Thursday, June 19, 2025

Delandistrogene moxeparvovec gene therapy in individuals with Duchenne Muscular Dystrophy

Oskoui M, Caller TA, Parsons JA, Servais L, Butterfield RJ, Bharadwaj J, Rose SC, Tolchin B, Puskala Hamel K, Silsbee HM, Dowling JJ. Delandistrogene Moxeparvovec Gene Therapy in Individuals With Duchenne Muscular Dystrophy: Evidence in Focus: Report of the AAN Guidelines Subcommittee. Neurology. 2025 Jun 10;104(11):e213604. doi: 10.1212/WNL.0000000000213604. Epub 2025 May 14. PMID: 40367405.

Abstract

This Evidence in Focus reviews the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy (DMD) and presents clinical considerations regarding use. The author panel systematically reviewed available clinical trial data on delandistrogene moxeparvovec in patients with DMD. The risk of bias was evaluated using the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Six clinical trials were identified, of which 4 had peer-reviewed data available. From the 4 studies with available data (2 Class I and 2 Class III), exposure data are available on 134 boys, of which 128 are ambulatory and aged ≥4 to <8 years. Both Class I studies failed to meet the primary functional motor outcome as assessed by change in the North Star Ambulatory Assessment score. Several secondary functional motor outcomes demonstrated improvement in the treatment group with small effect sizes, not meeting statistical significance from hierarchical analysis. Corticosteroid dose exposure was higher in the treatment group in the first 12 weeks after infusion, potentially contributing to measured differences between groups. Safety outcomes were similar across studies with multiple treatment-related adverse events, including peri-infusion effects, immune myositis and myocarditis, thrombocytopenia, and liver toxicity. One death has been reported in an individual who was treated with delandistrogene moxeparvovec outside of a trial. Despite not demonstrating efficacy in its primary outcome, delandistrogene moxeparvovec has been approved by the US Food and Drug Administration (FDA) for use in boys with DMD. This decision was supported by the relative safety of the product and secondary outcome measures data in the phase 3 clinical trial. As the drug may now be actively prescribed in the United States and other countries after FDA approval, providers should be aware of the limitations of the treatment and the need to monitor for immune-related side effects including myocarditis, liver injury, and thrombocytopenia, which may require expanded clinical infrastructure. Additional clinical trials and careful collection of real-world evidence from treated patients will be essential to establish short-term and long-term effectiveness and inform understanding of benefits and risks of delandistrogene moxeparvovec across the lifespan.

Wednesday, June 18, 2025

Adolescent late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency

Adolescent late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency manifesting with severe multi-organ failure: A case report. Zhao Y, Li Z, Cui L, Chen J, Zhong W. Front. Pediatr.

Volume 13 - 2025 | doi: 10.3389/fped.2025.1513288https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2025.1513288/abstract


Abstract

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive disorder characterized by dysfunctional acyl-CoA dehydrogenases, leading to lipid accumulation in various tissues, including skeletal muscles, liver, and cardiac muscles, etc. Late-onset MADD presents with progressive muscular symptoms (muscle weakness, atrophy, and myalgia) and even multisystem disorders (metabolic encephalopathy, dilated cardiomyopathy, liver failure, acute kidney injury, respiratory failure, and cardiac arrest). Over the past decade, only one case of childhood late-onset MADD with severe multi-organ failure has been reported.

Case Presentation: We report a 15-year-old girl with worsening muscle weakness, atrophy, myalgia, hepatic insufficiency, respiratory failure and even cardiac arrest. Laboratory tests showed significantly elevated levels of creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH). A weakly positive serum small ubiquitin-like modifier 1 activating enzyme (SAE1) antibody suggested antibody-negative polymyositis (PM), but serum acylcarnitine analysis indicated increased concentrations of various acylcarnitines, while urine organic acids was normal. Muscle biopsy revealed significant lipid deposition within muscle fibers pointing to the diagnosis of lipid storage myopathy (LSM). Genetic testing identified a homozygous c.250G>A (p.Ala84Thr) mutation in electron transfer flavoprotein dehydrogenase (ETFDH), inherited from her parents. Although this pathogenic mutation is known in MADD, it has not been associated with adolescent late-onset MADD with severe multi-organ failure. After riboflavin supplementation, the patient regained mobility without ventilator support, with no recurrence of myopathic symptoms upon follow-up.

Conclusion: MADD is a rare but treatable disease and its diagnosis is challenging due to its high clinical heterogeneity. Therefore, based on clinical, biochemical and pathological findings, gene analysis is critical for accurate diagnosis and clinical intervention, as riboflavin supplementation has shown lifesaving therapeutic benefit even in adolescent late-onset MADD with severe multi-organ failure.

Effects of intracranial pressure monitoring in pediatric severe traumatic brain injury

Xue S, Zhang Z and Liu Y (2025) Effects of intracranial pressure monitoring in pediatric severe traumatic brain injury: a meta-analysis of cohort studies. Front. Neurol. 16:1557820. doi: 10.3389/fneur.2025.1557820

Introduction: As Severe traumatic brain injury (TBI) is a major cause of pediatric morbidity and mortality. The clinical benefits of intracranial pressure (ICP) monitoring in pediatric TBI remain debated. This meta-analysis aims to assess the impact of ICP monitoring on outcomes in children with severe TBI.

Methods: Following PRISMA guidelines, a comprehensive search was conducted in PubMed, EMBASE, Cochrane Library, and Web of Science. Studies comparing pediatric severe TBI patients with and without ICP monitoring were included. Primary outcomes included in-hospital mortality and complications, while secondary outcomes included craniotomy/craniectomy rate, length of hospital stay and ICU stay, mechanical ventilation duration, and medical costs. Quality assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) for cohort studies. The weighted mean difference (WMD) for continuous variables and odds ratio (OR) for dichotomous variables were calculated, along with 95% confidence intervals (CIs). Meta-analysis was performed using RevMan 5.4.1 software.

Results: Eight studies (12,987 patients) were included. ICP monitoring showed no significant impact on overall in-hospital mortality (OR, 1.14; p = 0.65), though propensity score matching (PSM) studies indicated a lower mortality rate with ICP monitoring (OR, 0.62; p = 0.005). However, ICP monitoring was associated with higher risks of infection-related (OR, 7.21; p < 0.001) and respiratory complications (OR, 5.79; p < 0.001), thromboembolic events (OR, 5.37; p < 0.001), increased craniotomy/craniectomy rates (OR, 2.34; P = 0.01), longer hospital (OR, 12.00; p < 0.001) and ICU stays (OR, 7.82; p < 0.001), extended mechanical ventilation durations (OR, 5.82; p < 0.001), and higher medical costs (WMD, 10.49; p = 0.006).

Conclusion: This meta-analysis found no overall reduction in in-hospital mortality with ICP monitoring in pediatric severe TBI, potentially due to baseline severity imbalances in retrospective studies. However, PSM studies suggest a mortality benefit, indicating that ICP monitoring may be effective when confounding is minimized. Increased complication risks, longer hospital/ICU stays, prolonged ventilation, and higher costs were associated with monitoring, though these may reflect injury severity rather than monitoring itself. Given the limitations of this study, these findings should be interpreted cautiously.

Meningococcemia

A 14-year-old boy in South Carolina died of a rare infection within days of showing symptoms.

William “Will” Hand of Greenville died on Sunday, June 8, according to his online obituary and local news outlet Fox Carolina. His mother, Megan, told the outlet that Will had meningococcal septicemia, also known as meningococcemia, and that the infection got into his bloodstream.

Dr. Anna-Kathryn Burch, an infectious disease specialist at Prisma Health Children’s Hospital, where Will was treated, told Fox Carolina that infections of this nature happen “so quickly,” adding, “sometimes it is very hard to save the person who is infected with the bacteria.”

Dr. Burch told the outlet that the illness spreads through saliva and respiratory secretions and through sharing everyday items like beverages.

Symptoms include high fever, severe headache, sensitivity to light, nausea and vomiting, per the Cleveland Clinic. It can also cause a rash that does not fade when pressed.

“We call it a petechial rash because it looks like broken blood vessels underneath the skin,” Dr. Burch said of the rash while speaking to Fox Carolina. “It’s not a typical rash that you would get with, let’s say, a viral infection. If you put your finger on it and press down really hard, the rash will stay there."

