Monday, September 6, 2021

Separation of craniopagus twins in Israel

For the first time in Israel, twins conjoined at the head were separated successfully. 

The operation, conducted by Soroka Medical Center in the southern city of Be’er Sheba, was a huge success. Doctors expect the girls, who were born last year in August, will live completely normal lives. 

“They are breathing and eating on their own,” Eldad Silberstein, head of the hospital’s plastic surgery department, told Israel’s Channel 12 news. 

“This was a rare and complex surgery that has been conducted only 20 times worldwide and now, for the first time, in Israel,” said Mickey Gideon, Soroka’s chief pediatric neurosurgeon. 

The 12-hour procedure, with the assistance of dozens of experts from Israel and abroad, involved cranial reconstruction and scalp grafts. 

Dr. Isaac Lazar, director of the Pediatric Intensive Care Unit at Soroka, described to Times of Israel the moment on Sunday when the girls looked at each other for the first time and the “unbelievable joy” felt by the parents. 

“When the nurses brought the babies together, newly separated, they looked at each other, made noises, and gently touched each other — it was beautiful,” Lazar told Times of Israel in an interview. “You could see the communication between them, and it was just so special.” 

“Any wrong decision could have been the difference between life and death,” Lazar said. “It was so delicate, as the surgery was performed between major blood vessels in the babies’ heads. We all knew that any bleed could have catastrophic consequences.” 

The operation was “complicated beyond anything one could imagine,” he added. “The babies were connected by the back of their heads in an area where there was no skin and no skull. We had to take action to make them grow more skin.” 

“Because the babies couldn’t move their heads for the first 12 months of their lives, there’s a physical handicap, but with the right rehabilitation for their physical and cognitive development, we expect them to catch up with their milestones,” the doctor explained. 

“One of the reasons for doing this now, as early as possible, is to allow normal development, and our hope is that this is now very likely.”

Friday, September 3, 2021

Alta Fixsler

Every life is precious, no matter what one’s circumstances!

Little Alta Fixsler was born eight weeks prematurely in Royal Manchester Children’s Hospital.  A traumatic birth deprived Alta of oxygen for twenty-five long minutes causing severe brain injury and no expectation for her to live more than a day.  But with HaShem’s help coupled with the loving embrace of her parents and Modern Medicine’s gift of the ventilator, this beloved Jewish daughter survived her first harrowing days of life.  Despite Alta’s strides in weaning off ventilation and transitioning to a lower level of respiratory support or that plans were being formulated to bring her home, someone at the hospital made a series of unilateral decisions that resulted in Alta having to go back on ventilation.   After that it was only a matter of time before pressure began to mount on her parents to withdraw life support under the guise of concern for her pain and no promise of recovery or a normal life.  When Alta’s parents refused to consent, Manchester University Foundation Trust (NHS) went to Court against them and were granted guardianship and the right to withdraw her life support, r”l.

In conjunction with efforts being made on Alta’s behalf, Crown Heights Women for the Safety and Integrity of Israel and its many members around the world have sent the below appeal to British Prime Minister Boris Johnson.


To the Rt Hon Prime Minister Boris Johnson,

We were duly impressed with the United Kingdom’s humanitarian commitment pledged by yourself and fellow parliamentarians on August 18th to rescue tens of thousands of Afghanis from certain persecution and death as the Taliban take over in the wake of the US withdrawal from Afghanistan.

At the same time, however, we cannot understand why the same kind of compassion and political will has not been shown towards Alta Fixsler.

Across the globe people of goodwill from all walks of life and religions are praying for this special little girl to be given a chance.

The Lubavitcher Rebbe, the greatest lover of humanity in our time, repeatedly emphasized that acts of goodness and kindness bring light and peace to the entire world.

And so, Mr. Prime Minister, we plead with you to immediately intercede on Alta’s behalf to find a way she can leave the UK either to the US or to her home country in the State of Israel.

As we’ve no doubt you are already familiar with the particulars of Alta’s birth and her medical issues as well as the High Court’s decision, we only ask that you to consider the following three key points.

To be clear, we respect the strict separation of powers that make up the UK government and are not asking you to override in any way the Court’s ruling.

Alta and the Fixslers are Israeli citizens.

