Tuesday, May 31, 2022

Exclusively breastfed girls had higher IQ and SI results compared with bottle-fed girls (but not statistically significant)

AlThuneyyan DA, AlGhamdi FF, AlZain RN, AlDhawyan ZS, Alhmly HF, Purayidathil TS, AlGindan YY and Abdullah AA (2022) The Effect of Breastfeeding on Intelligence Quotient and Social Intelligence Among Seven- to Nine-Year-Old Girls: A Pilot Study. Front. Nutr. 9:726042. doi: 10.3389/fnut.2022.726042

Background: Breastfeeding is an optimal infant feeding method that provides adequate nutrients, achieves healthy growth and development, and enhances the health status of both infants and mothers. Breast milk contains a variety of substances that might positively affect cognition and the development of children's psychomotor abilities.

Objective: This study aimed to examine the variations in intelligence quotient (IQ), social intelligence (SI), and body mass index (BMI) among 7- to 9-year-old girls who were exclusively breastfed, exclusively bottle-fed, or mixed-fed during their first 6 months of life.

Methods: This study involved 111 healthy girls, aged 7 to 9 years, who were recruited from nine government and private schools in Dammam, Kingdom of Saudi Arabia. Raven's Coloured Progressive Matrices were used to measure the participants' IQs, and the Vineland Social Maturity Assessment was used to measure their SI through individual interviews. Anthropometric measurements were obtained using standard methods.

Results: The breastfed group showed a greater number of above-average IQ test scores (35 vs. 23%; P = 0.479) and better SI scores (78 vs. 55%; P = 0.066) compared with the bottle-fed group. The number of girls with normal BMIs was significantly higher in the breastfed group than in the bottle-fed (68 vs. 41%; P = 0.045) or mixed-fed groups.

Conclusion: Exclusively breastfed girls had higher IQ and SI results compared with bottle-fed girls. However, unlike the BMI differences, these results were not statistically significant. This study provides fundamental observational data and can be further modified for use on a larger national-scale level.

KCNC2 mutations

Schwarz N, Seiffert S, Pendziwiat M, Rademacher AV, Brünger T, Hedrich UBS, Augustijn PB, Baier H, Bayat A, Bisulli F, Buono RJ, Bruria BZ, Doyle MG, Guerrini R, Heimer G, Iacomino M, Kearney H, Klein KM, Kousiappa I, Kunz WS, Lerche H, Licchetta L, Lohmann E, Minardi R, McDonald M, Montgomery S, Mulahasanovic L, Oegema R, Ortal B, Papacostas SS, Ragona F, Granata T, Reif PS, Rosenow F, Rothschild A, Scudieri P, Striano P, Tinuper P, Tanteles GA, Vetro A, Zahnert F, Goldberg EM, Zara F, Lal D, May P, Muhle H, Helbig I, Weber Y. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. Neurology. 2022 May 17;98(20):e2046-e2059. doi: 10.1212/WNL.0000000000200660. Epub 2022 Mar 21. PMID: 35314505.


Background and objectives: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.

Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.

Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.

Discussion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Rademacher A, Schwarz N, Seiffert S, Pendziwiat M, Rohr A, van Baalen A, Helbig I, Weber Y, Muhle H. Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy. Neuropediatrics. 2020 Oct;51(5):368-372. doi: 10.1055/s-0040-1710524. Epub 2020 May 11. PMID: 32392612.


Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype-phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.

Rydzanicz M, Zwoliński P, Gasperowicz P, Pollak A, Kostrzewa G, Walczak A, Konarzewska M, Płoski R. A recurrent de novo variant supports KCNC2 involvement in the pathogenesis of developmental and epileptic encephalopathy. Am J Med Genet A. 2021 Nov;185(11):3384-3389. doi: 10.1002/ajmg.a.62455. Epub 2021 Aug 27. PMID: 34448338.


