Wednesday, September 28, 2022

Melatonin revisited

American Academy of Sleep Medicine

Health Advisory: Melatonin Use in Children and Adolescents 

Melatonin is a natural hormone that helps us regulate our own sleep timing. Even though our body makes its melatonin in the brain, some people use extra melatonin to improve their sleep. Melatonin can improve sleep in children whose body clocks are “off schedule” and in some children with developmental problems.

Melatonin use has increased in the last two decades across all ages.3 Melatonin is the secondmost popular “natural” product that parents give to their children, next to multivitamins. With this increased use, there are growing reports of melatonin overdose, calls to poison control centers, and emergency room visits for children, even more so during the COVID-19 pandemic. 

Parents should talk to a health care professional before giving melatonin or any supplement to children. 6 Be aware that in the U.S., melatonin is considered a “dietary supplement.” Melatonin is not under FDA oversight like other over-the-counter (OTC) or prescription medications. Melatonin content in supplements can vary widely. In one study, melatonin ranged from less than one-half to more than four times the amount stated on the label. The most significant variability in melatonin content was in chewable tablets - the form children are most likely to use. Some products even contained other chemicals that need medical prescriptions.  

To address the safe use of melatonin in children and teens, we advise that: 1. Melatonin should be handled as any other medication and kept out of reach of children. 2. Before starting melatonin or any supplement in their children, parents should discuss this decision with a pediatric health care professional. Many sleep problems can be better managed with a change in schedules, habits, or behaviors rather than taking melatonin. 3. If melatonin is used, the health care professional can recommend the melatonin dose and timing for the sleep problem. Parents should select a product with the USP Verified Mark to allow for safer use...

A USP Verified Mark indicates the supplement was produced in a facility that followed the FDA's Good Manufacturing Practice standards.

"These products meet some product quality control measures, including containing the amount of an ingredient on the label without harmful levels of specific contaminants," the AASM wrote. "However, this is a voluntary program, and only four melatonin products, all with either 3 mg or 5 mg of melatonin, have received the USP Verified Mark."

The American Academy of Sleep Medicine (AASM) issued a health advisory Wednesday encouraging parents to seek medical advice before giving melatonin or any supplement to children.

"While melatonin can be useful in treating certain sleep-wake disorders like jet lag, there is much less evidence it can help healthy children or adults fall asleep faster," M. Adeel Rishi, MD, MBBS, of Indiana University Health Physicians in Indianapolis and vice chair of the AASM Public Safety Committee, said in a statement.

"Instead of turning to melatonin, parents should work on encouraging their children to develop good sleep habits, like setting a regular bedtime and wake time, having a bedtime routine, and limiting screen time as bedtime approaches," he added.

The advisory comes on the heels of a report published by the CDC indicating that reported pediatric poisonings from melatonin jumped by over 500% from 2012 to 2021.

In that period, 260,435 pediatric melatonin ingestions were reported to poison control centers. The number skyrocketed from 8,337 in 2012 to 52,263 in 2021, with the largest increase occurring from 2019 to 2020.

Nearly all ingestions were unintentional, occurred in the home, and managed on-site. Most involved boys ages 5 and younger.

Symptoms of melatonin overdose can include headache, dizziness, and irritability. Most children were asymptomatic, but 27,795 children required treatment at a healthcare facility. While most were discharged, 4,097 children were hospitalized and 287 required intensive care. Five children required mechanical ventilation, and two died.

Other pediatric research showed that, during the COVID-19 pandemic, melatonin supplanted analgesics as the most frequently ingested substance reported to U.S. poison control centers.

Melatonin is the second most popular "natural" product that parents give to their children, next to multivitamins, the AASM said.

"Be aware that in the U.S., melatonin is considered a dietary supplement," the group wrote in its advisory. This means that melatonin is not under FDA oversight like over-the-counter or prescription medications.

It also means the melatonin content in supplements may be inconsistent. A study of 30 commercial supplements showed that melatonin ranged from less than one-half to more than four times the amount stated on the label. Some products contained other substances that require medical prescriptions.

The most significant variability in melatonin content was in chewable tablets, the AASM cautioned. "The availability of melatonin as gummies or chewable tablets makes it more tempting to give to children and more likely for them to overdose," Rishi said.

Thursday, September 22, 2022

Specific genetic changes causing the main symptoms of KCNMA1-linked channelopathy

Inspired by two patients

So far, only 70 patients around the world have been diagnosed with a newly identified rare syndrome known as KCNMA1-linked channelopathy. The condition is characterised by seizures and abnormal movements which include frequent ‘drop attacks’, a sudden and debilitating loss of muscle control that causes patients to fall without warning. 

The disease is associated with mutations in the gene for KCNMA1, a member of a class of proteins important for controlling nerve cell activity and brain function. However, due to the limited number of people affected by the condition, it is difficult to link a particular mutation to the observed symptoms; the basis for the drop attacks therefore remains unknown. Park et al. set out to ‘model’ KCNMA1-linked channelopathy in the laboratory, in order to determine which mutations in the KCNMA1 gene caused these symptoms. 