The Centers for Disease Control states that meningococcal disease is “uncommon,” though they note that early intervention with antibiotics is critical for treatment. Vaccines are the “best protection” against the infection, per the CDC.

Will is described by loved ones as having “a joyful spirit, quick smile and magnetic energy,” per his online obituary.

"His loss leaves a void that can never be filled," they added.

“Will was a highlight of many people’s day — equal parts athlete, comedian, music lover, and loyal friend,” the obituary states, adding, "His teammates, coaches, and friends knew him as the life of party.”

The teen was also known for “turning everyday moments into unforgettable memories. Whether it was walking to CVS ... with his friends, or re-enacting WWE wrestling, he brought joy everywhere he went,” the obituary continued.

Will had just completed 8th grade at Hughes Academy in Greenville. He is survived by his parents, William and Megan, as well as two sisters and a brother, per the obituary.

A celebration of Will's life was held at Westminster Presbyterian Church in Greenville on Friday, June 13.

In lieu of flowers, Will’s parents asked that donations be sent to Prisma Health Children's Hospital, “where the critical care team fought tenaciously to keep our son alive.”

https://people.com/south-carolina-boy-14-dies-of-rare-bacterial-infection-meningococcemia-11754979

Tuesday, June 17, 2025

DDX3X-related neurodevelopmental disorder 2

Kennis MGP, Rots D, Bouman A, Ockeloen CW, Boelen C, Marcelis CLM, de Vries BBA, Elting MW, Waisfisz Q, Suri M, Font-Montgomery E, Peck DS, Donnelly DE, Rogers RC, Richardson R, Caumes R, Chaumette B, Louveau C, Sallevelt SCEH, Maas SM, Smits JJ, van Haelst MM, Levy RJ, Stewart H, Loeys BL, Pfundt R, Kleefstra T, Snijders Blok L. DDX3X-related neurodevelopmental disorder in males - presenting a new cohort of 19 males and a literature review. Eur J Hum Genet. 2025 Mar 31. doi: 10.1038/s41431-025-01832-x. Epub ahead of print. PMID: 40164730.

Abstract

DDX3X-related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X variants in clinical practice. In this study, we present a new cohort of 19 affected males (from 17 unrelated families) with (possibly) disease-causing DDX3X variants, for whom we collected clinical and molecular data. Additionally, we reviewed the existing literature on 13 males with DDX3X variants. The phenotype in males is diverse, including intellectual disability, speech/language delays, behavioural challenges and structural brain abnormalities. The vast majority of males have missense variants, including two recurrent variants (p.(Arg351Gln) and p.(Arg488Cys)). No truncating variants have been reported, consistent with the presumed embryonic lethality of complete loss-of-function of DDX3X in males. In our novel cohort, 6/17 variants are de novo in the affected male and 3/17 variants are de novo in the mother. This study provides significant insights in the genetic and phenotypic spectrum of males with DDX3X variants, by presenting the data of a combined cohort (n = 32) of novel and published individuals. Our data show that variants in DDX3X can cause an X-linked neurodevelopmental disorder in males, with unaffected or mildly affected carrier females. These findings will aid the interpretation of hemizygous missense variants in DDX3X and can guide clinical management and counselling, in particular with regard to recurrence risks in the respective families.

Parra A, Pascual P, Cazalla M, Arias P, Gallego-Zazo N, San-Martín EA, Silván C, Santos-Simarro F; Spanish OverGrowth Registry Initiative (SOGRI); Nevado J, Tenorio-Castano J, Lapunzina P. Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder. Clin Genet. 2024 Feb;105(2):140-149. doi: 10.1111/cge.14440. Epub 2023 Oct 30. PMID: 37904618.

Abstract

DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.

von Mueffling A, Garcia-Forn M, De Rubeis S. DDX3X syndrome: From clinical phenotypes to biological insights. J Neurochem. 2024 Sep;168(9):2147-2154. doi: 10.1111/jnc.16174. Epub 2024 Jul 8. PMID: 38976626; PMCID: PMC11449660.

Abstract

DDX3X syndrome is a neurodevelopmental disorder accounting for up to 3% of cases of intellectual disability (ID) and affecting primarily females. Individuals diagnosed with DDX3X syndrome can also present with behavioral challenges, motor delays and movement disorders, epilepsy, and congenital malformations. DDX3X syndrome is caused by mutations in the X-linked gene DDX3X, which encodes a DEAD-box RNA helicase with critical roles in RNA metabolism, including mRNA translation. Emerging discoveries from animal models are unveiling a fundamental role of DDX3X in neuronal differentiation and development, especially in the neocortex. Here, we review the current knowledge of genetic and neurobiological mechanisms underlying DDX3X syndrome and their relationship with clinical phenotypes.

Levy T, Siper PM, Lerman B, Halpern D, Zweifach J, Belani P, Thurm A, Kleefstra T, Berry-Kravis E, Buxbaum JD, Grice DE. DDX3X Syndrome: Summary of Findings and Recommendations for Evaluation and Care. Pediatr Neurol. 2023 Jan;138:87-94. doi: 10.1016/j.pediatrneurol.2022.10.009. Epub 2022 Oct 27. PMID: 36434914.

Abstract

DDX3X syndrome is a surprisingly common newly discovered genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities. Two hundred individuals with DDX3X syndrome have been described in the literature to date, with varied levels of detail. Individuals with DDX3X syndrome often have complex presentations including symptoms in the neurological, psychiatric/psychological, ophthalmologic, and gastrointestinal domains. Owing to this complex presentation, an overview of symptom prevalence, medical recommendations, and suggested medical surveillance is vital for the care and health of individuals with DDX3X syndrome. In this article, we summarize the present clinical knowledge of DDX3X syndrome and provide recommendations for clinical assessments and care based on a comprehensive review of the existing literature and of new, not yet published DDX3X syndrome cohorts. As more is learned about DDX3X syndrome, we anticipate that these recommendations will evolve.

See: https://childnervoussystem.blogspot.com/2022/09/ddx3x-related-neurodevelopmental.html

Sunday, June 15, 2025

Recovery from traumatic brain injury

For many young girls, their father is the childhood hero who carries their bike, puts the Band-Aid on their injuries, and – in my case – caught me when I fell off the horse. 

But when I was 15, Dad did a lot more than clean a scraped knee. On my way to softball practice, I was in a head-on collision that left me with a traumatic brain injury and in a coma for more than two weeks. 

I didn’t know it at the time, but my father, who is a first responder for our county, was on the scene. 

He stabilized my neck as the emergency team extracted me from the car and lifted me into the ambulance. For many fathers, that might be the most heroic and most difficult thing they do for a child.

But a few months after the accident, Dad did something even harder: he told me that there was a bigger hero in my life – God – and that my recovery was between me and Him. 

In rural Nebraska, where I live, most 15-year-olds are learning how to drive, stressing over geometry and working on their family farms. That year, however, I was in a brain trauma rehabilitation facility, learning how to walk, identify colors and eat properly.

It was the hardest thing I’d ever done, especially as someone who had played softball, raised horses and coached Special Olympian barrel racers. Now I needed help for things as basic as brushing my teeth, getting dressed and going to the bathroom. 

One day, I was done with it all. Discouraged, exhausted and resigned to a helpless existence, I told the therapist to take me back to my room at Madonna Rehabilitation Hospital. There was Dad, once again my biggest supporter, who literally had saved my life.

Only this time, he wasn’t the hero. "I can’t make you walk," he said. "This is a conversation you need to have with God."

I was floored, but Dad was right. I was stuck in my own misery and had never taken my circumstances to my Heavenly Father. Part of it was pride. I had been the one who was competitive and took care of others. Now I was totally dependent on others. 

In total humility, I stared at the ceiling of my rehab room, and I asked God for help. The next day, I was ready to try again and to try and stand for the first time.

Almost three years after that conversation, I still don’t know why God allowed me to be in that accident. But I’ve come to realize that my story isn’t about me – but about what it can do for others. 

For example, I was ticked when I found out that 98,000 people on my Caring Bridge page saw images of me on a hospital bed. But I’ve also heard from some of those people directly that seeing my struggle gave them hope and increased their faith. 