Developmental and epileptic encephalopathies (DEE) are a heterogenous group of conditions characterized by the co-occurrence of epilepsy and intellectual/developmental disability. Despite several known DEE-related genes, including these encoding ion channels, still many cases remain without molecular diagnosis. Here, we present a 2-year-old girl with severe DEE in whom whole exome sequencing revealed de novo p.(Val471Leu) variant in the KCNC2 encoding Kv3.2, a voltage-gated potassium channel. To the best of our knowledge, this is the third DEE case due to KCNC2 mutation. Our clinical and molecular findings, particularly the recurrence of p.(Val471Leu) in patient with similar clinical phenotype, further support KCNC2 as a novel DEE-associated gene.

Sunday, May 29, 2022

A role for insulin-like growth factor 1 in the generation of epileptic spasms

Courtesy of a colleague

Ballester-Rosado CJ, Le JT, Lam TT, Mohila CA, Lam S, Anderson AE, Frost JD Jr, Swann JW. A Role for Insulin-like Growth Factor 1 in the Generation of Epileptic Spasms. Ann Neurol. 2022 Apr 25. doi: 10.1002/ana.26383. Epub ahead of print. PMID: 35467038.


Objective: Infantile spasms are associated with a wide variety of clinical conditions, including perinatal brain injuries. We have created a model in which prolonged infusion of tetrodotoxin (TTX) into the neocortex, beginning in infancy, produces a localized lesion and reproduces the behavioral spasms, electroencephalogram (EEG) abnormalities, and drug responsiveness seen clinically. Here, we undertook experiments to explore the possibility that the growth factor IGF-1 plays a role in generating epileptic spasms.

Methods: We combined long-term video EEG recordings with quantitative immunohistochemical and biochemical analyses to unravel IGF-1's role in spasm generation. Immunohistochemistry was undertaken in surgically resected tissue from infantile spasms patients. We used viral injections in neonatal conditional IGF-1R knock-out mice to show that an IGF-1-derived tripeptide (1-3)IGF-1, acts through the IGF-1 receptor to abolish spasms.

Results: Immunohistochemical methods revealed widespread loss of IGF-1 from cortical neurons, but an increase in IGF-1 in the reactive astrocytes in the TTX-induced lesion. Very similar changes were observed in the neocortex from patients with spasms. In animals, we observed reduced signaling through the IGF-1 growth pathways in areas remote from the lesion. To show the reduction in IGF-1 expression plays a role in spasm generation, epileptic rats were treated with (1-3)IGF-1. We provide 3 lines of evidence that (1-3)IGF-1 activates the IGF-1 signaling pathway by acting through the receptor for IGF-1. Treatment with (1-3)IGF-1 abolished spasms and hypsarrhythmia-like activity in the majority of animals.

Interpretation: Results implicate IGF-1 in the pathogenesis of infantile spasms and IGF-1 analogues as potential novel therapies for this neurodevelopmental disorder.

Tuesday, May 24, 2022

Neonatal brain injury influences structural connectivity and childhood functional outcomes

Ramirez A, Peyvandi S, Cox S, Gano D, Xu D, Tymofiyeva O, McQuillen PS. Neonatal brain injury influences structural connectivity and childhood functional outcomes. PLoS One. 2022 Jan 5;17(1):e0262310. doi: 10.1371/journal.pone.0262310. PMID: 34986206; PMCID: PMC8730412.


Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12-18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury.


While using brain connectivity as a predictive tool is the ultimate aim of their work, Dr. McQuillen said it was encouraging to see that, overall, the children had good outcomes given their conditions—a testament to the value of therapeutic hypothermia for HIE, or birth asphyxia.

“One way to put it would be, they did surprisingly well,” he said. For the congenital heart disease cohort, he said, “we could find some more areas that they performed worse in, but by and large they're doing OK. This is not a devastating brain injury that babies with congenital heart disease have. It's just that they have a lot of problems in a lot of different areas.”...

“We found distinct differences in how the brains are wired in children with congenital heart disease as compared with children with birth asphyxia,” Dr. McQuillen said.