Mr. Prime Minister, Alta and her parents are Israeli citizens.  Avraham Fixsler is also an American citizen and Mrs. Fixsler additionally holds Hungarian citizenship.  The Fixslers always intended to return to their home country and have made no application for British citizenship. 

As such there can be no justification for expropriating the Fixsler’s parental rights – who are neither British citizens nor have they committed any crime on UK soil – or Alta’s right to live, simply because she sadly suffered brain injuries at birth.

Palliative care is a horribly painful way to end life.

Benign sounding terms like palliative and hospice care disguise the true ordeal a person endures when life support is taken away.

Here is what happens when ventilation is withdrawn:  First there is a physically painful struggle by the patient to breathe accompanied by panic, fear, and agitation – especially when the fight to live is deliberately being suppressed.   Saliva and secretions begin pooling in the lungs and the sounds of death rattle in the chest.

In order to “calm and comfort” the patient during this “merciful” form of legalized murder, a powerful mix of opiates, barbiturates or analgesics must be given to keep the person sedated until he or she succumbs and dies.

As much as an adult in this state might be able to reconcile their final moments – if this has been a deliberate decision to do so [and one we do not agree with] – for anyone else, especially a child, this can only be terrifying!

How can this possibly be in Alta’s best interests?!

Yet NHS has taken it even one step further.  The Court’s ruling gave room for Alta to pass away in the comfort of her parents’ home in Manchester surrounded by her loving family.

Instead, NHS unilaterally decided that Alta may only die in a hospice or in the hospital which they themselves concede is a cold, windowless environment.

Surely Mr. Prime Minister you realize the above scenarios are far more “painful” and distressing than anything that might occur during a responsible transport with appropriate pain control.

Alta does not have to die

No doubt Mr. Prime Minister you are aware that medical facilities in Israel are ready to admit Alta as a patient under their care.  Surely, there is room to reevaluate this option.

But if not, we beg you to find a way Alta can be transferred to the US where Senator Charles Shumer has procured a visa for Alta to enter the country for care and where there is widespread bi-partisan support in Congress endorsing her move.

A highly qualified medical transport is already in place to transfer Alta at absolutely no cost to NHS or the UK.

Mr. Prime Minister, Rosh HaShana, the Jewish New Year, is fast approaching.  This is the birthday of Mankind when Adam and Eve were created and judged.   The fate of Alta should be emblematic of Humanity’s appreciation for the preciousness of every life, no matter what one’s circumstances. 


Thursday, September 2, 2021

Primary amebic meningoencephalitis 5

A California boy who was on life support after he contracted a brain-eating amoeba likely while swimming in a lake has died, his family recently told news outlets. David Pruitt, 7, had been flown to UC Davis Medical Center on July 30, according to the family’s fundraising page. 

About a week later, the boy died. His aunt, Crystal Hayley, said he was diagnosed with primary amebic meningoencephalitis (PAM), a rare, devastating infection of the brain. The Associated Press reported that earlier this month, health officials in Tehama County said that a child under 10 was likely infected in a Tehama County lake, but did not reveal exactly where or the child’s age. 

According to the Tehama County Health Services Agency, there have only been 10 PAM cases reported in California since 1971. 

PAM is caused by Naegleria fowleri, also known as a brain-eating amoeba, which is found in warm freshwater and soil. It usually infects people when contaminated water enters the body through the nose, and travels to the brain where it causes PAM. Usually, most PAM cases are fatal, according to the Centers for Disease Control and Prevention (CDC).

It was not clear exactly when David had gone swimming, as symptoms of PAM typically begin one to nine days after. Death typically occurs between one and 18 days after symptoms begin. The CDC notes that PAM is difficult to detect due to rapid progression of illness.

Monday, August 30, 2021

Association of Tourette syndrome and chronic tic disorder with cervical spine disorders

Isung J, Isomura K, Larsson H, Sidorchuk A, Fernández de la Cruz L, Mataix-Cols D. Association of Tourette Syndrome and Chronic Tic Disorder With Cervical Spine Disorders and Related Neurological Complications. JAMA Neurol. 2021 Aug 23. doi: 10.1001/jamaneurol.2021.2798. Epub ahead of print. PMID: 34424277.