I went to prom this spring with a young man named Carson, a friend I made at Madonna. He was in an accident like mine and is confined to a wheelchair. While his body is still struggling, it’s clear that his light is very much alive. What he needs more than anything as he continues on his recovery is to feel a real connection with other people, especially those his age.

And this summer, I’ll be going to New Orleans with 20,000 teenagers, young adults and supportive adults for the Lutheran Church-Missouri Synod Youth Gathering. 

My story won’t be plastered on the screens, but it’ll certainly come up in conversation, especially since I attended the last Gathering just months before my accident. Answering "What have you been up to?" could help kids recovering from their own traumas, impacted by family abuse, or simply stuck in the mental health challenges common in my generation. 

On Father’s Day, I’m eternally grateful that I get to spend yet another one with my dad, the man who held me as a baby and also when I was being loaded into an ambulance. And I’m even more grateful to the Heavenly Father, who is still the other hero by my side. 

Saige Scheele recently graduated from Centennial Public School near her hometown of Gresham, NE and she plans to enroll this fall at Northeast Community College in Norfolk, NE where she will study Veterinary Technology.

https://www.foxnews.com/opinion/this-fathers-day-im-celebrating-the-two-dads-my-life


Tuesday, June 10, 2025

BRF1 mutations (cerebellofaciodental syndrome)

Yin H, Yu Y, Shen Y. Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies. Int J Dev Neurosci. 2024 Nov;84(7):679-687. doi: 10.1002/jdn.10365. Epub 2024 Jul 14. PMID: 39005000.

Abstract

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14-month-old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation.

Borck G, Hög F, Dentici ML, Tan PL, Sowada N, Medeira A, Gueneau L, Thiele H, Kousi M, Lepri F, Wenzeck L, Blumenthal I, Radicioni A, Schwarzenberg TL, Mandriani B, Fischetto R, Morris-Rosendahl DJ, Altmüller J, Reymond A, Nürnberg P, Merla G, Dallapiccola B, Katsanis N, Cramer P, Kubisch C. BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. Genome Res. 2015 Feb;25(2):155-66. doi: 10.1101/gr.176925.114. Epub 2015 Jan 5. Erratum in: Genome Res. 2015 Apr;25(4):609. PMID: 25561519; PMCID: PMC4315290.

Abstract

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

Valenzuela I, Codina M, Fernández-Álvarez P, Mur P, Valle L, Tizzano EF, Cuscó I. Expanding the phenotype of cerebellar-facial-dental syndrome: Two siblings with a novel variant in BRF1. Am J Med Genet A. 2020 Nov;182(11):2742-2745. doi: 10.1002/ajmg.a.61839. Epub 2020 Sep 8. PMID: 32896090.

Abstract

Cerebellofaciodental syndrome (MIM #616202) is an autosomal recessive condition characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features, and short stature. To date, eight patients carrying biallelic BRF1 variants have been reported. Here, we describe two siblings with congenital microcephaly and corpus callosum hypoplasia, pre and postnatal growth retardation, congenital heart defect and severe global developmental delay. We also detected additional findings not previously reported in this syndrome, including bilateral sensorineural hearing impairment and inner ear malformation. Whole exome sequencing identified a novel homozygous missense variant (c.654G>C, p.[Trp218Cys]) in BRF1, predicted to affect the protein structure. Expression assessment showed extremely low BRF1 protein expression caused by the identified variant, supporting its causal involvement. The description of new patients with cerebellofaciodental syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Jee YH, Sowada N, Markello TC, Rezvani I, Borck G, Baron J. BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies. Clin Genet. 2017 May;91(5):739-747. doi: 10.1111/cge.12887. Epub 2016 Dec 12. PMID: 27748960; PMCID: PMC5389939.

Abstract

Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C > G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.

Folinic acid supplementation in children with autism spectrum disorder

Panda PK, Sharawat IK, Saha S, Gupta D, Palayullakandi A, Meena K. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024 Nov;183(11):4827-4835. doi: 10.1007/s00431-024-05762-6. Epub 2024 Sep 7. PMID: 39243316.

Abstract

Oral folinic acid has shown potential to improve symptoms in children with autism spectrum disorder (ASD). However, randomized controlled trials (RCTs) are limited. This double-blind, placebo-controlled RCT aimed to compare changes in Childhood Autism Rating Scale (CARS) scores in children with ASD aged 2-10 years, among folinic acid (2 mg/kg/day, maximum of 50 mg/day) and placebo groups at 24 weeks, in comparison with baseline. Both the groups received standard care (ABA and sensory integration therapy). Secondary objectives included changes in behavioral problems measured by the Child Behavior Checklist (CBCL) and serum levels of anti-folate receptor autoantibodies and folic acid, correlated with changes in autism symptom severity. Out of the 40 participants recruited in each group, 39 and 38 participants completed the 24-week follow-up in the folinic acid and placebo groups, respectively. The change in CARS score was higher in the folinic acid group (3.6 ± 0.8) compared to the placebo group (2.4 ± 0.7, p < 0.001). Changes in CBCL total score and CBCL internalizing score were also better in the folinic acid group (19.7 ± 9.5 vs. 12.6 ± 8.4 and 15.4 ± 7.8 vs. 8.5 ± 5.7, p < 0.001 for both). High-titer anti-folate receptor autoantibodies were positive in 32/40 and 33/40 cases in the folinic acid and placebo groups, respectively (p = 0.78). In the placebo group, improvement in CARS score was comparable regardless of autoantibody status (p = 0.11), but in the folinic acid group, improvement was more pronounced in the high-titer autoantibody group (p = 0.03). No adverse reactions were reported in either group.

Conclusions: Oral folinic acid supplementation is effective and safe in improving ASD symptoms, with more pronounced benefits in children with high titers of folate receptor autoantibodies.

Trial registration: CTRI/2021/07/034901, dated 15-07-2021.

What is known: • Folate receptor autoantibodies are more prevalent in children with autism spectrum disorder (ASD) compared to typically developing children. • Folate receptor autoantibodies play a significant role in the neuropathogenesis of autism spectrum disorder.

What is new: • Add-on oral folinic acid supplementation is safe and effective in reducing the severity of symptoms in children with ASD. • The clinical benefits are more pronounced in children with high titers of folate receptor autoantibodies.

Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18. PMID: 27752075; PMCID: PMC5794882.

Abstract

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Batebi N, Moghaddam HS, Hasanzadeh A, Fakour Y, Mohammadi MR, Akhondzadeh S. Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children with Autism: A Double-Blind and Placebo-Controlled Randomized Trial. Child Psychiatry Hum Dev. 2021 Oct;52(5):928-938. doi: 10.1007/s10578-020-01072-8. Epub 2020 Oct 7. PMID: 33029705.

Abstract

This is a double-blind, placebo-controlled randomized trial to investigate the potential therapeutic effects of folinic acid/placebo as an adjuvant to risperidone on inappropriate speech and other behavioral symptoms of autism spectrum disorder (ASD). Fifty-five ASD children (age (mean ± standard deviation) = 13.40 ± 2.00; male/female: 35/20) were evaluated for behavioral symptoms at baseline, week 5, and week 10 using the aberrant behavior checklist-community (ABC-C). Folinic acid dosage was 2 mg/kg up to 50 mg per day for the entire course of the study. The repeated measures analysis showed significant effect for time × treatment interaction on inappropriate speech (F = 3.51; df = 1.61; P = 0.044), stereotypic behavior (F = 4.02; df = 1.37; P = 0.036), and hyperactivity/noncompliance (F = 6.79; df = 1.66; P = 0.003) subscale scores. In contrast, no significant effect for time × treatment interaction was found on lethargy/social withdrawal (F = 1.06; df = 1.57; P = 0.336) and irritability (F = 2.86; df = 1.91; P = 0.064) subscale scores. Our study provided preliminary evidence suggesting that folinic acid could be recommended as a beneficial complementary supplement for alleviating speech and behavioral symptoms in children with ASD.Clinical trial registeration: This trial was registered in the Iranian Registry of Clinical Trials ( www.irct.ir ; No. IRCT20090117001556N114).

Rossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J Pers Med. 2021 Nov 3;11(11):1141. doi: 10.3390/jpm11111141. Erratum in: J Pers Med. 2022 Apr 29;12(5):721. doi: 10.3390/jpm12050721. PMID: 34834493; PMCID: PMC8622150.

Abstract

The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.

