intractable epilepsy with the classic KD protocol. The total development quotient as well as the development quotients for adaptability, gross motor movements, fine motor movements, language, and individual-social interaction on the Gesell developmental scales were assessed before and after 3, 6, 12, and 18 months of KD treatment. The efficacy assessment was based on changes in seizure frequency after KD as recorded by the parents. We conducted 24-h video-EEG before and after 1 month of KD treatment.
Developmental quotients of five energy regions in the Gesell developmental scales assessment were used to compare adaptability (P1=0.000), gross motor movements (P2=0.010), and fine motor movements (P3=0.000); the results showed significant differences. After KD treatment at different time points, 69.0%, 54.8%, 40.5%, and 33.3% patients, respectively, achieved a ≥50% reduction in seizure frequency. The reduction of epileptiform discharges in the awake state after 1 month of KD treatment correlated with the efficacy after 3 months of KD treatment.
Ketogenic diet treatment tends to be associated with improved neurobehavioral development, and more significant improvement can be obtained with prolonged treatment. The KD is safe and effective in treating children with intractable epilepsy. Early EEG changes correlate with clinical efficacy, to a certain degree.

Symptom profiles of autism spectrum disorder in tuberous sclerosis complex

Jeste SS, Varcin KJ, Hellemann GS, Gulsrud AC, Bhatt R, Kasari C, Wu JY, Sahin
M, Nelson CA 3rd. Symptom profiles of autism spectrum disorder in tuberous
sclerosis complex. Neurology. 2016 Aug 23;87(8):766-72.

To determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC.
Measures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests.
Children with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC.
This study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.

Tuesday, August 30, 2016

Backpack palsy

Rose K, Davies A, Pitt M, Ratnasinghe D, D'Argenzio L. Backpack palsy: A rare
complication of backpack use in children and young adults - A new case report.
Eur J Paediatr Neurol. 2016 Sep;20(5):750-3.

Backpack palsy is a well-recognised, albeit rare, complication of carrying backpacks. Although it has been mostly described in cadets during strenuous training, sporadic cases of brachial nerve impairment have been reported in children and young adults. Here we reported the case of a 15-year-old girl who presented with a left-side brachial palsy with axonal denervation of C5C7 motor roots following a school challenge for the Duke of Edinburgh Award. Her symptoms began soon after starting the challenge and included weakness of shoulder abduction and elevation, as well as forearm, wrist and fingers extension. After 6 months of physiotherapy her motor function was completely restored. Backpack palsy can sometimes present in children and young adults. This disorder should be taken in consideration when planning for daily, as well as more challenging, physical activities in these age groups.

From the article

A 15-year-old female student took part in the 2015 challenge for the Duke of Edinburgh Silver Award Expedition. The girl had been otherwise healthy with no previous symptoms of peripheral neuropathy and with unremarkable personal and family medical history. She was of Indo-Asian ethnicity, post-menarche and weighed 36.1 kg with a BMI of 14.2.

The exact weight of her backpack was not checked at the time but based on items included it was estimated to be about 10 kg. She used a soft shell backpack with a waist strap. During the expedition she walked with her classmates for 8–10 h/day for two consecutive days. Short rests were taken several times each day. At the end of the first day, she began to develop numbness in her left hand, which did not improve after rest. She subsequently developed a profound left arm weakness during the second day with inability to extend it against gravity at the elbow, wrist or fingers with minimal shoulder abduction; of significance she did not experience any painful symptoms. After 10 days of no improvement, her primary care physician referred her to the local paediatric team for an urgent review.

The neurological examination of her left arm showed no reduced muscle bulk or fasciculations. There was full range of passive movements; however, active movements were markedly reduced when compared to the contralateral arm. The most marked limitations were seen at wrist, fingers (MRC 0) and elbow extension (MRC 1). Less marked deficit was detected at shoulder elevation and abduction (MRC 3), elbow flexion, finger flexion and thumb abduction and adduction (MRC 4) ( Fig. 1 a,b). Brachial, triceps and brachioradial deep tendon reflexes were absent. Sensory examination was normal. Coordination could not be tested for the left arm but was normal on the right side and lower limbs. The rest of her neurological examination was normal. The overall findings were suggestive of a peripheral motoneuropathy involving the lateral and posterior chords of the brachial plexus 
(C5 C7)…

Electromyography (EMG) and nerve conduction studies were performed approximately 2 and 6 weeks after the onset of initial symptoms. The initial results showed normal sensory conduction with EMG showing a mixture of conduction block, seen in triceps, and active denervation found prominently in deltoid and to a lesser extent, extensor digitorum communis (EDC). Evidence of involvement outside of the posterior cord was suggested by abductor pollicis brevis (APB) and adductor digiti minimi, demonstrating F-wave abnormalities. The repeated study at 6 weeks post injury confirmed axonotmesis had taken place with reinnervation in deltoid and EDC. Triceps appeared still only affected by conduction block. F-waves had returned when APB was studied. EMG of biceps was normal.

The patient was managed conservatively. She was reviewed by the community physiotherapy team and instructed with daily exercises. She gradually started to recover her motor function about 4 months after the injury. A follow-up visit 6 months after the initial presentation revealed a complete recovery.

Courtesy of:

Saturday, August 27, 2016

A risk for sudden death in epilepsy that often goes unmentioned

Shena Pearson nearly froze in her seat, terrified, as she stared at a power-point slide. She was at her first meeting of an epilepsy foundation, seeking help for her 12-year-old son Trysten, when a neurologist flashed the slide about something called Sudep.

It stands for sudden unexpected death in epilepsy. Her son’s neurologist had never mentioned it.

“Oh dear God, my child is at risk, seriously at risk,” Ms. Pearson thought to herself.

Sudden death in epilepsy is a little-known and seldom-mentioned phenomenon, but now, after a push by advocates, the federal government has begun a concerted program to understand it. Yet a question remains: When, if ever, should patients be warned?...

Neurologists say sudden unexpected death in epilepsy is second to stroke as a cause of years of life lost because of a neurological disorder. Sudep kills an estimated 2,600 people a year in the United States — some neurologists say the real figure is almost certainly higher — or one in 1,000 people with epilepsy. For people whose seizures are not controlled with the medication, the fatality rate is one in 150.

Some three million Americans and 50 million people worldwide have epilepsy. About a third of Americans with epilepsy have uncontrolled seizures, said Dr. Daniel Friedman, an epilepsy researcher at New York University. That means about a million Americans could be at high risk of sudden death…

Ms. Pearson’s son was having at least 24 seizures a year despite anti-seizure medication. She could not bear to tell him about the sudden death risk. But he found out anyway three months later. He was meeting with an epilepsy support group meeting near their home in Galveston County in Texas and overheard people discussing it.

Ms. Pearson and her son were not alone in finding out about sudden death in epilepsy by accident. Despite the urging of professional organizations like the American Epilepsy Society and leading researchers to give patients the full picture, neurologists shy from a discussion of this phenomenon. The problem is that, at least for now, risk estimates are uncertain, and there are no proven ways to prevent it.

A national study of neurologists found that very few always told people with epilepsy about sudden death. That prompted Dr. William Gaillard, the director of the epilepsy program at the Children’s National Health System, to survey the children’s neurologists in his program. Most said they usually did not mention it to families.

“Many of my colleagues, myself included, are paternalistic creatures,” Dr. Gaillard said in an interview. “Many don’t talk about it because it is a low risk, and there is nothing you can do about it. They’ve made that decision for their patients.”

But Dr. Gaillard and others say families have a right to know. In addition, said Dr. Orrin Devinsky, the director of the epilepsy center at NYU Langone Medical Center, knowing about it could provide an impetus for patients to work with doctors to get their seizures under control, as death occurs just after a seizure.