Importance: Severe forms of Tourette syndrome or chronic tic disorder (TS/CTD) may involve repeated head jerking. Isolated case reports have described a spectrum of severe neck disorders in individuals with TS/CTD. However, the nature and prevalence of cervical spine disorders in TS/CTD are unknown.

Objective: To establish if TS/CTD are associated with an increased risk of cervical spine disorders and related neurological complications compared with individuals from the general population.

Design, setting, and participants: All individuals born from 1973 to 2013 and living in Sweden between 1997 and 2013 were identified. Individuals with a record of TS/CTD diagnosed in specialist settings were matched on age, sex, and county of birth with 10 unexposed individuals randomly selected from the general population. Cox proportional hazards regression models were used to estimate the risk of vascular and nonvascular cervical spine disorders among exposed individuals, compared with unexposed individuals. Models were adjusted for other known causes of cervical spine injury. Data were analyzed from March 19 to May 16, 2021.

Exposures: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of TS/CTD in the Swedish National Patient Register.

Main outcomes and measures: Records of cervical vascular disorders (ie, aneurysm, cerebral infarction, transitory cerebral ischemia) and cervical nonvascular disorders (ie, spondylosis, cervical disc disorders, fractures of the cervical spine, cervicalgia) and cervical surgeries. Covariates included rheumatic disorders, traffic injuries, fall- or sport-related injuries, and attention-deficit/hyperactivity disorder comorbidity.

Results: A total of 6791 individuals with TS/CTD were identified (5238 [77.1%] were male; median [interquartile] age at first diagnosis, 15.6 [11.4-23.7] years) and matched to 67 910 unexposed individuals. Exposed individuals had a 39% increased risk of any cervical spine disorder (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.59). Adjusted hazard ratios for cervical vascular and nonvascular disorders were 1.57 (95% CI, 1.16-2.13) and 1.38 (95% CI, 1.19-1.60), respectively. Risks were similar among men and women.

Conclusions and relevance: Individuals with severe TS/CTD are at increased risk of cervical spine disorders. These outcomes are relatively rare but may lead to persistent disability in some individuals and thus require close monitoring to facilitate early interventions.

Courtesy of:

NGLY1 mutation

 No boy should have a last stretch of days. But Bertrand Might lived his as well as any boy could: There was a “Star Trek” marathon with his brother and sister, sunrises on the lakeshore, and visits with family in parks, beaches, and backyards — anywhere they could safely gather during the pandemic.

His father, Matt Might, said it ended up being an unplanned farewell for 12-year-old Bertrand, whose health had always been precarious. He was the first person in the world diagnosed with a particular neurodegenerative condition that causes developmental delays, seizure-like activity in the brain, and frequent infections.

One of those infections, unrelated to Covid-19, led to his death on Oct. 23 after he spiraled into septic shock. But if his passing came too soon, it did not come before his life led to crucial discoveries for dozens of children with his condition.

“What he did with NGLY1 alone was pretty powerful,” said Matt Might, referring to the gene involved in his son’s disease. After years of research, it was the discovery of a double mutation in Bertrand’s NGLY1 gene, and the constellation of symptoms linked to it, that explained the cause of the illness and built a worldwide community around it.

“There are 70 families on the patient mailing list right now for a disease that eight years ago didn’t exist,” Might said.

Bertrand also inspired a quest by his father, an artificial intelligence expert and computer programmer, to employ precision medicine on a wider scale, using genetic data to help tailor treatments to patients with rare and hard-to-treat diseases like his son’s.

Might began that work initially to help Bertrand, but it led to a stint on President Obama’s precision medicine initiative and the creation of a new precision medicine institute (PMI) he now leads at the University of Alabama, Birmingham.

“PMI was founded on this algorithm that Bertrand taught me,” Might said. “How do you try to therapeutically modulate a specific genetic target? There is a central game plan we use every time somebody comes in.”

Might and his team examine what gene is involved in a person’s condition and whether it is under-reactive, over-reactive, toxic, or missing altogether. The answers to those questions form the basis for a scientific process that often gives patients hope when conventional medicine has failed to provide an accurate diagnosis or effective treatments. A permanent endowment has been established at UAB in Bertrand’s name to fund advanced diagnostics and research to identify novel therapies for patients with no other options.