Three groups of mice were each genetically engineered to carry either one of the two most common mutations in the gene for KCNMA1, or a very rare mutation associated with the movement symptoms. Behavioural experiments and studies of nerve cell activity revealed that the mice carrying mutations that made the KCNMA1 protein more active developed seizures more easily and became immobilized, showing the mouse version of drop attacks. Giving these mice the drug dextroamphetamine, which works in some human patients, stopped the immobilizing attacks altogether. 

These results show for the first time which specific genetic changes cause the main symptoms of KCNMA1-linked channelopathy. Park et al. hope that this knowledge will deepen our understanding of this disease and help develop better treatments. 

Park SM, Roache CE, Iffland PH 2nd, Moldenhauer HJ, Matychak KK, Plante AE, Lieberman AG, Crino PB, Meredith A. BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models. Elife. 2022 Jul 12;11:e77953. doi: 10.7554/eLife.77953. PMID: 35819138; PMCID: PMC9275823. 


KCNMA1 forms the pore of BK K+ channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of KCNMA1 mutations and the basis for clinical heterogeneity in PNKD3 has not been established. Here, we evaluate the relative severity of three KCNMA1 patient variants in BK channels, neurons, and mice. In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties. The relative degree of channel activity was BKN999S > BKD434G>WT > BKH444Q. BK currents and action potential firing were increased, and seizure thresholds decreased, in Kcnma1N999S/WT and Kcnma1D434G/WT transgenic mice but not Kcnma1H444Q/WT mice. In a novel behavioral test for paroxysmal dyskinesia, the more severely affected Kcnma1N999S/WT mice became immobile after stress. This was abrogated by acute dextroamphetamine treatment, consistent with PNKD3-affected individuals. Homozygous Kcnma1D434G/D434G mice showed similar immobility, but in contrast, homozygous Kcnma1H444Q/H444Q mice displayed hyperkinetic behavior. These data establish the relative pathogenic potential of patient alleles as N999S>D434G>H444Q and validate Kcnma1N999S/WT mice as a model for PNKD3 with increased seizure propensity.


Wednesday, September 21, 2022

Neurologic and cardiologic assessment in breath holding spells

Yilmaz U, Doksoz O, Celik T, Akinci G, Mese T, Yilmaz TS. The value of neurologic and cardiologic assessment in breath holding spells. Pak J Med Sci 2014;30(1):59-64.   doi:


Objective: To evaluate the value of neurologic and cardiologic assessment and also the frequency of iron deficiency anemia in children with Breath Holding Spells (BHS).

Methods: The hospital charts of patients diagnosed with BHS between 2011 and 2013 were reviewed retrospectively.

Results: A total of 165 children (90 boys, 75 girls) with BHS comprised the study group. A matched group of 200 children with febrile convulsions served as controls. Among the first-degree relatives, 13.3% had BHS, 1.8% had febrile convulsions and 12.1% had epilepsy. The spells were cyanotic in 140 (84.8%) children and pallid or mixed in the remainder. BNS type was simple in 46.7% of patients and complicated in the remainder. Eighteen patients had abnormalities in electroencephalography, however only one patient was diagnosed with epilepsy. Sixty nine (47.9%) patients were found to have iron deficiency anemia.

Conclusion: Referral of children with clinically definite BHS to pediatric neurology or pediatric cardiology clinics and performance of echocardiography and EEG investigations for exclusion of heart disease or epilepsy appear unnecessary. However, performance of an electrocardiogram to search for prolonged QT syndrome should be considered although no patient in our series had any cardiologic abnormalities. 

Tuesday, September 20, 2022

One chiropractic manipulation patient injury. Two case reports. Two editor’s notes.


via Neurology

What happens when two different groups from two different medical specialties see a patient, and then write up separate case reports?

Ask teams of doctors in the neurology and rheumatology departments of the Faculdade de Medicina, Universidade de São Paulo in Brazil. They both published case reports about a patient was injured after undergoing chiropractic spinal cord manipulation. And now both journals have editor’s notes acknowledging dual publication.

The patient’s case appeared in Neurology as “Spinal Cord Injury, Vertebral Artery Dissection, and Cerebellar Strokes After Chiropractic Manipulation” and as “Breaking the diagnosis: ankylosing spondylitis evidenced by cervical fracture following spine manipulation” in the journal Internal and Emergency Medicine. The two publications included the same figure and reported many of the same details about the patient with undiagnosed ankylosing spondylitis who experienced spinal cord injury and cerebellar strokes after experiencing  spinal cord manipulation.

The editors of both journals published notes flagging the cases, an expression of concern in Internal and Emergency Medicine and a “notice of dual publication” in Neurology

The notices are nearly identical, and state, in part:

Both case reports were written by authors from the Faculdade de Medicina, Universidade de São Paulo. The authors of the article published in Internal and Emergency Medicine were affiliated with the Department of Rheumatology, and the authors of the Neurology article were affiliated with the Department of Neurology.

The authors of both articles were contacted and asked for an explanation for the dual publication. Both teams of authors explained that they cared for the patient during the hospital admission and that they were unaware of the submission by the other team.