Dr. Walter Koroshetz, the director of the National Institute of Neurological Disorders and Stroke, faced the disclosure question in his own family. In 1990, his father, who developed epilepsy late in life, walked to his refrigerator one day to get something to eat. He had a seizure, fell and died. Five years earlier, an uncle on his father’s side had died as a result of Sudep after developing late-life epilepsy. But Dr. Koroshetz, who as a neurologist knew about sudden death in epilepsy, had not mentioned it to his father.

“I did not think it would help him,” Dr. Koroshetz said.

Three years later, another of his father’s brothers developed epilepsy. This time, Dr. Koroshetz said, he had a long discussion about the risk of death with that uncle. He is still alive and doing well.

Dr. Koroshetz says there is not much adults can do to protect themselves except to take anti-seizure medications religiously, because the sudden death risk is associated mainly with uncontrolled seizures…

John Popovich lost his son John Paul to sudden death in epilepsy. A 19-year-old freshman at the University of Virginia, he had come home to celebrate the holidays last year. His father found him lying face down on his bed one morning, dead. He had had only three seizures in his entire life.

The death certificate did not mention sudden death in epilepsy, and Mr. Popovich and his family, who live in Northern Virginia, had never heard of Sudep until his brother told him about it several weeks after his son’s funeral. Mr. Popovich could not understand doctors’ reluctance to bring it up.

“As a parent who lost a child, I can say that the medical community is not doing anyone a favor,” he said.

The toxicology report after his son’s death indicated that he had not taken his seizure medication for at least a day — the drug was not in his system. If he had known about the risk of sudden death, he would never have missed a dose, his father said.

Courtesy of Doximity


Friday, August 26, 2016

Pitt-Hopkins syndrome

Sweatt JD. Pitt-Hopkins Syndrome: intellectual disability due to loss of
TCF4-regulated gene transcription. Exp Mol Med. 2013 May 3;45:e21.

TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.

Sepp M, Pruunsild P, Timmusk T. Pitt-Hopkins syndrome-associated mutations in
TCF4 lead to variable impairment of the transcription factor function ranging
from hypomorphic to dominant-negative effects. Hum Mol Genet. 2012 Jul

Transcription factor TCF4 (alias ITF2, SEF2 or E2-2) is a broadly expressed basic helix-loop-helix (bHLH) protein that functions as a homo- or heterodimer. Missense, nonsense, frame-shift and splice-site mutations as well as translocations and large deletions encompassing TCF4 gene cause Pitt-Hopkins syndrome (PTHS), a rare developmental disorder characterized by severe motor and mental retardation, typical facial features and breathing anomalies. Irrespective of the mutation, TCF4 haploinsufficiency has been proposed as an underlying mechanism for PTHS. We have recently demonstrated that human TCF4 gene is transcribed using numerous 5' exons. Here, we re-evaluated the impact of all the published PTHS-associated mutations, taking into account the diversity of TCF4 isoforms, and assessed how the reading frame elongating and missense mutations affect TCF4 functions. Our analysis revealed that not all deletions and truncating mutations in TCF4 result in complete loss-of-function and the impact of reading frame elongating and missense mutations ranges from subtle deficiencies to dominant-negative effects. We show that (i) missense mutations in TCF4 bHLH domain and the reading frame elongating mutation damage DNA-binding and transactivation ability in a manner dependent on dimer context (homodimer versus heterodimer with ASCL1 or NEUROD2); (ii) the elongating mutation and the missense mutation at the dimer interface of the HLH domain destabilize the protein; and (iii) missense mutations outside of the bHLH domain cause no major functional deficiencies. We conclude that different PTHS-associated mutations impair the functions of TCF4 by diverse mechanisms and to a varying extent, possibly contributing to the phenotypic variability of PTHS patients.

Forrest MP, Hill MJ, Quantock AJ, Martin-Rendon E, Blake DJ. The emerging
roles of TCF4 in disease and development. Trends Mol Med. 2014 Jun;20(6):322-31.

Genome-wide association studies have identified common variants in transcription factor 4 (TCF4) as susceptibility loci for schizophrenia, Fuchs' endothelial corneal dystrophy, and primary sclerosing cholangitis. By contrast, rare TCF4 mutations cause Pitt-Hopkins syndrome, a disorder characterized by intellectual disability and developmental delay, and have also been described in patients with other neurodevelopmental disorders. TCF4 therefore sits at the nexus between common and rare disorders. TCF4 interacts with other basic helix-loop-helix proteins, forming transcriptional networks that regulate the differentiation of several distinct cell types. Here, we review the role of TCF4 in these seemingly diverse disorders and discuss recent data implicating TCF4 as an important regulator of neurodevelopment and epithelial-mesenchymal transition.

Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ. Functional
analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum Mutat.
2012 Dec;33(12):1676-86.

Pitt-Hopkins syndrome (PTHS) is a rare developmental disorder associated with severe mental retardation, facial abnormalities, and intermittent hyperventilation. Autosomal dominant PTHS is caused by mutations in the transcription factor 4 (TCF4) gene, whereas NRXN1 and CNTNAP2 mutations are associated with autosomal recessive PTHS. To determine the impact of missense mutations on TCF4 function, we tested a panel of PTHS-associated mutations using a range of quantitative techniques. Mutations in the basic helix-loop-helix (bHLH) domain of TCF4 alter the subnuclear localization of the mutant protein and can attenuate homo- and heterodimer formation in homogenous time-resolved fluorescence (HTRF) assays. By contrast, mutations proximal to the bHLH domain do not alter the location of TCF4 or impair heterodimer formation. In addition, we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. Here we find variable, context-specific deficits in the ability of the different PTHS-associated TCF4 mutants to transactivate these promoters when coexpressed with different bHLH transcription factors. These data demonstrate that PTHS-associated missense mutations can have multiple effects on the function of the protein, and suggest that TCF4 may modulate the expression of NRXN1 and CNTNAP2 thereby defining a regulatory network in PTHS.

Inspired by a patient

Thursday, August 25, 2016

GLUT-1 deficiency

Zeesy Bruk, all of 5, is no stranger to overcoming challenges. Her parents, Rabbi Chaim and Chavie Bruk are co-directors of Chabad-Lubavitch of Montana in the city of Bozeman (population about 42,000), which serves one of the smallest and most isolated Jewish populations in the United States.

In fact, her father says that it’s their family’s faith and inspiration that helped them reach their most recent milestone: her appointment as Montana’s 2016 Children’s Miracle Network Hospitals Champion Child. This coming year, Zeesy and her family will serve as local, state and national spokespeople advocating for charitable needs at children’s hospitals throughout America.

“Zeesy was named the ‘2016 Champion Child’ for the state due to her courageous battle with a rare genetic metabolic disorder characterized by deficiency of a protein required for glucose to cross the blood-brain barrier,” read a statement from Shodair Children’s Hospital in Helena, Mont., the only Children’s Miracle Hospital in the state. “This disease can sometimes be misdiagnosed as epilepsy, which is what Zeesy was initially diagnosed with due to her frequent seizures. However, her parents continued to look for answers as Zeesy continued to experience tantrums and developmental regressions.”

Living far from large hospitals—children do not come to Shodair for medical treatment, but for genetic counseling—the Bruks determinedly took their daughter to see specialists in Utah, Colorado and New Jersey in their quest for answers. The challenge was compounded by the fact that Zeesy, like her siblings, was adopted as an infant, so the Bruks were short on details about her genetic history.

Eventually, it was determined that Zeesy had GLUT-1 Deficiency, a disorder so rare that she is the only person known to have it in the entire state of Montana. 

Working with experts at Shodair, the Bruks put Zeesy on a glucose-free diet. As one of the few families who keep kosher in Montana, the Bruks were no strangers to special diets, so they took cutting out glucose in stride. Seven months later, they report seeing developmental increases, and are looking forward to more positive progress in the coming months and years.

