Posted on Autism

Autism can be detected during toddlerhood using a brief questionnaire

Blood Cancer research

New research led by the University of Cambridge suggests that autism can be detected at 18-30 months using the Quantitative Checklist for Autism in Toddlers (Q-CHAT), but it is not possible to identify every child at a young age who will later be diagnosed as autistic. The results are published today in The BMJ Paediatrics Open.

The team at the Autism Research Centre in Cambridge conducted a prospective population screening study of nearly 4,000 toddlers using a parent-report instrument they developed, called the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Toddlers were screened at 18 months and followed up at 4 years.

The Q-CHAT is a revision of the original CHAT first published by the same authors in the 1990s. It retains the key items but includes additional items that examine language development, repetitive and sensory behaviours, as well as other aspects of social communication behaviour. Each of the 25 items contains a range of response options, allowing for the endorsement of a reduced rate of key behaviours. In effect, this ‘dimensionalises’ each item (using a five-point scale of frequency), allowing for variability in responses and a better understanding of the distributions across the specific traits. The revision was motivated by trying to improve on the accuracy of screening toddlers for autism.

In the new research, in phase one, 13,070 caregivers were invited to complete the Q-CHAT about their child at 18-30 months. 3,770 caregivers returned the Q-CHAT, of whom 121 were invited for an autism diagnostic assessment.

In phase two, the sample was followed up when the children were 4, using the Childhood Autism Screening Test (CAST), and a checklist enquiring whether any of the children had been referred or diagnosed with any developmental conditions, including autism. Autism assessments were made using internationally recognized methods.

The sensitivity (the proportion of autistic children correctly identified by the Q-CHAT as being autistic) of the Q-CHAT in predicting autism at phase two is 44%, and the specificity (the proportion of children who are not autistic and who are correctly identified by the Q-CHAT as not being autistic) is 98%. Results also showed that the ‘positive predictive value’ (the proportion whose screened positive on the Q-CHAT who were found to be autistic) is 28%.

This study demonstrates that early detection and diagnosis of autism is possible using the Q-CHAT, since all 11 children who were classified as autistic scored at or above the cut-point of 39. The Q-CHAT did not identify all children during toddlerhood who were later diagnosed with autism at age 4. This likely reflects that some autistic children do not show symptoms of sufficient severity until later in childhood.

In other studies the team have found some autistic people do not receive a diagnosis until their teens or even adulthood, perhaps because family support cushions the need for a diagnosis until social demands increase, for example at transition to secondary school or transition to adulthood.

Dr Carrie Allison, Director of Research Strategy at the Autism Research Centre, and who led the study, said: “This study tells us that autism can be detected during the toddler years, and that other children may only be identified as autistic later. Repeat screening and surveillance across development may be a better approach rather than relying on a single time-point.”

Professor Tony Charman, Professor of Clinical Child Psychology at Kings College London, and a member of the team, said: “Screening for autism in infancy means that children can be fast-tracked into early intervention, which we know can lead to better outcomes for many children. This is an exciting advance because most other autism screening measures in toddlers have not been subject to rigorous population studies of this kind.”

Professor Sir Simon Baron-Cohen, Director of the Autism Research Centre and a member of the team, said: “25 years ago our team was the first to show autism could be screened and diagnosed as young as 18 months of age. This new study shows how our original screening instrument – the CHAT – has been revised into a better instrument – the Q-CHAT, which can pick up children who need an autism diagnosis. Early detection means happier, healthier, children and families because they can be targeted with support.”

Posted on Autism

SUV39H2: A direct genetic link to the autism spectrum

H3K9 methylation levels in the cerebellum were lower in the Suv39h2-deficient mice than in control mice controls. CREDIT RIKEN

New research from the RIKEN Center for Brain Science (CBS) in Japan shows that a deficit in histone methylation could lead to the development of autism spectrum disorders (ASD). A human variant of the SUV39H2 gene led researchers to examine its absence in mice. Published in Molecular Psychiatry, the study found that when absent, adult mice exhibited cognitive inflexibility similar to what occurs in autism, and embryonic mice showed misregulated expression of genes related to brain development. These findings represent the first direct link between the SUV39H2 gene and ASD.

Genes are turned on and off throughout our development. But genetic variation means that what is turned off in some people remains turned on in others. This is why, for example, some adults can digest dairy products and others are lactose intolerant; the gene for making the enzyme lactase is turned off when some people become adults, but not others. One way that genes can be turned on and off is through a process called histone methylation in which special enzymes transfer methyl groups to histone proteins that are wrapped around DNA.

Variations in genes related to methylation during brain development can lead to serious problems. One such variation occurs in a rare disorder called Kleefstra Syndrome, in which a mutation prevents methylation of H3K9–a specific location on histone H3. Because Kleefstra Syndrome resembles autism in some ways, RIKEN CBS researchers led by Takeo Yoshikawa looked for autism-specific variations in genes that can modify H3K9. Among nine such genes, they found one variant in an H3K9 methyltransferase gene–SUV39H2–that was present in autism, and the mutated SUV39H2 prevented methylation when tested in the lab. Similar loss-of-function results were found for the mouse version of the variant.

The next step was to see what happens in mice that lack the Suv39h2 gene. Behaviorally, the researchers found that the mice could learn a simple cognitive task, but had difficultly when the task required cognitive flexibility. In the simple task, mice learned to get a reward by poking a door at alternating diagonal corners of a cage. After they could do this well, the possible reward locations switched to the other two diagonal corners. The genetically modified mice did this as well as wild-type mice. In another task, after learning to alternate between the two diagonal corners, only the location of one reward was switched. When the mice were challenged to alternate randomly between these two tasks, wild-type mice could adapt quickly, but the Suv39h2-deficient mice took much longer. “This serial reversal-learning task was essential,” says first author Shabeesh Balan. “Cognitive inflexibility is a core symptom of ASD, and our new task was able to address this behavioral feature in ways that previous mouse studies could not.”

