Tuesday, May 31, 2016

ACO2 mutations

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gérard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rötig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014Dec;51(12):834-8.


Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families.

We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families.

We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity.


Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.

Inspired by a colleague's sibship of 4 homozygotes and 3 heterozygotes.

Growth or performance mind-sets

My teacher was “pimping,” a core aspect of teaching on the hospital floors. The term, said to be derived from the German coinage pumpfrage, for “pump question,” refers to asking students a rapid series of questions, from thought-provoking and relevant to esoteric and unanswerable. It continues until teachers run out of questions, or doctors in training run out of answers. I’ll let you guess which usually comes first.

As a medical student, I was a frequent pimping recipient. Now, as a second-year resident, someone who both supervises and is still supervised, my relationship with it is more complicated: I find myself both dispensing and dodging questions. (When I do “pimp” others, I try to be gentle.)

Pimping has spawned many creative defense mechanisms, ranging from avoiding eye contact to pretending to choke. Some students use the “politician’s approach”: answer the question you want, not the one you’re asked. My favorite strategy is the “muffin technique,” whereby you hold a muffin close to your mouth so the questioner thinks you’re about to take a bite. If you’re pimped anyway, then, obviously, pretend to choke.

But medical training’s emphasis on demonstrating how many facts we know — typically in front of colleagues, nurses, patients and families — is problematic. It encourages us to learn to show, not grow — to project confidence, and dismiss uncertainty.

In her research on educational development, the psychologist Carol Dweck outlines two models for intellectual growth. Students who view intelligence as a fixed entity want to prove themselves and avoid looking unintelligent. Because they see intelligence as a stable trait, they avoid difficult tasks and treat failure as a threat. By contrast, students with a growth mind-set view intelligence as malleable. They’re more concerned with process than outcome and treat failure as an opportunity. Importantly, these mind-sets are not immutable. Educators can substantially influence the approach students adopt.

Consider the following example. Let’s say I leave medical school and begin my residency thinking: I’m slightly weaker in rheumatology than other specialties. I can’t remember which antibodies predict which disease. On rounds, I don’t speak up or ask clarifying questions. When accepting new patients into my clinic, I shy away from those with diseases like rheumatoid arthritis and lupus. At the end of training, I think: I’m just not that good at rheumatology.

Consider an alternative scenario. I’m subpar at inserting central lines — threading a catheter into a large neck vein. On my first few attempts, I fail. My supervisor takes over and easily passes the catheter. But I don’t fear looking incompetent or accept my lack of skill as an innate deficiency. I study anatomy. I watch videos. I ask supervisors to page me before placing lines. When E.R. doctors ask if they should place one before transferring a patient, I say I’ll do it. At the end of training, colleagues ask for my help inserting difficult central lines.

The most important medical learning comes not from memorization and recitation, but by thrusting yourself into situations just beyond your comfort zone. This controlled stretching makes us better, but is anathema in a performance mind-set. Trainees in a growth mind-set, however, gravitate toward — not away from — challenging clinical experiences.

Research suggests senior physicians’ teaching styles influence whether trainees embrace growth or performance mind-sets. Residents with supportive supervisors are more likely to seek and incorporate feedback. And our training environment affects how we practice throughout our careers.
Our approach to medical knowledge and learning has important consequences for the education of new doctors — and profound implications for patient care. We wear factual knowledge as a badge of honor. We disguise and avoid uncertainty. But if we can’t embrace uncertainty with our peers, can we do so with our patients?

Being unsure about a patient’s diagnosis or how a disease might progress is inherently uncomfortable for doctors. Studies find that patients are less satisfied when physicians communicate uncertainty, but also that how doctors communicate uncertainty matters, and that in general we’re not very good at it.

But uncertainty remains an integral part of medicine. Even the most rigorous trials rarely answer the questions most important to doctors and patients: how to weigh risks and benefits; how a patient will respond to treatment; how long he or she has to live.

Research on communicating uncertainty is fledgling, but it does suggest that, at the very least, we need to recognize it exists, clarify its sources, and acknowledge its challenges for patients and families. Research also suggests that younger physicians are less comfortable disclosing uncertainty to patients, but that our attitudes can evolve over time.

We’re educated in a model that demands certitude, confidence and rightness. But we work in a profession imbued with uncertainty. Ultimately, training doctors to grow — instead of show — may lead to more curious physicians, and more honest patient interactions.


The cost of becoming a doctor

I start this article with a disclaimer: I am not here to comment on the decreasing salaries of physicians or the knowledge that I will never get paid the way the prior generation of doctors got paid. It is hard for me (and the American public) to feel bad for anybody making more than $200,000 a year when the median household income is in the mid-$40,000 range.

What this article is about is the absurd costs of becoming a doctor (both in medical school and residency). Let me tell you my story to put things in perspective.

I went to a state undergraduate university and, thankfully, left that school with no debt. I then entered a public medical school, with no way of paying the tuition on my own. I faced the decision of taking out loans or dropping medicine and doing something else. I stuck with it — like many of my colleagues — because I could not imagine not being a doctor; and honestly, I was naive about the financial hardships I would undergo.  I lived at home for 2 of the 4 years of med school, was single for 3 of those 4 years, had no kids, and had amazing parents that subsidized my living arrangement with home cooked meals and car insurance payments. 

Despite that, at the end of my medical school education, I had acquired $180,000 in loans (close to the national average), almost all of them with an interest rate of 6.8 percent.

To put that into perspective: My monthly interest accrual was ~$1,020 a month, and good old Aunty Sallie would capitalize the interest into the principal at the end of every year.

Then came residency. Finally a salary of my own, or so I thought. The average resident’s salary starts between $40,000 and $50,000 a year. At 70 to 80 hours a week of work, that comes out to $9.50 to $12 an hour. Most residencies prohibit moonlighting (for reasons beyond my comprehension), so the money you get from your institution is the only money you get.

I live in northern Jersey, where monthly rent for a 1-bedroom apartment is around $1,000 to $1,400; a 2-bedroom ranges between $1,500 and $2,400. I lived in a 1-bedroom. I cleared about $3,000 a month after taxes. $1,000 went to paying just the interest on my loans and never touching the principal, and $1,200 went to paying rent.

I was left with $800 to spend on food ($100 to $300, thank God for a mother and mother-in-law who have phenomenal cooking skills), gas ($160), car payments ($200) because you cannot move between three hospitals on public transportation, insurance payments ($200), cell phones ($80) with no landline, internet ($50), and, well … there is no money left.

So, I guess I could have just paid the minimum on my loans and have had money for heat and electricity. The problem is, that after five years of residency, I would have owed Ms. Mae close to ~$250,000.

This is the thing: I was better off than many residents. I had parents who gave me money when I was short and paid my E-ZPass bills. I went to a public undergrad school (many people I know have debts in the $350,000 range when starting residency). I never had any large unexpected costs during my training (e.g., medical bills, big car bills/accidents). For much of my training, I was not yet a parent. Residency sucks, and not just because of the intensity of the training and the stress of trying your best to become a decent physician.

This article is not over yet. The real impetus for me to write this has to do with the loads of money I recently dumped to fulfill the next step of my training. What many people outside of medicine might not know about are the enormous costs of tests/licensing that doctors are required to practice medicine. USMLE Step 1, 2, 3 tests cost about $2,200. The American Board of Internal Medicine exam costs about $1,200, and the American Academy of Pediatrics exam costs a whopping $2,250. Most residents spend about $1,000 to $2,000 on prep courses and materials for each of these exams while in residency.