Although the patient was the same, as was much of the discussion, the two papers are not, the journal editors explained: 

The focus of the articles is different: one focuses on bone injury and emergency care, and the other on the neurological aspects of the case. Both author groups apologize for the duplicate submissions and agree with this statement.

The duplicate publication came to light after two chiropractors wrote to Neurology noting the similarities between the two cases, and expressing concerns that the patient in question did not receive care from a properly trained chiropractor.

In an email to Retraction Watch, Neurology journals executive editor Patricia Baskin said: 

We believe we detailed all the information in this situation of dual publication by two author groups in which each group was unaware that the other group was also writing a report about the same patient. We had encountered a similar situation in our journal in 2013, at which time we posted a similar notification

When someone notifies us of a duplicate publication, we do check with the authors and authorities of the institution to determine the circumstances surrounding the duplicate publication. In both these instances, we determined that the duplication was unintentional.

Marina Barguil Macêdo, who was the corresponding author of the article in Internal and Emergency Medicine and is now at the University of Washington, shared the statement that she and her colleagues drafted in response to the inquiry about possible duplicate publication:

We, from the Rheumatology division, were completely unaware that the Neurology division submitted a manuscript about the same case to a different journal. Our Hospital is the largest public teaching hospital of Latin America, so one patient is commonly seem by different teams, that, despite working together on case management, hold their scientific discussions separately. We truly lament this dual publication, but we cannot overemphasize it was by no means intentional.


Diffuse intrinsic pontine glioma 3

BILLINGS — Maylin Bell is like any other 4-year-old girl. She loves to be silly, she loves to dance, and she loves spending time with her two older sisters. She's also a huge superhero fan and loves Spider-Man and the Hulk.

For about eight months, the Billings girl had been acting different. Erratic sleep patterns, trouble maintaining balance and even night terrors. What doctors thought was behavioral problems quickly changed after an MRI was ordered, and that prompted an immediate trip to Salt Lake City for further tests.

That trip turned into any parents’ worst nightmare. On Aug. 12, she and her family's lives were flipped upside down.

Maylin was diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG). It's a rare form of pediatric brain cancer, almost unheard of, and without a cure.

"What we’ve heard and what we’ve found out about this type of brain tumor in particular. It’s one of the most aggressive types of pediatric brain tumors that exists," said Kendall Boecara, Maylin's aunt. (Full disclosure: Kendall Boecara is sister-in-law of reporter Phil Van Pelt.)

"Her brain biopsy was essentially a minor brain surgery, and Maylin was what seemed like a normal little girl the night before when I saw her. She was running around playing Nerf guns…. Running through the hospital showing everyone her Spider-Man pajamas. The next morning, they took her back for her second MRI and the brain biopsy, and they warned us that she could come out with some neurological deficit. We noticed pretty much immediately when she got back from the operating room that she had lost some movement in her left arm and left leg and her eyelids weren’t able to stay open," said Boecara.

Around 300 cases of this type of cancer are diagnosed every year in the U.S., and around the same amount in Europe. It's so rare that the doctors involved were floored by their finding.

"The doctor was devastated. He couldn’t believe this is what they found on imaging. It wasn’t even on his differential.... The neurosurgeon was very apologetic during the whole thing. I remember the attending neurosurgeon just looking at my sister and her husband and saying, I’m so sorry. I just dropped a ton of bricks on you. It was hard especially when you see the image pop up and you see a tiny little brain with a massive tumor in the middle of it," added Boecara.

Maylin is currently just finished week two of her six radiation treatments in Salt Lake City. The results are positive so far, but it's only a temporary solution and something that would've been a problem even if found earlier. 

"Because of the location of this tumor, it's inoperable. It's in the brain stem so it’s going to stay there regardless of when you catch it and because there is no known treatment for this tumor other than trying radiation to try to slow it down. It wouldn’t matter if we caught a year ago, six months ago or two months ago. We’d still be in this same spot getting Maylin ready to start radiation and trying to get her some more time to have full function of her body. Once the side effects and effects of radiation wears off then the tumor will likely just continue to grow pretty aggressively. So, our time is limited with Maylin but we’re just trying to take it day by day and give her the best day every day and just keep letting her have good days and be a happy little girl," Boecara said.

Radiation is the only form of treatment because currently no form of chemotherapy attack this type of tumor. Maylin's family is focused on spending the time they do have with their daughter and hope that their story can help make a difference for another family.

"Our goal for this is spreading awareness about this tumor. And I think the biggest thing that my sister wants to get across is that if you feel like something is wrong with your kid. Take them to the doctor and keep taking them to the doctor. And if they tell you it's behavioral and you truly feel like something is wrong. Keep pushing. And there’s been no serious advancements in treatment for this tumor in the last 40 years. So, that’s why we feel that getting the word out there, that this type of tumor exists and how aggressive and devastating it is, is so important. Because we obviously need funding and research directed towards this type of tumor so that hopefully treatments can be found for patients in the future," added Boecara.

