Thursday, June 30, 2016

Head transplant 4

The world’s first ever human head transplant operation will take place in Germany, The Daily Star reported, citing Italian neurosurgeon Sergio Canavero, who said he planned to operate in December 2017.

“Today, I am officially asking Germany to help me realize the first cephalosomatic anastomosis in human history on German soil and live up to what you are: a country that has set standards in medicine and technology for centuries,” Dr. Canavero said.

"In fact, German technology is already part of this incredible project I codenamed HEAVEN!”

Valery Spiridonov, a 30-year-old Russian computer programmer and wheelchair user who suffers from Werdnig-Hoffman disease, a debilitating and eventually fatal spinal muscular atrophy, has volunteered for the macabre operation.

The operation to fit the head of a living human being the body of a recently deceased person, will be performed as part of Project HEAVEN (HEad Anatomosis VENture) and is expected to last about 36 hours.

Dr. Canavero of the Turin Advanced Neuromodulation Group in Italy recently presented the results of his experiments on rats conducted in South Korea, which proved that spinal cord fusion is really possible.

Canavero’s idea has caused controversial reaction among specialists, as some are convinced that the technology is disputable, but still vital and requires huge investments, while others believe it to be totally unsustainable.

In an interview with Sputnik Dr. Canavero said that inability to reconnect a severed spinal cord had always been a major problem, but experiments with rats using technology to be employed during operations on humans resulted in rats with re-fused spinal cords able to move again.

“What is really important here is that the fused spinal cords functioned again, which means that the door is now open to perform such operations also on humans,” he emphasized.

MOPD1 versus MOPD2


Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is a genetic condition that is mainly characterized by intrauterine and post-natal growth retardation; an abnormally small head size (microcephaly); abnormal bone growth (skeletal dysplasia); distinctive facial features; and brain anomalies. Other signs and symptoms include sparse hair and eyebrows; dry skin; short limbs; dislocation of the hips and elbows; seizures; and intellectual disability. It is caused by mutations in the RNU4ATAC gene and is inherited in an autosomal recessive manner. Treatment is supportive only. The prognosis is poor with most affected individuals dying within the first year of life. MOPD types 1 and 3 were originally thought to be separate entities, but more recent reports have confirmed that the two forms are part of the same syndrome.

Microcephalic osteodysplastic primordial dwarfism (MOPD) types 1 and 3 are characterized by intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, skeletal dysplasia, low-birth weight and brain anomalies. Although MOPD types 1 and 3 were originally described as two separate entities on the basis of radiological criteria (notably small differences in pelvic and long bone structure), later reports confirmed that the two forms represent different modes of expression of the same syndrome.

The prevalence is unknown but less than 30 cases have been described in the literature so far.

The facial dysmorphism is characterized by a prominent nose with a flat nasal bridge, protruding eyes, a sloping forehead, and micrognathia. Sparse hair and eyebrows, dry skin, short limbs and dislocation of the hips and elbows are other common features. The most frequent neurological manifestations are seizures and intellectual deficit, and reported brain anomalies include lissencephaly, hypoplastic frontal lobes, and agenesis of the corpus callosum or cerebellar vermis.

Although the causative gene remains unknown, homozygosity mapping has allowed identification of a candidate gene region on chromosome 2q (2q14.2-q14.3). Histological studies suggest that MOPD types 1 and 3 result from a basic defect in cell proliferation and tissue differentiation.

Diagnosis is made on the basis of the clinical and radiological phenotype, with common radiological features including short tubular bones, enlarged metaphyses, vertebral and pelvic anomalies, elongated clavicles, bowing of the long bones and cleft vertebral arches.

The differential diagnosis should include MOPD type 2 (see this term) and other syndromes associated with primordial dwarfism (such as Seckel syndrome; see this term).

Prenatal diagnosis, by ultrasonography at around 20 weeks of gestation, has been reported in affected families.

MOPD types 1 and 3 are transmitted as autosomal recessive traits.

Treatment is supportive only.

The prognosis is poor with most of the reported patients dying within the first year of life.

Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2) is a condition characterized by short stature (dwarfism), skeletal abnormalities and an unusually small head size (microcephaly). Other signs and symptoms of MOPD2 may include hip dysplasia; thinning of the bones in the arms and legs; scoliosis; shortened wrist bones; a high-pitched voice; distinctive facial features (prominent nose, full cheeks, a long midface, and a small jaw); small teeth; abnormal skin pigmentation; and blood vessel abnormalities. Intellectual development is typically normal. It is caused by mutations in the PCNT gene and is inherited in an autosomal recessive manner.

'Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is a form of microcephalic primordial dwarfism (MPD; see this term) characterized by severe pre- and postnatal growth retardation, with marked microcephaly in proportion to body size, skeletal dysplasia, abnormal dentition, insulin resistance, and increased risk for cerebrovascular disease.'

MOPDII is one of the most common forms of MPD and accounts for more than 150 cases worldwide.

'MOPDII is congenital and is characterized by severe pre- and postnatal growth retardation, with proportionate severe microcephaly, skeletal dysplasia, abnormal dentition, an increased risk for cerebrovascular disease (aneurysms and Moya Moya disease (see this term) in 19%-52% of cases) and insulin resistance. Intrauterine growth restriction (IUGR) is common. The average length, weight, and head occipitofrontal circumference (OFC) at birth are respectively 7.0, 3.9, and 4.6 SDs below the population mean (after correcting for gestational age <37 weeks). Head growth appears to stop by 18 months of age giving rise to the appearance of progressive microcephaly. At maturity, the average height, weight, and OFC are respectively 10.3, 14.3, and 8.5 SDs below the population mean. Skeletal dysplasia with progressive scoliosis, radial head dislocation and coxa vara, may be seen. Distinct craniofacial features include prominent, small pinnae with attached lobes; small, dysplastic and poorly rooted, opalescent dentition and sparse hair. Further hallmarks of MOPD II include high-pitched nasal voice, areas of hypo- and hyperpigmentation (with cafÈ-au-lait spots), poikiloderma and acanthosis nigricans. A disorder initially named primordial short stature-microdontia-opalescent and rootless teeth was originally and mistakenly reported to have distinct MOPD, but it is now recognized to be the same entity as MOPD II.'

MOPD II is caused by mutations in PCNT (21q22.3), encoding pericentrin, which anchors a wide range of centrosomal proteins and protein complexes during cell division. Disruption of pericentrin is thought to cause mitotic spindle defects, and impaired cell proliferation. A role in ATR DNA damage dependent signaling has also been proposed.

Diagnosis relies on clinical features, radiographic examinations of bone age that usually show disharmonic maturation of centers and a retarded bone age. Diagnosis is confirmed by genetic screening of PCNT. Some individuals have elevated platelet counts.

Differential diagnosis includes Meier-Gorlin syndrome, LIG4 syndrome, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke immuno-osseous dysplasia, and Dubowitz syndrome (see these terms).

Pregnancies with affected children are often complicated by the observation of IUGR. Early age of delivery is noted. C-sections may be performed at earlier ages due to the IUGR. Prenatal diagnosis is possible if the causative mutation(s) in PCNT have been identified in the carrier parents.

Transmission is autosomal recessive and genetic counseling is possible.