And then, there is licensing: NJ state license is about $1,100, the DEA/CDS licenses cost another $760, and there are others, depending on your practice. All of this occurs before you make “doctor money,” all while your student loans continue to grow.

My concern is not for my own misery; that time has passed. My concern has to do with the next generation of physicians who have already started pre-med tracks in their undergrad colleges.  What type of candidates will medicine attract when the associated costs of becoming a doctor are no longer the extreme intellectual rigor and high academic expectations of the training … but instead, financial suffering?  To put it in plain English: Who in their right mind would do this when you know you are putting yourself, and potentially your family, in great financial peril?

My inner optimist tells me that there will always be a group of highly motivated people who will bear the difficulties, because the goal is lofty and righteous enough to keep their eyes on the prize. But what are we saying as a society when we make an education in healing so difficult to attain?

Ahmad Yousaf is an internal medicine physician who blogs at Insights on Residency Training, a part of NEJM Journal Watch.
Courtesy of Doximity

Monday, May 30, 2016

Rivky Deren Berman a"h

Rivky Berman, a young Chabad-Lubavitch emissary who inspired many throughout her lifelong struggle with illness passed away yesterday at the Duke University Hospital in Durham, N.C. She was 29.

Born in Stamford, Conn, to Rabbi Yisrael and Vivi Deren, Rivky Deren grew up in an atmosphere where serving Gd with joy and sharing Judaism with others was paramount—even when things were not easy.

Rivky was one of several siblings who were born with Blooms Syndrome. In addition to affecting her growth, the condition caused Rivky to be prone to many illnesses.

Nevertheless, throughout her life Berman maintained a spunky, upbeat attitude and a unique ability to share the hope and joy that defined her life with others, and she did so in blog posts, personal counseling and in every venue available to her.

Reflecting in a video posted to her blog on the medical hurdles she had faced, she maintained, “I dealt with it, I am here, and I have an incredible life . . . I don’t see those things as issues. I see them as challenges. Those are challenges that Gd gave me—and anyone else that has that challenge—because He truly believes that I can take that challenge and I will fulfill that challenge . . . I was given something that only I was given because Gd thought that I can handle it.”…

After a successful lung transplant, she married Rabbi Shmulie Berman in the summer of 2012, and the young couple looked forward to establishing themselves as Chabad-Lubavitch emissaries, something her family had devoted themselves to since great-grandparents, Rabbi Sholom and Chaya Posner moved to Pittsburgh in the mid 1940’s to head the Chabad educational system in that city…

In 2015, she was found to have lymphoma and was once again admitted to the hospital. Even from her hospital room, she continued to reach out, organize, and serve—orchestrating an entire Purim celebration from the confines of her bed.

In a speech she once joked that “You know you are in the ER way to often when you walk in and the nurses all scream, ‘Hey Deren! What’s up?’”

Yet, despite her frequent challenges, she said that “my family and I have gone through many difficult times. The teaching of ‘tracht gut vet, zein gut’ [think good, and it will be good] almost became a refrain in our lives…

“Sometimes this is on a simple level: starting your day with the attitude that it will be a good day can actually make that a reality. On a deeper level, we are taught that having this kind of bitachon, trust and confidence in Hashem, can actually help create the space for the good to happen. And that even in situations where it is difficult for human beings with our limitations to see good, that we can still find even small sparks of sunshine, because we are confident that even if not right now, ultimately Hashem will show us the good so we can see it with our own eyes. Maybe another way of saying this is that ‘Everything ends up okay in the end, and if it’s not okay, it’s not the end.’”…

In writing to his friends and congregants about his sister’s passing, Rabbi Asher Deren noted that “in a lifetime that some would describe as pain and illness, Rivky fought back to live a life of joy, celebration, adventure, ambition, fashion, and more than anything - purpose.”

He noted how his sister’s “smile, determination and fierce independence set a new standard of living, for all of us,” and that “the signature of Rivky’s email (and closing line of her Matric Valedictory Speech) was ‘in the end it will all be good, and if it’s not good, it’s not the end.’..

In addition to her parents and husband, Rivky Berman is survived by her siblings, Rabbi Yossi Deren, Rabbi Asher Deren, Rabbi Chezky Deren and Chanie Backman. She was predeceased by her siblings Shlomo Aharon Deren, Blumi Deren, and Rabbi Mendel Deren.


See video on link
See http://childnervoussystem.blogspot.com/2015/04/on-having-children-who-might-inherit.html
Courtesy of my daughter

Friday, May 27, 2016

Do the eyes have it?

Examining the retina may aid in the diagnosis of attention-deficit/hyperactivity disorder (ADHD), new research shows.

Confirming prior work, researchers observed that patients with untreated ADHD have elevated "background noise" on pattern electroretinography (PERG) compared with healthy controls.

They now report that the elevated noise normalizes with treatment for ADHD, with PERG patterns on par with those in healthy controls.

Emanuel Bubl, MD, from the Department of Psychiatry and Psychotherapy, Saarland University in Germany, reported their latest findings here at the American Psychiatric Association (APA) 2016 Annual Meeting.

"There is growing evidence for a special relevance of background noise, or non- stimulus-driven neural activity, in ADHD," Dr Bubl told Medscape Medical News. "Findings from animal studies as well as human research supports this line of thought, and our results directly support findings from basic research, which is intriguing."

PERG — which is akin to electrocardiography (ECG) of the retina — provides an electrophysiologic measurement of the activity of the retinal ganglion cells. "The great strength in investigating the retina is that you are investigating a local network, which you have good access to. We like to compare it to an ECG of the eye," said Dr Bubl.

The researchers used PERG to measure the response of the retina to a checkerboard visual stimuli in 20 patients with ADHD and 20 healthy controls. The patients with ADHD were tested before and after treatment with methylphenidate. 

Neuronal noise before treatment was higher in the ADHD group than the control group and significantly correlated with inattention measured with the Conners' Adult ADHD Rating Scales (CAARS), the researchers found. Treatment with methylphenidate normalized the elevated background noise in the patients with ADHD.

The data support that elevated background noise is associated with ADHD and point to a neural correlate for the disorder, the researchers say.

ADHD medication effectively reduces distractibility and improves attention, and animal studies suggest that a basic mechanism of action is by decreasing neuronal noise or background firing, Dr Bubl explained in his presentation.

"There is great research going on in neural correlates in ADHD, with a focus on alteration in the dopaminergic system in different brain regions," Dr Bubl told Medscape Medical News. "As with other findings, if we get more evidence for an elevated retinal noise in ADHD I think this is a promising tool."

"In ophthalmology," he added, "PERG is a standard diagnostic instrument, which has proven its great value in clinical practice. In psychiatry, it is a research tool at the moment. However, our results support further research to explore the potential as a clinical tool in the future."

Chandra Sripada, MD, PhD, from the Department of Psychiatry at the University of Michigan, Ann Arbor, who wasn't involved in the study, said, "The results do look very interesting [but] the sample size is small," he cautioned. Nonetheless, "I would say [this is] promising work and points to the need for future work in this area," he added.

American Psychiatric Association (APA) 2016 Annual Meeting. SCR-The Broad Interest in Psychiatry, No 2. Presented May 18, 2016.


Acute cerebellitis in children

Liora Kornreich, Vered Shkalim-Zemer, Yoel Levinsky, Wafa Abdallah, Esther Ganelin-Cohen, Rachel Straussberg.  Acute Cerebellitis in Children: A Many-Faceted Disease.   J Child Neurol  online.


