New brain disorder discovered caused by genetic mutation

A new genetic brain disorder was found by two independent research teams. This disorder is characterized by sensory and motor defects, as well as reduced brain size.

A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue ofCell.

The findings were generated by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego School of Medicine, the Academic Medical Center (AMC) in the Netherlands and the Yale University School of Medicine.

By performing DNA sequencing of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.

"What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features," said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego. "Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced."

Each child tested was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, teamed with James R. Lupski, MD, PhD, of the Baylor College of Medicine.

"Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig's disease," said Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.

These scientists performed DNA sequencing on children with neurological problems. Seven out of the more than 4,000 families studied shared an identical CLP1 mutation, which was associated with motor defects, speech impairments, seizures, brain atrophy and neuronal death.

Bass at the AMC said the neurological condition represents a new form of PCH. "Identification of yet another genetic cause for this neurodegenerative disorder will allow for better genetic testing and counseling to families with an affected child," he said.

In a published paper last year, Gleeson and colleagues identified a different gene mutation for a particularly severe form of PCH, and reported early evidence that a nutritional supplement might one day be able to prevent or reverse the condition.

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Poverty in children and brain development - A Neuro-Thanksgiving Consideration

A Neuro-Thanksgiving Consideration

This study looks at a link between poverty during early childhood and impaired brain development. JR


Poverty in early childhood appears to be associated with smaller brain volumes measured through imaging at school age and early adolescence, according to a study published byJAMA Pediatrics, a JAMA Network publication.

Poverty is known to be associated with a higher risk of poor cognitive outcomes and school performance, according to the study background.

Joan Luby, M.D., of the Washington University School of Medicine, St. Louis, and colleagues investigated the effect of poverty on brain development by examining white and cortical gray matter, as well as hippocampus and amygdala volumes in a group of children ages 6 to 12 years who were followed since preschool. The 145 children were recruited from a larger group of children who participated in a preschool depression study.

The authors report that "exposure to poverty during early childhood is associated with smaller white mater, cortical gray matter, and hippocampal and amygdala volumes," the authors write.

Study findings also indicate that the effects of poverty on hippocampal volume were mediated (influenced) by caregiving and stressful life events.

"The finding that the effects of poverty on hippocampal development are mediated through caregiving and stressful life events further underscores the importance of high-quality early childhood caregiving, a task that can be achieved through parenting education and support, as well as through preschool programs that provide high-quality supplementary caregiving and safe haven to vulnerable young children," the study concludes. 

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Dyslexia diagnosed by brain scans? Examine the arcuate fasciculus

Brain scans showing the brain's structure may soon be able to show a person is dyslexic. JR

About 10 percent of the U.S. population suffers from dyslexia, a condition that makes learning to read difficult. Dyslexia is usually diagnosed around second grade, but the results of a new study from MIT could help identify those children before they even begin reading, so they can be given extra help earlier.

The study, done with researchers at Boston Children's Hospital, found a correlation between poor pre-reading skills in kindergartners and the size of a brain structure that connects two language-processing areas.

Previous studies have shown that in adults with poor reading skills, this structure, known as the arcuate fasciculus, is smaller and less organized than in adults who read normally. However, it was unknown if these differences cause reading difficulties or result from lack of reading experience.

"We were very interested in looking at children prior to reading instruction and whether you would see these kinds of differences," says John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences and a member of MIT's McGovern Institute for Brain Research.

Gabrieli and Nadine Gaab, an assistant professor of pediatrics at Boston Children's Hospital, are the senior authors of a paper describing the results in the Aug. 14 issue of theJournal of Neuroscience. Lead authors of the paper are MIT postdocs Zeynep Saygin and Elizabeth Norton.

The path to reading

The new study is part of a larger effort involving approximately 1,000 children at schools throughout Massachusetts and Rhode Island. At the beginning of kindergarten, children whose parents give permission to participate are assessed for pre-reading skills, such as being able to put words together from sounds.

"From that, we're able to provide -- at the beginning of kindergarten -- a snapshot of how that child's pre-reading abilities look relative to others in their classroom or other peers, which is a real benefit to the child's parents and teachers," Norton says.

The researchers then invite a subset of the children to come to MIT for brain imaging. The Journal of Neuroscience study included 40 children who had their brains scanned using a technique known as diffusion-weighted imaging, which is based on magnetic resonance imaging (MRI).

This type of imaging reveals the size and organization of the brain's white matter -- bundles of nerves that carry information between brain regions. The researchers focused on three white-matter tracts associated with reading skill, all located on the left side of the brain: the arcuate fasciculus, the inferior longitudinal fasciculus (ILF) and the superior longitudinal fasciculus (SLF).

When comparing the brain scans and the results of several different types of pre-reading tests, the researchers found a correlation between the size and organization of the arcuate fasciculus and performance on tests of phonological awareness -- the ability to identify and manipulate the sounds of language.

Phonological awareness can be measured by testing how well children can segment sounds, identify them in isolation, and rearrange them to make new words. Strong phonological skills have previously been linked with ease of learning to read. "The first step in reading is to match the printed letters with the sounds of letters that you know exist in the world," Norton says.

The researchers also tested the children on two other skills that have been shown to predict reading ability -- rapid naming, which is the ability to name a series of familiar objects as quickly as you can, and the ability to name letters. They did not find any correlation between these skills and the size or organization of the white-matter structures scanned in this study.