Management is mainly symptomatic. Screening for CNS vascular abnormalities with brain MRI and MR angiography is recommended at diagnosis and every 12 to 18 months. Yearly screening for signs of insulin resistance including a lipid profile should be performed (beginning at grade school age), as well as monitoring for anemia, platelet counts, and hip and spine anomalies.

Life expectancy is generally decreased, but individuals live into their 30s. Many complications arise, but most can be handled by adapting modern medical techniques to the diminutive size. A common complication is vascular anomalies which as well as affecting neurovasculature in childhood, can also affect renal and coronary arteries in adulthood, which may be life threatening.

Immune system misfiring in autoimmune diseases

A person’s genetic makeup plays a role in autoimmune diseases such as multiple sclerosis that develop when the body is attacked by its own immune system. But little is known about how immune cells are pushed into overdrive.

Now, in new research that points to potential therapeutic targets for autoimmune diseases, researchers at Washington University School of Medicine in St. Louis have identified genetic master switches that turn up – or down – the activity of specific types of immune cells.

Surprisingly, the regions of DNA that make up these master switches include numerous genetic variants linked to a range of autoimmune diseases, the researchers found.

Oltz and co-senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology at Washington University, did not originally set out to link genetic variants associated with autoimmune diseases to these switches in immune cells. They were trying to understand how two different types of immune cells could play the same role in fighting pathogens.

Specifically, innate lymphoid cells act quickly when a pathogen invades the body, responding to non-specific danger signals released by the cells at the site of infection. In contrast, T helper cells take days to respond, and only activate when they encounter a pathogen they recognize.

Despite being activated at different times and by different signals, innate lymphoid cells and T helper cells both serve as a kind of control tower for the immune response, sending out powerful molecular signals to other immune cells to unsheathe their weapons and start killing invading microbes and destroying infected human cells.

If the signals are not tightly controlled, these weapons can be turned on human cells, resulting in chronic inflammation and the development of autoimmune conditions.

“How is it possible that innate lymphoid cells and T helper cells produce the same signaling molecules in response to invading pathogens despite being activated by different signals?” Colonna asked. “We started to look at the similarities and differences in the way gene expression in these two cell types was regulated.”

Using cells from human tonsils, the researchers compared the patterns of gene activity in the two types of cells. They were able to define a set of super-enhancers – regions of DNA that serve as master control switches – for innate lymphoid cells and T helper cells that regulate genes which give each cell type its unique identity and function.

“This is the first time that these sets of super-enhancers had been mapped for these cell types,” Oltz said. “By looking at these super-enhancers, we were able to identify a number of genes that are likely to be critical for eliminating pathogens, but which nobody had identified as important before.”

Furthermore, the researchers found that the super-enhancers contained many genetic variants associated with autoimmune diseases such as diabetes, rheumatoid arthritis, Crohn’s disease and ulcerative colitis. This observation could pave the way to more personalized treatments for autoimmune diseases, the researchers said. For example, patients could be divided into groups based on the super-enhancer in which their genetic variant falls, and therapies could be targeted to the genes regulated by each specific super-enhancer.
Courtesy of:  Neurologist Connect

Koues OI, Collins PL, Cella M, Robinette ML, Porter SI, Pyfrom SC, Payton JE, Colonna M, Oltz E. Distinct Gene Regulatory Pathways for Human Innate Versus Adaptive Lymphoid Cells. Cell. May 16, 2016


Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been extensively studied in model organisms, little is known about these "first responders" in humans, especially their lineage and functional kinships to cytokine-secreting T helper (Th) cell counterparts. Here, we report gene regulatory circuitries for four human ILC-Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell-identity genes in each lineage, uncovering new modes of regulation for signature cytokines, new molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC-Th subsets.

Sleep problems in epilepsy and their implications

Ozalp Ekinci, Uğur Isik, Serkan Gunes, Nuran Ekinci.  Understanding sleep problems in children with epilepsy: Associations with quality of life, Attention-Deficit Hyperactivity Disorder and maternal emotional symptoms.  Seizure - European Journal of Epilepsy, in press 06/28/2016.

This study aimed to (1) compare sleep problems between children and adolescents with epilepsy and non-epileptic controls, and (2) examine whether there is an association between sleep problems and quality of life, Attention-Deficit Hyperactivity Disorder (ADHD) and mothers’ emotional symptoms.

Fifty-three patients from a cohort of epilepsy (aged 7-18 years) and 28 controls with minor medical problems (aged 7-18 years) were included. Parents completed Children's Sleep Habits Questionnaire (CSHQ) and Kinder Lebensqualitätsfragebogen: Children's Quality of Life Questionnaire-revised (KINDL-R) for patients and controls. Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S) parent and teacher forms were used to assess ADHD symptoms for patients. Mothers of the patients completed Beck Depression Inventory and State-Trait Anxiety Inventory (STAI). Neurology clinic charts were reviewed for the epilepsy-related variables.

Children with epilepsy had a higher CSHQ Total score than the control group. Those with a CSHQ score >56 (which indicates moderate to severe sleep problems) had lower scores on KINDL-R. Parent-rated T-DSM-IV-S Total and Hyperactivity-Impulsivity scores, STAI trait and Beck scores were found to be higher in those with a CSHQ score >56. Significant positive correlations were found between CSHQ total score and T-DSM-IV-S, STAI trait and Beck scores. Binary logistic regression analysis revealed that T-DSM-IV-S Total, Inattention and Hyperactivity-Impulsivity scores were significantly associated with a higher CSHQ Total score. None of the epilepsy-related variables were found to be related with the CSHQ Total score.

Among children with epilepsy, sleep problems lead to a poor quality of life. The link between sleep problems and psychiatric symptoms must be conceptualized as a bilateral relationship. ADHD appears to be the strongest predictor of sleep problems.

Article summary:


Included 53 patients from a cohort of epilepsy (aged 7-18 years) and 28 controls with minor medical problems (aged 7-18 years).
For patients and controls, parents completed Children's Sleep Habits Questionnaire (CSHQ) and Kinder Lebensqualitätsfragebogen: Children's Quality of Life Questionnaire-revised (KINDL-R).
To assess ADHD symptoms for patients Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S) parent and teacher forms were used.
In this study, mothers of the patients completed Beck Depression Inventory and State-Trait Anxiety Inventory (STAI).
For the epilepsy-related variables neurology clinic charts were reviewed.


CSHQ Total score was higher in children with epilepsy than the control group.
Those with >56 CSHQ score (which indicates moderate to severe sleep problems) had lower scores on KINDL-R.
Parent-rated T-DSM-IV-S Total and Hyperactivity-Impulsivity scores, in those with a CSHQ score >56 STAI trait and Beck scores were found to be higher.
The study found a remarkably positive correlation between CSHQ total score and T-DSM-IV-S, STAI trait and Beck scores.
In this study, binary logistic regression analysis revealed that T-DSM-IV-S Total, Inattention and Hyperactivity-Impulsivity scores were significantly associated with a higher CSHQ Total score.
As exhibited by the work done in this study, none of the epilepsy-related variables were found to be related with the CSHQ Total score.