In Bertrand’s case, the double mutation in NGLY1 left him without an enzyme that facilitates the recycling of cellular waste. It severely limited his mobility, requiring him to use a wheelchair, and also impaired his liver function and ability to communicate.

Still, Bertrand drove the science of his condition while enduring countless hospitalizations, often due to infections that made it difficult to breathe.

Throughout his life, he developed a love for dolphins and an aquarium his parents set up in his bedroom. He spent hours learning words and reading with his father and mother, Cristina, and he bonded with his younger brother and sister over movies and video games.

“I’m proud of Bertrand in multiple ways,” Might said. “I would often tell people to imagine a being created without the ability to even feel malice. He was just a pure being, and I loved that about him.”
In recent years, the science that led to his diagnosis has also begun to unravel the biology of NGLY1 deficiency and its impact on patients. A project sponsored by the National Institutes of Health is underway to screen hundreds of thousands of molecules for therapeutic potential against the illness, while Might has used computational methods to identify treatments that showed efficacy in animal subjects.

On Bertrand’s last day in the hospital, as his condition continued to deteriorate, his father read him an email from the father of another patient with his illness. It said that the Food and Drug Administration seemed pleased with pre-clinical studies of a gene therapy for NGLY1 and outlined a series of steps toward a clinical trial.

“It was so meaningful to know the community that Bertrand formed has spawned efforts well beyond my own,” Might said. “And in the end, he died in a world where the hope of a cure existed.”

Might and his wife, Cristina, celebrated the birth of their first child on Dec. 9, 2007. They named him Bertrand, in honor of British mathematician Bertrand Russell. But celebration soon turned to concern, as it quickly became apparent that something was wrong with the infant...

“It turns out he was the first human ever diagnosed with missing this gene and to have it linked to a disease,” Might says. “Our son was literally patient zero. Then the question became, what do we do with that information? We now know the exact molecular cause of this disease. Can we treat it?”
The Mights then needed to better understand the constellation of disorders caused by the genetic mutation and pathways to potential therapies. To achieve that, they needed to attract the attention of researchers, pharmaceutical companies, and the FDA. To achieve that, they needed to find more people with this ultra-rare disease.

Years earlier, Might had created a viral phenomenon with an online blog post called “The Illustrated Guide to a Ph.D.,” which was eventually translated into dozens of languages. He took lessons he had learned about viral marketing, search engine optimization, and leveraging social media and applied them to his search for more people like Bertrand.

In May 2012, he posted an essay to his personal website titled “Hunting Down My Son’s Killer.” The post was shared on social media and Reddit within hours. The next day, Might was contacted by the editor of Gizmodo, an influential tech blog, who asked for permission to republish it. Within 24 hours, the post had gone viral.

The exposure worked. Over the next few months, Might was contacted by other families struggling with the NGLY1 deficiency and researchers volunteering to help. Further tests revealed that without a functioning NGLY1 gene, Bertrand was deficient in a sugar called N-acetylglucosamine, which is a derivative of glucose. Far from being a rare resource, N-acetylglucosamine can be purchased on Amazon. Might ordered some and, after taking it himself with no ill effects, he began giving it to his son.

A mere three days later, Might walked into his son’s room and witnessed an incredible sight: Bertrand was crying. Not yelling—crying, with actual tears rolling down his cheeks.

“It was amazing to walk in at that moment and see him crying,” Might says. “They may have just been tears, but they were an ocean of science for the disease. They unlocked so much about this disorder.”


Tuesday, August 24, 2021

Prenatal caffeine exposure: association with neurodevelopmental outcomes

Zhang R, Manza P, Volkow ND. Prenatal caffeine exposure: association with neurodevelopmental outcomes in 9- to 11-year-old children. J Child Psychol Psychiatry. 2021 Jul 27. doi: 10.1111/jcpp.13495. Epub ahead of print. PMID: 34318489.


Background: Despite the widespread use of caffeine including consumption during prenancy, the effect of prenatal caffeine exposure on child brain development and behavior is unclear. 