Friday, June 6, 2025

Tatton-Brown-Rahman Syndrome

Inspired by a patient

Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, Zachariou A, Hanks S, O'Brien E, Aksglaede L, Baralle D, Dabir T, Gener B, Goudie D, Homfray T, Kumar A, Pilz DT, Selicorni A, Temple IK, Van Maldergem L, Yachelevich N; Childhood Overgrowth Consortium; van Montfort R, Rahman N. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014 Apr;46(4):385-8. doi: 10.1038/ng.2917. Epub 2014 Mar 9. Erratum in: Nat Genet. 2014 Jun;46(6):657. PMID: 24614070; PMCID: PMC3981653.

Abstract

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.

Thomas H, Alix T, Renard É, Renaud M, Wourms J, Zuily S, Leheup B, Geneviève D, Dreumont N, Schmitt E, Bronner M, Muller M, Divoux M, Wandzel M, Ravel JM, Dexheimer M, Becker A, Roth V, Willems M, Coubes C, Vieville G, Devillard F, Schaefer É, Baer S, Piton A, Gérard B, Vincent M, Nizon M, Cogné B, Ruaud L, Couque N, Putoux A, Edery P, Lesca G, Chatron N, Till M, Faivre L, Tran-Mau-Them F, Alessandri JL, Lebrun M, Quélin C, Odent S, Dubourg C, David V, Faoucher M, Mignot C, Keren B, Pisan É, Afenjar A, Julia S, Bieth É, Banneau G, Goldenberg A, Husson T, Campion D, Lecoquierre F, Nicolas G, Charbonnier C, De Saint Martin A, Naudion S, Degoutin M, Rondeau S, Michot C, Cormier-Daire V, Oussalah A, Pourié C, Lambert L, Bonnet C. Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients. J Med Genet. 2024 Aug 29;61(9):878-885. doi: 10.1136/jmg-2024-110031. PMID: 38937076.

Abstract

Background: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.

Methods: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.

Results: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.

Conclusion: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.

Jiménez de la Peña M, Rincón-Pérez I, López-Martín S, Albert J, Martín Fernández-Mayoralas D, Fernández-Perrone AL, Jiménez de Domingo A, Tirado P, Calleja-Pérez B, Porta J, Álvarez S, Fernández-Jaén A. Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings. Am J Med Genet A. 2024 Feb;194(2):211-217. doi: 10.1002/ajmg.a.63434. Epub 2023 Oct 5. PMID: 37795572.

Abstract

Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.

Ostrowski PJ, Tatton-Brown K. Tatton-Brown-Rahman Syndrome. 2022 Jun 30. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 35771960.

Excerpt

Clinical characteristics: Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors.

Diagnosis/testing: The diagnosis of TBRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in DNMT3A identified by molecular genetic testing

Management: Treatment of manifestations: Treatments are primarily supportive and based on symptoms. Developmental delay / intellectual disability, behavioral/psychiatric diagnoses, epilepsy, joint hypermobility, kyphoscoliosis, sleep apnea, cryptorchidism, and acute leukemia are all treated in the standardized fashion.

Surveillance: Monitoring of growth parameters, developmental progress, behavior, mobility, and self-help skills at each visit. Assessment for new neurologic manifestations, seizures, and signs and symptoms of sleep apnea and hematologic malignancies at each visit. Low threshold for complete blood count with differential and further investigations in those who have concerning signs and symptoms of hematologic malignancy; there are no consensus guidelines regarding screening for hematologic malignancy in individuals with TBRS.

Genetic counseling: TBRS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with TBRS have the disorder as the result of a DNMT3A pathogenic variant inherited from a parent. Each child of an individual with TBRS has a 50% chance of inheriting the DNMT3A pathogenic variant. Once the DNMT3A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Thursday, June 5, 2025

If you can't take the heat

A California doctor is suing a Thai restaurant after she was served a dish that was so spicy it reportedly "permanently" harmed her, according to her claims.

Dr. Harjasleen Walia, a board-certified neurologist in San Jose, is suing over Coup de Thai's Dragon Balls dish, which she ate in 2023, according to lawsuit documents obtained by the Mercury News.

The lawsuit was filed in July 2023, but Walia made recent headlines after she elected to represent herself in court pro se, according to a May filing. Walia has claimed that the Los Gatos restaurant's appetizer burned her vocal cords, esophagus and the inside of her right nostril.

The dish is made of "spicy chicken ball[s] fried with mint, shallot [and] green onion," according to Coup de Thai's website.

The dish, which also features "cilantro, kaffir lime leaves, chili and rice powder," is served hot.

The culprit in the meal is Thai chili, or bird's eye chili.

Measuring between 50,000 to 100,000 Scoville Heat Units (SHU), the peppers are spicier than cayenne and serrano peppers but fall below habanero peppers.

The lawsuit states, as the Mercury News reported, that Walia asked her server to make the dish with less spice because "she does not tolerate spicy foods."

The server agreed, according to the lawsuit — but then Walia took a bite of the dish.

Walia "felt her entire mouth, the roof of her mouth, her tongue, her throat and her nose burn like fire," according to the suit — to the point that her "eyes and nose watered, and she began coughing."

The doctor also said she lost her voice and was diagnosed with internal "chemical burns" from the chilis in the dish.

"[Walia] drank an entire glass of coconut water and more water, but the burning did not subside."

"[She] incurred permanent injuries and will forever be damaged," the lawsuit claims.

Walia's suit also claims that she asked a waitress for a dairy product to help with the burns, but no help came.

No "milk, ice cream, yogurt, sour cream or other dairy product was provided or offered to Ms. Walia to quell the obvious burning," the suit said.

"[Walia] drank an entire glass of coconut water and more water, but the burning did not subside."

The lawsuit claims the dish in question was "unfit for human consumption."

The restaurant "failed to take precautions by consulting with health officials or emergency service personnel regarding the risks associated with serving too much Thai chili in an appetizer like Dragon Balls," the lawsuit claims.

No one else required medical attention due to the food, the restaurant said.

Coup de Thai has denied causing any harm.

A representative told the Mercury News the dish couldn't be made less spicy because the chili is inside the meatballs, and that no one else required medical attention due to the restaurant's food.

Fox News Digital reached out to Walia for additional comment. An attorney for Coup de Thai declined to comment.

Spice is a popular addition to liven up a dish.

In 2019, a chef said that he temporarily lost his hearing after eating a spicy meal.

Andrea Margolis is a lifestyle writer for Fox News Digital and Fox Business. Readers can follow her on X at @andreamargs or send story tips to andrea.margolis@fox.com.




Cerebral venous thrombosis

Preston Patton was just 6 years old when he suffered a stroke caused by a blood clot in the brain. Doctors performed a rare procedure called a thrombectomy, which ultimately saved his life.

Christmas Eve is usually an evening of fun and festivity — but for one Illinois family in 2023, it came with a life-threatening medical emergency.

After enjoying a few holiday traditions, the Patton family had just gotten settled at the dinner table when Preston Patton, who was 6 years old at the time, suddenly slid onto the floor.

"He just fell off the chair and was limp," recalled Shawn Patton, Preston’s father, according to a press release from OSF HealthCare. "I didn’t think it was a stroke, but I just knew something was wrong."

Patton immediately called 911 and first responders rushed his son to OSF HealthCare.

At the hospital, a team of emergency and pediatric doctors assessed the situation. A brain scan revealed that Preston had a blood clot in his brain, and his heart function had dropped to just 10%.

Also known as cerebral venous thrombosis (CVT), this condition is rare in children, generally affecting only around one or two in every 100,000 kids and teens, statistics show.

"He had complete paralysis on the left side of his body," said Sourabh Lahoti, M.D., a vascular and interventional neurologist with OSF HealthCare Illinois Neurological Institute, in the release.

"No movement was possible, and the vision in his left visual field was lost. He could not move his eyes to the left, either," added Lahoti, who led the boy's care.

"He had the telltale signs of a stroke affecting the right side of his brain."

The scan showed that the clot was blocking blood flow to the right side of Preston’s brain.

"No movement was possible, and the vision in his left visual field was lost."

"We had to take that clot out. If we hadn’t, chances are he would have gone on to develop a very big stroke," Lahoti said.

"This would have not only left him paralyzed potentially for the rest of his life, but it could have been life-threatening."