“There is no doubt that our family was greatly buoyed by our faith in Gd and the inspiration we gain from the teachings of the Rebbe [Rabbi Menachem M. Schneerson, of righteous memory], whose vision prompted us to make Montana our home nearly a decade ago,” says Rabbi Bruk. “The fact that Zeesy will now be traveling and inspiring others is the natural outgrowth of how we live our lives.”For its part, the hospital notes that she “continues to have a carefree attitude and doesn’t let this diagnosis get in the way of her living and loving her life.”

As Dr. Abe Elias, director of medical genetics at Shodair, puts it: “Zeesy’s spunk and tenacity will serve her as she learns, with the help of her parents, how to navigate and manage this genetic disorder, and live life to the fullest.”

During her time as a Champion Child, the 5-year-old will serve as ambassador for the Treasure State, bringing awareness to the various medical challenges facing many young people today. Along those lines, she will unite later this year with Champion Children from each state; they will visit Washington, D.C, and Orlando, Fla., as part of an official Ambassador Tour to highlight the vital work of children’s hospitals nationwide.

Zeesy’s first appearance is scheduled to take place on Monday, March 14, at the Children’s Miracle Network Spring Kickoff Luncheon in her hometown of Bozeman.

Inspired by meeting Zeesy and her father. 

The small things really aren’t so small after all

I remember the way the night sky looked right after the horrific car accident. I was in eighth grade at the time, but I can still see the way the stars glinted like shards of diamonds through the smoke of the burning cars. I couldn’t believe that I had just crawled out of the smoking car. That I could still move. That I could still breathe. That I could still look up and see the branches of a tree glowing in the light of the moon.

I had literally seen my life flash before me. Suddenly, the life that I had taken for granted was a sheer miracle. I was not only alive, I was whole. I had emerged from a totaled car with just a few cuts from the broken glass, and as young as I was, I knew that this was an undeserved gift. My hands. My feet. My sight. These were all suddenly sufficient reasons to be overjoyed and immensely grateful, to thank God every moment for giving me my life and then returning it to me again.

Sometimes I lose touch with this memory. I forget what the stars look like the second after you almost die. I forget what it feels like to have happiness distilled into such a simple, expectation-free formula: appreciate what you have.

Dr. BJ Miller’s story brought me back to the power of that kind of gratitude and taught me so much more about what it means to appreciate the gift of life. Dr. Miller is a palliative care physician who has dedicated his life to helping people navigate the process of dying in the hospice that he directs. BJ lost three of his limbs when he was tragically electrocuted when he was a student at Princeton. Faced with a drastically different future than he had imagined for himself, BJ began to search for what it meant to be “him” with just one arm left. He began trying to figure out what he was living for.
After a few months of isolation in the burn unit, BJ began to discover a secret to ongoing gratitude in life: the small things aren’t so small. 

The first time that BJ became acutely aware of this secret was a couple of months after his accident. There wasn’t even a window in his hospital room so he hadn’t seen the seasons change from autumn to winter and one day a nurse brought him a snowball. In BJ’s words:

“It was snowing outside, and I didn’t know that. I didn’t even know if it was night or day. This nurse had the bright idea of smuggling in a snowball to me, so that I could hold and feel the snow. It was so, man, it was just stunning. She put it in my hand and I just felt the contrast of the cold snow on my burnt skin. I watched it melt and become water. The simple miracle of it was just a stunner for me. And it really made it so palpable that we as human beings, as long we are in these bodies, we are feeling machines and if we’re cut off, if our senses are choked off, we are choked off and it was the most therapeutic moment I can imagine. And I would never have guessed this but just holding that snowball- first of all the sensation but also the implied inherent perspective it helped me make- that everything changes, snow becomes water, and that it’s beautiful because it changes. That things are fleeting, and it just felt so beautiful to be part of this weird world at that moment. And I’ll never forget what it was like to hold that snowball.”

BJ has taken that perspective and built a life dedicated to helping people appreciate their lives even as they are dying. To figure out a way to live in each moment and recognize how extraordinary the “little” things really are. BJ says that even today, decades after his accident, he feels blessed just to feel. “I get thrilled that I can feel anything. Sometimes even pain. I remind myself sometimes how amazing it is to feel anything at all.”

We think that being grateful for the little things is a cliché or a waste of time. How wrong we are.
We can get so distracted by routines and obligations and “big” things in our lives that we think that being grateful for the little things is a cliché or a waste of time. How wrong we are. In the morning after I pray, I write down three “little” things that I am grateful for. Air. Water. Food. Birds. Trees. I started doing this about half a year ago and it has transformed my life. It reminds me at the start of my day that the small things really aren’t so small.

BJ’s words remind me of that moment after my car accident when I was sitting on the curb on the side of the road and looking up at the stars. He writes:

“The small things ain’t so small actually. Just the joy of feeling anything, of having a body at all, being capable of movement at all is so profound. It’s so potent, and yet most of us take that for granted. Most nights, you can usually look up and find a star. Look up. Ponder the night sky for a minute. Realize that we’re all on the same planet at the same time, and then you start looking at the stars and realize that the light that is hitting your eyes is ancient, that the stars that you are seeing may no longer exist by the time the light gets to you. And just sort of mulling the bare facts of the cosmos, for me it’s enough to just thrill me, awe me, freak me out and kind of put all my neurotic anxieties in their proper place.”

Sometimes we get a gift. We get a moment when we see past the surface and recognize what a miracle it is just to be alive. We get a gift that teaches us how to trade our entitlement for appreciation, our distraction for awe, our discontent for gratitude.

But we have to strive to hold onto the gift.

Look up. You can always find one star. And even though it looks like a tiny point of light, it can connect us to the infinite light within us all.

The small things really aren’t so small after all.

Wednesday, August 24, 2016

Shades of Questcor 3

Indeed, the price of an EpiPen standard two-pack gradually grew to about $600. The same two-pack cost only about $100 in 2009.

Meanwhile, epinephrine, which can be purchased alone, costs just a few dollars. The EpiPen, manufactured by the pharmaceutical company Mylan, offers a portable way to administer doses. "Some patients and physicians are resorting to buying epinephrine ampoules and filling their own syringes," said Dr. Thomas Casale, a professor of medicine at the University of South Florida and executive vice president of the American Academy of Allergy, Asthma, and Immunology (AAAAI).
Many adults and families of children with severe allergies are facing sticker shock when they pay for their EpiPens, especially amid back-to-school season.

Theresa Ray, a 30-year-old mother in Cincinnati, was surprised to find that purchasing two EpiPen two-packs for her 6-year-old son would have cost her family about $1,300, she said. Her son was diagnosed with food allergies five years ago.

"When we first bought them (about five years ago), it was around $100 or $150 for a twinpack, and at that time I remember thinking, 'Wow, that's kind of expensive.' Then, the next year, I found out they expired and we have to get them every year. They were more expensive, but by that time, only a couple hundred dollars," Ray said.

"Last year, we spent around $650 for a twinpack and this year, same thing," she said. "It was funny, I told my husband, 'I wonder why no one's talking about this. It's really weird no one's talking about EpiPens.' ... And then, I saw a news article on Facebook about it."…

Albuterol, an asthma medicine, has also increased in price in recent years.

A House of Representatives report found in 2014 that 10 generic drugs experienced price increases just a year prior, ranging from a 420% hike to more than 8,000%.

Now, the new study suggests that a combination of market exclusivity provisions granted to drug manufacturers, and coverage requirements imposed on government-funded drug benefits, are both driving the high costs of prescription drugs nationwide…

Kesselheim and his colleagues reviewed and analyzed previous papers published in medical and health policy journals from January 2005 to July 2016, taking a close look at how each explained the cause of rising drug prices and how to possibly reduce costs.

Based on their analysis, the researchers found that the primary reason for increasing drug spending is the high price of branded products.