Because the CHD group had the worse developmental scores in language, researchers examined pathways that have been associated with language in adults. They found connectivity in two areas—superior longitudinal fasciculus (SLF) tract 2 and SLF tract 3—to be linked with language scores. The greater the connectivity of SLF2, which connects the inferior parietal to the frontal lobe, the lower the expressive language scores were at 30 months. And the greater the connectivity of SLF3, which connects the supramarginal gyrus to the frontal lobe, the lower the overall language scores were at 12 to 18 months.

It might seem counterintuitive that greater connectivity might lead to worse outcomes, but it makes sense given the complex nature of brain connectivity and function, Dr. McQuillen said.

“In order to get normal language function, you have to have the orchestrated involvement of a number of different pathways,” he said. “So, any sort of imbalance can lead to dysfunction.”...

Gabrielle deVeber, MD, a pediatric neurologist and professor of pediatrics at the Hospital for Sick Children in Toronto, noted how well the children fared. “Cardiac kids actually still do quite well even in this study,” she said. “The majority, 50 percent or above, scored normally in cognitive, language, or motor [domains] by 30 months. However, an important point is that outcomes may be even better than this report if the full spectrum of children with congenital heart disease are studied and not just the ones who are sick newborns, in-patients, and are imaged in the newborn period,” meaning they are more likely have more severe versions of CHD.

She said the study also shows that the presence of intact connectivity may not be sufficient to ensure normal network function.


Clinical and magnetic resonance imaging characteristics of pediatric acute disseminating encephalomyelitis with and without antibodies to myelin oligodendrocyte glycoprotein

Lei M, Cui Y, Dong Z, Zhi X, Shu J, Cai C and Li D (2022) Clinical and Magnetic Resonance Imaging Characteristics of Pediatric Acute Disseminating Encephalomyelitis With and Without Antibodies to Myelin Oligodendrocyte Glycoprotein. Front. Pediatr. 10:859932. doi: 10.3389/fped.2022.859932

Background: Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated disorders (MOGADs) have been considered as a new inflammatory disease entity of the central nervous system (CNS) and have heterogeneous clinical and imaging presentations. Acute disseminated encephalomyelitis (ADEM) is one of the most important phenotypes. Our research is aimed to compare the clinical and magnetic resonance imaging (MRI) characteristics of ADEM with or without MOG-IgG in pediatric-acquired demyelinating syndromes (ADSs).

Methods and Results: We retrospectively reviewed the clinical characteristics, MRI features, and outcomes of pediatric patients with ADSs from March 2017 to February 2021 in our center. MOG-IgG was analyzed by transfected cell-based assay (CBA). Among 46 children with ADEM, 21 children (11 girls and 10 boys) were positive for MOG-IgG. Headache, fever, vomiting, vertigo, ataxia, and decreased muscle strength were common in all enrolled children. No significant difference existed in demographic characteristics, symptoms at an initial episode, or laboratory cerebrospinal fluid (CSF) findings between children with MOG-IgG and children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed widespread, poorly demarcated bilateral lesions, especially in cortical and subcortical white matter, and spinal MRI often showed lesions spanning more than three segments. The significant difference in MRI features between the two groups was the presence of lesions in the thalamus and cortical area (p < 0.05). Most children in both groups showed clinical improvement 1 week after immunotherapy and achieved recovery during their hospital stay. Three children with MOG-IgG and four children without MOG-IgG had one or more relapsing courses with median interattack intervals of 4 (range: 1–7) months and 10 (range: 1–24) months, respectively. New clinical symptoms and lesions on cerebral and spinal MRI were found during relapsing courses in two groups. No recurrences were recorded 6–51 months after each patient’s last episode.

Conclusions: There was no significant difference in clinical characteristics between ADEM children with MOG-IgG and ADEM children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed large, bilateral lesions and spinal MRI often showed lesions spanning more than three segments. Children achieved a favorable outcome regardless of MOG-IgG serostatus.