When the researchers examined what happened in the mouse brain when H3K9 methylation failed to occur, they found that important genes that are usually silenced in early development were turned on in the experimental mice. “Suv39h2 is known to be expressed in early neurodevelopment and to methylate H3K9,” explains Yoshikawa. “This keeps a check on genes that should be switched-off. But without it, genes in the protocadherin β cluster were abnormally expressed at high levels in embryonic mice.” Because protocadherins are critical for the formation of neural circuits, the researchers believe they have found an important biological pathway that could be central to several neurodevelopmental disorders.

The team then verified the importance of SUV39H2 in human ASD by finding that its expression was lower in the postmortem brains of people with ASD than of controls. “What began with a loss-of-function mutation in only one person with ASD,” says Yoshikawa, “has led to a general causal landscape for ASD that culminates in brain circuit abnormality.”

Protocadherins have already been proposed to be related to a broad range of mental disorders. This study shows that activating the SUV39H2 gene is a potential therapy for mental disorders–including ASD–that should be investigated more thoroughly in future studies.

Posted on Patient Talk

Progressive Multiple Sclerosis Prognosis Explained by Neurologist [Data From MS Base]

Channel Introduction (Brandon Beaber, M.D.) [Multiple Sclerosis] - YouTube


What is the average prognosis in progressive multiple sclerosis? Does sex matter? Does secondary vs. primary progressive MS matter? Do relapses matter? Does disease modifying therapy reduce risk? What is the probability of requiring a wheelchair? This video examines data from the MS EPIC study and MS Base to answer these questions.

Posted on Diabetes

Body mass index as a risk factor for diabetes varies throughout the world

Body mass index as a risk factor for diabetes varies throughout the world
Body mass index as a risk factor for diabetes varies throughout the world


The unprecedented increase in overweight and obesity in low- and middle-income countries (LMICs) has led to an alarming rise in diabetes in these regions. Of the estimated 463 million people with diabetes worldwide, 79% live in LMICs.

Until now, however, there were scant empirical data to guide clinicians and health systems in determining which individuals should be screened for diabetes based on body mass index (BMI). “There are guidelines from the World Health Organization that recommend screening individuals age 40 and older with a BMI of 25 kg/m2 and above for diabetes,” says Jennifer Manne-Goehler, MD, ScD, faculty member at the Medical Practice Evaluation Center at Massachusetts General Hospital (MGH). “But it’s long been suspected that these BMI and age thresholds may not be optimal for diabetes screening in all regions of the world. Our goal was to estimate the relationship between BMI and diabetes risk across many low- and middle-income countries to help resource-strapped health systems devise the most effective screening programs for their populations,” says Manne-Goehler, senior author of a new study published in The Lancet.

Manne-Goehler and investigators from 57 countries spent five years compiling and leveraging existing datasets of more than 680,000 people in LMICs that included every individual’s weight, height and a diabetes biomarker–either a blood glucose measurement or hemoglobin A1c.

The study, the first of its kind, found substantial regional differences in the association between BMI and diabetes risk. Across all LMICs, people with a BMI of 23 kg/m2 or greater had an increased risk of diabetes. There was, however, variability in the optimal BMI to choose for diabetes screening among regions and genders, ranging from 23.8 kg/m2 among men in East/Southeast Asia to 28.3 kg/m2 among women in the Middle East, North Africa, Latin America and the Caribbean. The investigators also found differences in the risk of diabetes across BMI categories in several regions. For example, men and women in sub-Saharan Africa and East/Southeast Asia had more than a 100% increase in the risk of diabetes between being overweight and obese. These findings, in part, reinforced a growing literature from Asian and South Asian countries that recommends using lower BMI thresholds to better characterize metabolic risk in these populations.

And while diabetes increased in middle age and beyond, the proportion of individuals with diabetes rose steeply across all regions in the 35-to-44 age group, and among men 25 to 34 years old in sub-Saharan Africa. “Diagnosing diabetes in younger adults can prevent long-term complications of the disease,” says Manne-Goehler.

“Although the data aren’t prescriptive, our hope is that policymakers in LMICs will find this evidence useful as they try to decide how they will spend limited resources to optimize diabetes screening for their particular populations,” she adds.

The research also demonstrates the power of collaborations among countries to create important evidence to inform public health guidelines. “It’s difficult to draw meaningful high-level global conclusions when individual countries are examining diabetes risk in only one country’s survey,” says Manne-Goehler. The World Health Organization is creating a global strategy called the Global Diabetes Compact to scale up care for people with diabetes, for example. “We believe that our collaboration of many investigators across these 57 countries can help inform best diabetes screening practices throughout the world,” she says.

“LMICs now have evidence-based specific answers to the ‘Who? When? and How much?’ regarding diabetes prevention and screening in relation with BMI,” writes Siméon Pierre Choukem, MD, dean of the faculty of Medicine and Pharmaceutical Sciences, University of Dschang, Cameroon, in a related commentary in The Lancet. “These results have major public health implications as the actual burden of diabetes in LMICs is probably underestimated because of the current screening guidelines, and it is unclear to what extent.”

The global team of investigators are now studying how waist circumference might increase the accuracy of diabetes risk assessment when used with BMI, and they are also examining the relationship between behavioral factors–alcohol, smoking, physical activity and diet–and risk of diabetes across these 57 countries. In the future, the researchers also hope to create collaborations that include surveys from high-income countries to facilitate direct comparisons across a wider spectrum of global health settings. “Health systems in every country in the world have to make the best use of their resources to improve the health of their populations,” says Manne-Goehler.