Wednesday, June 29, 2016

Dummheit 4

A Canadian woman’s heartbreaking photos of her newborn in the hospital have reignited an online conversation about the effects of not vaccinating children. reported that Annie Mae Braiden’s 10-week-old daughter, Isabelle, is in an intensive care unit recovering from whooping cough after an unvaccinated child reportedly infected her. Braiden expressed her outrage and updated on her daughter’s condition in a Facebook post Friday.

“So I wasn't going to do this, but I think people need to see what not vaccinating their kids do to the OTHER kids, like my 6 week old daughter,” she wrote in the post. “Isabelle has been in the PEDS ICU since she was 6 weeks old (now 10 weeks) with whooping cough. She was on a ventilator for 3 weeks and CPAP for 3 days (she was the lucky baby, the other ones have been ventilated for months) and we're still facing another 2 months in the hospital.”

According to the Centers for Disease Control and Prevention (CDC) the childhood vaccine DTaP is the best prevention method for whooping cough, or pertussis, a highly contagious respiratory tract infection. The CDC recommends children get five dosese of DTaP, which also protects against tetanus and diphtheria: one each at ages 2, 4, 6, one more between 15 to 18 months old, and another 4 through 6 years old.

In her Facebook post, Braiden, who lives in Victoria, British Columbia, explains that another parent’s decision not to vaccinate their child resulted in her daughter needing to learn how to eat again. Isabelle is also suffering from morphine and sedative withdrawals, as she needed to take the medication while she was ventilated.

Braiden wrote in the post that she decided to share photos of baby Isabelle online to encourage other parents to get their kids vaccinated not only to protect their own children, but also others’.

“What you do with your kids is your choice but do not tell me that not vaccinating your kids isn't hurting anyone but your own kids,” she wrote. “Isabelle is proof that it harms the other little babes who aren't old enough to get their vaccines yet.”

Magnetic attraction

Animal magnetism may be a more literal concept than it's given credit for, according to a new study that finds that people are more attracted to their romantic partners after playing with magnets.

The research is an example of a social priming effect, an old idea in psychology that has recently become more controversial. The idea holds that when people are "primed" or prompted to think about a particular concept — such as physical magnetic attraction — it affects their cognition in surprising ways.

In this case, the magnets may make the metaphor of love as a physical force more prominent in people's minds, leading them to report closer feelings with their partners, said Andrew Christy, a graduate student in psychology at Texas A&M University and a co-author of the new study.

Social priming effects have become a battleground in social psychology in recent years. The entire field is in the midst of a "replication crisis," because scientists have failed to replicate the results of many famous experiments when trying to repeat them. Social priming studies have been some of the highest-profile failures: In 2012, researchers failed to replicate one classic study of social priming, which found that people walked slower after being exposed to words related to old age, kicking off a firestorm of debate.

Today, some psychologists are unsure whether social priming really exists; others think it does, but that the effects are subtle and very context-dependent, making the effects hard to measure.

In the new research, Christy and his colleagues attempted to guard against a false result by conducting their experiments twice, replicating their own research. However, independent replication by other researchers will be necessary to show that the magnetism effect truly exists, the researchers said.

In the new study, researchers focused on the metaphor of love as a physical force. They asked 120 students who were 18 to 22 years old and who were either in relationships or had been in relationships within the last few months, to fill out questionnaires about their connection with their partners. Before they began, the students were told to take a "mental break" by playing with blocks, putting them together and taking them apart. Some of the students were given magnetized blocks that attracted each other, while some had magnetized blocks that repelled each other, and some had blocks without magnets. 

The participants who played with the magnetically attracting blocks reported greater attraction, satisfaction and commitment in their relationships or recent relationships compared with those students given the other two block types, Christy told Live Science.

"The nonmagnetic and the repel condition didn't seem to differ from one another at all," he said.

So in their next experiment, this one with 150 students, the researchers included only blocks with magnets that attracted, and nonmagnetized blocks. The people who played with the magnetized blocks again reported greater levels of attraction, satisfaction and commitment in their relationships than those who played with nonmagnetized blocks, the researchers said in their article, published May 26 in the open-access journal PLOS ONE...

Although the effects of the magnets on people's levels of attraction and intimacy were larger than in the first experiment, the effects on people's satisfaction and commitment were smaller, the researchers found. The reason for those smaller effects may have been that the second experiment took place later in the semester, and more students who originally reported being in relationships had broken up, the researchers wrote. Thus, more participants may have been remembering past relationships instead of thinking of current ones.

Christy AG, Hirsch KA, Schlegel RJ (2016) Animal Magnetism: Metaphoric Cues Alter Perceptions of Romantic Partners and Relationships. PLoS ONE 11(5): e0155943. doi:10.1371/journal.pone.0155943

Fidgety movements during the fidgety movement period

Sæther R, Støen R, Vik T, Fjørtoft T, Vågen RT, Silberg IE, Loennecken M, Møinichen UI, Lydersen S, Adde L. A change in temporal organization of fidgety movements during the fidgety movement period is common among high risk infants. Eur J Paediatr Neurol. 2016 Jul;20(4):512-7.

General movement assessment (GMA) at 9-20 weeks post-term, can effectively predict cerebral palsy. Our aim was to evaluate intra-individual variability of the temporal organization of fidgety movements (FMs) in high risk infants.
104 High risk infants (66 males) with at least two video recordings from the FMs period participated. 45 of the infants had GA <28 weeks and/or BW ≤800 g. Mean post-term age at first and second assessments was 11.0 (8-16) and 14.0 (11-17) weeks, respectively, and median time-difference between the assessments was 2.0 (range: three days to six weeks) weeks. Video recordings were analyzed according to Prechtl's GMA.
33 (32%) Infants were classified differently at first and second assessments. Six infants (6%) changed from normal to abnormal, and 10 (10%) changed from abnormal to normal FMs. Seven of the ten who changed classification from abnormal to normal were born before GA 26 weeks. A change between intermittent and continual, which are both considered normal, was observed in 17 (16%) infants.
A change in temporal organization of FMs is common in high risk infants. Especially in extremely preterm infants with abnormal FMs, more than one assessment should be performed before long-term prognosis is considered.

From the article

The assessment of general movements (GMs) is a non-invasive, reliable and valid method to predict severe neurological impairments.  In particular the absence or sporadic occurrence of fidgety movements (FMs), during the fidgety movement's period (9–20 weeks post term age), is highly predictive of cerebral palsy (CP).  Knowledge of the intra-individual variability of FMs in high risk infants during this period is sparse.  However, such knowledge is essential for appropriate prediction of neurological outcome…

Fidgety movements can be classified as either normal or abnormal. Normal FMs are present either intermittently (F+) or in a continual pattern (F++), whereas abnormal FMs are present sporadically (interspersed with long pauses, F+/−), exaggerated with respect to speed and amplitude (Fa), or as absent (F−).  As absent or only sporadically present FMs are found to be a good predictor of neurological impairment,  and accurate classification of the temporal organization of FMs is essential.

The reliability of GM assessment is found to be very good  however, variability of infants temporal organization of FMs during the time period when normal FMs are considered essential for a normal neurodevelopment, have not been well described in large groups of high risk infants.  