Doctors performed a procedure called a thrombectomy, in which a small, thin catheter is inserted into a blood vessel to remove the clot from the blocked artery.

Preston is one of the few children in the world to undergo this life-saving intervention, according to the press release.

By the time the doctors began the procedure, the clot had traveled to a smaller blood vessel, which made it more difficult to remove.

"The further out the clot is, the higher the risk it is to get it out, because we're getting into very tiny blood vessels in the brain," noted Lahoti. "We decided to take that risk and prevent a lifelong disability."

Soon after the clot was removed, the doctors saw a "complete reversal" of Patton’s symptoms.

It was "truly magical," Dr. Lahoti recalled in the release, particularly after the boy had arrived at the hospital in a state of complete paralysis.

"After the anesthesia was taken off, he woke up and was able to move his left arm and leg again."

Before thrombectomy therapy became available, patients didn’t have other options, the doctor noted.

"The usual course was they were left with paralysis for life, and they were never able to live normally again," said Lahoti.

Doctors now believe that Preston’s stroke was caused by a "rare complication" from a recent flu infection.

"Because of the flu, there was a cross-reaction of the immunity his body built up," Lahoti said. "His immune system attacked the flu virus, but also his kidneys and heart."

"Because of that, his heart pumping got really weak, and we think that led to the formation of a clot in his heart. The clot then traveled from the heart to his brain."

Preston’s father noted that his late wife (mother of Preston and his sister, Carter), had died of a pulmonary embolism, which made the young boy’s medical emergency even more "emotionally challenging."

After a couple of weeks in the hospital, Preston is now doing well and is enjoying his favorite activities again.

"He goes to OT (occupational therapy) once a week and PT (physical therapy) once a month now," Shawn Patton said in an interview with OSF HealthCare. "He’s getting along pretty good."

"We had to take that clot out. If we hadn’t, chances are he would have gone on to develop a very big stroke."

"My leg is better," Preston added.

"Yes, your leg is getting better. Your hand is going to get better, too," his father reassured him.

The boy has not yet been able to return to playing baseball, but he's started riding his bike again.

"It’s hard to hold onto the handlebars and stuff like that. We've just got to keep working hard," Shawn Patton noted.

Inspired by his challenge and recovery, Preston has now said he wants to become a nurse, according to the hospital — "because the nurses cared for him so well."

Melissa Rudy is senior health editor and a member of the lifestyle team at Fox News Digital. Story tips can be sent to melissa.rudy@fox.com.

https://www.foxnews.com/health/boy-suffers-life-threatening-stroke-causes-paralysis-rare-complication




Congenital Insensitivity to pain with SCN9A mutation

At the University of Minnesota there was an adolescent male patient with congenital insensitivity to pain. I performed a muscle biopsy and sural nerve biopsy on him with no local anesthesia.

PATTERSON, Ga. - Ashlyn Blocker didn't cry when she was born.

A severe diaper rash when she was 2 weeks old didn't faze her. She never fussed when she was hungry, so her parents had to remind themselves to feed her every two hours. At 6 months, she laughed and cooed as a nurse administered stinging drops to dilate her eyes.

Doctors found that Ashlyn had a one-in-a-billion condition: She couldn't feel pain. And unlike most people in medical literature with a documented insensitivity to pain, she was otherwise normal and healthy.

It sounds like a gift. Imagine never having to worry about the discomfort of paper cuts, skinned knees or going to the dentist.

However, being immune to pain is also a curse, both physiologically and philosophically.

You wouldn't know if you were getting too hot or too cold. A sudden medical emergency like a heart attack or appendicitis might go unnoticed until it was too late. And how would you ever feel empathy for the suffering of others if you had never suffered yourself?

Studying Ashlyn in the hope of unlocking the mysteries of pain presents a similar conundrum.

With 30 percent to 40 percent of Americans below the age of 50 suffering from chronic pain, a gene-based cure would improve the quality of millions of lives as well as make its developer very rich. Drugmakers AstraZeneca and Xenon Pharmaceuticals are among those looking for clues in people with an inherited insensitivity to pain.

The researcher who has been studying the Southeast Georgia girl and her family for the past six years admits he is excited about where the field may lead. But Roland Staud also expresses concern about the potential for abuse, citing the temptation for athletes to use a new treatment to perform superhuman feats.

"This is a Pandora's box," said Staud, a rheumatologist and pain expert at the University of Florida College of Medicine in Gainesville.

Her life story, he added, offers "an amazing snapshot of how complicated a life can get without the guidance of pain."

Feeling no pain

By all appearances, Ashlyn is like most any 11-year-old girl.

She wears her maple-brown hair in a single ponytail, runs where she's going, often when walking would be more prudent, and is torn between playing the trumpet or the trombone in the school band. She is the second of three children in a family that lives on the wooded outskirts of Patterson, a town north of Waycross.

Ask her what it's like not to be able to feel pain and she'll simply shrug her shoulders.

It's not that she feels nothing. She can feel pressure, when something's hot or cold, different textures and even burning. But her body's nervous system doesn't relay messages of pain.

That was apparent when she bit a chunk of skin off the side of her hand as a toddler. And when she chewed her bottom lip so much that the swelling hid her top lip. And when she ripped out two front baby teeth trying to remove the cap on a ketchup bottle.

"She can fall down and get up like nothing happened," said her mother, Tara.

But there are exceptions. She has complained at times that her stomach "hurts." That, her parents have learned, is almost always followed immediately by a bathroom episode.

Tara and her husband, John, are extra protective of her.

The living room coffee table was turning into a magnet for injuries, so the family went without one for years. She isn't allowed to join her friends at recess if it's too hot outside. And she has been instructed to tell someone right away if she ever sees blood.

Neither Ashlyn's brother nor her sister share her insensitivity to pain.

Much of what the Blockers do is in unchartered parenting territory. There are no support groups or advice books for families like theirs.

"We decided we would write our book as we go along," Tara said.

Genetic clues

Ashlyn is a researcher's dream. For one thing, she is one of only a few people known in the United States to be impervious to pain. (There are a handful of others around the world, including people in Pakistan, Great Britain and Canada.)

Staud learned about Ashlyn's existence when he was contacted by a TV news reporter for a story about her. Soon, the family was making the 21/2-hour drive to Gainesville once or twice a year so Staud could get to the bottom of what caused her condition.

Last week, Staud and other UF researchers published their findings in the European Journal of Pain.

They found that she had anomalies on a gene known as SCN9A. Other scientists had implicated the gene in pain insensitivity a few years earlier, but the UF researchers found that Ashlyn's condition involved two previously unknown mutations.

They also suspect the mutations are responsible for her inability to detect scents. She has no sense of smell - a realization that eluded her parents until just a year ago, when they conducted an informal "smell test" at home.

Treatments that target how the SCN9A gene functions may hold the key to ending chronic pain for good, Staud said. But he warns against shutting down its rival: acute pain.

Just ask Ashlyn's mother about the pitfalls of that.

"I'd give her my pain mechanism if I could," Blocker said.

jeremy.cox@jacksonville.com, (904) 359-4083

https://www.jacksonville.com/story/news/healthcare/2010/08/29/georgia-girl-who-doesnt-feel-pain-helps-researchers-understand-condition/15932878007/

Staud R, Price DD, Janicke D, Andrade E, Hadjipanayis AG, Eaton WT, Kaplan L, Wallace MR. Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain. Eur J Pain. 2011 Mar;15(3):223-30. doi: 10.1016/j.ejpain.2010.07.003. Epub 2010 Aug 7. PMID: 20692858; PMCID: PMC2978801.