Acute cerebellitis is a rare inflammatory condition. It may have a benign, self-limiting course or present as a fulminant disease resulting in severe cerebellar damage or even sudden death. We present the clinical, laboratory, and radiologic data in 9 children diagnosed with acute cerebellitis, who were identified by database search in our pediatric medical center from January 2000 to November 2014. The main presenting symptom was headache, and the main presenting sign was ataxia. Bilateral diffuse hemispheric involvement was the most common imaging finding at presentation. Mycoplasma pneumoniae was the most common infectious pathogen found. Treatment included steroids in all cases, antibiotics in 4, and intravenous immunoglobulins in 6. Six patients had a full recovery, and 3 had residual neurologic complications. Magnetic resonance imaging (MRI) is the modality of choice for diagnosis. The course of acute cerebellitis varies from a commonly benign and self-limiting disease to an occasionally fulminant disease, resulting in severe cerebellar damage or sudden death.

From the article:

Acute cerebellitis is a rare disease that poses both diagnostic and therapeutic challenges. The clinical manifestations at presentation are variable and nonspecific, including nausea, vomiting, headache, fever, seizures, and altered mental status.  In the present cohort of 9 children diagnosed with cerebellitis at a single pediatric medical center over a 15-year period, headache was the most common symptom at presentation and ataxia was the most common sign (6 patients each). Meticulous physical examination is extremely important, as it may yield more specific findings such as ataxia, nystagmus, dysarthria, dysmetria, and tremor.  Laboratory findings are usually not contributory . There are no specific indices of the diagnosis in blood chemistry, and markers of infection may be absent. Cerebrospinal fluid test may yield normal-range results (as in patient 1) or reveal pleocytosis and may assist with diagnosis, by revealing a causative infectious pathogen.  In some cases, lumbar puncture is not conducted because of a suspected increase in intracranial pressure…

Imaging of the brain is essential for the diagnosis of cerebellitis. MRI is the modality of choice, as brain computed tomographic scan may be normal in the early stage of the disease.  Several patterns of imaging findings have been described in acute cerebellitis. Imaging patterns vary widely.  In only 3 of our patients did we find the most frequently reported imaging picture of bilateral symmetric hyperintensity on T2-weighted and fluid-attenuated inversion recovery images  whereas 4 had unilateral involvement, reported less often, including 2 with an additional focus in the vermis or in the other hemisphere. One patient demonstrated isolated involvement of the vermis , and 1 had small defined bilateral foci …

There are no consensus guidelines for the management of acute cerebellitis. Most cases of acute cerebellitis are self-limited and do not require treatment. Antimicrobial therapy should always be considered, because ataxia can be a presenting sign of both viral encephalitis and bacterial meningitis. The use of steroids is controversial. Göhlich-Ratmann et al reviewed the outcome of 7 patients with acute cerebellitis: all 3 treated with high-dose recovered completely, whereas the 4 who did not either died or suffered from sequelae. There are a few case reports of patients with parainfectious cerebellitis in whom steroid treatment may have improved long-term outcome and shortened disease duration. The authors suggested that the corticosteroids act by inhibiting the autoimmune cascade and stabilizing the blood-brain barrier.  All our patients were empirically treated with steroids. Seven also received antibiotics (azithromycin or doxycycline). Four patients were treated with intravenous immunoglobulin. The administration of intravenous immunoglobulin in our cases was prompted by reports of a successful outcome of immune-modulating therapy in patients with cerebellar ataxia.

Childhood acute cerebellitis generally has a good outcome. Most patients (50% to 86%) show full clinical recovery.  Reported long-term cognitive sequelae include poor spatial visualization and decreased language skills and concentration.34-36 Mild but persistent cerebellar symptoms, such as dysmetria, intentional tremor, and ataxia, have been observed in 10% to 50% of patients.  In the present study, 3 of the 9 children (nos. 1 to 3) were neurologically impaired on follow-up, both verbally and functionally.

Wednesday, May 25, 2016


A little boy diagnosed with a rare epilepsy syndrome now has doctors around the world — and supportive Facebook users — keeping up with his condition.

In March, Maryland 5-year-old Cameron Longley was admitted to the hospital after having seizures that seemed to be prompted by a fever. At first, doctors couldn’t determine the boy’s diagnosis. As physicians tried different tests, his parents started a Facebook page for him and began sharing posts with the hashtag #AnswersForCameron. The page includes photos of the boy in the hospital as well as updates on his symptoms, which have included a collapsed lung, a rash, a swollen tongue and kidney issues.

He is now at Children’s National Medical Center in Washington, D.C., where Dr. Elizabeth Wells is the medical director of inpatient neurology. Wells told The Huffington Post that Cameron didn’t respond to the initial seizure treatment he received from doctors, which later helped clue her in on a specific diagnosis. After running several tests, the team at Children’s National Medical Center has determined that Cameron meets the criteria for FIRES, or febrile infection-related epilepsy syndrome. Part of its diagnosis includes not responding to traditional treatment for seizures.

According to Wells, less than 100 cases of FIRES have been reported worldwide. Because of its rarity, the medical center has shared information about Cameron’s condition with doctors around the world. His parents are using the Facebook page they set up to look for more answers and are glad the hospital is asking for help as well.

“I feel like this hospital is willing to reach out to other avenues and not just try to keep it in house and solve the problem on their own,” Zarinah Cuffee, Cameron’s mom, said.

The hospital also implements family-centered rounds that focus on including families as much as possible in patients’ cases. These rounds can include patients, their families, physicians, nutritionists, therapists and social workers. Wells explained that Children’s National isn’t the only hospital to incorporate family-centered rounds, but the way they provide them for patients with brain diseases and complex medical diseases is what makes the hospital stand out. Referring to the rounds, Shaun Longley, Cameron’s dad, said “it’s nice to not feel out of the loop.”

Other people don’t want to feel out of the loop either when it comes to Cameron. As of Thursday more than 1,700 people are following the Facebook page set up to share updates about his health and progress now that he’s been responding to treatment. Shaun told HuffPost they’re preparing for his son to transfer to a rehabilitation center next week, and according to a recent Facebook post, Cameron and his family are “taking it one day at a time.”

Courtesy of Doximity


See https://childnervoussystem.blogspot.com/2015/10/mri-evolution-in-fires.html

Tuesday, May 24, 2016

Growth attenuation

When I visited Cloudcroft two summers ago, Ricky was small for his age — just 42 inches tall and 37 pounds, about the size of an average 4-year-old boy. In part this was because of genetics and his various health problems, but it was also partly a result of his having been through a controversial medical intervention known as growth-attenuation therapy. From the time he was 4 until just shy of his 7th birthday, he received doses of estrogen high enough to stimulate the premature closing of the epiphyseal or “growth” plates, the thin wedges of cartilage found at the end of the long bones in children and adolescents. (Long bones include the femurs, tibias and fibulas of the legs and the humeri, radii and ulnas of the arms.) The younger the child when treatment begins — usually between 3 and 6 years of age — the greater the reduction in height…