The aim of our study was to evaluate intra-individual variability of the temporal organization of FMs in infants with high risk for neurodevelopmental sequelae…

General movement assessment (GMA) is a non-invasive method that estimates the integrity of the infant nervous system by observing the quality of spontaneous movement patterns involving the limbs, neck, and trunk, which emerge over the first few months of life.  There is good evidence that lack of normal FMs, normally present at 9–20 weeks post-term,  5  can accurately predict the development of CP in high risk populations. 

GMA were performed 9–20 weeks post term age, during the fidgety movement's period. The infant's GMs were video recorded using a standardized video set-up consisting of a mattress and a stationary digital video camera (Sanyo VPC HD-200)…

The FMs were classified as normal if they were continual (F++) or intermittent (F+) and abnormal if absent (F−), sporadic (F+/−), or exaggerated with respect to speed and amplitude (Fa). The temporal organization of FMs was classified according to the duration of their interspersed pauses. Continual FMs are interspersed with short pauses, the intermittent FMs have prolonged pauses (giving the impression that FMs are present for only half the observation time), and the sporadic FMs are interspersed with even longer pauses...

Among infants who changed from abnormal to normal FMs there was a predominance of extremely preterm infants. Extremely preterm infants are delayed in motor development, and little is known about the neural mechanisms underlying GM changes. However, it has been suggested that brain maturational processes like intra- and supraspinal reorganization may be possible neural mechanism underlying GM changes during the fidgety movement's period.  Hence, it could be speculated that the instability of the temporal organization of FMs in extremely preterm infants found in our study may be related to such delayed brain maturational processes. This underscores the importance of assessing GMs along a developmental trajectory also within the mid-fidgety movement's period (10–15 weeks post term age).  Moreover, the classification of extremely preterm infants may be challenging, as these infants have shorter periods in an optimal behavioral state (active wakefulness).  It may also be challenging to classify the sporadic FMs correctly, particular from the absent ones, as they occur in periods lasting less than 3 s. 

The clinical implications of our study are in line with previous research: “ …a single assessment is not enough ”, and it emphasizes that this is of particular importance for extremely preterm infants, and infants classified with sporadic FMs. However, future research is needed to explore these findings further and to reveal if sporadic FMs at one assessment are of any clinical relevance in infants who are later identified with normal FMs. The natural course of temporal organization of FMs should be further explored in future studies. Our findings indicate that this is especially important in extreme preterm infants.

Variable manifestations of ATP1A3 mutation

A novel missense mutation in the ATPase, Na+/K+ transporting, alpha 3 polypeptide (ATP1A3) gene has been identified in a family affected by two distinctly different neurodegenerative conditions — alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP), according to a new study presented here June 21 at the International Congress of Parkinson's Disease and Movement Disorders.                        

Sergio A. Rodríguez-Quiroga, MD, of the neurogenetics unit and movement disorders section of the University Centre of Neurology in the JM Ramos Mejia Hospital, and his colleagues described the clinical and molecular features in 13 members of a family whose genetic history came to light after a 19-year-old was first diagnosed with RDP.

Clinical histories and the sequencing of the ATP1A3 gene in dozens of family members revealed that 12 others shared the symptoms of both conditions. Many of them also had a diagnosis of epilepsy.                      

The scientists identified a novel missense mutation in ATP1A3 that was present only in the affected members of this family. This mutation has not been reported in RDP or AHC before.

"We believe that AHC and RDP represent a phenotypic continuum of ATP1A3-related disorders," said Dr. Rodríguez-Quiroga. While in the original case, the young man, now 22, had classic symptoms of RDP — anarthria, mild dysphagia, hypotonia, and severe bradykinesia in four limbs with a rostrocaudal gradient of involvement — other family members with the mutation had hemiplegia, epilepsy, and cognitive impairment.

"The family history was consistent with an autosomal dominant inheritance," he said. The phenotypes range from seizures only, cognitive impairment, and development delay, to hemiplegia, dystonia, parkinsonism, and bulbar impairment. 

 "Our study highlights the variability in the neurological spectrum of symptoms that subjects with ATP1A3 mutations could have," both in severity and age of onset, he said.

"Variants in other genes or other triggers could influence the symptom severity and age of onset," Dr. Rodríguez-Quiroga added. Identifying these triggers could lead to the development of prevention strategies and treatments. The researchers are evaluating other affected members of the family for a more precise description of the distinct phenotypes.

That these conditions fall on a continuum "is not a surprise," said Kenneth Silver, MD, associate professor of pediatrics and neurology at the University of Chicago, who has consulted on a few hundred cases of AHC and was not involved with the study. "As we expand the spectrum, there will be cases that share many of the features of these conditions."

"Now, we need to figure out what is wrong with the gene to produce these symptoms," he added. "The findings from this case study suggest that this is a spectrum of disorders that appear in one family.  It's the same genetic mutation, but it is expressed differently."    

"This new finding lends support to the idea of an intermediate phenotype and intrafamilial variability," said Suzanne D. DeBrosse, MD, clinical assistant professor of genetics and genome sciences, pediatrics, and neurology at Case Western Reserve University, who was not involved with the study. "This could make a valuable contribution to our understanding of the variability of ATP1A3-related disorders within families."

S.A. Rodríguez-Quiroga, D. González-Moron, S.A. Vishnopolska, G.L. Vigo, M. Cordoba, N. Medina, T. Arakaki, N.S. Garretto, M.A. Kauffman. Expanding the spectrum of ATP1A3 related disorders: Continuum from alternating hemiplegia of childhood to rapid-onset dystonia parkinsonism? [abstract]. Mov Disord. 2016; 31 (suppl 2).

Children's pain

It began with a simple roller-skating accident three years ago. Taylor Aschenbrenner, then 8 years old, lost her balance amid a jumble of classmates, tumbled to the floor and felt someone else’s skate roll over her left foot. The searing pain hit her immediately.
The diagnosis, however, would take much longer. An X-ray, M.R.I.s, a CT scan and blood tests over several months revealed no evidence of a break, sprain or other significant problem. Taylor’s primary symptom was pain — so severe that she could not put weight on the foot.
“Our family doctor first told us to give it some time,” said Taylor’s mother, Jodi Aschenbrenner, of Hudson, Wis.
But time didn’t heal the pain. After about a month, an orthopedist recommended physical therapy. That didn’t end the problem, either. “I couldn’t walk or play outside or do anything,” Taylor said.
After she had spent a year and a half on crutches, her orthopedist suggested she see Dr. Stefan Friedrichsdorf, the medical director of pain medicine, palliative care and integrative medicine at Children’s Hospitals and Clinics of Minnesota. He and his team promptly recognized Taylor’s condition as complex regional pain syndrome, a misfiring within the peripheral and central nervous systems that causes pain signals to go into overdrive and stay turned on even after an initial injury or trauma has healed.
He came up with a treatment plan for Taylor that included cognitive behavioral therapy, physical therapy, mind-body techniques, stress-reduction strategies, topical pain-relief patches and a focus on returning to her normal life and sleep routine, among other things.
“That turned things around so fast, if I didn’t see it myself, I wouldn’t have believed it,” Mrs. Aschenbrenner said. “I thought, ‘finally, someone understands what this is, has experience with it, and knows how to fix it!’”
But why did it take so long for a child in unbearable pain to find relief? Experts say children’s pain is, for the most part, grossly underrecognized and undertreated.
“Unfortunately, in 2016 pain management in the United States and all Western countries is still abysmal,” said Dr. Friedrichsdorf, who noted that pediatric pain receives the least attention. “Data shows that adults with the same underlying condition will get two to three times as many pain medication doses as children. We also know that the younger a child is, the less likely it is that he or she will get proper pain management in the hospital.”…
“Research shows that poorly managed pain exposures early in life can actually change the wiring in the brain and prime children to be more sensitive to it later on, putting them at risk for developing chronic pain in childhood and adulthood,” said Anna C. Wilson, a child psychologist and assistant professor of anesthesiology at the Pediatric Pain Management Center at Oregon Health & Science University. And while babies or young children may not consciously remember it later in life, their nervous systems will. 
But there is reason for optimism. Contrary to previous conventional thinking, the effective use of pain medication for children does not hinder brain development, according to several studies. “We know that giving strong pain medications to very young children does not interfere with their neurodevelopment later on,” Dr. Friedrichsdorf said. 
Research has also shown that the appropriate medical use of prescription pain medications, such as opioids, when properly monitored, does not lead to addiction in young children and adolescents, Dr. Friedrichsdorf added. 
A host of other behavioral interventions have been shown to prevent and treat pain as well. Pain experts say these can and should be used even during seemingly minor medical procedures, such as vaccinations. Parents can hold their children during the procedure, breast-feed or give them a sweet solution (or a lollipop for older children) to suck on, distract them with a song or breathing exercises, and use a topical numbing cream if needed. 