Serious cardiac arrhythmias detected by subcutaneous long-term cardiac monitors in patients with drug-resistant epilepsy

Shobi Sivathamboo, Zining Liu, Fiona Sutherland, Erica Minato, Pablo Casillas-Espinosa, Nigel C. Jones, Marian Todaro, Udaya Seneviratne, Varduhi Cahill, Raju Yerra, Christopher French, John-Paul Nicolo, Piero Perucca, Patrick Kwan, Paul Sparks, Terence J. O'Brien. Serious Cardiac Arrhythmias Detected by Subcutaneous Long-term Cardiac Monitors in Patients With Drug-Resistant Epilepsy.Neurology May 2022, 98 (19) e1923-e1932; DOI: 10.1212/WNL.0000000000200173


Background and Objectives Epilepsy is associated with an increased risk of cardiovascular disease and premature mortality, including sudden unexpected death in epilepsy (SUDEP). Serious cardiac arrythmias might go undetected in routine epilepsy and cardiac investigations.

Methods This prospective cohort study aimed to detect cardiac arrhythmias in patients with chronic drug-resistant epilepsy (≥5 years duration) using subcutaneous cardiac monitors for a minimum follow-up duration of 12 months. Participants with known cardiovascular disease or those with abnormal 12-lead ECGs were excluded. The device was programmed to automatically record episodes of tachycardia ≥140 beats per minute (bpm), bradycardia ≤40 bpm for ≥3 seconds, or asystole ≥3 seconds.

Findings Thirty-one patients underwent subcutaneous cardiac monitoring for a median recording duration of 2.2 years (range 0.5–4.2). During this time, 28 patients (90.3%) had episodes of sustained (≥30 seconds) sinus tachycardia, 8/31 (25.8%) had sinus bradycardia, and 3 (9.7%) had asystole. Three patients (9.7%) had serious cardiac arrhythmias requiring additional cardiac interventions. Among them, 2 patients had prolonged sinus arrest and ventricular asystole (>6 seconds), leading to pacemaker insertion in one, and another patient with epileptic encephalopathy had multiple episodes of recurrent nonsustained polymorphic ventricular tachycardia and bundle branch conduction abnormalities. The time to first detection of a clinically significant cardiac arrhythmia ranged between 1.2 and 26.9 months following cardiac monitor insertion.

Discussion Implantable cardiac monitors detected a high incidence of clinically significant cardiac arrhythmias in patients with chronic drug-resistant epilepsy, which may contribute to the incidence of premature mortality, including SUDEP.

Monday, May 23, 2022

Does having children cause dementia?


Does Having Children Cause Dementia? What To Make Of A New Study

Elizabeth Bauer Senior Contributor

Earlier this month, a dramatic headline appeared at the New York Post: 

“No kidding: Rearing 3 or more children could make you literally lose your mind, study says.” 

The dramatic statement from the article, three sentences in? 

“The scientists found that having three or more kids vs. two children has a “negative effect on late-life cognition” — the equivalent of being 6.2 years older.” 

Wowza. Score one for the Zero Population Growth folks, I guess. Surely there are all manner of factors playing into the equation, right? But it turns out that there is a “there” there, if you pay close attention to what the study does and does not say, and it’s not about childbearing decisions but a much bigger picture. 

The actual study (with free public access to the PDF), “Does Childbearing Affect Cognitive Health in Later Life? Evidence From an Instrumental Variable Approach,“ by Eric Bonsang and Vergard Skirbekk, was published last month in the journal Demography. It does not intentionally try to assess the effect of three vs. two kids but that’s a side effect, so to speak, of the statistical method the study uses. Here’s how it works: 

If one were simply to take a look at the number of children an older adult has and their cognition according to the tests that measure this, you wouldn’t really know whether one caused the other, in which direction, or whether something else entirely caused both. In other words, you’d just have a correlation. It could be possible that some unknown predisposition to dementia also causes people to have more rather than fewer children. Hypothetically, you could get around that by randomly assigning the number of children people have, but that would rightly be considered seriously unjust, so scholars have developed econometric methods in which they try to find situations in real life that resemble random experiments, and that’s what they did here, using the expectation that at least some of the time, couples who have either two boys or two girls will try for a third child.

