Stories about: epilepsy

Patients’ brain tissue unlocks the cellular hideout of Sturge-Weber’s gene mutation

A diagram of the skull and brain showing the leptomeninges, which is affected by Sturge-Weber syndrome
Sturge-Weber syndrome causes capillary malformations in the brain. They occur in the brain’s leptomeninges, which comprise the arachnoid mater and pia mater.

A person born with a port-wine birthmark on his or her face and eyelid(s) has an 8 to 15 percent chance of being diagnosed with Sturge-Weber syndrome. The rare disorder causes malformations in certain regions of the body’s capillaries (small blood vessels). Port-wine birthmarks appear on areas of the face affected by these capillary malformations.

Aside from the visible symptoms of Sturge-Weber, there are also some more subtle and worrisome ones. Sturge-Weber syndrome can be detected by magnetic resonance imaging (MRI). Such images can reveal a telltale series of malformed capillaries in regions of the brain. Brain capillary malformations can have potentially devastating neurological consequences, including epileptic seizures.

Frustratingly, since doctors first described Sturge-Weber syndrome over 100 years ago, the relationship between brain capillary malformations and seizures has remained somewhat unexplained. In 2013, a Johns Hopkins University team found a GNAQ R183Q gene mutation in about 90 percent of sampled Sturge-Weber patients. However, the mutation’s effect on particular cells and its relationship to seizures still remained unknown.

But recently, some new light has been shed on the mystery. At Boston Children’s Hospital, Sturge-Weber patients donated their brain tissue to research after it was removed during a drastic surgery to treat severe epilepsy. An analysis of their tissue, funded by Boston Children’s Translational Neuroscience Center (TNC), has revealed the cellular location of the Sturge-Weber mutation. The discovery brings new hope of finding ways to improve the lives of those with the disorder.

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News Notes: Pediatric science roundup

A quick look at recent research Vector finds noteworthy.

Tracking infants’ microbiomes

cute microbes-shutterstock_317080235-croppedMicrobiome studies are blooming as rapidly as bacteria in an immunocompromised host. But few studies have been done in children, whose microbiomes are actively forming and vulnerable to outside influences. Two studies in Science Translational Medicine on June 15 tracked infants’ gut microbiomes prospectively over time. The first, led by researchers at the Broad Institute and Massachusetts General Hospital, analyzed DNA from monthly stool samples from 39 Finnish infants, starting at 2 months of age. Over the next three years, 20 of the children received at least one course of antibiotics. Those who were repeatedly dosed had fewer “good” bacteria, including microbes important in training the immune system. Overall, their microbiomes were less diverse and less stable, and their gut microbes had more antibiotic resistance genes, some of which lingered even after antibiotic treatment. Delivery mode (cesarean vs. vaginal) also affected microbial diversity. A second study at NYU Langone Medical Center tracked 43 U.S. infants for two years and similarly found disturbances in microbiome development associated with antibiotic treatment, delivery by cesarean section and formula feeding versus breastfeeding.

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News notes: Headlines in science & innovation

An occasional roundup of news items Vector finds interesting.

Blood-brain barrier on chip

vector news - blood brain barrier chip
(Wyss Institute at Harvard University)

The blood-brain barrier protects the brain against potentially damaging molecules, but its gate-keeping can also prevent helpful drugs from getting into the central nervous system. Reporting in PLoS One, a team at the Wyss Institute for Biologically Inspired Engineering describes a 3-D blood-brain barrier on a chip — a hollow blood vessel lined with living human endothelial cells and surrounded by a collagen matrix bearing human pericytes and astrocytes.

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CDKL5: Understanding rare epilepsies, patient by patient, neuron by neuron

CDKL5 epilepsy
Haley with her parents and neurologist Heather Olson (right)

Nine-year-old Haley Hilt has had intractable seizures all her life. Though she cannot speak, she communicates volumes with her eyes. Using a tablet she controls with her gaze, she can tell her parents when her head hurts and has shown that she knows her letters, numbers and shapes.

Haley is one of a growing group of children who are advancing the science around CDKL5 epilepsy, Haley’s newly recognized genetic disorder. When Boston Children’s Hospital geneticist Joan Stoler, MD, diagnosed Haley in 2009, there were perhaps 100 cases known in the world; today, there are estimated to be a few thousand. Haley’s neurologist, Heather Olson, MD, leads a CDKL5 Center of Excellence at the hospital that is bringing the condition into better view.

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TriVox Health: improving care through shared online tracking

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Since we spoke with the founders of TriVox Health in 2014, their disease management program has taken off. The program began in Boston Children’s Hospital’s Division of Developmental Medicine as a way to more efficiently collect information on children’s ADHD symptoms from parents and teachers. It is now a user-friendly, web-based platform for tracking multiple conditions, incorporating medication confirmation, side effects reporting, disease symptom surveys and quality of life measures.