Tuesday, June 28, 2016

Newborn screening for X-linked adrenoleukodystrophy

Kemper AR, Brosco J, Comeau AM, Green NS, Grosse SD, Jones E, Kwon JM, Lam WK, Ojodu J, Prosser LA, Tanksley S. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med. 2016 Jun 23. doi: 10.1038/gim.2016.68. [Epub ahead of print]

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.

From the article

X-ALD overview

X-ALD (OMIM 300100) is a peroxisomal disorder caused by mutations in the ABCD1 gene and is estimated to affect approximately 1 in 42,000 males. Additionally, 1 in 28,000 females are estimated to be heterozygous for an ABCD1 mutation.2 The disorder has a broad phenotype and there is no genotype–phenotype correlation, even within families. Data extrapolated from reported incident cases suggest that the most severe form, childhood cerebral ALD (CCALD), affects between 31 and 57% of hemizygous males.  CCALD typically presents between 2 and 10 years of age and is associated with rapid neurologic decline; without treatment, death or severe disability typically occurs within approximately 3 years. For boys who have been determined to have CCALD, treatment is HSCT administered at an early stage of progressive brain involvement. Because most boys with X-ALD will not develop CCALD, and because of the risks associated with HSCT, HSCT is reserved for those with a clear diagnosis of CCALD in its early stages.

Most males with CCALD will also develop adrenal insufficiency. If unrecognized, delayed treatment of adrenal insufficiency can lead to death from even minor illnesses. Little is known about how often signs or symptoms of adrenal insufficiency lead to the diagnosis of X-ALD or about the timing of clinical recognition of adrenal insufficiency relative to the development of cerebral involvement. HSCT treatment for CCALD does not treat adrenal hormone insufficiency; therefore, lifelong hormone replacement therapy is required for all X-ALD patients with adrenal insufficiency.

Affected males with or without CCALD may develop progressive spastic paraparesis, sensory ataxia, and other peripheral nerve and spinal nerve involvement, collectively referred to as adrenomyeloneuropathy (AMN). Relatively little is known about the natural history of AMN. Although the literature indicates that the typical age of AMN onset is after age 30, the neurological symptoms may begin to manifest in later childhood or adolescence. Patients with AMN can develop adrenal insufficiency years or even decades before the disease is recognized based on the onset of neurological symptoms. The course of AMN is highly variable; within a mean of 13 years from recognized onset in adults, the rate of death or severe disability is reported to be 12%.  Although AMN is not amenable to HSCT, identification and treatment of adrenal insufficiency in these patients can be lifesaving. No studies that characterized the morbidity associated with delayed recognition of adrenal insufficiency in any type of X-ALD were identified.

Heterozygous females can develop symptoms, usually of AMN, in mid- to late adulthood. Although potentially serious, the impact of heterozygous females manifesting some form of X-ALD was not explicitly considered by the Condition Review Workgroup because of the adult onset of symptoms…

A limitation of the evidence reviewed was that no published study directly compared treatment outcomes for individuals detected presymptomatically (e.g., through newborn screening or family history) with those diagnosed symptomatically. Indirect evidence suggests that earlier age of treatment with HSCT is associated with better outcomes. For example, more advanced disease, as indicated by increased white matter pathology found on brain MRI, is associated with worse outcomes following HSCT. Unpublished data in small numbers of subjects suggest that detection through family testing (i.e., presymptomatic identification of a young child who had a relative previously identified with X-ALD), compared with clinical detection resulting from testing based on signs or symptoms, is associated with less cerebral disease at the initiation of HSCT and also with longer survival and improved neurocognitive outcomes…

An important potential harm of X-ALD newborn screening is direct clinical harm related to treatment following early diagnosis. No recent data are available regarding the mortality risk associated with HSCT for X-ALD. However, among studies reporting transplant follow-up at 1 year or later, the overall 1-year risk of mortality following HSCT appears to be approximately 15% or less. The mortality rate is a function of several factors, including the health of the child at the time of HSCT, the type of transplantation performed, the degree of match between donor and recipient, and the treatment regimen used by those performing the HSCT…

In general, HSCT has a significant risk of mortality and morbidity. For example, a case series of 51 infants treated with HSCT between 1992 and 2010 with long-term follow-up found an overall survival rate of 70% after a median follow-up of 8.9 years, and 30% had acute graft-versus-host disease. Although such harms might occur in children with X-ALD regardless of how the condition was detected, some children who would not have undergone transplantation in the absence of screening might undergo HSCT. There is also the potential harm that individuals could receive inappropriate or ineffective treatment…

Although it is too early to assess whether screening in New York has led to improvements in health outcomes, unpublished evidence from other sources suggests that earlier detection of CCALD can improve survival and neurologic function through HSCT. In addition, screening could identify individuals who will develop adrenal insufficiency, which can be asymptomatic and can be treated with cortisol. Challenges include the poor genotype–phenotype correlation and the need to develop an infrastructure for both screening and follow-up care. Harms of screening include false-positive results, overdiagnosis, and the risks associated with HSCT performed earlier than needed.

Attention-deficit/hyperactivity disorder and academic demands

Study Summary

This research letter reviews recent literature on academic demands in young children. The authors hypothesized that increasing academic demands on children might contribute to the rise in the prevalence of attention-deficit/hyperactivity disorder (ADHD). This study evaluated published literature from 1970 onward to identify studies that documented the time children spend on both academic and leisure activities. They began by looking at the time children spent studying per week, dividing children into age groups of 3-5 years old, 6-8 years old, and 9-12 years old, as well as all children combined.