If you'd like to donate to help Maylin and her family through this trying time, please visit the following site: GOFUNDME. You can also go to any Wells Fargo and donate directly into an account set up for Maylin. The name of the account is #MightyMay. 

If you'd like to follow Maylin's story, please check out her page at

Tuesday, September 13, 2022

Xq28 duplication syndrome

Inspired by a patient

Ballout RA, El-Hattab AW, Schaaf CP, et al. Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated. 2016 Mar 10 [Updated 2021 Feb 25]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:


Clinical characteristics.

The int22h1/int22h2-mediated Xq28 duplication syndrome is an X-linked intellectual disability syndrome characterized by variable degrees of cognitive impairment (typically more severe in males), a wide spectrum of neurobehavioral abnormalities, and variable facial dysmorphic features. Affected males also exhibit a peculiar combination of recurrent sinopulmonary infections and atopy, findings that have not been observed in affected females. All males reported to date with the syndrome have moderate-to-severe intellectual disability; in contrast, a minority of heterozygous females have been reported to have mild intellectual disability, while the majority have no discernible health or learning issues and are considered clinically unaffected. 


The diagnosis of int22h1/int22h2-mediated Xq28 duplication in a hemizygous male or a heterozygous female is established by detection of a 0.5-Mb duplication within the q28 region of the X chromosome extending between 154.1 Mb and 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19). 


Treatment of manifestations: Early intervention with speech and physical therapy for children with neurodevelopmental delays; enrollment in special education programs of school-aged children with intellectual disability; cognitive behavioral therapy and standard treatment with antidepressants and/or antipsychotics for individuals with mood and psychotic disorders; standard treatment per orthopedist for those with kyphoscoliosis; bacterial culture-driven antibiotic treatment of affected individuals who have recurrent infections; vaccinations against Strep pneumoniae, Haemophilus influenzae, and Neisseria meningitidis and annual influenza A vaccine; standard medical treatment of sleep issues, asthma, allergic rhinitis, eczema, hearing loss, and refractive error; standard surgical correction of congenital malformations (e.g., strabismus, hypospadias, cryptorchidism, heart defects, limb anomalies). 

Surveillance: Measurement of growth parameters and assessment of neurodevelopmental progress, cognitive abilities, behavioral/psychiatric symptoms, and motor functioning at each visit; reassessment of special education needs annually in childhood and adolescence; routine follow up with orthopedist for those with contractures and/or kyphoscoliosis; pulmonary function testing as clinically indicated for those with severe asthma; at least annual audiologic and ophthalmologic evaluations. 

Evaluation of relatives at risk: Clinically asymptomatic sibs of affected individuals who also have the duplication should be regularly assessed and carefully monitored for achievement of neurodevelopmental milestones with the goal of instituting early intervention if or when neurodevelopmental delays are noted. 

Genetic counseling.

The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. Most affected individuals inherited the duplication from their heterozygous and often asymptomatic mother. However, individuals with de novo duplications have also been identified. Because offspring inherit one X chromosome from the mother, each child of a mother with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of inheriting the duplication. In other words, a female with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of passing the duplication to her offspring at each conception. Being hemizygous for X-linked genes, males who inherit the duplication are affected. In contrast, females who inherit the duplication will be heterozygous and thus, will either exhibit a milder phenotype or be clinically unaffected. Females in whom the X-inactivation pattern is skewed toward inactivation of the X chromosome bearing the duplication are more likely to be clinically unaffected. Once an int22h1/int22h2-mediated Xq28 duplication has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Monday, September 12, 2022

Perinatal stroke 2

In early February 2016, after reading an article featuring a couple of scientists at the Massachusetts Institute of Technology who were studying how the brain reacts to music, a woman felt inclined to email them. “I have an interesting brain,” she told them.

EG, who has requested to go by her initials to protect her privacy, is missing her left temporal lobe, a part of the brain thought to be involved in language processing. EG, however, wasn’t quite the right fit for what the scientists were studying, so they referred her to Evelina Fedorenko, a cognitive neuroscientist, also at MIT, who studies language. It was the beginning of a fruitful relationship. The first paper based on EG’s brain was recently published in the journal Neuropsychologia, and Fedorenko’s team expects to publish several more.

For EG, who is in her fifties and grew up in Connecticut, missing a large chunk of her brain has had surprisingly little effect on her life. She has a graduate degree, has enjoyed an impressive career, and speaks Russian—a second language–so well that she has dreamed in it. She first learned her brain was atypical in the autumn of 1987, at George Washington University Hospital, when she had it scanned for an unrelated reason. The cause was likely a stroke that happened when she was a baby; today, there is only cerebro-spinal fluid in that brain area. For the first decade after she found out, EG didn't tell anyone other than her parents and her two closest friends. “It creeped me out,” she says. Since then, she has told more people, but it's still a very small circle this is aware of her unique brain anatomy.

Over the years, she says, doctors have repeatedly told EG that her brain doesn’t make sense. One doctor told her she should have seizures, or that she shouldn’t have a good vocabulary—and “he was annoyed that I did,” she says. (As part of the study at MIT, EG tested in the 98th percentile for vocabulary.) The experiences were frustrating; they “pissed me off,” as EG puts it. “They made so many pronouncements and conclusions without any investigation whatsoever,” she says.