While only about 10% of all prescription drugs in the country are brand-name drugs, such as the EpiPen, they account for a whopping 72% of drugs being sold, the researchers discovered...

Minnesota Sen. Amy Klobuchar has called on the Senate Judiciary Committee to hold a hearing to investigate the rising price of EpiPens.

"Patients all over the United States rely on these products, including my own daughter. Not only should the Judiciary Committee hold a hearing, the Federal Trade Commission should investigate these price increases immediately," Klobuchar, a Democrat, said in a written statement that was released on Saturday. "The Commission should also report to Congress on why these outrageous price increases have become common, and propose solutions that will better protect consumers within 90 days."

Iowa Sen. Chuck Grassley, a Republican, announced Monday that he had contacted the company Mylan seeking answers as to why there has been a steep price increase in the product in recent years. As the cost of EpiPens has been gradually rising, so has the number of patients in high-deductible health plans -- alas, the impact of the cost on patients seems to be a problem that's two-fold, said Dr. Purvi Parikh, an allergist and immunologist at NYU Langone Medical Center and an allergist with the Allergy & Asthma Network.

"While the price is increasing, the other issue now is that the health insurance plans have now put more and more responsibility on the patient," said Parikh, who also serves as Levin's doctor.
"It's definitely unfortunate because it's a necessary lifesaving medication. It's not really a luxury," Parikh said. "It's a single-use medication and you need it available everywhere you go, so often our patients will have multiple sets of EpiPens at home, school, work. So it's a huge cost on the patient. "Not only have I seen it save lives, but I've seen the opposite happen, of when an EpiPen wasn't available and both children and adults passed away."…

A spokeswoman for Mylan emailed a written statement from the company to CNN. In the statement, company officials indicated that they know more is needed to help patients with high-deductible insurance plans.

"With changes in the healthcare insurance landscape, an increasing number of people and families are enrolled in high-deductible health plans, and deductible amounts continue to rise. This shift has presented new challenges for consumers, and they are bearing more of the cost. This change to the industry is not an easy challenge to address, but we recognize the need and are committed to working with customers and payors to find solutions to meet the needs of the patients and families we serve," according to the company's statement.

Levin, the patient in New York, said that her EpiPen costs are partly covered by insurance, but she has to first pay a separate deductible under the category of injectables before she can purchase her EpiPens at the discounted insurance price.

"Five years ago, the deductible was only $100, but as the price increased, so did the deductible. So every new year, I always have to anticipate and pay the dreaded cost," she said.

Mylan offers a My EpiPen Savings Card to help consumers with cost. Last year, nearly 80% of commercially insured patients used the card to receive the device for free, according to Mylan. The company also has distributed more than 700,000 free EpiPens to schools nationwide.

Additionally, "there are some coupons available, which help lower the cost to patients, but there still is a considerable copay for most patients," said Casale, the AAAAI executive vice president. "Although the cost of epinephrine auto injectors has risen considerably, they are lifesaving and patients should do whatever they can to secure them."

Meanwhile, Kesselheim and his colleagues suggested short-term strategies to reducing high drug prices in their paper.

"We need to re-examine the market exclusivities provided by the government to manufacturers to ensure that they adequately protect innovative products without similarly applying to less innovative treatments that add cost without adding value," Kesselheim said. "More patients and physicians need to talk about the costs of medications with each other -- and express concern to their legislators -- so that evidence-based lower-cost alternatives can be found, if possible."

Muscle biopsy in mitochondrial disease

Hardy SA, Blakely EL, Purvis AI, Rocha MC, Ahmed S, Falkous G, Poulton J, Rose
MR, O'Mahony O, Bermingham N, Dougan CF, Ng YS, Horvath R, Turnbull DM, Gorman
GS, Taylor RW. Pathogenic mtDNA mutations causing mitochondrial myopathy: The
need for muscle biopsy. Neurol Genet. 2016 Jun 23;2(4):e82.

Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary mitochondrial DNA (mtDNA)-related disease despite accounting for only 5%-10% of the mitochondrial genome.(1,2) Although some common mt-tRNA mutations, such as the m.3243A>G mutation, exist, the majority are rare and have been reported in only a small number of cases.(3) The MT-TP gene, encoding mt-tRNA(Pro), is one of the less polymorphic mt-tRNA genes, and only 5 MT-TP mutations have been reported as a cause of mitochondrial muscle disease to date (table e-1 at, P6-10). We report 5 patients with myopathic phenotypes, each harboring different pathogenic mutations in the MT-TP gene, highlighting the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.

From the article

 We report  5 adult patients with mitochondrial disease due to different mutations in the MT-TP gene with a predominantly myopathic phenotype. Ptosis (+/− progressive external ophthalmoplegia), proximal myopathy, and marked perceived fatigue appear to be salient features. In each case, the marked degree of COX deficiency and downregulation of both complex I and complex IV subunits in muscle was strongly suggestive of a defect in mitochondrial translation and entirely in keeping with an mt-tRNA mutation. To date, only 5 patients have been reported, each with different MT-TP mutations, and variable clinical features have been observed including ataxia, deafness, dilated cardiomyopathy, myoclonic epilepsy with ragged-red fibers–like disease, and retinitis pigmentosa; a myopathic phenotype is reported in all cases (table e-1).

Patients 1, 2, and 3 showed restricted expression of their MT-TP mutations to muscle, strongly indicative of a de novo mutational event, whereas patients 4 and 5 showed a hierarchical segregation pattern as observed in many pathogenic mtDNA mutations. Screening of maternal samples was undertaken for patients 2, 4, and 5, with maternal inheritance being confirmed in patient 4 only. Of note, only one of the previous studies demonstrated maternal inheritance of the MT-TP mutation, with 4 of the remaining studies also reporting apparent or likely de novo mutational events.
Single muscle fiber segregation studies remain the gold standard test to confidently establish pathogenicity of novel mtDNA variants. Although the m.15975T>C5 and m.16002T>C6 mutations have been reported previously, functional studies were not undertaken to confirm pathogenicity. Subsequent studies in muscle biopsies of all 5 patients confirm that mutation loads segregated with the mitochondrial histochemical defects in muscle (figure 1C; table e-2), powerfully illustrating an ongoing requirement to access pathologically relevant tissue—skeletal muscle—to support the investigation and diagnosis of patients with mitochondrial myopathy, even in the current era of high-throughput next-generation sequencing technologies.

Prenatal and postnatal findings with Zika virus

Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, Amorim MM, Batista AG,
Chimelli L, Tanuri A, Aguiar RS, Malinger G, Ximenes R, Robertson R, Szejnfeld J,
Tovar-Moll F. Congenital Brain Abnormalities and Zika Virus: What the Radiologist
Can Expect to See Prenatally and Postnatally. Radiology. 2016 Aug 23:161584.
[Epub ahead of print]


Purpose To document the imaging findings associated with congenital Zika virus infection as found in the Instituto de Pesquisa in Campina Grande State Paraiba (IPESQ) in northeastern Brazil, where the congenital infection has been particularly severe.

Materials and Methods From June 2015 to May 2016, 438 patients were referred to the IPESQ for rash occurring during pregnancy or for suspected fetal central nervous system abnormality. Patients who underwent imaging at IPESQ were included, as well as those with documented Zika virus infection in fluid or tissue (n = 17, confirmed infection cohort) or those with brain findings suspicious for Zika virus infection, with intracranial calcifications (n = 28, presumed infection cohort). Imaging examinations included 12 fetal magnetic resonance (MR) examinations, 42 postnatal brain computed tomographic examinations, and 11 postnatal brain MR examinations. Images were reviewed by four radiologists, with final opinion achieved by means of consensus.