Abstract

Insensitivity to pain is a rare disorder that is commonly associated with Hereditary Sensory and Autonomic Neuropathies (HSAN I-V) resulting often in autonomic dysfunction and premature death. Very few individuals have been reported with pain insensitivity lacking such autonomic neuropathies. We performed genetic, neurologic, psychological, and psychophysical evaluations in such an individual (OMIM 243000) and her first degree relatives. Sequence analysis of genomic DNA revealed two novel SCN9A mutations in this index case (IC). One was a non-conservative missense mutation (C1719R) in exon 26 present only in the IC and one parent. Further sequence analysis of the child's DNA revealed a 1-bp splice donor deletion in intron 17 which was also present in the other parent and one sibling. Detailed psychophysical testing was used to phenotypically characterize the IC, her family members, and 10 matched normal controls. Similar to family members and controls the IC showed normal somatosensory functioning for non-nociceptive mechanoreception and warmth. However, she demonstrated diminished ability to detect cool temperatures combined with profound deficits in heat and mechanical nociception. Congenital insensitivity to pain in our IC was associated with two novel SCN9A mutations which most likely resulted in a Nav1.7 channelopathy. However, in contrast to individuals with other SCN9A mutations, the observed pain insensitivity was relative and not absolute, which may be consistent with hypomorphic effects of one or both mutations. The ability to sense at least some danger signals may be advantageous and ameliorate the otherwise increased morbidity and mortality of some individuals with congenital insensitivity to pain.






Wednesday, May 28, 2025

Harel Yoon syndrome (ATAD3A mutation)

Inspired by a patient

Harel T, Yoon WH, Garone C, Gu S, Coban-Akdemir Z, Eldomery MK, Posey JE, Jhangiani SN, Rosenfeld JA, Cho MT, Fox S, Withers M, Brooks SM, Chiang T, Duraine L, Erdin S, Yuan B, Shao Y, Moussallem E, Lamperti C, Donati MA, Smith JD, McLaughlin HM, Eng CM, Walkiewicz M, Xia F, Pippucci T, Magini P, Seri M, Zeviani M, Hirano M, Hunter JV, Srour M, Zanigni S, Lewis RA, Muzny DM, Lotze TE, Boerwinkle E; Baylor-Hopkins Center for Mendelian Genomics; University of Washington Center for Mendelian Genomics; Gibbs RA, Hickey SE, Graham BH, Yang Y, Buhas D, Martin DM, Potocki L, Graziano C, Bellen HJ, Lupski JR. Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007. Epub 2016 Sep 15. PMID: 27640307; PMCID: PMC5065660.

Abstract

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Yap ZY, Park YH, Wortmann SB, Gunning AC, Ezer S, Lee S, Duraine L, Wilichowski E, Wilson K, Mayr JA, Wagner M, Li H, Kini U, Black ED, Monaghan KG, Lupski JR, Ellard S, Westphal DS, Harel T, Yoon WH. Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes. Genome Med. 2021 Apr 12;13(1):55. doi: 10.1186/s13073-021-00873-3. PMID: 33845882; PMCID: PMC8042885.

Abstract

Background: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.

Methods: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.

Results: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.

Conclusion: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

Tawfik CA, Zaitoun R, Farag AA. Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum. Ophthalmic Genet. 2023 Jun;44(3):226-233. doi: 10.1080/13816810.2023.2183223. Epub 2023 Mar 1. PMID: 36856321.

Abstract

Background: Harel-Yoon syndrome (HAYOS) is a recently described neurodevelopmental disorder characterized by psychomotor delay, truncal hypotonia, appendicular spasticity, and peripheral neuropathy. It is caused by mutations in ATAD3A gene located on chromosome 1p.36.33 whose functions include mitochondrial DNA stabilization, the regulation of mitochondrial fission/fusion, and cholesterol homeostasis.

Materials and methods: An 11-year-old male patient of consanguineous Egyptian parents, who present with neuroregression and ptosis along with progressive impaired vision, undergoes complete ophthalmological and neurological examination. Additionally, color fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT) of both the macula and optic nerve head, full field electroretinogram (ERG), and visual field perimetry were obtained. Whole-exome sequencing and mitochondrial genome sequencing were done in a commercial laboratory from a peripheral blood sample.

Results: A novel mutation in ATAD3A gene c.624_644del was identified by whole-exome sequencing consistent with a diagnosis of Harel-Yoon Syndrome (HAYOS). The 11-year-old boy had characteristic features of neurodevelopmental delay, hypotonia, and peripheral neuropathy. However, we documented some novel features as fatiguable ptosis, facial weakness, progressive bulbar palsy, obsessive-compulsive disorder (OCD) in addition to cone system dysfunction.

Conclusion: Our study reports a novel mutation in ATAD3A gene and expands the clinical spectrum of Harel-Yoon Syndrome. Future research aiming at better understanding of gene function will lead to better genotype-phenotype correlation and could pave the way to more treatment options.

Skopkova M, Stufkova H, Rambani V, Stranecky V, Brennerova K, Kolnikova M, Pietrzykova M, Karhanek M, Noskova L, Tesarova M, Hansikova H, Gasperikova D. ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability. Orphanet J Rare Dis. 2023 Apr 24;18(1):92. doi: 10.1186/s13023-023-02689-3. PMID: 37095554; PMCID: PMC10127305.

Abstract

Background: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses.

Results: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3-4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients.

Conclusion: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.

Tuesday, May 27, 2025

Child abuse controversy, continued

UF Health Jacksonville pediatrician, Dr. Barbara Knox, is facing staff accusations of bullying coworkers, violating patient privacy and making racist remarks.

In June 2022, UF Health Jacksonville hired Knox to serve as a physician at the First Coast Child Protection Team, which treats children suspected of facing abuse.

Knox’s hiring at UF raised eyebrows given her controversy-marred professional history. In both Wisconsin and Alaska, the doctor faced complaints about workplace misconduct and misdiagnoses while serving in similar roles related to child abuse. Ultimately, she left both states amid investigations and lawsuits into her conduct.

Three staff members and one former staff member at First Coast Child Protection Team, who spoke anonymously for fear of retribution, shared accounts of Knox’s behavior.

New complaints

One employee, a longtime child welfare worker, said issues with Knox began around January 2024 when the doctor became chief of UF Health Jacksonville’s division of child protection and forensic pediatrics.

“She was targeting a lot of people… that had discussed her previous positions in Wisconsin and Alaska,” the welfare worker said. “She very quickly became highly interested in running them off.”

Knox asked employees to report on colleagues who the doctor viewed as a threat, instructing them to find any information that could potentially justify termination, according to the source.

This behavior became especially threatening when Dr. Mark Hudak, UF department of pediatrics chair, visited the CPT office to inform employees that he “personally vetted Dr. Knox” and that “anybody who’s speaking about her is subject to termination,” the welfare worker said.

One CPT employee recounted several instances in which Knox used her authority in the office for personal ends, including having employees drive her children places, insisting child abuse cases had to be scheduled around a 5K race and offering employees promotions in exchange for information about employees who opposed Knox.

“You don’t bring anything up to Dr. Knox; you’re afraid to get fired,” the CPT employee said. “You don’t say anything to her unless you want to look for another job.”

A second CPT employee said she had experienced similar interactions with Knox.

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“Only a few weeks after being employed there, I was summoned to her office privately, multiple times, with her requesting me to talk negatively and talk poorly about my supervisor so she had a reason to get them out of the office so she could kind of curate her own management,” she said. “She would practically back me into a corner.”

Those supervisors have since resigned due to the intimidation and pressure Knox placed upon them, she added.

Knox has also commented on employees’ skin color. The second CPT employee, who is mixed race, said Knox once asked her, “Why are you getting so dark?”

According to the first CPT employee, Knox complained that the receptionist for CPT’s Tallahassee office, a Black woman, looked “ghetto” due to having long, decorated fingernails.

In her account, Knox also wanted a case built against the Tallahassee receptionist and described her as “lazy” and someone who “looks like one of our clientele.”

The second CPT employee also said Knox had instructed her not to call her for any cases coming in past 10 p.m. A doctor is required to complete a patient examination before further medical actions can take place. The CPT employee received a call shortly after the 10 p.m. curfew was instigated about a child who was thrown head-first into a wall.

“Dr. Knox forbid me from calling her, so she’s now putting patients’ safety in jeopardy, because that kid should have gone to the hospital,” the CPT employee said.

The second CPT employee also said Knox’s conduct during sexual assault exams was inappropriate.

A mother brought her child in for an exam but said, due to her own experience of sexual assault, she could not watch. Instead, she would look away while remaining in the room for emotional support. The CPT employee relayed the request to Knox, who ignored it.

“Dr. Knox spread the child’s legs open in front of the mother… unclothed and put the child in the mother’s lap and started doing the swab,” the employee said. “The mom was just sitting there with tears down her face.”

Knox would treat families of color differently than white families, according to all three employees.