Brian Wandell, director of Stanford University's Center for Cognitive and Neurobiological Imaging, says the study is a valuable contribution to efforts to find biological markers that a child is likely to need extra help to learn to read.

"The work identifies a clear marker that predicts reading, and the marker is present at a very young age. Their results raise questions about the biological basis of the marker and provides scientists with excellent new targets for study," says Wandell, who was not part of the research team.

Early intervention

The left arcuate fasciculus connects Broca's area, which is involved in speech production, and Wernicke's area, which is involved in understanding written and spoken language. A larger and more organized arcuate fasciculus could aid in communication between those two regions, the researchers say.

Gabrieli points out that the structural differences found in the study don't necessarily reflect genetic differences; environmental influences could also be involved. "At the moment when the children arrive at kindergarten, which is approximately when we scan them, we don't know what factors lead to these brain differences," he says.

The researchers plan to follow three waves of children as they progress to second grade and evaluate whether the brain measures they have identified predict poor reading skills.

"We don't know yet how it plays out over time, and that's the big question: Can we, through a combination of behavioral and brain measures, get a lot more accurate at seeing who will become a dyslexic child, with the hope that that would motivate aggressive interventions that would help these children right from the start, instead of waiting for them to fail?" Gabrieli says.

For at least some dyslexic children, offering extra training in phonological skills can help them improve their reading skills later on, studies have shown.

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Scientists grow mini human brains

Scientists found a way to grow mini three-dimensional human brains in a lab. This will help in the discovery of brain development and how different disorders may develop.

Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Natureallows pluripotent stem cells to develop into cerebral organoids -- or "mini brains" -- that consist of several discrete brain regions.

Instead of using so-called patterning growth factors to achieve this, scientists at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the "mini brains," the scientists were also able to model the development of a human neuronal disorder and identify its origin -- opening up routes to long hoped-for model systems of the human brain.

The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain's development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has just changed that.

Brain Size Matters

Starting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: "We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed."

After only 15 -- 20 days, so-called "cerebral organoids" formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 -- 30 days, defined brain regions, including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.

Microcephaly in Mini Brains

The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease.

Knoblich's group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size.

Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size. Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder.

"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," explains Dr. Madeline A. Lancaster, team member and first author of the publication. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development."

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Using Brain Size Determine If You Are Good at Keeping Friends

Researchers are suggesting that there is a link between the number of friends you have and the size of the region of the brain -- known as the orbital prefrontal cortex -- that is found just above the eyes. A new study shows that this brain region is bigger in people who have a larger number of friendships.

Their study is published on 1 February 2012 in the journal,Proceedings of the Royal Society B.

The research was carried out as part of the British Academy Centenary 'Lucy to Language' project, led by Professor Robin Dunbar of the University of Oxford in a collaboration with Dr Joanne Powell and Dr Marta Garcia-Finana at Liverpool University, Dr Penny Lewis at Manchester University and Professor Neil Roberts at Edinburgh University.

The study suggests that we need to employ a set of cognitive skills to maintain a number of friends (and the keyword is 'friends' as opposed to just the total number of people we know). These skills are described by social scientists as 'mentalising' or 'mind-reading'- a capacity to understand what another person is thinking, which is crucial to our ability to handle our complex social world, including the ability to hold conversations with one another. This study, for the first time, suggests that our competency in these skills is determined by the size of key regions of our brains (in particular, the frontal lobe).

Professor Dunbar, from the Institute of Cognitive and Evolutionary Anthropology, explained: '"Mentalising" is where one individual is able to follow a natural hierarchy involving other individuals' mind states. For example, in the play 'Othello', Shakespeare manages to keep track of five separate mental states: he intended that his audience believes that Iago wants Othello to suppose that Desdemona loves Cassio [the italics signify the different mind states]. Being able to maintain five separate individuals' mental states is the natural upper limit for most adults.'

The researchers took anatomical MR images of the brains of 40 volunteers at the Magnetic Resonance and Image Analysis Research Centre at the University of Liverpool to measure the size of the prefrontal cortex, the part of the brain used in high-level thinking. Participants were asked to make a list of everyone they had had social, as opposed to professional, contact with over the previous seven days. They also took a test to determine their competency in mentalising.

Professor Robin Dunbar, said: 'We found that individuals who had more friends did better on mentalising tasks and had more neural volume in the orbital frontal cortex, the part of the forebrain immediately above the eyes. Understanding this link between an individual's brain size and the number of friends they have helps us understand the mechanisms that have led to humans developing bigger brains than other primate species. The frontal lobes of the brain, in particular, have enlarged dramatically in humans over the last half million years.'

Dr Joanne Powell, from the Department of Psychology, University of Liverpool, said: 'Perhaps the most important finding of our study is that we have been able to show that the relationship between brain size and social network size is mediated by mentalising skills. What this tells us is that the size of your brain determines your social skills, and it is these that allow you have many friends.'

Professor Dunbar said: 'All the volunteers in this sample were postgraduate students of broadly similar ages with potentially similar opportunities for social activities. Of course, the amount of spare time for socialising, geography, personality and gender all influence friendship size, but we also know that at least some of these factors, notably gender, also correlate with mentalising skills. Our study finds there is a link between the ability to read how other people think and social network size.'

Professor Dunbar's research was funded by the British Academy Centenary Research Project and by the British Academy Research Professorship. His research has already examined the different brain sizes of different species, but this study looks at the differences within species. Professor Dunbar published a paper last year, which found that people living near to the Poles needed larger brains for visual processing because of the dimmer light conditions.

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