Results Brain abnormalities seen in confirmed (n = 17) and presumed (n = 28) congenital Zika virus infections were similar, with ventriculomegaly in 16 of 17 (94%) and 27 of 28 (96%) infections, respectively; abnormalities of the corpus callosum in 16 of 17 (94%) and 22 of 28 (78%) infections, respectively; and cortical migrational abnormalities in 16 of 17 (94%) and 28 of 28 (100%) infections, respectively. Although most fetuses underwent at least one examination that showed head circumference below the 5th percentile, head circumference could be normal in the presence of severe ventriculomegaly (seen in three fetuses). Intracranial calcifications were most commonly seen at the gray matter-white matter junction, in 15 of 17 (88%) and 28 of 28 (100%) confirmed and presumed infections, respectively. The basal ganglia and/or thalamus were also commonly involved with calcifications in 11 of 17 (65%) and 18 of 28 (64%) infections, respectively. The skull frequently had a collapsed appearance with overlapping sutures and redundant skin folds and, occasionally, intracranial herniation of orbital fat and clot in the confluence of sinuses.

Conclusion The spectrum of findings associated with congenital Zika virus infection in the IPESQ in northeastern Brazil is illustrated to aid the radiologist in identifying Zika virus infection at imaging.

Courtesy of a colleague

Long-term outcomes associated with traumatic brain Injury in childhood and adolescence

Sariaslan A, Sharp DJ, D'Onofrio BM, Larsson H, Fazel S. Long-Term Outcomes
Associated with Traumatic Brain Injury in Childhood and Adolescence: A Nationwide
Swedish Cohort Study of a Wide Range of Medical and Social Outcomes. PLoS Med.
2016 Aug 23;13(8):e1002103.

Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes.
In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers. We subsequently assessed these individuals for the following outcomes using multiple national registries: disability pension, specialist diagnoses of psychiatric disorders and psychiatric inpatient hospitalisation, premature mortality (before age 41 y), low educational attainment (not having achieved secondary school qualifications), and receiving means-tested welfare benefits. We used logistic and Cox regression models to quantify the association between TBI and specified adverse outcomes on the individual level. We further estimated population attributable fractions (PAF) for each outcome measure. We also compared differentially exposed siblings to account for unobserved genetic and environmental confounding. In addition to relative risk estimates, we examined absolute risks by calculating prevalence and Kaplan-Meier estimates. In complementary analyses, we tested whether the findings were moderated by injury severity, recurrence, and age at first injury (ages 0-4, 5-9, 6-10, 15-19, and 20-24 y). TBI exposure was associated with elevated risks of impaired adult functioning across all outcome measures. After a median follow-up period of 8 y from age 26 y, we found that TBI contributed to absolute risks of over 10% for specialist diagnoses of psychiatric disorders and low educational attainment, approximately 5% for disability pension, and 2% for premature mortality. The highest relative risks, adjusted for sex, birth year, and birth order, were found for psychiatric inpatient hospitalisation (adjusted relative risk [aRR] = 2.0; 95% CI: 1.9-2.0; 6,632 versus 37,095 events), disability pension (aRR = 1.8; 95% CI: 1.7-1.8; 4,691 versus 29,778 events), and premature mortality (aRR = 1.7; 95% CI: 1.6-1.9; 799 versus 4,695 events). These risks were only marginally attenuated when the comparisons were made with their unaffected siblings, which implies that the effects of TBI were consistent with a causal inference. A dose-response relationship was observed with injury severity. Injury recurrence was also associated with higher risks-in particular, for disability pension we found that recurrent TBI was associated with a 3-fold risk increase (aRR = 2.6; 95% CI: 2.4-2.8) compared to a single-episode TBI. Higher risks for all outcomes were observed for those who had sustained their first injury at an older age (ages 20-24 y) with more than 25% increase in relative risk across all outcomes compared to the youngest age group (ages 0-4 y). On the population level, TBI explained between 2%-6% of the variance in the examined outcomes. Using hospital data underestimates milder forms of TBI, but such misclassification bias suggests that the reported estimates are likely conservative. The sibling-comparison design accounts for unmeasured familial confounders shared by siblings, including half of their genes. Thus, residual genetic confounding remains a possibility but will unlikely alter our main findings, as associations were only marginally attenuated within families.
Given our findings, which indicate potentially causal effects between TBI exposure in childhood and later impairments across a range of health and social outcomes, age-sensitive clinical guidelines should be considered and preventive strategies should be targeted at children and adolescents.

Courtesy of:

Sunday, August 21, 2016

Medical child abuse revisited 4

Gypsy was a tiny thing, perhaps 5 feet tall as far as anyone could guess. She was confined to a wheelchair. Her round face was overwhelmed by a pair of owlish glasses. She was pale and skinny, and her teeth were crumbling and painful. She had a feeding tube. Sometimes Dee Dee had to drag an oxygen tank around with them, nasal cannula looped around Gypsy’s small ears. Ask about her daughter’s diagnoses, and Dee Dee would reel off a list as long as her arm: chromosomal defects, muscular dystrophy, epilepsy, severe asthma, sleep apnea, eye problems. It had always been this way, Dee Dee said, ever since Gypsy was a baby. She had spent time in neonatal intensive care. She had leukemia as a toddler.

The endless health crises had taken a toll. Gypsy was friendly, talkative even, but her voice was high and childlike. Dee Dee would often remind people that her daughter had brain damage. She had to be homeschooled, because she’d never be able to keep up with other kids. Gypsy had the mind of a child of 7, Dee Dee said. It was important to remember that in dealing with her. She loved princess outfits and dressing up. She wore wigs and hats to cover her small head. A curly, blonde Cinderella number seems to have been her favorite. She’s wearing it in so many photographs of herself with her mother. She was always with her mother…

Sometimes, listening, Amy Pinegar found herself overwhelmed. “I wondered,” Pinegar told me over the phone last fall, “keeping this child alive… Is she that happy?” All she could do was be a good neighbor and pitch in when she could. She’d drive Dee Dee and Gypsy to the airport for their medical trips to Kansas City, bring them things from Sam’s Club. Ultimately, they did seem happy. They went on charity trips to Disney World, met Miranda Lambert through the Make-a-Wish Foundation. Looking back on it, Pinegar was sometimes even jealous of them…

She had met Dee Dee and Gypsy in 2009 at a science fiction and fantasy convention held in the Ozarks, where Gypsy could wear costumes and not be particularly out of place. “They were just perfect,” Kim said. “Here was this poor, sick child who was being taken care of by a wonderful, patient mother who only wanted to help everybody.”…

It turned out that, in fact, Gypsy hadn’t used a wheelchair from the moment she left her house a few days earlier. She didn’t need one. She could walk just fine, there was nothing wrong with her muscles, and she had no medication or oxygen tank with her either. Her hair was short and spiky, but she wasn’t bald — her head had simply been shaved, all her life, to make her appear ill. She was well-spoken, if shaken by recent events. The disabled child she’d long been in the eyes of others was nowhere to be found. It was all a fraud, she told the police. All of it. Every last bit. Her mother had made her do it…

Gypsy was healthy at birth, Rod said. But when she was 3 months old, Dee Dee became convinced that her baby had sleep apnea, that Gypsy would stop breathing in the night. It was then when Dee Dee began taking her to the hospital. As Rod remembers it, the doctors couldn’t find anything, in spite of three rounds of tests and a sleep monitor. The conviction that Gypsy was a sickly child took hold. She explained the increasingly bewildering array of problems to Rod by saying that Gypsy had a chromosomal defect. Many of Gypsy’s health issues, she claimed, stemmed from that one thing…

Dee Dee always had a new idea about what was wrong with Gypsy, a new doctor, a new drug. She had once worked as a nurse’s aide; she had a knack for remembering medical terminology and spitting it back. The information overload acted as a kind of wall around mother and daughter. It always seemed that Dee Dee had things under control. She knew so much, and she was never troubled by questions — she always had an answer…

Dee Dee and Gypsy spent their years in Slidell living in public housing and visiting doctors at the Tulane University Hospital & Clinic and the Children’s Hospital. Dee Dee told doctors there that Gypsy had seizures every couple of months, so they put her on anti-seizure medications. Dee Dee insisted to one doctor after another that her daughter had muscular dystrophy even after a muscle biopsy proved she didn’t. There were problems with her eyes and ears, too, Dee Dee insisted, poor vision and frequent ear infections. Doctors dutifully operated on her. If Gypsy had a cold or cough, she was taken to the emergency room…

She told the shelter staff she didn’t have Gypsy’s medical records with her because they’d been destroyed in the flood.