Since 1970, for all age subgroups, there was an increase in weekly time spent studying, but the difference was largely concentrated in the 6-8 years age group, whose weekly time spent studying more than doubled, from approximately 50 hours to approximately 125 hours. Other studies have demonstrated an inverse relationship between the time spent on academic activities each week and the time spent playing or in leisure activities each week. Time spent reading tripled in children aged 3-5 years, from approximately 30 minutes to approximately 1.5 hours each week. Of note, since 1970, the proportion of young children who participate in full-day preschool programs significantly increased, from 17% in 1972 to almost 60% by the mid-2000s.

This brief evaluation of the temporal relationship between time spent on academic activities and the epidemiologic increase in ADHD diagnoses can only show association, not causation. Competing hypotheses for the rise in ADHD include increased screen time and lower levels of physical activity.

…Although many children can indeed finish kindergarten knowing how to read, I remain very concerned that there is a lack of appreciation for the degree of variation that should be considered normal, and there is certainly a need to consider that classroom environments should be adjusted to accommodate the wide range of skills and abilities for preschool and early school-age children. In a similar vein, not every 5- or 6-year-old will want to follow the rigidity of full-day preschool or kindergarten, so we should always consider developmental stage when we are evaluating a child for ADHD.

Brosco JP, Bona A. Changes in Academic Demands and Attention-Deficit/Hyperactivity Disorder in Young Children. JAMA Pediatr. 2016 Apr 1;170(4):396-7.

Dysmorphology in identifying syndromic causes of epilepsy

Dixit A, Suri M. When the face says it all: dysmorphology in identifying syndromic causes of epilepsy. Pract Neurol. 2016 Apr;16(2):111-21.

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient.
From the paper:

In this paper, we outline the salient features of selected genetic conditions in which epilepsy is an important feature. Typically, an affected person will have other medical problems, including congenital malformations and a degree of intellectual disability. Almost all the conditions we describe are associated with a minimum 25% risk of developing epilepsy. The only exception is Coffin–Lowry syndrome with an incidence of epilepsy of only 5%, although 20% develop non-epileptic drop attacks that might lead to referral to an epilepsy clinic.

The seizure semiology or EEG features are not a strong clue to the diagnosis of these conditions. Rather, we focus on the genetic conditions that give distinctive findings on physical examination, particularly highlighting the facial 'gestalt' and other typical clinical features. Traditionally, genetic 'syndromes' are diagnosed in childhood. However, the clinical phenotype of many of the conditions we discuss has been clearly delineated only within the last two decades; it is therefore quite probable that affected individuals might present to an adult epilepsy clinic. We do not discuss conditions where facial features give no specific clues to the underlying diagnosis, for example, Rett syndrome, Dravet syndrome and CDKL5 mutations; nor genetic disorders in which neuronal migration defects are a major feature and neuroimaging strongly suggests the genetic aetiology, for example, lissencephaly or subcortical band heterotopia. We have also not included conditions that would have been diagnosed on a standard karyotype, for example, 4p deletion in Wolf–Hirschhorn syndrome, as most adults with intellectual disability, with or without epilepsy, will have been karyotyped in childhood…
Although array-comparative genomic hybridisation (aCGH) analysis is now widely available and has become a first-line investigation for a child presenting with developmental delay, we have included three chromosomal deletions or microdeletion syndromes that are detectable by aCGH (1p36 deletion, Koolen–deVries syndrome and Kleefstra syndrome) for two reasons:

Many adults with intellectual disability have not had aCGH analysis.

In Koolen–deVries and Kleefstra syndromes, some patients have a mutation within the causative gene that aCGH would not detect, who would require specific analysis of the relevant gene…

Traditionally, descriptions of dysmorphic features that may aid a clinician in the diagnosis of genetic conditions refer to the findings in children. Indeed, many genetic conditions have a 'diagnostic window' in which the facial gestalt is characteristic. For example, individuals with Sotos syndrome have a distinctive facial appearance that is most recognisable between the ages of 1 and 6 years. However, the adult phenotype and natural history of many genetic conditions are now much better described in the medical literature. Overall, the clinical picture in the conditions described below is characteristic, even in adults, and the facial features provide one of the strongest clues to the diagnosis. Coarsening of facial features may develop in many conditions with age. Other aspects of physical examination can be very important in certain conditions. For example, progressive loss of scalp hair is typical of Nicolaides–Baraitser syndrome, whereas silvery, hypopigmented hair occurs in Koolen–deVries syndrome. The hands provide specific clues in Coffin–Lowry syndrome (short, soft hands with hyperextensible joints and tapering fingers), Nicolaides–Baraitser syndrome (prominent interphalangeal joints) and Kabuki syndrome (persistent fetal fingertip pads). Growth features can provide supportive evidence. Microcephaly with or without short stature occurs in many disorders; Sotos syndrome is the only condition with overgrowth features (tall stature and macrocephaly).

A 19-year-old girl with Mowat–Wilson syndrome. Note the thick eyebrows, hypertelorism, deep-set eyes, prominent nasal bridge and particularly prominent nasal tip with overhanging columella, open mouth and prominent chin. There are also characteristic uplifted earlobes. 

Securing a specific diagnosis spares unnecessary further investigations and clarifies the prognosis and other implications for the health of the patient. We have illustrated nine conditions in which it is possible to make a clinical diagnosis in adults presenting to an epilepsy clinic, where characteristic facial features provide the strongest clue. In future, advances in genetic testing will allow a much better understanding of the genetic basis of syndromic and non-syndromic epilepsies. It is important for neurologists, as the main physicians caring for this group of patients, to keep up to date with developments in the field of epilepsy genetics.

Courtesy of: 

Monday, June 27, 2016

Gene therapy for spinal muscular atrophy

Gene-therapy research has been built on the idea that you can manipulate a virus — a natural invader — to act as a medical Trojan horse and carry a replacement gene. There have been notable and deadly failures. There have been starts powered by promise that fizzled in practice.

This time, the real excitement began to build in 2009 when the mice in which researchers tested the SMA therapy kept living.

Researchers at Children’s built a gene therapy with SMN1 constructed in the lab. It is designed to hitch a ride within a harmless virus found naturally in monkeys that also proved to cross the blood-brain barrier and land within motor neurons.

Rodents created at Ohio State University to model human SMA patients would die in a couple of weeks with no intervention.

But when researchers at the Children’s Research Institute infused them with the therapeutic agent shortly after birth, they lived on.

“We had animals that were living past 30 days and 50 days and the results were looking too good to be true,” said Brian Kaspar, whose lab became singularly focused on the work.

They’d work late into the night, drive in on Christmas Day to check on the mice. They were energized and staggered by the results, he said.

An increasingly skeptical Kaspar even ordered tests on the rodents to make sure they were SMA mice and that they didn’t mistakenly start with healthy animals.

“Lo and behold, they were SMA mice. We had them living out 100 days and 200-plus days. We had some that lived past 400 days to the point where we end the experiment,” he said.

After tests in pigs with SMA, then nonhuman primates to ensure the therapy crossed the blood-brain barrier in an animal most like a person, steps toward human research began.
Was it possible, they wondered, that this would hold up in children?...

Tenley, in December, became one of eight babies who’ve so far had the one-time, one-hour infusion of experimental gene therapy that researchers are beginning to let themselves believe might rescue babies from this disease.