Then, in 2006, Douglas Diekema, the director of education at the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Hospital, and Daniel Gunther, a pediatric endocrinologist, announced in the Archives of Pediatrics and Adolescent Medicine that they had resurrected the treatment once known as estrogen therapy for a different population: what Diekema and Gunther described as “nonambulatory children with severe, combined neurologic and cognitive impairment.” In other words, children like Ricky Preslar, expected to rely on caregivers for every basic need for the rest of their lives. When such dependents enter adolescence and adulthood, the doctors posited, the simple tasks of caring for them — dressing, toileting, bathing, holding and carrying — can become prohibitively difficult for parents. Arresting a child’s growth could benefit both child and parent. A smaller person who required no hoisting apparatuses, Diekema and Gunther reasoned, would in all likelihood benefit from more attention and greater inclusion in family activities. And he or she would be more likely than someone fully grown and similarly impaired to be cared for in the home, rather than an institution. “We propose,” the authors concluded, “that in situations in which parents request such an intervention, it is both medically feasible and ethically defensible.”…

After Diekema and a hospital ethics committee gave their approval, Gunther administered the estrogen estradiol, which effectively reduced her future predicted height by approximately 13
inches.  Additionally, the child — unidentified in the original paper but soon known as Ashley, her first name, or “Ashley X” — underwent a hysterectomy to preclude the discomfort of painful menses as well as the uterine bleeding that can accompany estrogen in high doses, and the removal of her breast nodules to forestall the growth of breasts. For the treatment they called “growth-attenuation therapy” to be most effective — resulting in a shorter and lighter child — a careful monitoring of calories was also required…

According to the disability activists’ criticism, growth-attenuation therapy and its associated procedures violated Ashley X’s rights to privacy and freedom from unnecessary bodily manipulation, which are the sorts of things the Americans With Disabilities Act, the Rehabilitation Act and even the 14th Amendment were supposed to protect people from. Her care did not constitute a “treatment” or “therapy” at all, they said, because it did not treat an illness. A statement issued by the American Association on Intellectual and Developmental Disabilities claimed that “this practice, if judged acceptable, will open a doorway leading to great tragedy.”…

Still, the treatments were now a known option for the families of children with profound disabilities. They congregated on Pillowangel.org, a website and private message board maintained by Ashley’s parents, who have never made their names public, identifying themselves only as “Ashley’s Mom” and “Ashley’s Dad,” or AM and AD. (Their site’s name comes from the endearment given to Ashley and other children like her who spend most of their hours propped up by pillows in bed.) The carefully screened message boards became a supportive oasis in an online environment where, one Washington State mother told me, “parents looking for information about this are made to feel like monsters.”…

But then last summer, the Pediatric Endocrine Society published a survey of its members in The Archives of Diseases in Childhood indicating that at least 65 children have received the therapy. (The survey did not break down participants by sex or note whether they had hysterectomies or breast-bud removal.) And by many doctors’ accounts, the demand for it is increasing even as doctors prefer not to talk about the practice publicly…

Kappy initially prescribed 2 milligrams daily of estradiol, but on the private message boards at Pillowangel.org, Cindy learned that there were no regulations on how much estrogen physicians could prescribe off-label; other children were getting much higher dosages than Ricky, and their bone age (measured by the degree to which the growth plates are closed) was increasing more rapidly, which would lead to an overall greater reduction in height. She persuaded Kappy to increase the dosage incrementally over the next three years to 8 milligrams daily. Kappy told me that he closely monitored Ricky “to be sure we weren’t going to do him harm.” The higher doses, he said, were “quite effective in speeding up the rate of skeletal maturation.” Within six months, Ricky’s bone age jumped three years, up to that of a 6-year-old. When he began to develop breast tissue, a side effect of the estrogen, Kappy told Cindy that Ricky could have his breast buds removed for cosmetic purposes….

“My daughter is trapped in a wheelchair all her life, and she’s more comfortable” being smaller, says Nancy, who believes her daughter, Nykkole, may have been the second girl ever to undergo the three interventions that make up the Ashley Treatment…

Like Ashley’s parents, she believed that if her daughter had no breasts, she would be less likely to be a target of sexual abuse. Before undergoing growth-attenuation therapy, Nykkole was given both a hysterectomy and a bilateral mastectomy at the University of Minnesota Masonic Children’s Hospital. When the family then met with the hospital’s ethics committee to discuss Nykkole’s growth attenuation, Nancy recalls, “We brought her out of her chair and into our laps, and said: ‘This is why we want to do this. She needs to be in our laps for our whole life.’ ”…

Ricky Preslar is now 9. Two years after completing growth-attenuation therapy, his height has stabilized around 43 inches. He is still nonverbal (unless you count his easy laugh), but in the past year, Cindy says, he has shown signs of purposeful movement, an important developmental milestone, by using a head-motion-activated assistive-communication device to stop and start videos at his school for the visually impaired. He can move around the kitchen in a gait trainer and goes to hippotherapy (a kind of physical therapy on horseback) once a week. Cindy’s goal this year is to run a marathon while she and her husband push him the whole way. She says that Ricky, who is now 43 pounds, is beginning to seem conspicuously smaller and lighter than many of his peers at school. The Preslars have never regretted their decision to attenuate Ricky’s growth. For Cindy, there are times — like when she recently strained her back — when she is particularly grateful that her boy is, and always will be, small.

Courtesy of my mother.

Intrauterine stroke and COL4A1 mutation

Inspired by a recent patient

Shaheen Durrani-Kolarik, Kandamurugu Manickam and Bernadette Chen.  COL4A1 Mutation in a Neonate with Intrauterine Stroke and Anterior Segment Dysgenesis. Pediatric Neurology in press.

COL4A1 , located on chromosome 13q34, encodes the alpha 1 chain of type IV collagen that is a component of basal membranes. It is expressed mainly in the brain, muscles, kidneys and eyes. COL4A1 mutations can vary in presentation, from asymptomatic carriers to severe devastating disease secondary to the effects on small vessels, including porencephaly, intracerebral hemorrhage, infantile hemiparesis in neonates and children, intracerebral hemorrhage, intracranial aneurysms and retinal arteriolar tortuosities in adults. Given its limited description in the medical literature, diagnosis of this mutation can be overlooked. This is important, as identification of this mutation in affected individuals has implications for perinatal management and genetic counseling with availability of prenatal testing to determine inheritance in additional family members. In addition, making this diagnosis may help tailor appropriate screening tests for organs typically involved with COL4A1 mutations. In this case report, we describe a term infant with an extensive intrauterine stroke and anterior segment dysgenesis with a de novo mutation in COL4A1 .

Non-contrast Brain MRI with coronal fast spin echo (FSE) T2-weighted (a) and sagittal T1-weighted (b) imaging demonstrating bilateral hemorrhagic MCA infarction with severe cystic encephalomalacia/absent parenchyma with mass effect on brainstem. Bilateral cerebellar hemisphere infarction with severe cystic encephalomalacia also demonstrated.

From the article:

At present, no diagnostic criteria have been established for COL4A1 -related disorders. There is a wide spectrum of clinical symptoms that variably include brain, ocular, renal, and muscle involvement, as well as reports of Raynaud phenomenon and supraventricular arrhythmia.  Brain involvement can include infantile hemiplegia, migraines with or without aura, seizures, dementia, intellectual disability, intracerebral hemorrhage presenting at various ages, including antenatal  and recurrent episodes, and ischemic stroke.    Neuroimaging demonstrates the features of brain small-vessel disease such as porencephaly characterized by a fluid-filled cavity in the brain; leukoencephalopathy, usually bilateral and symmetric, located mainly in the supratentorial posterior periventricular areas; cerebral microhemorrhages; lacunar infarcts; deep intracerebral hemorrhages; dilated perivascular spaces; and single or multiple intracranial aneurysms.   On ophthalmologic examination, a multitude of findings have variably been described including bilateral tortuosity of the second- and third-order arteries, hemorrhagic spots, and Axenfeld-Reiger anomaly with microcornea, congenital or juvenile cataract, increased intraocular pressure, iris hypoplasia, retinal detachment and optic nerve excavation.  Renal involvement includes hematuria and renal cysts.  Muscle cramps have been reported involving a variety of muscles with associated persistent elevation of serum creatine kinase concentrations.