“We have African American, Hispanic, Muslim families that come in, and… she will go ahead and verify a report against them [over the smallest of issues], say it’s child abuse, and put the family in terrible, terrible situations,” one employee said.

When the child of a white doctor arrived to the clinic with gonorrhea — which is highly indicative of sexual abuse — Knox decided not to verify the case and claimed the child contracted gonorrhea from unwashed hands, the employee said.

Over 20 former CPT employees claimed to have quit over Knox’s conduct, according to both current and former employees.

One former employee who resigned described Knox’s behavior as “constant berating.”

“She would scream and yell and tell me what a terrible person I was,” the former employee, who worked under Knox in Florida, said.

Ultimately, the employee said the abuse broke her down to the point she had to resign.

UF public records revealed employees have also filed complaints to the Florida Office of Inspector General.

An anonymous complainant stated “[Knox] steps outside the guidelines of child welfare protocols, making inappropriate and unprofessional comments to colleagues and other agencies,” and she had stolen others’ work to create “presentations or published work about cases she was not directly associated with.”

On March 7, another complainant reported to UF’s Human Resources Department that Knox jumped to conclusions about a child’s injuries, labeling them as indications of abuse without examining the child’s full medical history.

“She took a small set of data and decided on a story of abuse without bothering to zoom out and investigate all possible reasons,” the report said.

According to the complainant, the child had a medical condition which provided a non-abuse cause of the child’s injuries.

“[Knox’s] bias on abuse leads her to find it where it doesn’t truly exist,” the complainant wrote.

A troubled history

The complaints workers at CPT have brought against Knox closely reflect those raised by her past employees in Wisconsin and Alaska.

In 2019, Knox left her position leading the University of Wisconsin’s Child Protection Program after the university placed her on paid leave while investigating complaints that she had bullied colleagues. In the letter UW sent to Knox notifying her of her paid leave status, the university explained that part of its decision was due to concerns about “unprofessional acts that may constitute retaliation against and/or intimidation of internal and external colleagues.”

One of Knox’s UW colleagues, Dr. Michael Stier, said he felt Knox had pressured him to make inaccurate abuse diagnoses, according to an article by the Wisconsin Watch. Wisconsin families filed lawsuits against Knox after her medical opinions caused them to lose custody of their children and, in some cases, even serve time in jail.

In Alaska, Knox led Alaska CARES, a child abuse clinic servicing the state. Investigations into Knox’s conduct there found that the clinic's entire medical staff had either quit or been fired in the two years Knox had worked there and staffers had complained once again of inaccurate medical diagnoses.

What’s next?

Neither Knox nor Hudak responded to requests for comment via email and phone call, though UF Health Jacksonville media relations manager Dan Leveton confirmed they received both. Leveton instructed that all communications related to Knox should come through the university via UF spokesperson Steve Orlando.

In an email statement, Orlando said Knox was hired due to her expertise and “positive contributions on behalf of children.”

“Dr. Knox is a key part of the faculty, and since her arrival her background and understanding in the field have enhanced our program and have made the community a safer place for children and their families,” Orlando wrote. As for allegations of Knox’s misconduct, he added, “the university does not comment on personnel matters.”

Several current and former employees confirmed that UF has launched an internal investigation, though with seemingly little results.

According to a former employee, one of UF’s investigators privately suggested that “it’s time to go public.”

University involvement has not inspired confidence among CPT employees concerned with Knox’s behavior.

“We do feel like the university has been negligent and nobody will step up to the plate [to address Knox’s behavior],” a welfare worker said. “She’s gotta go.”

Avery Parker

https://www.alligator.org/article/2025/01/uf-health-physician-accused-of-misconduct

Child abuse controversy

A controversial doctor. A disputed abuse diagnosis. Two convicted Wisconsin men say they are innocent

Wisconsin Watch

May 2, 2022

This story was produced by Wisconsin Watch, a nonprofit, nonpartisan investigative reporting organization that focuses on government integrity and quality of life issues in Wisconsin.

Dakota Black and Joshua Gehde are in prison for homicide after former UW Dr. Barbara Knox accused them of inflicting abusive head trauma.

By Brenda Wintrode, Wisconsin Watch

Nearly nine years after her son, Brayden, died, Shannon Turnbill still replays the image of the 5-year-old lying on the bed, unresponsive.

“It’s a picture I’ll never get out of my head,” she said of the encounter in October 2013. “His eyes were rolled back. It almost looked like he was having a seizure but not moving.”

After a University of Wisconsin doctor trained in identifying child abuse said Brayden had suffered from abusive head trauma, law enforcement blamed the only adult home with Brayden: Turnbill’s boyfriend, Dakota Black of Sun Prairie, Wisconsin.

In April 2016, Josh Gehde found his girlfriend’s 2-year-old daughter lying lifeless on the floor of their Madison, Wisconsin, apartment. Just minutes before, Gehde had given the toddler crackers and went to the bathroom to shave. When he came out, he saw chewed-up crackers on the rug near her face. He turned over her already cold body, struck her back to dislodge food and called 9-1-1.

The 9-1-1 operator coached him through CPR as he waited for paramedics. The girl died two days later after being removed from life support. Dr. Barbara Knox, the same UW child abuse pediatrician from Black’s case — who has been suspended and investigated by two hospitals in two states — said abusive head trauma caused the brain injuries that killed the girl.

Courts, legal experts and medical specialists are increasingly scrutinizing the abusive head trauma diagnosis, an umbrella term that includes the controversial diagnosis of shaken baby syndrome, for lacking a scientific basis and criteria for diagnosis. Earlier this year, a New Jersey judge labeled abusive head trauma “junk science” and refused to allow testimony about the diagnosis in his courtroom.

In both cases, Knox said the injuries happened within minutes of the child’s collapse, blaming the last person with the child. Records show that police and prosecutors, confident in Knox’s credentials, looked no further.

During each trial, attorneys and experts battled for the jury’s trust.

In the Gehde case, prosecutors showed jurors photos of a small, lifeless body still on life support, and in Black’s case, painted him as someone Brayden feared. Knox testified to a “reasonable degree of medical certainty” that each child died from abuse. Defense experts, who specialized in pediatric neurology and forensic neuropathology, blamed other possible conditions, saying they saw no signs of abuse.

“It would be most unusual to have a fatal head injury without an obvious large bruise on the scalp and a skull fracture,” Black’s expert, neuropathologist Dr. Jan Leestma, said in a report. “This child doesn’t have any of these things.”

But in the end, the juries in both cases believed Knox.

Black and Gehde are serving lengthy sentences in Wisconsin prisons, convicted of murdering the children in their care. They pleaded not guilty and refused prosecutors’ plea deals, despite facing decades behind bars. Both have lost their appeals.

The men insist they are innocent. Some family members of the children who died, including Turnbill, say they do not believe these men killed the children.

And Wisconsin Watch has identified at least eight cases in which Knox determined a child had suffered head trauma from abuse that investigators and medical specialists said were caused by benign medical conditions, injuries from severe birth trauma, accidental falls, a bleeding disorder and a possible stroke.

Knox did not respond to attempts to reach her for comment.

A national debate

These controversies are not unique to Wisconsin. In late April, a Texas appeals court halted the execution of Melissa Lucio, convicted of killing her 2-year-old daughter — a death the state’s medical examiner said was caused by “blunt force trauma” to the head in 2007.

Lucio and other family members had told police the girl fell down the stairs and was not abused — but then Lucio confessed to killing her after five hours of interrogation. The high court, citing several factors including Lucio’s possible innocence, sent the case back to a lower court for review.

Nationally, since 1992, 26 people have been exonerated following convictions on charges stemming from diagnoses of abusive head trauma or shaken baby syndrome, according to The National Registry of Exonerations.

The human instinct to protect children can snowball momentum around a child abuse allegation, making it “all too easy to sweep innocent people up in the process,” said Keith Findley, co-founder of the Wisconsin Innocence Project, who has written extensively about the problems of this type of diagnosis.

Knox’s fraught tenure

During her 13-year tenure in Wisconsin, Knox acted as a crucial liaison between the UW’s Child Protection Program and law enforcement, providing medical diagnoses, consultations or expert testimony in over 200 criminal cases, according to open records responses from 14 district attorneys in southern and central Wisconsin and an analysis of electronic court records by Court Data Technologies.