One of the doctors at the shelter, Janet Jordan, was from the Ozarks. (She declined to be interviewed for this article.) She was charmed by Gypsy in the shelter: “When I first met her, I had to cry a little bit, and she goes, ‘It’s okay, you’re only human.’” Jordan told a local news station in 2005…

While Gypsy had been involved with charities for children with disabilities from the time she was quite small — Dee Dee often stayed at Ronald McDonald houses — this was obviously the largest benefit Dee Dee had managed to arrange. It seemed to give her an appetite for more. While in Springfield, they’d benefit from free flights from a volunteer pilots organization, stays at a lodge for cancer patients, free trips to Disney World through various charity organizations. (None of the organizations with which the Blanchards had confirmed links returned requests for comment.)…

“I think Dee Dee’s problem was she started a web of lies, and there was no escaping after,” Rod said. “She got so wound up in it, it was like a tornado got started, and then once she was in so deep that there was no escaping. One lie had to cover another lie, had to cover another lie, and that was her way of life.”…

Gypsy’s medical records are sobering. All the way back in 2001, doctors at Tulane University Hospital tested Gypsy for muscular dystrophy. Her tests came back negative. In fact, all scans of her brain and spine were relatively clear. The records of all those tests survived Katrina. Nonetheless, Dee Dee continued to insist to doctor after doctor in Louisiana and Missouri that Gypsy had muscular dystrophy. Most doctors appear from these records to have taken her assertion at face value and didn’t probe. Instead they proceeded to treat Gypsy for various vision, hearing, sleep, and salivation problems that were presumed to flow from the muscular dystrophy. (The records I reviewed for this article appeared to cover only some of Gypsy’s care. It’s impossible to say how many other relevant records might exist.)…

Some interventions were surgical. Gypsy’s eye muscles were repeatedly operated on for alleged weakness. Tubes were put in her ears for alleged ear infections. She was given a feeding tube and ate very little by mouth, surviving on cans of the meal replacement PediaSure well into her twenties. Her salivary glands were first injected with Botox, then removed because her mother complained that she drooled too much. Gypsy’s teeth rotted out and had to be extracted, though whether that was because of poor dental hygiene or a mixture of medications and severe malnutrition, it’s hard to say.

The repeated invasions of Gypsy’s body in the name of these illnesses she turned out not to have were, in short, serious and prolonged. It is difficult to say now whether any of it was medically needed at all. What is not difficult to say is that all of it began when Gypsy was impossibly young and could hardly have been expected to challenge authority figures — her mother or her doctors — about how she was feeling.

For their part, doctors did not pick up on innumerable hints that Dee Dee’s stories did not add up — not even the sleep doctor, Robert Beckerman, who saw Gypsy both in New Orleans and in Kansas City. Instead he featured his treatment of Gypsy in the hospital newsletter and mentioned repeatedly in the medical files that she and Dee Dee were his “favorite mother, daughter patient.” (Beckerman did not reply to requests for comment for this story.)

There was one exception. In 2007, a pediatric neurologist named Bernardo Flasterstein, consulting on the case in Springfield, became suspicious. In a recent phone conversation, Flasterstein told me he had his doubts from the first time he saw Dee Dee and Gypsy. Dee Dee’s stories about Gypsy’s myriad illnesses didn’t fly with him. In his notes to Gypsy’s primary care doctor after the first visit, he wrote, in bold, underlined type, “The mother is not a good historian.”

There was an “unusual distribution” to Gypsy’s weakness for a muscular dystrophy patient, he wrote in his notes. Still, Flasterstein says, he gave the case the “benefit of the doubt” and sent Gypsy for all the usual tests, the MRIs and the blood work. It all came back normal. “I remember having her stand up,” he told me, “and she could hold her own weight!” He said he told Dee Dee, “I don’t see any reason why she doesn’t walk.”

In between his visits with Gypsy, Flasterstein tracked down a doctor who had seen Gypsy in New Orleans. That doctor told him that the muscle biopsy in New Orleans had been negative for muscular dystrophy, and that Gypsy’s previous neurologist had explained that to Dee Dee. When confronted with the problem, Dee Dee simply stopped seeing those New Orleans doctors.

“Analyzing all the facts, and after talking to her previous pediatrician,” Flasterstein wrote in the file, “there is a strong possibility of Munchausen by proxy, with maybe some underlying unknown etiology to explain for her symptoms.” Dee Dee stopped seeing him after that visit. “I assume she got my notes,” Flasterstein says. He said nurses told him later that on the way out of his office on that last visit, Dee Dee was complaining that he didn’t know what he was talking about.

Flasterstein never followed up. He told me that in the network of Springfield doctors Dee Dee saw, “everyone bought their story.” He remembers being told to treat the pair with “golden gloves.” He says he thought that if he reported it to social services, they wouldn’t believe him either…

It was not the only missed opportunity for authorities to intervene. In the fall of 2009, someone made an anonymous call to the Springfield Police Department, asking for a wellness check. The person said that they had doubts that Gypsy was suffering from all the ailments her mother described. (Flasterstein says it was not he who made that call.) The police drove over to the house, but Dee Dee put their fears to rest…

Gypsy is now an inmate being processed at the Women’s Eastern Reception, Diagnostic and Correctional Center in Vandalia, Missouri. Her hair is long, her skin clear and healthy, and she wears proper adult glasses. She’s off all her medications, and there have been no health problems in the year she’s been out of her mother’s control. “Most of my clients lose weight in prison,” Stanfield pointed out, because the food is so bad. Gypsy gained 14 pounds in the 12 months she spent in Greene County Jail before her plea.

Kim Blanchard, who visited Gypsy once in jail, told me, “She looked much more like the person that she was, which was the complete opposite of the person that I knew, and it was like she had a costume on that whole time and then took it off.”…

About her mother, her opinion seems to waver. “The doctors thought that she was so devoted and caring,” Gypsy said. “I think she would have been the perfect mom for someone that actually was sick. But I’m not sick. There’s that big, big difference.”

Gypsy still doesn’t feel she actively deceived anyone. “I feel like I was just as used as everybody else,” she said. “She used me as a pawn. I was in the dark about it. The only thing I knew was that I could walk, and that I could eat. As for everything else… Well, she’d shave my hair off. And she’d say, ‘It’s gonna fall out anyway, so let’s keep it nice and neat!’” Gypsy said her mother told her she had cancer, too, and would tell her that her medication was cancer medication. She just accepted it…

She will admit only to frustration. “It makes me frustrated that none of the other doctors could see that I was perfectly healthy. That my legs were not skinny, like someone who was [really] paralyzed. That I can’t… I don’t need a feeding tube. Stuff like that.”

Courtesy of my daughter 

Friday, August 19, 2016

Genetic teasers

1) A 19 month old girl has a clinical and radiographic course consistent with Joubert syndrome.  Molecular genetic testing shows her heterozygous for a ANKS6 gene sequence variant c.532G>A, resulting in the amino acid substitution p.Glu178Lys.  Prediction programs suggest this is benign, however functional and genetic evidence is deemed inconclusive.  She is also heterozygous in the TMEM67 gene for an intronic variant c.1289-7A>G.   The c.1289-7A>G variant may activate a cryptic AG acceptor site and interfere with normal splicing.  If this new acceptor site is used, it is predicted to result in an in-frame insertion of two amino acids.  In neither case was a second pathogenic mutation identified.