The inheritance of COL4A1 mutation is autosomal dominant with near 100% penetrance with expression varying in age of onset and severity of clinical symptoms, even within the same family. Therefore, if a parent of the proband is affected, the risk to the siblings is 50%. There may also be de novo mutations or low-level parental mosaicism; however, the proportion of these cases in the population remains unknown.

In our patient and as others have shown, the clinical onset of small vessel disease in the brain as a result of COL4A1 mutations can occur as early as the antenatal period. In neonatology and pediatrics, patients diagnosed with stroke, both in utero and postnatal, often do not have an etiology identified. Therefore, a detailed family history as well as ophthalmologic exam may be warranted to determine other small-vessel organ involvement, as COL4A1 mutations may be grossly underestimated in this patient population.  Despite not having a family history of small-vessel disease with the associated clinical spectrum of COL4A1 mutations, this mutation needs to be recognized by practitioners and be considered on the list of differential diagnoses in patients with no known etiology for an in utero or postnatal stroke. In one case series, three of the four neonates with extensive prenatal porencephaly had no known family history and were found to have sporadic COL4A1 mutations.

The implications for making a diagnosis of COL4A1 mutation in a patient such as the one presented herein are considerable. Prenatal testing can be performed by chorionic villus sampling or by amniocentesis if one of the parents is known to carry the mutation. Preimplantation genetic diagnosis may also be an option for these families. In animal studies of mice with the COL4A1 mutation, it was demonstrated that none of the surgically delivered mutant pups had severe cerebral hemorrhage as was observed in the heterozygous mutant pups that were born naturally.  Therefore, preventive measures could be taken in cases of known familial COL4A1 mutation, specifically cesarean delivery.

Courtesy of:  http://www.mdlinx.com/neurology/medical-news-article/2016/05/16/fetal-porencephaly-hemorrhagic-stroke-cataract-axenfeld/6645193/?category=sub-specialty&page_id=3&subspec_id=317

My patient (see comment):

Monday, May 23, 2016

Infant creativity

I have a grandson who is second to none in this regard.


Intermittent explosive disorder

Remember the motorist who was so upset at your driving that he pulled up next to you in traffic, blew his horn, pounded on the steering wheel, and cursed?
A lot of people simply might label him a jerk. The psychiatry profession takes a different view.
If the driver yells and pounds often enough, he could have intermittent explosive disorder (IED), a formal mental condition characterized by uncontrolled bouts of verbal or physical anger that are out of proportion to whatever triggered the outburst.
According to some published studies, up to 16 million U.S. adults -- or 7.3% of the population -- have had it at some point in their lives. And the rate in any given year is an estimated 3.9%.
Yet one of the researchers who came up with the figure a decade ago says he now is uncertain about it.
"I think it is very safe to say it is either more or less or the same," said Ronald Kessler, MD, the lead author of the 2006 paper that established the figures and a professor of healthcare policy at Harvard Medical School.
"In other words, who the hell knows?"
Another survey found a dramatically lower rate of the disorder.
Instead of being a condition that affects millions, the National Survey on Drug Abuse and Health found an annual rate of just 0.4%, or 911,000 adults. It was based on diagnostic surveys conducted by clinicians between 2008 and 2012.
Whatever the number, formalizing the condition as a mental disorder is way to rationalize bad behavior, said Joseph Wyatt, PhD, an emeritus professor of psychology at Marshall University.
"It is nothing more than grown-up tantrums," he said. "It is not something that people have. It is something that people do."
Wyatt has written about the medicalization of behavior, which he said can lead to the prescribing of drugs that often don't work well and can have serious side effects.
The FDA has not approved any medicine to treat intermittent explosive disorder, but that may change.
Azevan Pharmaceuticals is testing a drug for the condition in an 8-week trial involving about 100 people ages 21 to 55. The study was started in May 2014 and is expected to be completed this month…
Should the drug ultimately win FDA approval, it has the potential to be a blockbuster, said psychiatrist Emil Coccaro, MD, a consultant to the company. Blockbusters generally are defined as drugs that produce annual sales of more than $1 billion.
Coccaro, a professor of psychiatry at the University of Chicago who has authored more than 30 papers on the condition, said not only is intermittent explosive disorder real, it is as common as many other psychiatric disorders.
He said research shows that people with the condition have different brain structures. The condition also can be passed through genes, he said.
"Any behavior that gets you in trouble like that is a real disorder," he said.
"You see this with all mental disorders," said Joel Paris, MD, a professor of psychiatry at McGill University in Montreal and author of the book Prescriptions for the Mind: A Critical View of Contemporary Psychiatry.
"Every time they revise the manual, if they redefine it at all, they redefine it in a way that more people have it."
Consider what happened with intermittent explosive disorder.
The 1994 definition required at least three instances of physical aggression directed at property or people in an individual's lifetime.
In the 2013 manual, the definition was changed so that verbal aggression alone was enough, provided it occurred at least twice a week over a period of 3 months. But it also reduced the timeframe for physical aggression from a lifetime to three acts in a single year.
It is not known how many people qualify under the new definition; no new survey has been done.

Adult ADHD

In 2006, interest in attention deficit hyperactivity disorder (ADHD) reached new heights after a major study found that 4.4% of adults in America had the condition.

For decades, ADHD primarily had been a diagnosis in children, but the new study found it also affected as many as 10 million adults.

"It changed ADHD," said Peter Conrad, PhD, a professor of social sciences at Brandeis University who wrote The Medicalization of Society. "It became a lifespan disorder."

What happened next followed a familiar pattern: More research papers -- many of them based on research funded by drug companies -- were published.

The 2013 edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, relaxed the definition for adult ADHD.

The previous definition, in effect since 1994, said adults needed to have at least six of a possible nine symptoms from either of two categories. The symptoms include the inability to focus on tasks, fidgeting, and interrupting others. The new definition reduced it to five of the nine.

It also increased the age at which some of those symptoms first must have been present -- from before age 7 to before age 12.

Seventy-eight percent of those among the work group of experts who oversaw the changes had financial ties to the pharmaceutical industry, according to a 2012 analysis by the journal PLoS Medicine.

Psychiatrist Darrel Regier MD, MPH, a spokesman for the American Psychiatric Association, said financial conflicts were limited to $10,000 a year in income such as working as industry consultants, advisers, and speakers.

Regier, who served as vice chairman of the diagnostic manual's task force, defended the inclusion of adult ADHD in the document. He said that while it was once thought that children would age out of the disorder, for some, it remains in adulthood.

"Is it believable that this one mental disorder is one that kids would totally outgrow?" he said. "I think not."

Finally, the cumulative result of these factors was as expected: Prescriptions spiked.

And, since many of those drugs are amphetamines and stimulants that can lead to abuse, thousands more people began showing up in hospital emergency rooms.

At the same time, the growing focus on adult ADHD prompted questions from skeptics:

.How valid was the diagnosis?

.How many people are truly impaired?

.What role does promotion by drug-makers have in the rapidity of ADHD diagnoses?

.Has the spike in prescriptions for ADHD caused more harm than good?