Methods: To address this, we used data from the Adolescent Brain and Cognitive Development Study (n = 11,875 children aged 9-11 years from 22 sites across the United States). We explored the associations between prenatal caffeine exposure and various developmental outcomes including birth outcomes, physical health, behavior problems, cognition, substance use and brain structure in children, and evaluated dose effects.                                          

Results: Among 9,978 children (4,745 females) who had valid data for prenatal caffeine exposure and whose mothers did not use drugs of abuse after knowing of pregnancy, 4,170 (41.79%) had no prenatal caffeine exposure, 2,292 (22.97%) had daily, 1,933 (19.37%) had weekly, and 1,583 (15.86%) had less than weekly exposures. Prenatal caffeine exposure including the widely recommended 'safe' dose was associated with greater externalizing problems, whereas greater BMI and soda consumption were only observed in children with high dose exposures (3+ per day). Notably, the effect size for association of externalizing problems with prenatal caffeine exposure was comparable with that reported for prenatal alcohol (The American Journal of Psychiatry, 177, 2020 and 1060) and prenatal cannabis (JAMA Psychiatry, 78, 2020 and 64) exposures from previous ABCD publications. Additionally, prenatal caffeine exposure was associated with brain structural changes that included greater posterior and lower frontal cortical thickness and altered parietooccipital sulcal depth. 

Conclusions: The recommended 'safe' dose of caffeine during pregnancy should be carefully studied to assess whether the behavioral and brain correlates observed here are clinically relevant and determine whether it needs adjustment. Because of the high prevalence of caffeine use in the general population, studies on prenatal exposure to drugs of abuse should include prenatal caffeine use as a covariate.

Courtesy of:

Sleep problems in children with autism spectrum disorder

Chen H, Yang T, Chen J, Chen L, Dai Y, Zhang J, Li L, Jia F, Wu L, Hao Y, Ke X, Yi M, Hong Q, Chen J, Fang S, Wang Y, Wang Q, Jin C, Li T. Sleep problems in children with autism spectrum disorder: a multicenter survey. BMC Psychiatry. 2021 Aug 16;21(1):406. doi: 10.1186/s12888-021-03405-w. PMID: 34399715; PMCID: PMC8365936.


Background: High prevalence of sleep problems have been reported in children with Autism Spectrum Disorder (ASD). This study aims to investigate the sleep conditions of ASD children in China, and explore the relationship between the common sleep problems and core symptoms and developmental levels.

Methods: Using a cross-sectional design, we included 2 to 7-year-old children from 13 cities in China: 1310 with ASD and 1158 with typically-developing (TD) children. The neurodevelopmental level was evaluated with the revised Children Neuropsychological and Behavior Scale (CNBS-R2016). ASD were diagnosed with DSM-5 and Child Autism Rating Scale (CARS). the Social Responsiveness Scale (SRS), the Autism Behavior Checklist (ABC) and the communication warning behavior sub-scale in CNBS-R2016 valued autism behaviors. The children' s sleep habits questionnaire (CSHQ) assessed sleep conditions.

Results: The prevalence of sleep disorders in ASD children was significantly higher than that in TD (67.4% vs. 51%, p < 0.01), and among them the four dimensions with the highest prevalence of sleep problems were bedtime resistance (25.6%), sleep anxiety (22.7%), sleep onset delay (17.9%) and daytime sleepiness (14.7%). ASD children with sleep onset delay or sleep anxiety had higher ABC, SRS scores and higher scores on communication warning behavior with sleep anxiety, with daytime sleepiness had higher ABC, SRS and CARS scores, and with bedtime resistance had higher SRS total scores. Differences in the neurodevelopmental level were not significant.

Conclusion: Children with ASD have a higher prevalence of sleep problems. Bedtime resistance, anxiety, sleep onset delay and daytime sleepiness may be related to the core symptoms, but not be related to the developmental level in ASD children. In the clinic, sleep assessment should be included in the routine of ASD visits, and during the intervention, sleep hygiene education is as important as the treatment of biological factors.