It turns out that this is actually true (or at least was true) and the study authors can demonstrate it. Using a major ongoing survey of older adults (ages 50+) across Europe, the authors calculated that, as expected, of those survey participants who had at least two children, 50% of the time, those children were both of the same sex, and 50% of the time they had one of each sex. And a couple with two same-sex first- and second-born children turns out to have been seven percentage points more likely to have gone on to have more children, than a couple with one of each. Because of this difference, researchers can look at the effect of having one of each or a matched pair, on dementia later in life, do some further math around the proportion of people in this situation, and voila, you’ve got a calculation which, if it passes the statistical significance tests, is considered to truly show causality: among those who have three or more children because they missed having a boy (or a girl), compared to those who would have tried for that desired boy (or girl) but didn’t need to because they already had one, there is a greater incidence of dementia. 

Specifically, taking the dementia screening scores from this study, and creating a composite score where the average score is set at 0 and the standard deviation set to 1, having more than 2 children reduces a woman’s dementia score by 0.311 and a man’s dementia score by 0.355.

This math is legitimate, though in order to take the final step in this mathematical method, called an “instrumental variable,” it requires making an assumption that the difference in dementia risks and likelihoods for the group of people who have an “extra” child because they really wanted at least one boy and girl, compared to those who got the desired mix on the first try, can be generalized to everyone else.

But what explains this result and what do we do with it? The answer is not “have fewer children.” Instead, what matters is understanding what the reason is for this effect and here what’s crucial is their result dividing up the countries in the study into four quarters: in all four regions of Northern, Western, Eastern, and Southern Europe, parents were more likely to have three or more children if their first two children were of the same sex, but only in Northern Europe did the overall analysis produce the statistically significant result that dementia was more likely as a result. On the same measure where the average score on a cognitive test was set at 0 and the range of scores was adjusted so that a -1 was 1 standard deviation lower, here are the 3+ child effects on scores for the four regions: 

Northern Europe: -0.781 (p = .01) 

Western Europe: -0.269 (p = .31) 

Eastern Europe: -0.211 (p = .48) 

Southern Europe: -0.204 (p = .57) 

The p values are a statistical method for telling how likely a result is just by random chance; for all regions except Northern Europe, there is a strong likelihood that the apparent reduction in cognition is just due to flukes in collecting the random sample, but for Northern Europe the effect is strong enough that it’s no longer credible that it is just random. 

So why should this effect be seen in Northern Europe in particular? The method used in this study doesn’t have any answers to offer but can only suggest potential explanations. Specifically, there are effects which have the potential to balance each other out, depending on circumstances: the more children one has, the more likely it is that one has financial stress due to added costs and reduced family income due to interrupted employment by mothers; at the same time, though, having more children boosts the degree of having contact with children which increases social engagement and reduces the likelihood of dementia in that way. In Northern Europe, the cost of living is particularly high so that stresses of a large family may likewise be higher, despite the social insurance support. At the same time, however, survey participants in Northern Europe with three or more children do not benefit from increased rates of contact with their children, in the same was as elders in other regions do, so they experienced a lose-lose set of circumstances — greater costs in rearing children without even the payoff of more time spent with family as they age. 

It is also striking to consider the historical context when looking at this number-of-children cutoff, which, again, they didn’t choose for any reason other than that only with two children is it possible to have “one of each.” The waves of the survey took place between 2004 and 2015; while the survey covered adults beginning at age 50, dementia is most likely after age 80, so that the individuals involved were having their families in the 1960s or thereabouts. This was the point in time at which, in the United States, we were transitioning from a Baby Boom to a Baby Bust — as the World Bank data below makes clear — but the various European countries had much lower birth rates all along. (To be clear, the World Bank data begins in 1960 so the lack of data before this point is a matter of availability and says nothing about the significance of pre-1960 changes.)