"It is very easy to fake the symptoms of ADHD," said Daniel Carlat, MD, a psychiatrist at Tufts University School of Medicine and author of Unhinged: the Trouble with Psychiatry, a Doctor's Revelation about a Profession in Crisis.

A 2010 study found that 22% of adults tested for ADHD exaggerated their symptoms, exaggeration often made easier by the wide availability of online symptom check lists.

For years, the legitimacy of the adult ADHD was based on the belief that it was a condition that started in childhood and, for some, persisted into adulthood.

But last year that hypothesis was shaken by the publication of a provocative, long-term study that began in the early 1970s and followed more than 1,000 New Zealand children until age 38.

In that study Terrie Moffitt, PhD, a psychologist at Duke University, and her colleagues found that in childhood, 6% of those in the study had ADHD. At age 38, that number had dropped to 3%.

And the biggest surprise was the lack of evidence of significant overlap between the two groups.

Only 5% of those with ADHD in childhood still met the criteria at age 38. And only 10% of those who met the definition at age 38 were among those with the condition in childhood.

That, in turn, led the researchers to speculate that some of the adult patients were substance abusers who had attention problems stemming from drugs and alcohol, and that others may have had a personality disorder and were trying to game the system to obtain stimulants to abuse.

Moffitt noted that while childhood ADHD is considered a brain development condition, adult ADHD patients in her study scored normally on neuropsychological tests.

"It seems to be a different disorder," Moffitt said.

Adults with ADHD may have trouble completing tasks, prioritizing, and keeping appointments. Some research even shows a connection between the condition and higher rates of divorce, unemployment, and car accidents.

However, those only are associations, not proof that ADHD causes the problems or -- more importantly -- that ADHD drugs will prevent them.

In 2014, the pharmaceutical company Shire paid $56 million to settle a U.S. Department of Justice allegation that it illegally promoted Vyvanse and two other ADHD drugs, Adderall XR, and Daytrana.  

Between 2007 and 2010, according to the Justice Department, company sales representatives claimed Vyvanse would prevent car accidents, divorce, arrests, and unemployment.

Friday, May 20, 2016

The "round the houses" sign as a clinical clue for Niemann-Pick disease type C

Eggink H, Brandsma R, van der Hoeven JH, Lange F, de Koning TJ, Tijssen MA. Teaching Video NeuroImages: The "round the houses" sign as a clinical clue for Niemann-Pick disease type C. Neurology. 2016 May 10;86(19):e202.

A 58-year-old man presented with progressive involuntary jerky movements. In addition to a cortical myoclonus, supported by polymyographic evaluation, we saw a “looping” trajectory of the vertical saccades, also referred to as the “round the houses” sign (video on the Neurology® Web site at http://neurology.org/lookup/doi/10.1212/WNL.0000000000002660.)

This sign has been reported as an early indicator of vertical supranuclear gaze palsy in progressive supranuclear palsy. However, vertical supranuclear gaze palsy is not disease specific and in our patient led to the genetically confirmed diagnosis of Niemann-Pick disease type C.2 This shows that the presence of the “round the houses” sign should raise suspicion of a treatable diagnosis of Niemann-Pick disease type C.

[-may perform vertical saccades by performing a lateral arc movement = "round the houses" sign-

In some patients in whom the range of ocular movements are still preserved, the so-called “round the houses” sign can be observed early, denoting a laterally curved trajectory of vertical saccades."]

Genetic counseling and testing for Huntington's disease

Nance MA. Genetic counseling and testing for Huntington's disease: A historical review. Am J Med Genet B Neuropsychiatr Genet. 2016 May 13. doi:10.1002/ajmg.b.32453. [Epub ahead of print]


This manuscript describes the ways in which genetic counseling has evolved since John Pearson and Sheldon Reed first promoted "a genetic education" in the 1950s as a voluntary, non-directive clinical tool for permitting individual decision making. It reviews how the emergence of Huntington's disease (HD) registries and patient support organizations, genetic testing, and the discovery of a disease-causing CAG repeat expansion changed the contours of genetic counseling for families with HD. It also reviews the guidelines, outcomes, ethical and laboratory challenges, and uptake of predictive, prenatal, and preimplantation testing, and it casts a vision for how clinicians can better make use of genetic counseling to reach a broader pool of families that may be affected by HD and to ensure that genetic counseling is associated with the best levels of care.

From the article:

Despite the high levels of interest in genetic testing that CCHD survey respondents expressed in the 1970s, before the HD gene was discovered, clinical reports have shown that in most countries the uptake of tests has been relatively low, with a variable rate of predictive testing ranging from an estimated 10% in the United States to as high as 80% in the Netherlands. Even in the Netherlands and Australia, two countries with a relatively high uptake of predictive testing, prenatal, and/or preimplantation tests are uncommon. Tassicker et al. [2006] report on 2,036 predictive tests and 63 prenatal tests over a 10-year period, and van Rij et al. [2014a,2014b] report on 262 prenatal and 54 preimplantation tests, also over a 10-year period. In the van Rij study, a number of pregnancies were continued to term after prenatal testing revealed a gene positive fetus. Moreover, Bernhardt et al. [2009] document a declining rate of predictive test uptake at a single center in Germany over a 10-year study period…

Despite the complex psychosocial dynamics within HD families and the psychiatric symptoms of the disease itself, most of the many studies of the psychosocial outcomes of predictive testing have confirmed the early findings of Almqvist et al. [1999], whose worldwide survey of centers performing predictive tests showed a very low risk of severe or catastrophic mental health outcomes (e.g., hospitalization, suicide attempt, or suicide; see Table I).

Unusual clinical HD predictive testing situations abound, creating fertile material for discussions of the ethical, legal, and social implications of these tests. For example, the literature has included discussions about the testing of at-risk children at parental request, prenatal or predictive testing of individuals when some family members do not want to know the results (e.g., prenatal testing at maternal request when the at-risk father does not want to know or predictive testing of an adult child with a 25% risk of HD when a parent does not want to know), testing of twins, and other family issues related to tests. Some of these discussions focus on the ethical principles involved, and others focus more on the clinical outcomes (see Tables V and VI, respectively). Other ethical challenges for clinical practitioners include anonymous testing, counseling of patients and family members when an affected person learns he or she is unexpectedly homozygous (or, more likely, compound heterozygous) for an expanded CAG repeat, and counseling regarding expansions and contractions in and across the intermediate CAG repeat boundaries…

One of the most dramatic societal changes since John Pearson proposed a treatment model emphasizing genetic counseling in 1955 is the immediate availability of information to anyone with Internet access. This information access may make us feel more autonomous and more in control of our lives, but information without context is commonly forgotten, misinterpreted, or entirely misunderstood.

We recall a recent referral to our center of an at-risk patient who had previously obtained predictive testing through a local physician and was told that “the HD gene is normal.” Subsequent review by a genetics professional 3 years—and two pregnancies—later showed that although the patient's first allele (described on the first page of the laboratory report) was normal, the second allele (described on the next page of the report) had a CAG repeat expansion. Apparently the report that the physician saw was missing a page, but neither the physician nor the patient thought to make sure that they saw results for both alleles, even though both had likely learned in the past that humans have two copies of each gene.