Courtesy of:


Sunday, August 22, 2021

SELENON (SEPN1)-related myopathy

Inspired by a patient

Villar-Quiles RN, von der Hagen M, Métay C, Gonzalez V, Donkervoort S, Bertini E, Castiglioni C, Chaigne D, Colomer J, Cuadrado ML, de Visser M, Desguerre I, Eymard B, Goemans N, Kaindl A, Lagrue E, Lütschg J, Malfatti E, Mayer M, Merlini L, Orlikowski D, Reuner U, Salih MA, Schlotter-Weigel B, Stoetter M, Straub V, Topaloglu H, Urtizberea JA, van der Kooi A, Wilichowski E, Romero NB, Fardeau M, Bönnemann CG, Estournet B, Richard P, Quijano-Roy S, Schara U, Ferreiro A. The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series. Neurology. 2020 Sep 15;95(11):e1512-e1527. doi: 10.1212/WNL.0000000000010327. Epub 2020 Aug 13. PMID: 32796131; PMCID: PMC7713742.


Objective: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series.

Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.

Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification.

Conclusion: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, van Tilburg WCM, Buckens SCFM, Dittrich ATM, Draaisma JMT, Janssen MCH, Kamsteeg EJ, van Kleef ESB, Koene S, Smeitink JAM, Küsters B, van Tienen FHJ, Smeets HJM, van Engelen BGM, Erasmus CE, Voermans NC. Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study. BMC Neurol. 2021 Aug 12;21(1):313. doi: 10.1186/s12883-021-02336-z. PMID: 34384384; PMCID: PMC8357962.


Background: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.

Methods: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.

Discussion: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.

Conclusion: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.

Varone E, Pozzer D, Di Modica S, Chernorudskiy A, Nogara L, Baraldo M, Cinquanta M, Fumagalli S, Villar-Quiles RN, De Simoni MG, Blaauw B, Ferreiro A, Zito E. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biol. 2019 Jun;24:101176. doi: 10.1016/j.redox.2019.101176. Epub 2019 Mar 23. PMID: 30921636; PMCID: PMC6438913.


Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a congenital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON-devoid cells, and blunt the insulin-mediated glucose uptake of SELENON-devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations.

Bachmann C, Noreen F, Voermans NC, Schär PL, Vissing J, Fock JM, Bulk S, Kusters B, Moore SA, Beggs AH, Mathews KD, Meyer M, Genetti CA, Meola G, Cardani R, Mathews E, Jungbluth H, Muntoni F, Zorzato F, Treves S. Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies. Hum Mutat. 2019 Jul;40(7):962-974. doi: 10.1002/humu.23745. Epub 2019 Apr 1. PMID: 30932294; PMCID: PMC6660981.


Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation-contraction coupling. The mechanism by which recessive SELENON variants cause Multiminicore disease (MmD) is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification, and noncoding RNA expression, to understand the pathomechanism of MmD. We identified biochemical changes that are common in patients harboring recessive RYR1 and SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with RYR1 and SELENON variants identified >3,500 common aberrantly methylated genes, many of which are involved in calcium signaling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies.




Thursday, August 19, 2021

Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or multisystem inflammatory syndrome

LaRovere KL, Riggs BJ, Poussaint TY, Young CC, Newhams MM, Maamari M, Walker TC, Singh AR, Dapul H, Hobbs CV, McLaughlin GE, Son MBF, Maddux AB, Clouser KN, Rowan CM, McGuire JK, Fitzgerald JC, Gertz SJ, Shein SL, Munoz AC, Thomas NJ, Irby K, Levy ER, Staat MA, Tenforde MW, Feldstein LR, Halasa NB, Giuliano JS Jr, Hall MW, Kong M, Carroll CL, Schuster JE, Doymaz S, Loftis LL, Tarquinio KM, Babbitt CJ, Nofziger RA, Kleinman LC, Keenaghan MA, Cvijanovich NZ, Spinella PC, Hume JR, Wellnitz K, Mack EH, Michelson KN, Flori HR, Patel MM, Randolph AG; Overcoming COVID-19 Investigators. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol. 2021 May 1;78(5):536-547. doi: 10.1001/jamaneurol.2021.0504. PMID: 33666649; PMCID: PMC7936352.


Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear.

Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19.

Setting, design, and participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features.

Exposures: Severe acute respiratory syndrome coronavirus 2.

Main outcomes and measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge.

Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died.

Conclusions and relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.