Vector sat down with founders Eric Fleegler, MD, MPH and Eugenia Chan, MD, MPH to learn about TriVox Health’s rapid growth over the past year, and what their plans are for the future.

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An eye on epilepsy: The work, life and innovations of Tobias Loddenkemper, MD

Epileptologist Tobias Loddenkemper, MD, director of clinical epilepsy research at Boston Children’s Hospital, is a seizure whisperer. He keeps a close watch on his patients, trying to discern seizure patterns and head off the developmental and learning problems that seizures can cause. A pioneer in the emerging field of chronoepileptology, he has partnered with Empatica and other companies to develop reliable seizure detection devices that could help doctors better time medication dosing and help prevent death from seizures, a real risk in children with severe epilepsy.

Mouse over the icons above to learn more.

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Brain stimulation for status epilepticus?

Seizure-storm concept-Linda Bucklin-shutterstock_172455803Status epilepticus, a state of prolonged seizures, is a life-threatening medical emergency. The average mortality rate is 20 percent, and people who survive sustain lasting neurologic damage. Aborting the seizures is of the essence, but about 30 to 40 percent of patients don’t respond to lorazepam, the first-line drug usually given, and the drug itself can cause respiratory depression.

A study in rat model of status epilepticus, led by Alexander Rotenberg, MD, PhD, of Boston Children’s Hospital’s Department of Neurology, is the first to test an emerging approach known as transcranial direct-current stimulation (tDCS) as a way of halting acute seizures. tDCS applies a weak, direct current to the brain via scalp electrodes, to either increase or—more relevant for seizures—decrease excitability in selected areas. In the study, tDCS reduced the duration of acute seizures in the rats. When it was used together with lorazepam, the combination appeared to have a synergistic effect, also preventing new seizures from starting.

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Hillary Savoie: Parents as citizen scientists

hillary-and-esme
The author with 3-year-old Esmé at their home in New York. (Tracey Buyce Photography)

In my last post I explained the genetic testing process that led to my daughter Esmé receiving results of two mutations of unknown significance. One, on the gene PCDH19, was discovered in 2012 with the GeneDx infantile epilepsy panel. The other, on SCN8A, was found with whole exome sequencing, also through GeneDx, in 2014.

When we received the SCN8A result, I was fascinated by the notion that it would have been included in our original epilepsy panel had we only waited a handful of months. In fact, in the time since Esmé’s original test in 2012, almost 20 new genes have been added to the GeneDx Infantile Epilepsy panel.

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When your child isn’t just rare, but probably one of a kind

Savoie at home with 4-year-old Esmé in New York.
Savoie at home with 4-year-old Esmé in New York.

Hillary Savoie, PhD, founder and director of The Cute Syndrome Foundation, is author of Around And Into The Unknown, chronicling her family’s journey to find a diagnosis for Esmé, and Whoosh, about coming to terms with Esmé’s early medical complications.

I think my daughter Esmé is extraordinarily unique—from her tiny pudgy feet that she likes to stuff in her mouth to her beautifully lashed blue eyes and outrageously untamed hair. It’s a mom thing. I guess it is a symptom of loving another person more than life itself.

But my daughter is also unusual in a more scientific way: in her genes. 

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New Human Neuron Core to analyze ‘disease in a dish’

Human Neuron CoreLast week was a good week for neuroscience. Boston Children’s Hospital received nearly $2.2 million from the Massachusetts Life Sciences Center (MLSC) to create a Human Neuron Core. The facility will allow researchers at Boston Children’s and beyond to study neurodevelopmental, psychiatric and neurological disorders directly in living, functioning neurons made from patients with these disorders.

“Nobody’s tried to make human neurons available in a core facility like this before,” says Robin Kleiman, PhD, Director of Preclinical Research for Boston Children’s Translational Neuroscience Center (TNC), who will oversee the Core along with neurologist and TNC director Mustafa Sahin, MD, PhD, and Clifford Woolf, PhD, of Boston Children’s F.M. Kirby Neurobiology Center. “Neurons are really complicated, and there are many different subtypes. Coming up with standard operating procedures for making each type of neuron reproducibly is labor-intensive and expensive.”

Patient-derived neurons are ideal for modeling disease and for preclinical screening of potential drug candidates, including existing, FDA-approved drugs. Created from induced pluripotent stem cells (iPSCs) made from a small skin sample, the lab-created human neurons capture disease physiology at the cellular level in a way that neurons from rats or mice cannot.

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