Cases like this one emphasize the importance of one-on-one genetic counseling to ensure that patients have the knowledge base to understand their results. Despite the widespread availability of information about the genetics of HD on the Internet and in books, textbooks, videos, and many other media, we routinely see patients, students, and physicians who fail to understand basic concepts. Counseling sessions allow genetics experts to emphasize or review certain points or to rephrase their descriptions of concepts to match the particular levels of education and medical sophistication of their patients. Such sessions also provide a context for information to be retained; attending a seminar at an HD conference about predictive testing is not nearly as valuable for patients as discussing their particular reasons for considering predictive testing with a genetic counselor…

If the goal is to get more people tested, then we could assess quality by looking at the proportion of patients counseled by a particular counselor who subsequently undergo testing. If there is a sense that we should strive to reduce the total burden of HD in the next generation through counseling and educational activities, as Dr. Pearson (1955) advocated 60 years ago, then the current approach to genetic counseling and testing is not succeeding. In fact, a very recent study has documented a dramatic increase in the prevalence of HD in Northern England between 1990 and 2010; the estimated prevalence of HD there has risen from 5.4/100,000 (95% CI 3.8–7.5) in 1990 to 12.3 (11.2–13.5)/100,000 in 2010 [Bargiela et al., 2015]. Although this is likely due in large part to improved ascertainment of the disorder in older individuals with a vague or absent family history, it does not appear that the availability of genetic counseling, predictive testing, or prenatal or preimplantation testing has led to any reduction in the prevalence of the disease. And if the goals are to provide information (recalled or not) that allows people to make the right decisions for themselves about whether to have a predictive, prenatal, or preimplantation test, then perhaps we are succeeding, at least with the patients that we are reaching. Future researchers should work to develop metrics to evaluate the success of one counseling approach over another in this regard.

Another problem for the future is the potential necessity to upscale genetic testing services to meet what could be a significant influx of requests for testing from at-risk applicants who need a positive gene test result in order to qualify for a research study of a putative disease-modifying treatment. Phase 1 trials of gene-silencing therapy in HD have begun, and as this and other treatments move into larger clinical trials, this may change the perceived potential rewards of the gene test. Genetic service providers need to be aware as such trials become available, as patients who seek predictive tests so that they can get into research studies may be unprepared for the uncertainty and potential disappointment that may accompany a test result, and then they may be disappointed again if for some reason they are unable to participate in the research study.

The cornerstone of the genetic management of HD remains genetic counseling. In the 1950s, Reed rejected the terms “genetic consultation,” “genetic advice,” and “genetic hygiene” in favor of the term “genetic counseling,” and that term remains apt today [Holtan, 2011]. Neither genetic counseling, available since the 1950s, nor accurate genetic testing, available since 1993, have reduced the prevalence of HD. Indeed, most genetics practitioners would agree that a “public health” goal, such as a reduction in the prevalence of the disease, should not be in our minds as we counsel individual patients and families. It seems, then, that the goal of genetic care in HD should be to provide accurate information to individual patients at the correct time, in a supportive environment, and in a context that is relevant to their lives, while simultaneously navigating the thorny challenges of the family, which is truly the unit of care in genetic medicine. Reaching a broader pool of families and determining which aspects of, or approaches to, genetic counseling are associated with high-quality care are the key challenges for the future.

Thursday, May 19, 2016

GLB-1 related disorders

Inspired by my colleague's diagnosis of such a patient through whole exome sequencing.

Clinical characteristics.
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB).

GM1 gangliosidosis includes phenotypes that range from severe to mild. Type I (infantile) begins before age one year; progressive central nervous system dysfunction leads to spasticity, deafness, blindness, and decerebrate rigidity. Life expectancy is two to three years. Type II can be subdivided into the late-infantile form and juvenile form. Type II, late-infantile form begins between ages one and three years; life expectancy is five to ten years. Type II, juvenile form begins between ages three and ten years with insidious plateauing of motor and cognitive development followed by slow regression. Type II may or may not include skeletal dysplasia. Type III begins in the second to third decade with extrapyramidal signs, gait disturbance, and cardiomyopathy; and can be misidentified as Parkinson disease. Intellectual impairment is common late in the disease; skeletal involvement includes short stature, kyphosis, and scoliosis of varying severity.

MPS IVB is characterized by skeletal changes, including short stature and skeletal dysplasia. Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, and the attenuated form in late childhood or adolescence. In addition to skeletal involvement, significant morbidity can result from respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, and spinal cord compression. Intellect is normal unless spinal cord compression leads to central nervous system compromise.

The diagnosis of GLB1-related disorders is suspected in individuals with characteristic clinical, neuroimaging, radiographic, and biochemical findings. The diagnosis is confirmed by either deficiency of β-galactosidase enzyme activity or biallelic pathogenic variants in GLB1.

Treatment of manifestations: Best provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology and therapists knowledgeable about GLB1-related disorders; surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders; occupational therapy to optimize activities of daily living (including adaptive equipment) and physical therapy to optimize gait and mobility (including orthotics and bracing); early and ongoing interventions to optimize educational and social outcomes.

For those with GM1 gangliosidosis: Adequate nutrition to maintain growth; speech therapy to optimize oral motor skills; aggressive seizure control; routine management of risk of aspiration, risk of chronic urinary tract infection, and cardiac involvement; when disease is advanced: hospice services for supportive in-home care.

Prevention of secondary complications: Anesthetic precautions to anticipate and manage complications relating to skeletal involvement and airway compromise; routine immunization; bacterial endocarditis prophylaxis in those with cardiac valvular disease.


Wednesday, May 18, 2016

Between a rock and a hard place

A Georgia mother was faced with a horrifying choice on Wednesday, when her 5-year-old son got in trouble for hitting and spitting on other students. The school said they can suspend the boy or paddle him, the Atlanta Journal-Constitution reported. While Shana Marie Perez was against school corporal punishment, which is allowed with parental consent in the Jasper County school district, she feared that one more absence for her son would land her in jail.

Just two weeks prior, Perez was arrested for truancy and temporarily locked up when her son missed 18 days of school. She claimed the some of the absences were due to doctor appointments, yet she was told that one more absence would land her back in jail. Fearing that the suspension would have meant just that, she opted for paddling, even though she had previously denied consent for her school to punish her son in that fashion.

While Principal Pam Edge and Assistant Principal Lynn McElheney tried to get the boy under control to administer the paddling, Perez recorded them on video, pretending to be texting.

The video doesn’t show the child getting hit, as the boy refused to cooperate, and reports vary as to whether he was actually paddled. School Superintendent Mike Newton did email Perez, saying that a suspension for her son would be an excused absence. Newton also told her that he would like to set up assistance to address the child’s behavior.


A single MHCI molecule, HLA-F, protects motor neurons from ALS astrocyte toxicity

New research shines a light on the role of MHCI in astrocyte-induced death of motor neurons in amyotrophic lateral sclerosis and pointing to a potential therapeutic target.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating progressive neurodegenerative disease that results in the death of motor neurons, the nerve cells that control muscles. Eventually, individuals with ALS will lose their ability to walk, move, swallow and breathe.

Until recently, the role of astrocytes, glial cells that normally support motor neurons, in motor neuron death has been a mystery, but research from scientists at Nationwide Children’s Hospital sheds new light on molecular mechanisms responsible for motor neuron death in ALS. In a study published in Nature Medicine, Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s, and his team demonstrate the explicit loss of major histocompatibility complex I (MHCI) expression in the outer membrane of motor neurons in ALS, leading to motor neuron vulnerability to ALS astrocyte toxicity.

“We wanted to find out what astrocytes were doing — or not doing — to kill motor neurons,” explains Dr. Kaspar. “We found unequivocal evidence of the role of MHCI on the motor neurons in signaling the astrocytes.”