Wednesday, August 18, 2021

Pathogenic MAST3 variants in the STK domain are associated with epilepsy

Spinelli E, Christensen KR, Bryant E, Schneider A, Rakotomamonjy J, Muir AM, Giannelli J, Littlejohn RO, Roeder ER, Schmidt B, Wilson WG, Marco EJ, Iwama K, Kumada S, Pisano T, Barba C, Vetro A, Brilstra EH, van Jaarsveld RH, Matsumoto N, Goldberg-Stern H, Carney PW, Andrews PI, El Achkar CM, Berkovic S, Rodan LH; Undiagnosed Diseases Network (UDN), McWalter K, Guerrini R, Scheffer IE, Mefford HC, Mandelstam S, Laux L, Millichap JJ, Guemez-Gamboa A, Nairn AC, Carvill GL. Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy. Ann Neurol. 2021 Aug;90(2):274-284. doi: 10.1002/ana.26147. Epub 2021 Jul 13. PMID: 34185323; PMCID: PMC8324566.


Objective: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. 

Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. 

Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. 

Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex.

Tuesday, August 17, 2021

MicroRNAs as biomarkers of Charcot-Marie-Tooth Disease Type 1A

Hongge Wang, Matthew Davison, Kathryn Wang, Tai-he Xia, Katherine M. Call, Jun Luo, Xingyao Wu, Riccardo Zuccarino, Alexa Bacha, Yunhong Bai, Laurie Gutmann, Shawna M.E. Feely, Tiffany Grider, Alexander M. Rossor, Mary M. Reilly, Michael E. Shy, John Svaren. MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A. Neurology Aug 2021, 97 (5) e489-e500; DOI: 10.1212/WNL.0000000000012266


Objective To determine whether microRNAs (miRs) are elevated in the plasma of individuals with the inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.

Methods We performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next-generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rasch-modified CMT Examination and Neuropathy Scores, ulnar compound muscle action potentials, and motor nerve conduction velocities.

Results After an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve. Comparison to other candidate biomarkers for CMT1A (e.g., neurofilament light) measured on the same sample set shows a comparable elevation of several miRs (e.g., miR133a, -206, -223) and ability to discriminate cases from controls. Neurofilament light levels were most highly correlated with miR133a. In addition, the putative Schwann cell miRs (e.g., miR223, -199a, -328, -409, -431) correlate with the recently described transmembrane protease serine 5 (TMPRSS5) protein biomarker that is most highly expressed in Schwann cells and also elevated in CMT1A plasma.

Conclusions These studies identify a set of miRs that are candidate biomarkers for clinical trials in CMT1A. Some of the miRs may reflect Schwann cell processes that underlie the pathogenesis of the disease.

Classification of Evidence This study provides Class III evidence that a set of plasma miRs are elevated in patients with CMT1A.


Friday, August 13, 2021

Food selectivity is associated with more severe autism symptoms in toddlers with autism spectrum disorder

Stolar O, Zachor DA, Itzchak EB. Food selectivity is associated with more severe autism symptoms in toddlers with autism spectrum disorder. Acta Pediatrica|August 13, 2021 

Background: Studies of children with autism spectrum disorder (ASD) report a high prevalence of eating abnormalities (46-92%) compared to typically developed (TD) toddlers (25-50%), and food selectivity is considered the most frequent eating problem in ASD. Notwithstanding, there is no consensus regarding the meaning of the term "food selectivity". Children with ASD and food selectivity are at a greater risk for having inadequate intake of various minerals and vitamins that might affect development. Previous research reported that food selectivity was positively related to parent-reported autism symptoms but unrelated to autism severity or linguistic and cognitive abilities as measured by professionals. Two possible mechanisms may underlie co-morbid food selectivity in ASD: sensory over-responsivity and inflexible adherence to routines or rituals that are part of the restricted and repetitive behaviors (RRB) criterion for ASD. In addition, as meals often have social facets, food selectivity might also be related to deficits in the social-communication domain. The current study investigates these possibilities with two major aims: 1. To examine the association between significant food selectivity and autism severity in toddlers, as assessed by parents and intervention staff; and 2. To compare autism severity in toddlers as assessed by parents and intervention staff.  