At the same time, this was the time when women began entering the workforce in much larger numbers in these countries. Again, per the World Bank (and by decade in part due to significant gaps in the earlier years):

Women in Spain and Italy have had much lower labor force participation rates, in general — does this mean that the effect of an extra child might not have affected them in the same way as Scandinavian women? And, of course, the social supports now prevalent across Europe were in their infancy two generations ago. All in all, these differences suggest that it would be very interesting to see the same study repeated in the United States, where the equivalent study, the Health and Retirement Study, has been conducted for a decade and a half longer, perhaps, indeed, long enough to see whether there have been changes over time in the association between three children and dementia, and drill down further into what sorts of circumstances produce this. 

So what’s to be learned? Not that children are bad, of course — but this does serve as an additional piece of evidence that dementia is not as simple as unsolvable genetic predispositions, but that there is much more to be learned about the condition.





Mendelian etiologies identified with whole exome sequencing in cerebral palsy

Chopra M, Gable DL, Love-Nichols J, Tsao A, Rockowitz S, Sliz P, Barkoudah E, Bastianelli L, Coulter D, Davidson E, DeGusmao C, Fogelman D, Huth K, Marshall P, Nimec D, Sanders JS, Shore BJ, Snyder B, Stone SSD, Ubeda A, Watkins C, Berde C, Bolton J, Brownstein C, Costigan M, Ebrahimi-Fakhari D, Lai A, O'Donnell-Luria A, Paciorkowski AR, Pinto A, Pugh J, Rodan L, Roe E, Swanson L, Zhang B, Kruer MC, Sahin M, Poduri A, Srivastava S. Mendelian etiologies identified with whole exome sequencing in cerebral palsy. Ann Clin Transl Neurol. 2022 Feb;9(2):193-205. doi: 10.1002/acn3.51506. Epub 2022 Jan 24. PMID: 35076175; PMCID: PMC8862420.


Objectives: Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP.

Methods: We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline.

Results: We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES.

Interpretation: WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.

Wednesday, May 18, 2022

Melatonin overdoses

Fox News Four Tennessee daycare workers who were charged earlier this month with overdosing children under their care were giving them up to 10 times the legal limit of the hormone melatonin to make them sleep longer, according to a report.  

Jaime Clark, 45, Kristin Clark, 22, and Jordan Darnell, 22, of now-closed MiMi’s Daycare in Indian Mound, Tennessee, were charged on May 5 with child abuse and neglect following parent's complaints in March. Ethan Pulley, 21, was charged with fabricating/tampering with evidence.  

An attorney representing nine of the 26 children who were allegedly overdosed told FOX 17 Nashville that a whistleblower just told his team how high the dosages allegedly were.  

"There was a whistleblower who came forward and talked to us early this week and told us she worked there for a day and during her employment they requested she give the students three 10 milligram melatonin gummy bears with their lunch," attorney Rocky McElhaney told FOX 17. "She didn't feel comfortable with that. She didn't do it and she didn’t report for her job the next day."   

The doses of melatonin allegedly given to the children were more than one and a half times the maximum adult dose. 

Parents would sometimes be unable to wake their children when they picked them up at the end of the day, Stewart County Sheriff’s Detective Dana Saltkill said, according to People magazine.  

"When they would pick them up, they would sleep all the way home and sometimes reports of children staying up most of the night, so their sleeping habits are off," she said earlier this month. "They also made some disclosures that there was melatonin going on at lunchtime at the daycare center." 

Investigators said the children ranged in age from infants to six years old and this had been going on for at least two years. 


Monday, May 16, 2022

Butyrylcholinesterase is a potential biomarker for sudden infant death syndrome

 Researchers at The Children’s Hospital at Westmead (CHW) have made a ground-breaking discovery, identifying the first biochemical marker that could help detect babies more at risk of Sudden Infant Death Syndrome (SIDS) while they are alive. 