Some had a low-dose infusion, others a dose that Dr. Jerry Mendell calls “intermediate.” The goal is to find a sweet spot, where you reap optimal benefit but don’t deliver a deadly dose…

So far, the babies who’ve had the heftier dose have done significantly better, which was expected. And it appears that delivering the treatment as early as possible is critical, said Mendell, who directs the Children’s Center for Gene Therapy.

On a graph that plots their developmental progress over time, every baby is either not getting worse or is improving. If you looked at a similar graph of untreated SMA babies, the lines would all go down.

“No one in this trial has succumbed to the disease, which is really exceptional,” Mendell said, pointing to one baby’s chart. The measures have hit a normal range.

If the babies continue to do well and the Food and Drug Administration eventually OKs the treatment for any baby with SMA, routine testing after birth could find newborns with the disease and prompt immediate treatment, Mendell said…

Mendell said it’s unlikely that motor neurons already lost to the disease can be recovered, so speeding the treatment is critical.

After about a year of testing in children (the oldest is about 18 months now), Mendell cautions that he and his collaborators still have much to learn about dosage, timing and what happens in the long term.

So far, the most concerning side effect has been liver trouble, which has proven manageable with medication, Mendell said.

Hope for Batten disease

Just a little more than a year after Miracle film producer Gordon Gray and his wife Kristen learned both their young daughters Charlotte and Gwenyth were afflicted with the rare and fatal brain disease Batten CLN6, Gray’s desperate race against time for a cure has led to a potential medical breakthrough. The girls were the pioneer recipients of the first gene therapy of its kind in humans in a clinical trial begun at Nationwide Children’s Hospital in Columbus, OH. Gray tells Deadline that he is already seeing signs of a rebound in Charlotte, the 5-year old whose motor and verbal skills were eroding at a heartbreakingly fast rate.

In March, Charlotte was given the equivalent of a magic bullet: a virus infused with the healthy CLN6 gene that was missing from her brain, and which allows cells to purge built-up wastes and restore balance in the brain. That virus was introduced intrathecally into Charlotte’s spinal fluid, for a short ride to her brain. This was done almost exactly a year after the Grays were given the death sentence diagnosis by doctors and told there was nothing to be done except prepare for Charlotte to go blind, lose her motor and verbal functions and ability to feed herself, progressing to eventual death between ages 6 and 12. And then prepare to live the same nightmare once again, because even though Charlotte’s younger sister Gwenyth hasn’t shown symptoms, she too was diagnosed with the rare brain disorder. Gwenyth was given a preventive dose of the gene therapy clinical trial last week…

Charlotte’s deterioration has been halted, and she has begun to show slow signs of recovery. There are no guarantees in life, but the producer of so many inspirational underdog sports movies, who told Deadline last June that he needed a Doug Flutie-like Hail Mary pass to save his daughters, is cautiously optimistic this breakthrough may in fact have saved both their lives. But the ongoing trial is expensive, and he has pledged to help four more children who are lined up to receive the treatment by the fall. Another six, maybe more, are out there in the world, also hoping for a chance to stop the disease’s progression. So Gray continues to try and rally financial support and the appeal can be viewed here for what he feels could be an historic medical breakthrough for children afflicted with Batten CLN6 and other similar brain diseases.

“The news is good,” Gray said. “We fought really hard after being told Batten was rare, fatal with no cure and when we refused to accept that, we were told even if you want to get FDA approval to get a clinical trial going, it would take five to six years. We didn’t have that time and we’ve managed to get something done. The doctors won’t say they treated anyone because it’s all investigational, but Charlotte was the first patient in the clinical trial on March 10. This past Friday, April 22, we entered my second daughter Gwenyth, into it. I’m so grateful to have gotten to this point but it feels like we’re starting from day one again. We need to keep this trial going, and Charlotte has lost so much ability because of this disease.

“I used to call her the mayor, because she never stopped talking, and she knew everyone’s name,” Gray said. “She went from being that kind of child to, right before we entered her into the trial, being down to one-word sentences, with no word more than two syllables. She’d gone from this girl who’d get on her little scooter going up and down the beach to having real difficulty walking. There’s receptive and expressive communication, and she seemed to understand most of what I say to her, but she has difficulty communicating and it’s only because we spend so much time with her that we understand what she wants,” Gray said. “The one thing about Charlotte is she was a happy vibrant child with a big expressive personality and hasn’t lost any of that joy and happiness, despite the difficulties walking, talking and eating and going through her daily life.”
Things have improved since the treatment that have given the Grays real hope for the first time in a long time.
“She seems to be making progress,” Gray said. “It seems like she’s more present, more engaged; she’s joking a little bit, in her own way. If there’s a song that mentions happy, she’ll say, ‘no, sad,’ and laugh. That’s her way of joking. She’s sitting up a little straighter, and she’s walking better. Doctors and especially scientists, they are very conservative, but I’m incredibly hopeful and they are optimistic and that’s the best they are going to give me. But she is making strides. If this worked, and God I hope it did, we now have to just put her back together. There’s something called Neuroplasticity, where the brain can sort of rebuild itself. But the first thing we had to do was arrest the progression of the disease.”…
Then came the miracle Gray was looking for, in the form of a doctor named Brian Kaspar, another named Jerry R. Mendell and a third named Emily C. De Los Reyes. They had taken Spinal Muscular Atrophy to clinical trial and even though this had nothing to do with Batten CLN6, there was a common thread.
“I asked Brian if he would be willing to pursue a clinical trial with the girls and everyone else afflicted with this disease, and when I got on the call, he wasn’t even really familiar with Batten,” Gray said. “He said he would look into it, and based on some of the work he’d done with SMA, he was not unfamiliar with gene therapy, something he was pursuing. He asked my daughters’ names, and told me, ‘I too have a daughter named Charlotte.’…
Gray sees signs of improvement in Charlotte, and even though he’s made a career out of producing movies with happy endings, he said all this constitutes just one giant step on a long road. “There are no biomarkers to see if the therapy worked,” he said. “It’s like if someone put a bomb under your table and you try to defuse it. The only way you’re going to know you haven’t been successful at defusing the bomb if it blows up. The only way we’ll know if the treatment for my youngest daughter Gwenyth didn’t work is if she starts to decline. And the only way I’ll know with Charlotte is if she becomes overtly better, or she starts to decline again. You just have to wait.”


Added 12/17/20:

There is no preparation for being told your child has no future

A mother whose daughter has a fatal and incurable disease has opened up about what it's like to live with a dying child.

Peta Murchison, a mother from Sydney's northern beaches, gave hundreds of people a glimpse into her 'weird universe' at TedX at the Opera House in Sydney this week.

'I am a mother of two; Toby is 4 and likes Lego, and jumping off things. My daughter Mia is 6 and likes warm baths, horse riding and hugs,' Ms Murchison started.

'When my daughter dies I will wash her and dress her. I will put flowers in her hair. We will play music, light candles and hold her.’...

But at the age of three, when the family was living in Singapore, she suffered her first seizure.

At first she was diagnosed with epilepsy, but the seizures started to become more regular.

Her language and memory deteriorated, and she began to suffer frequent falls.