Method: The study was approved by the Helsinki committee of the Assaf Harofeh Medical Center and included 180 toddlers (147 boys; 33 girls), aged 16-39 months (M = 28.88; SD = 4.73), diagnosed with ASD based on DSM IV or DSM 5 criteria, according to the date of the diagnostic evaluation. Two assessment instruments were utilized. The Social Communication Questionnaire (SCQ), based on the original Autism Diagnostic Interview (ADI), consists of 40 yes/no questions to be completed by a parent/caregiver. It yields scores for: 1. reciprocal social interaction (RSI); 2. language/communication; 3. restricted, repetitive, and stereotyped behaviors (RRBS) and interests. Higher scores reflect more severe ASD symptoms.  Eating habit evaluation was based on two sources of information. Parents filled out a detailed questionnaire on the foods the participant would eat, eating behaviors (i.e., licking food, spitting food out, or stuffing food), type of textures, and a detailed dietary intake (vegetables, meat, carbohydrates, and dairy). If food selectivity was reported, parents were requested to complete a three-day dietary intake. Additionally, the Early Intervention Day Care Centers (EIDCC) staff recorded the toddlers' eating habits during mealtimes. We defined 'moderate-severe food selectivity' as eating fewer than 16 different food items and a lack of diversity in food groups, meaning eating fewer than three different foods from each food group and only when supported by reports of both parents and staff. 

Procedure: This study was conducted in 11 different government funded EIDCCs for toddlers with ASD. During the first two months in the EIDCC, autism severity was assessed using the SCQ, which was completed separately by the parents and the behavioral analyst or psychologist in each intervention center. Of the study population (N = 180), fifty-eight participants (32.2%) were excluded from the study due to having other eating problems (only baby formula or puree food fed (n=6) and mild food selectivity (n=31) and abnormal eating such as, spitting, stuffing and licking food (n=21). Of the remaining participants, two subgroups were defined: one with 'moderate -severe food selectivity' (n = 49, 27.2%) and the second without food selectivity (n =73, 40.6%). The two groups did not differ significantly in sex ratio 2 = 2.59, p > .05), age, maternal age, or maternal education (p > .05) 

Results: The prevalence of food selectivity (27.2%) in the current study was significantly higher than the reported prevalence in TD toddlers (9.5%)5 using a chi goodness of fit analysis 2 = 133.43, p < .001). A 2X2 (with/without food selectivity; parent/intervention staff evaluation) MANOVA with repeated measures for the rater, for the SCQ-RSI, and for the communication and RRSB subdomain scores, yielded a food selectivity main effect [F (3,80) = 4.58, p < .01, µ2 = .147). As presented in Table 1, the univariate ANOVAs revealed significant differences between the groups for the SCQ RSI and communication subscale scores. The group with food selectivity had higher scores in these measures, reflecting more severe ASD symptoms for this group. In addition, the analysis yielded a significant rater main effect [F (3,80) = 32.24, p < .001, µ2 = .547). The intervention staff rated participants significantly higher on the RSI and communication subscales than the parents did (Table 1). Interestingly, for the RRSB subscale, parents gave higher scores than the intervention staff did (a trend toward statistical significance). No significant interaction between the two variables - food selectivity and rater - was noted [F (3,80) = 0.35, p > .05, µ2 = .013). 

Discussion: We found food selectivity is common in toddlers with ASD in comparison to TD toddlers. In addition, having significant food selectivity in toddlers with ASD is associated with more severe social-communication symptoms as reported by parents and early intervention staff. This finding suggests that social-communication deficits in toddlers with ASD might interrupt the social aspects of mealtime and result in food selectivity behaviors. These communication deficits may result in reduced ability of parents to encourage and convince their child to experience a variety of foods. This study did not support the contribution of RRB to food selectivity, as proposed by previous studies.6 This is the first study conducted in toddlers to demonstrate the association between food selectivity and the severity of ASD symptoms. Interestingly, the intervention staff reported more severe impairments in reciprocal social interaction and communication, while the parents reported more severe RRB symptoms. It is possible that the intervention staff is experienced in recognizing social-communication deficits typical to ASD at this early stage, and that in the intervention program, children have fewer opportunities to exhibit stereotypical behaviors because they are participating in one-on-one therapy throughout the day. In addition, the intervention staff applies behavioral methods to reduce the intensity of the RRBs. To our best knowledge, this is the first report of differences in the perception of ASD symptoms between parents and intervention staff in toddlers. Important clinical implications from this study include the need to consider the child's variety of food as part of diagnostic procedures and intervention programs, since it is related to the severity of ASD symptoms.  

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