Then EG met Fedorenko. “She didn't have any preconceived notions of what I should or shouldn't be able to do,” she recalls. And for Fedorenko, an opportunity to study a brain like EG’s is a scientist’s dream. EG was more than willing to help.

Fedorenko’s lab is working to shed some light on the development of the vast array of brain regions thought to play a role in language learning and comprehension. The exact role of each has yet to be demystified, and exactly how the system emerges is a particularly tricky element to study. “We know very little about how the system develops,” says Fedorenko, as doing so would require scanning the brains of children between the ages of 1 and 3 whose language abilities are still developing. “And we just don't have tools for probing kids’ brains at that time,” she says.

When EG turned up at her lab, Fedorenko recognized that this could be a golden opportunity for understanding how her remaining brain tissue has reorganized cognitive tasks. “This case is like a cool window to ask that kind of question,” she says. “It’s just sometimes you'd get these pearls that you try to take advantage of.” It's incredibly rare for someone like EG to offer themselves up to be poked and prodded by scientists.

For most people, the majority of language processing takes place in the brain’s left hemisphere. For some, the load is split equally between the two hemispheres. Even more rarely, the right hemisphere takes up most of the task. (Scientists are not quite sure why, but if you're left-handed, it seems you're “likely to wire up your language system in the right hemisphere,” says Greta Tuckute, a doctoral student in Fedorenko’s lab and the first author of the paper.)

Language processing largely takes place in two major parts of the brain: the frontal and the temporal regions. The temporal lobes develop first; then the frontal areas develop later, at around 5 years old. At this point, the language network is considered fully mature. Because EG’s left temporal lobe is missing, Fedorenko’s team had a chance to answer an interesting question: Are the temporal regions a prerequisite for setting up the frontal language areas?

In their first paper based on studying EG’s brain, they wanted to know whether she showed language activity in her fully intact left frontal lobe. If she did, that would suggest frontal language areas can emerge without the need for a preexisting temporal lobe in the same hemisphere. But if she didn’t, it would suggest that temporal language areas are a must-have for the emergence of the frontal ones.

The researchers used functional magnetic resonance imaging, or fMRI, to capture EG’s brain activity while she performed certain word-related tasks, such as reading sentences. As she did, they looked for evidence of language activity in her left frontal lobe. Then they compared this brain activity to around 90 neurotypical controls (similar data from people with intact left temporal lobes). Ultimately, they found none, so they concluded that the existence of temporal language areas appears to be non-negotiable for the emergence of the frontal language areas.

Still, they found that her left frontal cortex is perfectly capable of supporting high-level cognitive functions, which they confirmed by asking her to perform math tasks while watching how her brain responded. They concluded that in the absence of her left temporal lobe, the task of language processing seems to have simply shifted over to EG’s right hemisphere. A single hemisphere appears to be sufficient to give her proficient language skills.

Just how remarkably little effect the uniqueness of EG’s brain has on her day-to-day life shows how sheerly expendable big chunks of our brains can be. Fedorenko points to a surgical practice called hemispherectomy used for children with epilepsy whose condition does not respond to medication. The practice entails removing the half of the brain where the seizures are taking place, and these children have been shown to retain typical cognition. “If you can remove half of a brain and you work fine, that suggests there's a lot of bits in our typical brains that are redundant,” says Fedorenko. “There's apparently a lot of stuff in our brain that is fully redundant, which is—engineering-wise—a pretty good way to build the system.”

The reality is that if the brain is damaged, it will often find a way to rewire itself. This is something Ella Striem-Amit, a cognitive neuroscientist at Georgetown University, understands well. She studies how the brain reorganizes itself in the absence of certain senses, such as in people born blind or deaf. “The remarkable thing about this patient—and other such patients who were missing large chunks of their language system at birth, or other systems at birth—is how well they can compensate,” she says.

Specifically, if the abnormality develops in childhood, when neuroplasticity is stronger, another part of the brain will usually just make up for the function of the missing bit by forming new neural connections that take up the task. “There's been ample research over decades showing that the brain is way more flexible in early life,” says Striem-Amit. 

Drawing any conclusions from the observation of a single person might seem premature. In recent years, studies of individuals have gotten a bad rap because smaller studies can return fluke results. There’s been a widespread move in research toward bigger being better. But case studies, by and large, laid the foundation of modern neuroscience. Take famous examples like Broca’s patient, who in 1861 taught scientists which part of the brain controlled speech production; the patient H.M., whose brain unraveled the mystery of how memories organize themselves in the brain; and perhaps the most famous, Phineas Gage, a railroad worker who had an iron rod driven straight through his brain in 1848 and whose personality changes following the injury are thought to have shown for the first time that some functions are associated with specific regions of the brain. “All the core discoveries leading to our understanding of the brain started out with case studies,” says Striem-Amit. “We couldn't have figured out as much as we did and say something about causality without those unique cases.”