In 2013, she was finally diagnosed with batten disease at Sydney Children's Hospital in Randwick.

'There is no preparation for being told your child has no future,' Ms Murchison said.

Breakthroughs in enzyme and gene therapy are too late for their daughter, Ms Murchison said.
'So giving up the fight for her life has been replaced with giving her the best life.'

The family moved back to Sydney after Mia's diagnoses and immediately set about finding a school for her…

Now, at 6-years-old, Mia is wheelchair bound and can no longer hug her mother. Her seizures are constant.

But Ms Murchison said she has come accept there is no cure for her daughter.

‘So when I put flowers in my daughter’s hair and friends and family come to say goodbye,’ she told the audience,

‘I will remember the human capacity for hope is so strong that even when you’re told there is no hope, somehow you still manage to find it." 

Read more:


Maladaptive perfectionism

Hong RY, Lee SS, Chng RY, Zhou Y, Tsai FF, Tan SH. Developmental Trajectories
of Maladaptive Perfectionism in Middle Childhood. J Pers. 2016 Feb 25. doi:
10.1111/jopy.12249. [Epub ahead of print]

The developmental trajectories of maladaptive perfectionism, along with their consequences and origins, were examined in middle childhood.
A sample of Singaporean children and their parents (N = 302) were recruited for a longitudinal study when the children were 7 years old. Subsequent follow-up assessments were made at ages 8, 9, and 11. A multimethod approach was adopted where parent reports, child reports, and observational data on a dyadic interaction task were obtained.
Using latent class growth modeling, four distinct classes were obtained for critical self-oriented perfectionism (SOP-C) whereas two classes emerged for socially-prescribed perfectionism (SPP). Children with high and/or increasing SOP-C and SPP trajectories constituted 60% and 78% of the sample, respectively. For both SOP-C and SPP, trajectories with high initial status were associated with higher internalizing and externalizing symptoms. Parental intrusiveness and negative parenting predicted high and/or increasing SOP-C trajectories whereas the child temperament dimension of surgency predicted high SPP trajectory. Both SOP-C and SPP trajectories tended to co-occur, suggesting a mutually-reinforcing process.
This study yields important findings that help advance current understanding on the emergence and developmental pathways of maladaptive perfectionism in children.

Children who have intrusive parents are more likely to be overly critical of themselves, according to a study by researchers from the National University of Singapore (NUS).

It also found that this tendency increased over the years. 

Children in the study who demonstrated high or increased levels of being self-critical also showed elevated symptoms of depression or anxiety.

"When parents become intrusive in their children's lives, it may signal to the children that what they do is never good enough," said Assistant Professor Ryan Hong, who led the study, which was conducted by a team of researchers from the Department of Psychology at NUS' Faculty of Arts and Social Sciences.

"The child may become afraid of making the slightest mistake and will blame himself or herself for not being 'perfect'," he explained.

Over time, such behaviour, known as maladaptive perfectionism, may be harmful to the child's well-being as it increases the risk of depression, anxiety and even suicide in the most serious cases, he added….

Parental intrusiveness was assessed in the first year of the study using a game.

In the game, the child had to solve puzzles within a time limit, and the parent was told that he or she could help the child whenever necessary. The purpose of this task was to observe whether the parent interfered with the child's problem-solving attempts, regardless of the child's actual needs.

Researchers observed the participants' behaviours, and coded intrusive behaviours exhibited by the parents.

Subsequent assessments on the children were carried out at ages eight, nine and 11.
An analysis of the data showed that about 60 per cent of the children were classified as high and/or increasing in self-criticalness, while 78 per cent were classified as high in socially prescribed perfectionism. Both aspects of maladaptive perfectionism tend to occur together, with 59 per cent of the children having both self-criticalness and socially prescribed perfectionism.

"Our findings indicate that in a society that emphasises academic excellence, which is the situation in Singapore, parents may set unrealistically high expectations for their children," said Assistant Prof Hong.

"As a result, a sizable segment of children may become fearful of making mistakes. Also, because they are supposed to be 'perfect', they can become disinclined to admit failures and inadequacies and seek help when needed, further exacerbating their risk for emotional problems," he added.

He advised parents to be mindful of not pushing their children over the edge.

"Children should be given a conducive environment to learn, and part of learning always involves making mistakes and learning from them. When parents become intrusive, they may take away this conducive learning environment."

- See more at:


Saturday, June 25, 2016

Autism glass

Like many children with autism, Julian Brown has trouble reading emotions in people's faces, one of the biggest challenges for people with the neurological disorder.

Now the 10-year-old San Jose boy is getting help from "autism glass" - an experimental device that records and analyzes faces in real time and alerts him to the emotions they're expressing. 

The facial recognition software was developed at Stanford University and runs on Google Glass, a computerized headset with a front-facing camera and a tiny display just above the right eye.

Julian is one of about 100 children participating in a Stanford study to see if "autism glass" therapy can improve their ability to interpret facial expressions.

"There's not a machine that can read your mind, but this helps with the emotions, you know, recognizing them," Julian said.

Julian wears the device each day for three 20-minute sessions when he interacts with family members face-to-face - talking, playing games, eating meals. The program runs on a smartphone, which records the sessions.

When the device's camera detects an emotion such as happiness or sadness, Julian sees the word "happy" or "sad" - or a corresponding "emoji" - flash on the glass display. The device also tests his ability to read facial expressions.

"The autism glass program is meant to teach children with autism how to understand what a face is telling them. And we believe that when that happens they will become more socially engaged," said Dennis Wall, whose lab is running the study.

Stanford student Catalin Voss and researcher Nick Haber developed the technology to track faces and detect emotions in a wide range of people and settings.

"We had the idea of basically creating a behavioral aide that would recognize the expressions and faces for you and then give you social cues according to those," said Voss, who was partly inspired by a cousin who has autism… 

Google provided about 35 Google Glass devices to Stanford, but otherwise hasn't been involved in the project. The Silicon Valley tech giant stopped producing the headset last year after it failed to gain traction, but the device found new life among medical researchers.

Brain Power, a Cambridge, Mass.-based startup, is also developing Google Glass-based applications to help children with autism improve their face-reading abilities and social skills.

"Glass and wearable technology are the future. They're going to play a pivotal role in how we understand, manage and diagnose disorders like autism," said Robert Ring, chief science officer at Autism Speaks.

Currently, many autistic children learn to read facial expressions by working with therapists who use flashcards with faces expressing different emotions. The Stanford team hopes autism glass can provide a convenient, affordable therapy that families can do at home.

"Kids with autism are not getting enough of the care that they need for as long as they need it, and we need to fix the problem," Wall said.

If the study shows positive results, the technology could become commercially available within a couple years, Wall said.

"Anything that can help this population is very welcome and very important, but even the best technology will never be enough because we are dealing with a population with often very, very profound needs," said Jill Escher, president of Autism Society San Francisco Bay Area.

The study is still in its early stages, but Wall said participating children have shown gains in their face-reading abilities and family feedback has been encouraging.

"It has helped our son who's using the Google Glasses connect with the family more," said Kristen Brown, Julian's mother. "I think the glasses are a positive way to encourage a kid to look someone else in the face."

Julian also gives the device positive reviews: "I really think it would help autistic people a lot."