In a study published on May 6, 2022, by The Lancet’s eBioMedicine, researchers found the activity of a specific enzyme, Butyrylcholinesterase (BChE), was significantly lower in babies who subsequently died of SIDS compared to living controls and other infant deaths. 

The study analyzed BChE activity in 722 Dried Blood Spots (DBS) taken at birth as part of the Newborn Screening Program, only utilizing samples parents approved for use in de-identified research. BCHE was measured in both SIDS and infants who died from other causes, and each was compared to 10 surviving infants with the same date of birth and gender. 

The researchers discovered infants with lower BChE levels had a much higher risk of dying from SIDS. BChE plays an important function in the brain’s arousal pathway and researchers believe its deficiency likely indicates an arousal deficit, which reduces an infant’s ability to wake or respond to the external environment, making them vulnerable to SIDS. 

Dr. Carmel Harrington, study lead and Honorary Research Fellow at CHW, said the findings are game-changing and not only offer hope for the future, but answers for the past. 

“An apparently healthy baby going to sleep and not waking up is every parent’s nightmare and until now there was absolutely no way of knowing which infant would succumb. But that’s not the case anymore. We have found the first marker to indicate vulnerability prior to death,” Dr. Harrington said.


“Babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don’t have this same robust arousal response.” 

“This has long been thought to be the case, but up to now we didn’t know what was causing the lack of arousal. Now that we know that BChE is involved we can begin to change the outcome for these babies and make SIDS a thing of the past.” 

Dr. Harrington lost her own child to SIDS 29 years ago and has dedicated her career to researching the condition, supporting much of her research through her crowd-funding campaign, Damien’s Legacy. 

“This discovery has opened up the possibility for intervention and finally gives answers to parents who have lost their children so tragically. These families can now live with the knowledge that this was not their fault,” Dr. Harrington said. 

SIDS is the unexplained death of an apparently healthy infant less than one year of age, during a period of sleep. 

The incidence of SIDS has been more than halved in recent years due to public health campaigns addressing the known major risk factors of prone sleeping, maternal smoking and overheating. However, the rate of SIDS remains high, contributing to almost 50 percent of all post-neonatal deaths in Western countries. 

“There is this perception that SIDS isn’t a problem anymore or that the problem can be solved if all babies had the correct sleep conditions, but two children still die from SIDS in Australia every week. This finding gives our research a clear direction so that in future we will be able to do something to prevent it,” Professor Karen Waters, Head of the SIDS and Sleep Apnoea Research Group at CHW, said. 

Currently, the “triple risk model” is used to explain the occurrence of SIDS deaths, hypothesizing that three factors need to occur simultaneously; vulnerable infant, a critical developmental period and an exogenous stressor, however until now there has never been a way to identify those vulnerable infants. 

The identification of the BChE biochemical marker gives researchers a clear direction for the future, enabling them to focus attentions on introducing this marker into newborn screening and developing specific interventions to address the enzyme deficiency. 

It is expected the next stages of research will take around five years to complete. 

“This discovery changes the narrative around SIDS and is the start of a very exciting journey ahead. We are going to be able to work with babies while they are living and make sure they keep living,” Dr. Harrington said. 


Carmel Therese Harrington, Naz Al Hafid and Karen Ann Waters. Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome. 6 May 2022, eBioMedicineDOI: 10.1016/j.ebiom.2022.104041



Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death.


In this case-control study we measured BChE activity and total protein in the eluate of 5μL spots punched from the dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week-104 weeks) = Cases, were compared to 10 date of birth - and gender-matched surviving controls (Controls), with five cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year.


Conditional logistic regression showed that in groups where cases were reported as “SIDS death” there was strong evidence that lower BChE specific activity (BChEsa) was associated with death (OR=0·73 per U/mg, 95% CI 0·60-0·89, P=0·0014), whereas in groups with a “Non-SIDS death” as the case there was no evidence of a linear association between BChEsa and death (OR=1·001 per U/mg, 95% CI 0·89-1·13, P=0·99).


BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude that a previously unidentified cholinergic deficit, identifiable by abnormal -BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death.