Fedorenko says that looking at high-quality data in an individual, as opposed to at a group-level map, is akin to “using a high-precision microscope versus looking with a naked myopic eye, when all you see is a blur.” Done carefully, an n=1 approach can offer trailblazing illuminations, such as in the case of EG, Fedorenko argues. “We can learn a huge amount of information from cases where something is a little bit different,” she says. “It just seems a shame not to take advantage of these accidents of nature.” 

“It's really important to study unique cases,” Striem-Amit agrees. “There's a trend toward big data, and we need to emphasize the importance of deep data—of studying very detailed experimental designs of individuals to understand how an individual brain is organized.”

Going forward, Fedorenko’s lab hopes to learn much more from EG’s brain. In a preprint posted online last month that has not yet been peer reviewed or published by a journal, they looked at a brain region called the visual word form area, which is thought to be responsible for decoding the written forms of words. In neurotypical people, the region is found in the left ventral temporal cortex; but for EG, the function is distributed throughout her brain, and she’s a “really good, fast reader,” says Fedorenko. For a future study, they’re also looking into how EG’s missing temporal lobe affects her auditory system. 

Remarkably, EG’s sister is missing her right temporal lobe and is largely unaffected by it, suggesting there's likely some genetic component to the early childhood strokes that can explain the missing brain regions, Fedorenko says. Next up, the team wants to use both EG and her sister—who has also volunteered to be studied—to try to understand how social and emotional processing takes place predominantly in the right hemisphere. In fact, the whole family is getting involved. A third sibling and EG’s father have also had their brains scanned, although it turns out they each have two intact temporal lobes—or a “boring brain,” as EG dubs it. A fourth sibling will be scanned in the near future. For a long time, it had never occurred to EG that anybody would want to study her, so she is just glad that the neuroscience field has been able to learn something from her brain. “And I hope that it will also take some stigma away from atypical brains,” she says.



DDX3X-related neurodevelopmental disorder

Inspired by a patient

Johnson-Kerner B, Snijders Blok L, Suit L, Thomas J, Kleefstra T, Sherr EH. DDX3X-Related Neurodevelopmental Disorder. 2020 Aug 27. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 32852922.


Clinical characteristics: DDX3X-related neurodevelopmental disorder (DDX3X-NDD) typically occurs in females and very rarely in males. All affected individuals reported to date have developmental delay / intellectual disability (ID) ranging from mild to severe; about 50% of affected girls remain nonverbal after age five years. Hypotonia, a common finding, can be associated with feeding difficulty in infancy. Behavioral issues can include autism spectrum disorder, attention-deficit/hyperactivity disorder and hyperactivity, self-injurious behavior, poor impulse control, and aggression. Other findings can include seizures, movement disorders (dyskinesia, spasticity, abnormal gait), vision and hearing impairment, congenital heart defects, respiratory difficulties, joint laxity, and scoliosis. Neuroblastoma has been observed in three individuals.

Diagnosis/testing: The diagnosis of DDX3X-NDD is established in a female proband with suggestive findings and a heterozygous de novo DDX3X pathogenic variant identified by molecular genetic testing and in a male proband with suggestive findings and a hemizygous DDX3X pathogenic variant.

Management: Treatment of manifestations: Treatment is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach that should also include psychosocial support for family members. Management of feeding difficulty, ID, behavioral issues, seizures, spasticity and other movement disorders, vision and hearing impairment, congenital heart defects, respiratory difficulties, joint laxity, and scoliosis as per standard care.

Surveillance: Periodic evaluation by the multidisciplinary team regarding growth, developmental progress and educational needs, and psychiatric/behavioral issues; regular assessment of vision and hearing, of the spine for scoliosis, for seizure control (when relevant), and for cardiac and respiratory issues. Starting at age eight years, assess girls for evidence of precocious puberty.

Genetic counseling: DDX3X-NDD is an X-linked disorder.

  1. Females. Most female probands represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a de novo pathogenic variant.

  2. Males. DDX3X-NDD in males is caused by either a pathogenic variant inherited from an unaffected heterozygous mother or a de novo pathogenic variant. If the mother of an affected male has a DDX3X pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and are not expected to manifest a neurodevelopmental phenotype.

If the proband is female and represents a simplex case and if the DDX3X pathogenic variant cannot be detected in the leukocyte DNA of either parent – or the proband is male and the DDX3X pathogenic variant cannot be detected in the leukocyte DNA of the mother – the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Once the DDX3X pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Snijders Blok L, Madsen E, Juusola J, Gilissen C, Baralle D, Reijnders MR, Venselaar H, Helsmoortel C, Cho MT, Hoischen A, Vissers LE, Koemans TS, Wissink-Lindhout W, Eichler EE, Romano C, Van Esch H, Stumpel C, Vreeburg M, Smeets E, Oberndorff K, van Bon BW, Shaw M, Gecz J, Haan E, Bienek M, Jensen C, Loeys BL, Van Dijck A, Innes AM, Racher H, Vermeer S, Di Donato N, Rump A, Tatton-Brown K, Parker MJ, Henderson A, Lynch SA, Fryer A, Ross A, Vasudevan P, Kini U, Newbury-Ecob R, Chandler K, Male A; DDD Study, Dijkstra S, Schieving J, Giltay J, van Gassen KL, Schuurs-Hoeijmakers J, Tan PL, Pediaditakis I, Haas SA, Retterer K, Reed P, Monaghan KG, Haverfield E, Natowicz M, Myers A, Kruer MC, Stein Q, Strauss KA, Brigatti KW, Keating K, Burton BK, Kim KH, Charrow J, Norman J, Foster-Barber A, Kline AD, Kimball A, Zackai E, Harr M, Fox J, McLaughlin J, Lindstrom K, Haude KM, van Roozendaal K, Brunner H, Chung WK, Kooy RF, Pfundt R, Kalscheuer V, Mehta SG, Katsanis N, Kleefstra T. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. Am J Hum Genet. 2015 Aug 6;97(2):343-52. doi: 10.1016/j.ajhg.2015.07.004. Epub 2015 Jul 30. PMID: 26235985; PMCID: PMC4573244.


Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Sunday, September 4, 2022

Perinatal stroke

Helen Santoro

I barreled into the world — a precipitous birth, the doctors called it — at a New York City hospital in the dead of night.

In my first few hours of life, after six bouts of halted breathing, the doctors rushed me to the neonatal intensive care unit. A medical intern stuck his pinkie into my mouth to test the newborn reflex to suck. I didn’t suck hard enough. So they rolled my pink, 7-pound-11-ounce body into a brain scanner.

Lo and behold, there was a huge hole on the left side, just above my ear. I was missing the left temporal lobe, a region of the brain involved in a wide variety of behaviors, from memory to the recognition of emotions, and considered especially crucial for language.-

My mother, exhausted from the labor, remembers waking up after sunrise to a neurologist, pediatrician and midwife standing at the foot of her bed. They explained that my brain had bled in her uterus, a condition called a perinatal stroke.

They told her I would never speak and would need to be institutionalized. The neurologist brought her arms up to her chest and contorted her wrists to illustrate the physical disability I would be likely to develop.

In those early days of my life, my parents wrung their hands wondering what my life, and theirs, would look like. Eager to find answers, they enrolled me in a research project at New York University tracking the developmental effects of perinatal strokes.

But month after month, I surprised the experts, meeting all of the typical milestones of children my age. I enrolled in regular schools, excelled in sports and academics. The language skills the doctors were most worried about at my birth — speaking, reading and writing — turned out to be my professional passions.

My case is highly unusual but not unique. Scientists estimate that thousands of people are, like me, living normal lives despite missing large chunks of our brains. Our myriad networks of neurons have managed to rewire themselves over time. But how?

‘The Worst Participant’

My childhood memories are filled with researchers following me around with pens and clipboards. My brain was scanned several times a year, and I was tasked with various puzzles, word searches and picture-recognition tests. At the end of each day of testing, the researchers would give me a sticker, which I would keep in a tin container next to my bed.

When I was around 9 years old, researchers wanted to see how my brain would act when I was exhausted. I would sometimes stay up all night with my mom, eating Chinese food and watching Katharine Hepburn and Spencer Tracy movies. The next day I would stumble into the clinic half-awake, and scientists would stick electrodes on my scalp. As long wires fell from my head like Medusa’s snakes, I was finally allowed to fall asleep, blissfully unaware that the researchers were searching for abnormalities in my brain waves.

Over the years, the scientists realized that I wasn’t like the other children in the study: I didn’t have any deficits to track over time. When I was around 15, my dad and I met in the cluttered Manhattan office of Dr. Ruth Nass, the pediatric neurologist leading the research. She questioned if I had actually had a perinatal stroke. In any case, she said frankly that my brain was so different from the others’ that I could no longer be in the study.

I didn’t mind. I had other things going on in my life, like the beginning of high school, cross-country practice and crushes. But I had also learned enough about neuroscience to become consumed by the topic. When I was 17 and entering my senior year in high school, I wrote to Nass and asked if I could do an internship in her lab. She readily agreed.

One day in the lab, I asked if she could show me my study files. We walked into a room filled with stacks of plastic bins, each one brimming with folders and loose papers. She grabbed a folder and read it quietly. Then, peering over a piece of paper, she said, “You were the worst participant because you were perfectly fine! You threw off all of my data.”

Nass, who passed away in 2019, and her colleagues would go on to publish many studies on perinatal strokes. In a 2012 paper, for example, they found that babies suffering these strokes had a higher risk of attention and behavioral problems compared with the general pediatric population. Many of these children — recruited from 1983 to 2006 from Southern California and New York City — suffered from seizures and muscle weakness on one side of their bodies. Most also had damaged or missing areas, known as lesions, in their left hemispheres, like me. I assume that one of those data points was mine.

I went to college and majored in neuroscience. After graduating in 2015, I spent two years working in a lab studying concussions. I spent hours in the magnetic resonance imaging room, watching as other peoples’ brains appeared before me on a computer screen.

But I never thought much about my own brain until this spring, when I happened upon a story in Wired magazine (see about a woman just like me: astonishingly normal, apart from a missing temporal lobe.