2) An almost 19 year old male has a progressive spastic paraparesis.  Genetic testing identified a p.Ala510Val mutation in the SPG7 paraplegia gene.  No second pathogenic mutation identified. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. It describes 4 patients who had a similar kind of mutation and developed symptoms at age 47, 1 year, 44, and 50 years of age. These patients were carrier of only 1 mutation. The SPG7 A510V was found in 8 patients (one was homozygous and 3 were controls). The paper states that these findings suggested some SPG7 mutations could be associated with variable penetrance.

The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry ( J. Neurol 2013, 260: 1286-1294).  Based on review of this paper, the paper states that the change in the SPG7 was first described as a polymorphism in 1988. This was based on the frequency of 3 to 4% in 2 separate controls in the United Kingdom.

3) An 18 year old male with epilepsy has a MRI showing a linear band of T2-FLAIR hyperintense signal radiating from the subcortical white matter of the left posterior-superior temporal gyrus down  towards the atrium of the left lateral ventricle. In addition, perhaps three subependymal modules were identified. There was also a tiny, linear focus of T2-FLAIR hyperintense signal extending from the right midfrontal cortex down towards the right lateral ventricle.  These findings were deemed relatively mild intracranial stigmata of tuberous sclerosis.

Genetic testing revealed a sequence variant in the TSC1 gene at nucleotide position 2196 (T>C). This was deemed to be a variant of unknown significance. This variant was not predicted to change the amino acid sequence of the protein unless splicing might be affected. This was not a variant that had been identified in other index cases at Athena Diagnostics. Five splicing algorithms were used to analyze thepossible effect of this variant on splicing. None of the five algorithms predicted the elimination of a known splice site. Accordingly, data was generated to suggest that this variant may be more likely benign than pathogenic.

Treatment of fetal seizures

Melanie A. McNally MD, Julia Johnson MD, Thierry A.G.M. Huisman MD, Andrea Poretti MD, Kristin Baranano MD, PhD, Ahmet A. Baschat MD and Carl E. Stafstrom MD, PhD.  SCN8A epileptic encephalopathy: Detection of fetal seizures guides multidisciplinary approach to diagnosis and treatment .  Pediatric Neurology.  In press.



SCN8A mutations are rare and cause a phenotypically heterogeneous early onset epilepsy known as early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558). There are currently no clear genotype-phenotype correlations to help guide patient counseling and management.

Patient Description

We describe a patient with EIEE13 ( de novo heterozygous pathogenic mutation in SCN8A - p.Ile240Val (ATT>GTT)) who presented prenatally with maternally reported intermittent, rhythmic movements that, when observed on ultrasound, were concerning for fetal seizures. Ultrasound also revealed abnormal developmental states. With maternal administration of levetiracetam, the rhythmic fetal movements stopped. After birth, the patient developed treatment-refractory multi-focal epilepsy confirmed by electroencephalogram. Neuroimaging revealed restricted diffusion in the superior cerebellar peduncles, a finding not reported previously in EIEE13.


This is the first reported case of EIEE13 associated with clinical prenatal-onset seizures. Ultrasonography can be useful for identifying fetal seizures, which may be treatable in utero . Ideally, the clinical approach to fetal seizures should involve a multidisciplinary team spanning the pre- and postnatal course to expedite early diagnosis and optimize management, as illustrated by this case.


From the article

Around 26 WGA, the mother reported intermittent, rapid, repetitive, “jerky” fetal movements distinct from baseline fetal movements…
Fetal behavioral state assessment, a well-established obstetrical tool by which fetal heart rate, eye movements, limb movements, and other behavioral activity are assessed and quantified by ultrasound, revealed abnormalities in behavioral state development concerning for central nervous system dysfunction. Specifically, there were rapid eye movements during quiescence, rapid transition between states 1F (quiescence/quiet sleep) to 4F (vigorous body movements)  3 within 5 seconds, and dissociation of body movements, eye movements, and fetal heart rate variables – a profile consistent with a state of global cerebral hyperexcitability.

Serial ultrasounds also revealed epochs of rapid, repetitive movements of the extremities and trunk concerning for seizure activity. Interdisciplinary consultations with fetal therapy, pediatric neurology, and neonatology resulted in a recommendation to start the mother on anti-seizure drug (ASD) therapy. Levetiracetam (LEV) was begun at 500 mg BID, a standard adult dose, in an attempt to suppress the suspected fetal seizures. LEV was chosen because of its extensive transplacental transport, rapid titratability, and favorable side effect profile for both mother and fetus. 

On LEV, the mother reported a dramatic decrease in the jerky fetal movements and any residual abnormal repetitive movements occurred only prior to the next scheduled dose, prompting dose increases to 500 mg TID and then to 750 mg TID. On LEV 750 mg TID, only rare jerky movements were reported, but some episodes concerning for seizure were captured on ultrasound three days before delivery.

Her physical examination was notable for generalized edema and multiple dysmorphic features including low-set ears, high arched palate, hypoplastic supraorbital ridges, bilateral arm and leg contractures (arthrogryposis), and bilateral clenched fists with overlapping digits. Her weight was at the 98 th percentile, length at the 5 th percentile, and head circumference at the 90 th percentile for gestational age. Her neurologic exam revealed poor reactivity, axial hypotonia, and subtle but frequent low-amplitude flexion movements at hips and shoulders, contractions of abdominal muscles, and lip smacking.

Video-EEG revealed continuous cerebral activity with moderate reactivity, good spontaneous variability, and symmetric waveforms between hemispheres with normal neonatal physiological patterns including frontal sharp transients. The flexion movements and abdominal contractions did not correlate with seizure activity on EEG. However, a few hours after birth, generalized tonic seizures occurred involving posturing of all extremities that correlated with build-up of bilateral (left maximum) frontal sharp waves. Additional multifocal electrographic seizures were noted without clinical correlate…

Whole exome sequencing revealed a de novo heterozygous mutation in SCN8A (p.Ile240Val(ATT>GTT)) that was considered to be pathogenic. Neither parent carried this mutation…

Seizures proved refractory to multiple medications. LEV was initiated and titrated up to 60 mg/kg/day and phenobarbital was increased to 6 mg/kg/day with phenobarbital levels maintained in the 50-60 mcg/mL range. Seizure clusters recurred several times per week, with seizure semiology consisting of bilateral tonic extension of upper extremities and rhythmic oromotor movements associated with tachycardia and blood oxygen desaturation. Once the mutation was identified, oxcarbazepine was added and titrated to high dose (80 mg/kg/day), because of reports that sodium channel blockers have been beneficial, at least transiently, in other patients with SCN8A mutations.  Our patient’s seizures persisted so phenytoin was added and titrated to high therapeutic levels (15-20 mcg/mL), but still without improvement in seizure control. Lamotrigine, a third sodium channel blocker, was slowly uptitrated to 2 mg/kg/day, with reduction in seizure clusters to about 1-2 per week. Throughout her neonatal course, seizure exacerbations often responded transiently to phenobarbital boluses, despite a reported lack of consistent efficacy of GABA agonists in patients with SCN8A mutations.  At 6 months of age, the patient was discharged to a community hospital on a combination of phenytoin, oxcarbazepine, phenobarbital, lamotrigine, and continued to have 1-2 seizure clusters per week, managed with intermittent rectal diazepam…

When considering an ASD for treatment of fetal seizures, several factors should be considered including placental transfer of the ASD, risk of teratogenicity, maternal tolerability, changes in pharmacokinetics during pregnancy, and ability to rapidly titrate. 

Thursday, August 18, 2016

Emerging therapies for mitochondrial disorders

Nightingale H, Pfeffer G, Bargiela D, Horvath R, Chinnery PF. Emerging
therapies for mitochondrial disorders. Brain. 2016 Jun;139(Pt 6):1633-48.

Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.

From the article

A recent systematic review identified over 1300 reports using a variety of approaches expected to bypass or enhance components of mitochondrial function. However, the vast majority of these reports are open-labelled case series with less than five subjects. Although ~30 randomized trials have been carried out to date, no treatment has shown a clear cut benefit on a clinically meaningful end-point . It is therefore likely that components of the traditional 'mitochondrial cocktail' do not have a major therapeutic impact on most mitochondrial diseases. There is therefore a clear need for the field to 'think outside the box' when developing new treatments, harnessing the massive increase in our understanding of mitochondrial disease pathogenesis…

The delivery of wild-type nDNA  or mtDNA  using viral vectors is another possibility, or perhaps the replacement of dysfunctional proteins via the cell nucleus, hitch-hiking on the mitochondrial import mechanism. Moving away from the two genomes, small molecule screens may enhance function of the respiratory chain, stem cell therapies could correct enzyme defects due to nuclear gene defects, and treatments aimed at non-specifically preventing neurodegeneration may be the way forward…

As for all potential therapies, the multi-organ nature of mitochondrial disorders and difficulties of transferring therapies across cellular and mitochondrial membranes without causing toxic effects, makes therapeutic targeting difficult. However, as explored further below, methods exist to overcome these difficulties including the use of viral vectors, harnessing allotopic expression (nuclear expression of mtDNA encoded protein), or fusion of therapeutic molecules to targeting proteins…

Customized ZFNs [zinc finger nucleases] targeted to mitochondria cause shifts in heteroplasmy through the selective degradation of mtDNA containing the m.8993T > G point mutation, and the large scale (4977 bp) mtDNA 'common deletion', which is the most common cause of chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Pearson marrow pancreas syndrome. This work opens up the opportunity to develop a library of bespoke ZFNs against more common pathogenic mtDNA mutations, but the shifts in heteroplasmy have been limited to date. Longer-term studies, particularly using animal models, will hopefully show that ZFNs can improve biochemical function in vivo—but this will be technically demanding, not least because of the challenges delivering these agents at an appropriate concentration to affected tissues…

Sequence-specific peptide nucleic acids selectively bind mutant mtDNA and induce direct mtDNA strand degradation. Although conjugation with mitochondrial targeting peptides promotes importation and successful targeting into human cells in culture, this initially failed to modulate heteroplasmy in patient-derived cell lines… Although these examples show promise, evidence for therapeutic benefit remains sparse despite nearly two decades of research. Targeted delivery will be a common problem, and potential toxic effects need to be excluded in long-term animal studies. Again, limited availability of animal models of human mtDNA diseases has hindered progress…

Of particular interest are tRNA synthetases that catalyse the addition of specific amino acid molecules to cognate tRNA molecules during protein translation. Early work demonstrated that the overexpression of cognate aminoacyl mt-tRNA synthetase stabilized mt-tRNA (mitochondrial tRNA) molecules…

Harnessing viral vectors to transfer wild-type genes into the cell nucleus dates back to the late 1990's. Although initial excitement was tempered by the death of a patient in an early clinical trial, much progress has been made in developing new, less immunogenic vectors such as AAV…
In vitro and preclinical evidence support the therapeutic potential of increasing deoxyribonucleotides to treat rate autosomal recessive mtDNA depletion syndromes…

Studying a new treatment in a range of cellular and animal systems will reduce the chance of inappropriately rejecting a treatment based on adverse effects in one model. On the other hand, studying more than one model will reduce the chance of pursuing a drug that will never make it into clinical use…

Future pharmaceutical development focusing on disease-specific or patient-specific molecular targets aimed at boosting residual mitochondrial function is likely to be more successful than previous approaches, which were generally based on a non-specific bypass or amelioration of defective components of the respiratory chain…

Interestingly, a recent retrospective analysis of all the 24 patients with MNGIE known to undergo a haematopoietic stem cell transplantation between 2005 and 2011 reported that in the nine survivors, thymidine phosphorylase activity rose from undetectable to normal levels…

From a clinical perspective, nuclear-genetic enzyme defects show the greatest promise. Stem cell therapy is already being used in specific contexts, and its efficacy and safety being evaluated, and gene therapy trials in mouse models show clear benefits. 

Zika virus and the adult

Hongda Li, Laura Saucedo-Cuevas, Jose A. Regla-Nava, Guoliang Chai, Nicholas Sheets, William Tang, Alexey V. Terskikh, Sujan Shresta.  Zika virus infects neural progenitors in the adult mouse brain and alters proliferation.  Cell Stem Cell.  Published online: August 18, 2016.


•Zika virus (ZIKV) can infect neural progenitors in the adult mouse brain
•ZIKV-infected adult NPCs show evidence of cell death
•Cell proliferation is also impacted in ZIKV-infected adult NPC populations


Zika virus (ZIKV)-related neuropathology is an important global health concern. Several studies have shown that ZIKV can infect neural stem cells in the developing brain, but infection in the adult brain has not been examined. Two areas in the adult mouse brain contain neural stem cells: the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus. Here, using 6-week-old mice triply deficient in interferon regulatory factor (IRF) as a model, we show that blood-borne ZIKV administration can lead to pronounced evidence of ZIKV infection in these adult neural stem cells, leading to cell death and reduced proliferation. Our data therefore suggest that adult as well as fetal neural stem cells are vulnerable to ZIKV neuropathology. Thus, although ZIKV is considered a transient infection in adult humans without marked long-term effects, there may in fact be consequences of exposure in the adult brain.

Zika infection could put adults at risk of dementia and other neurological diseases and is likely even more dangerous than first thought, researchers at The Rockefeller University and La Jolla Institute for Allergy and Immunology report.

Based on a mouse study, they believe the virus could get into almost anyone’s brain—not just those of developing fetuses.

“Zika can clearly enter the brain of adults and can wreak havoc,” says Sujan Shresta, PhD, a professor at La Jolla.

Certain adult brain cells may be vulnerable to infection, including neural progenitor cells, also known as the stem cells of the brain.

Zika infection could put adults at risk of dementia and other neurological diseases and is likely even more dangerous than first thought, researchers at The Rockefeller University and La Jolla Institute for Allergy and Immunology report.

Based on a mouse study, they believe the virus could get into almost anyone’s brain—not just those of developing fetuses.

“Zika can clearly enter the brain of adults and can wreak havoc,” says Sujan Shresta, PhD, a professor at La Jolla.

Certain adult brain cells may be vulnerable to infection, including neural progenitor cells, also known as the stem cells of the brain.

The virus has already been associated with an increase in microcephaly in infants born to infected mothers. It can also cause , as well as shown to cause Guillain-Barre Syndrome, a rare illness in which the immune system attacks parts of the nervous system resulting in muscle weakness or even paralysis. 

Since that syndrome usually develops after the infection has cleared, Shresta says, “We propose that infection of adult neural progenitor cells could be the mechanism behind this," she added. 

Using mice, the researchers have shown that the virus was able to get into pockets of the rodents’ brains where these progenitor cells are located. Those are the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus, both vital for learning and memory.

According to Joseph Gleeson, MD, head of the Laboratory of Pediatric Brain Disease and an adjunct professor at The Rockefeller University in New York City, in a mouse model engineered by Shresta “It was very clear that the virus wasn’t affecting the whole brain evenly, like people are seeing in the fetus.” He added “In the adult, it’s only these two populations that are very specific to the stem cells that are affected by the virus,” cells that are “somehow very susceptible to the infection.”

The infection correlated with evidence of cell death and reduced generation of new neurons in these regions, which could set the stage for cognitive decline, depression, Alzheimer’s, or other neuropathological ailments.

The team added that some people may mount an effective immune response and halt the virus, but others, particularly those with weakened immune systems, may not. –