For each subtype of MHCI protein, there is a receptor that binds to it, much like a lock and key. If MCHI proteins are the keys, then killer inhibitory receptors (KIRs) are the locks. In their study, Dr. Kaspar and his team not only provide evidence of the protective effect of MHCI against astrocyte toxicity in ALS but also identify the killer inhibitory receptors (KIRs) associated with the specific subclass of MHCI (HLA-F) involved in human motor neurons.

“We showed, in both animal and human studies, the loss of MHCI is destructive to the motor neurons and increases in MHCI are protective,” says Dr. Kaspar, who is also associate professor in the Department of Pediatrics and Department of Neuroscience at The Ohio State University College of Medicine. “We knew from past research that ALS astrocytes were responsible for killing motor neurons. Now we have another piece to the puzzle.”

According to the study, a dramatic loss of MHCI (HLA-F) from motor neurons is observed in the spinal cords of subjects affected by ALS. This finding is supported by evidence obtained in animal models and in vitro experiments using animal and human cells, which give insight on the protective nature of MHCI (HLA-F). Specifically, MHCI expression in the animal model was modulated using adeno-associated viral vector serotype 9 (AAV9), resulting in increased expression of MHCI and markedly extended survival.

The protective nature of MHCI (HLA-F) points to a potential translational target to delay the progression of ALS, since HLA-F expression may significantly impact disease progression in patients. In the in vitro experiments, human motor neurons expressing higher levels of HLA-F experienced reduced astrocyte toxicity. However, it remains to be seen whether or not this can be translated into a clinical trial and meaningful therapy for patients.

“Taken together, the results provide strong evidence that a single MHCI molecule, HLA-F, can protect motor neurons from both inherited and spontaneous ALS astrocyte-induced toxicity, which is a prerequisite for delaying motor neuron death in these patients,” Dr. Kaspar says.

Not only is this work opening doors to new possibilities in ALS research and therapeutics, MHCI has also been shown to be instrumental in neural development, explaining how the brain prunes back unused connections early in life. According to Dr. Kaspar, studies now indicate that it may be integral in neurodegenerative situations as well.

“While we have gained much information about the role of MHCI and it’s involvement in eliminating some connections in the brain, including it’s involvement in neurodegeneration and the role of astrocyte toxicity, through this research, we are really just scratching at the surface of all we need to understand,” Dr. Kaspar says.



Just a decade ago, some scientists were calling optogenetics a long shot, a crazy idea. Then it turned out to be not so crazy.

This relatively new technology allows neuroscientists to use light to probe the inner workings of the brain to study—and even control—pinpointed regions believed to be implicated in disorders like addiction, epilepsy, and autism.

The formula involves light-sensitive algae proteins, a detoxified virus (which acts as the rocketship that delivers the payload protein into the brain), and LED light (sometimes in multiple colors) administered via superfine fiber optic cables. 

With support from MnDRIVE—an infusion of research dollars by the Minnesota Legislature into brain sciences, among other areas, at the University of Minnesota—and the federal BRAIN Initiative, a group of University neuroscientists is now all in on this groundbreaking work.

“One of the most exciting things about optogenetics,” says Patrick Rothwell, Ph.D., assistant professor in the Department of Neuroscience,“is that it may, in and of itself, one day be used as a treatment strategy, but it may also be used to identify other interventions … based on our discovery of what is actually going wrong in the brain.” 

Targeting relapse

There’s a lot scientists still don’t know about the brain and its billions of neural connections. Over time, though, they have identified areas that seem to hold the key for disorders like addiction.

“If you think of the brain as a powerful computer, it has specific circuits dedicated to controlling particular functions,” explains Mark Thomas, Ph.D., associate professor in the Department of Neuroscience. “Studying morphine addiction in mice over time, we’ve identified brain circuits that are involved in a relapse-like phenomenon.”

Using optogenetics, Thomas has recently shown that he can retool those circuits, returning them to what he calls a “drug naïve state”—a discovery that could ultimately lead to treatments that would help people struggling with addiction avoid relapse.

“The challenge with addiction is to identify which circuits are really producing the addiction-like pattern of behavior so that, ultimately, we can target them with therapeutic intervention,” he says. “That’s what optogenetics, which is so exquisitely precise, allows us to do.”

Precise seizure control

Every day in the United States, doctors diagnose 500 people with epilepsy, a condition that causes recurrent seizures. Current treatments, says assistant professor of neuroscience Esther Krook-Magnuson, Ph.D., tend toward a “hammer” approach: drugs, surgical removal of brain tissue, and deep brain stimulation surgery, all of which can have unwelcome side effects because they can’t be focused intently on only the disordered circuits.

Using optogenetics, however, Krook-Magnuson can target the circuits with great specificity.  In her lab, she monitors mice using brain electrodes and software that detects epileptic seizures. As soon as the seizure begins, the investigators shine LED light directly on to the targeted circuits, stopping the seizure.

“That specificity—seizure control without negative side effects—is what attracted me to optogenetics,” Krook-Magnuson says. “It’s like a classroom full of kids where only one is misbehaving. It doesn’t make sense to discipline the whole class.”

Zeroing in on autism

Rothwell, new to the U’s faculty this year, uses a different metaphor to describe his optogenetics work involving autism and addiction.

“Imagine the brain as an orchestra, with all of the cells working together. You might hear a problem in, say, the strings section. But then you have to break it down further, to the cellos, the violas, the violins, to find out which is out of tune.”

Rothwell has pinpointed a particular group of malfunctioning synaptic connections—say, the violins—in the brain’s striatum that he believes plays a role in autism; now he wants to pluck each string to find the discordant notes.

“My previous work got us to the violins,” he explains. “Now, using optogenetics, we’re looking closer in hopes of being able to ‘tune’ those cells, to restore healthy function.”

Rothwell keeps a foot in two camps—both autism and addiction research—because the same area of the striatum appears to be problematic in both disorders, he says. Addiction research in general is further along, he says, so he can learn from that and apply it, where indicated, to his autism investigations. He now has philanthropic backing for this work, too.

On a roll

The MnDRIVE and BRAIN Initiative funding were critical to producing this body of optogenetics knowledge, says Thomas, which is being shared with multiple labs across campus.

Now scientists are focused on the next steps: developing improved viruses to deliver the optogenetics proteins into the brain and using functional magnetic resonance imaging to actually watch what happens as the photosensitive neurons are activated.

“There’s so much promise here,” Thomas says. “Optogenetics has been a transformative tool, allowing us to work in the brain in a whole new way, to tackle the unknowns. And is it possible that it could be used as a therapeutic tool for humans? Yes, I think that’s on the horizon.”

How optogenetics works

The roots of optogenetics can be traced back to the 1970s, when scientists discovered that certain types of algae contained photosensitive proteins.

Jump forward several decades, when neuroscientists wondered whether, if they somehow put that algae protein into specific neurons in the brain, they could become light-sensitive. And could the scientists then control those neurons with light? Vastly simplified, the answers were yes and yes.

To deliver the protein, scientists use a benign virus (one that won’t replicate or cause sickness), injecting it into the target cells of interest in the brain of a mouse. Those brain cells take up the virus—and thereby, the protein—while other neurons nearby remain unaffected.

Then, with a superfine fiber optic probe, the scientist shines LED light on to the target area and essentially turns on a particular set of neurons. Or they can use another protein that, once lit, inhibits the neurons from firing.