A Critical Hemisphere

For more than a century, the left hemisphere of the brain has been considered the center of language production and comprehension.

This idea was first proposed in 1836 by Dr. Marc Dax, a physician who observed that patients who had injuries to the left side of their brains could no longer speak properly. Twenty-five years later, Dr. Pierre Paul Broca observed a young man who had lost the ability to speak and could utter only one syllable: “Tan.” A brain biopsy following the patient’s death revealed a large lesion in the frontal part of the left hemisphere, now known as Broca’s area.

In the early 1870s, Dr. Carl Wernicke, a neurologist, saw several patients who could speak fluently, but their utterances made little sense. One of these patients had a stroke in the back of her left temporal lobe, and Wernicke concluded that this section of the brain — now called Wernicke’s area — must serve as a second center for language, alongside Broca’s area.

Modern brain imaging studies have further expanded our understanding of language. Much of this work has shown that two brain regions — the left sides of the temporal and frontal lobes — activate when a person is reading or hearing words. Some researchers have called this the “language network.”

But other neuroscientists have argued that language processing is even broader and not confined to specific brain regions.

“I believe that language in the brain is distributed throughout the entire brain,” said Jeremy Skipper, the head of the Language, Action and Brain Lab at University College London (and my former college psychology professor).

Studies have shown that written words can activate the part of the brain associated with the word’s meaning. For example, the word “telephone” activates an area related to hearing, “kick” triggers a region involved in moving the legs, and “garlic” activates a part that processes smells.

The areas of the brain traditionally attributed to language have lots of other functions, Skipper said. “It just depends on what other sections of the brain they are talking to and at what time and in what context.”

Eight Interesting Brains

The Wired article described an anonymous woman from Connecticut who had no idea she lacked a left temporal lobe until undergoing an unrelated brain scan as an adult. For the past few years, the article explained, she had been part of a research project led by Evelina Fedorenko, a cognitive neuroscientist at the Massachusetts Institute of Technology.

In April, I wrote Fedorenko an email telling her about my missing left temporal lobe and offering to be part of her research. She replied 4 1/2 hours later, and soon I was booking an airplane ticket from my home in rural Colorado to Boston.

There are currently eight participants, including me, in Fedorenko’s Interesting Brain Project, she told me. I haven’t met them, but four of us had presumed perinatal strokes, resulting in damage to our left hemispheres. Two participants have benign cysts in their right or left hemispheres, one had a stroke in the right hemisphere, and one had brain tissue removed from the left hemisphere because of a tumor.

“The brain has incredible neuroplasticity,” said Hope Kean, a graduate student in Fedorenko’s lab who is running the Interesting Brain study as part of her dissertation.

It seems that networks in the brain arrange in a particular way, but if you lose crucial brain regions as a baby — when the brain is still very plastic — these networks can reroute, Kean said.

I arrived at Fedorenko’s lab in Cambridge on a hot day in July. I lay on a bed that slid into the MRI machine’s narrow tube, with a cagelike device placed over my head. Kean snapped a mirror onto the headpiece so I could see a screen at the back of the scanner. As the machine started to make its banging, booming sounds, I remembered all of the times I had dozed off inside as a kid, lulled to sleep by its thundering chords.

On the screen, words flashed quickly and a voice read them aloud, forming random sentences like, “Just the barest suggestion of a heel is found on teenage pumps.” Then, the words switched to a haphazard assortment of letters, creating incomprehensible sounds.

After the scan was completed, the researchers and I crowded around a computer screen, where I saw a slice of my brain for the first time. I stared in disbelief, stunned that my neuronal wiring could have rerouted around this large, oblong hole where my temporal lobe should have been in the space behind my left temple and eye socket.

In a typical person’s brain, the sentences that I heard and read in the scanner would robustly activate the left temporal and frontal lobes, whereas the nonsense sounds would not.

The researchers’ studies found that the brain of the Connecticut patient had adapted by switching sides: For her, these sentences activated the right temporal and frontal lobes, according to a case study published in the journal Neuropsychologia.

My brain, however, surprised everyone, yet again.

A preliminary analysis of the scans showed that, even without a left temporal lobe, I still process sentences using my left hemisphere.

“I had thought that any large left hemisphere early lesion leads to the migration of the language system to the right hemisphere!” Fedorenko said. “But science is cool this way. Surprises often mean cool discoveries.”

A possible reason behind this discovery, according to Fedorenko, is that my lesion is primarily in the front of my left hemisphere, leaving enough healthy tissue in the back for the language system to take root.

Over the next few years, I’ll be flying back to the lab for additional scans and tests, and Fedorenko hopes to recruit even more people with unusual brains to participate in this study.

I still think about the study I was in as a young child and about all of the other kids whose perinatal strokes had left many of them severely disabled. For some mysterious reason, my brain evolved around its missing lobe, whereas theirs struggled to do so. Why wasn’t I born with the developmental and cognitive problems, and they were? Why did my left side rewire to give me the syllables, words and phrases that have so enriched my life?

It’s these questions that make me grateful to have been involved in this study — and to be a research participant once again.