One of about 350 nationally certified child abuse pediatricians trained in recognizing child maltreatment and legal proceedings, Knox led the UW program until 2019, leaving after the hospital investigated whether she bullied her colleagues. Alaska CARES hired her that same year to lead the state’s forensic child abuse clinic. A joint investigation by Wisconsin Watch and the Anchorage Daily News found Knox generated similar allegations there.

During her brief tenure, the entire medical staff of Alaska CARES left or had their jobs reassigned. Knox submitted her resignation from Alaska CARES in January, scheduled to take effect on April 1. In March, online records show Knox was issued a medical license in Florida.

In all, the joint investigation also found 12 cases in which Knox’s diagnoses of abuse were rejected by juries, court officials, child welfare workers, investigators and other doctors.

Knox tied to 124 Dane County cases

But hundreds more cases funneled into the criminal justice system.

Dodge County District Attorney Kurt Klomberg said he stopped using Knox as an expert in 2017 after she failed to provide a timely report in an abusive head trauma case. He said he decided not to “support any child abuse or neglect cases for prosecution based on the work of Dr. Knox unless she had completed an opinion report prior to the decision to charge.”

Klomberg said he also advised law enforcement and human services to seek experts from other hospitals. After he made that decision, Klomberg got one referral for child neglect that Knox alleged. He declined to pursue it for lack of evidence.

“I seek to engage medical experts who I can rely upon,” Klomberg added. “I determined that I would not likely support a case involving Dr. Knox’s independent opinion several years ago.”

Juneau County District Attorney Kenneth Hamm said his office still has pending cases that originated on Knox’s medical opinions. After Knox left Wisconsin, he requested second opinions from other doctors, which Hamm said were “generally in line with what Dr. Knox stated and did not change the outcomes.” He added that none involved abusive head trauma or shaken baby syndrome.

Hamm and Portage County District Attorney Louis Molepske Jr. both told Wisconsin Watch they would consider re-examining closed cases if new evidence or concerns about Knox’s diagnoses emerge.

Of the 208 cases found by Wisconsin Watch, the Dane County District Attorney’s Office brought 124, over 70% of them since Ismael Ozanne’s election in 2010.

In an interview, Ozanne expressed confidence in convictions made by his office involving Knox’s diagnoses and said reviewing the cases because of questions about Knox’s job performance was an “oversimplification.”

“We were not just speaking with Dr. Knox alone,” Ozanne told Wisconsin Watch. “We were having to reach out to other experts . . . And, to my knowledge, none of those diagnoses were ever called into question. The hospital has never called us and said any of these diagnoses you should be worried about to my knowledge; and law enforcement has not reached out to us to say there’s other evidence that we have that basically shows that what was referred to you is false.”

Ozanne said he had not reached out to the UW to discuss possible misdiagnosis, adding, “I would assume if there were questions, they would reach out to us.”

Findley said the fact other doctors agreed with Knox “does not resolve the matter” because of the “repeated allegations and findings that Dr. Knox bullied colleagues” and that “plenty of other doctors and experts have raised concerns about some of her determinations.”

Findley described Knox as “an unusually aggressive and prolific advocate for concluding a child was the victim of abuse on vague, non-specific medical findings, which the research shows can have multiple etiologies, not just abuse.”

The hospital and law enforcement not alerting Ozanne to possible mistakes is “hardly surprising,” given the potential legal liability, Findley said. He added that Knox’s work history “ought at the very least prompt serious concerns about what wreckage she might have left in her wake in this jurisdiction,” he said.

Four witnesses noticed something off

The day Brayden Turnbill collapsed, his mother remembers her son waking up “happy.” She helped Brayden dress in one of his favorite superhero T-shirts and tied his shoes. The little boy who loved the Teenage Mutant Ninja Turtles and the Green Bay Packers had yet to master shoelaces.

Four people who saw Brayden after school that day told Sun Prairie police they noticed something off with the normally cheerful, fun-loving kindergartner. Two, who were children, described Brayden as looking “sad,” and as if he had been “crying without tears.”

Black said he repeatedly asked Brayden if he was OK after he came home from school with “bloodshot” eyes and acting “whiny.” Patricia Garwo, Turnbill’s cousin who picked Brayden and her children up from the bus that day, also asked him several times if he was alright, according to police reports.

The boy’s 5-year-old cousin told police that she twice saw Brayden fall on the playground. The following year an investigator for the defense reported more detail: “She said Brayden fell once off the gray monkey bars and landed on his knees, and fell once off the red monkey bars and landed on his feet . . . She said she saw with her own eyes that Brayden hurt his back, and almost his arm, on the big gray pole.” The girl said Brayden told the teacher supervising recess and went to the school nurse.

But the jurors who convicted Black never heard the girl’s testimony. Dane County Circuit Judge Stephen Ehlke barred details of the reported fall, ruling it irrelevant since she did not see Brayden hit his head.

Once he got home from school, Brayden visited a neighbor’s house briefly, played for about 15 minutes with his infant brother before telling Black he was tired and going downstairs for a nap.

Black told police he stayed upstairs with couple’s baby. The next time he saw Brayden was after Turnbill found him unresponsive in his bed.

Devastating news

As the mother of eight children, Turnbill saw some of Brayden’s older siblings experience fever-induced seizures when they were young. But when Brayden didn’t recover as her other children had, Turnbill yelled for Black to call 9-1-1. When she got on the phone, the operator walked her through CPR. And when she lifted his shirt she and Black saw a diagonal mark across his chest. Black said it looked like “he got hit with a stick.”

Doctors at St. Mary’s Hospital in Madison rushed Brayden by helicopter to the UW where doctors performed emergency brain surgery in an unsuccessful attempt to save his life. Turnbill followed with a friend to the UW.

Once there, Turnbill recalled how Knox delivered the devastating news: “We did what we could, but Brayden’s gone.” Turnbill remembered sliding off the chair to her knees and wailing.

Abuse was the only possible explanation for her son’s death. “ ‘Whoever was the last person with him is the one who did this.’ That’s exactly what she said,” Turnbill recalled.

Turnbill will never forget what Knox said next. Still standing over the grieving mother, the doctor said Brayden had bleeding on his brain “so severe that, that his, his brain pretty much fell into two pieces.”

Turnbill stammered as she recounted the episode almost nine years later, asking:

“How the hell are you going to come in and tell a mother that about her son?”

Police: ‘She has credentials’

After questioning Black at home for hours, police arrested him on an outstanding probation violation for a drug charge and took him to the Sun Prairie Police Department.

Detective Frank Smith ran the interrogation. He told Black he believed everything Knox told police — the boy’s collapse from a massive brain injury happened within minutes of being abused, according to a transcript.

“She’s an expert in her field,” Smith told Black. “She’s an expert witness for the state of Wisconsin. Okay? She has credentials.”

Then the officer added: “Something happened in the house. You did something to him.”

After Black denied harming Brayden — “I love that kid like he’s my own son” — the officer would have none of it.

“If I had any doubt or reserve of what she (Knox) told me, I wouldn’t be accusing you of doing this,” Smith said. “But I am because I believe her. I have that much faith in her science and her training.”

Black told Wisconsin Watch in a phone interview from Green Bay Correctional Institution that the interrogation was “intimidating” but “I wasn’t really scared, because . . . I didn’t have anything to hide.”

In court, Knox and pediatric radiologist Dr. Wilbur Smith testified for the state that the bruise across the boy’s chest looked to them like a “loop-mark injury” from someone striking him with a cord, like an extension cord or cell-phone charging cord. A police search of the home failed to find a cord fitting Knox’s description.

Ehlke’s ruling barring the testimony about falls on the playground kept defense experts from discussing how short falls can sometimes cause serious brain injuries in children, and in rare cases, death. In 12 of the 18 cases cited in that study, the children experienced a “lucid interval” of as long as two days before collapsing.

Knox acknowledged the possibility of lucidity between injury and collapse and referenced the 2009 death of actress Natasha Richardson, whose health declined hours after hitting her head in a skiing accident and died two days later.

Asked whether that could have happened in Brayden Turnbill’s case, Knox responded: “Absolutely not” — because their brain bleeds occurred within different, yet proximal, layers of the brain. However, a 2018 Medscape article reported that more than half of the patients who had the same type of bleeding as Brayden “had lucid intervals and were able to make conversation between the time of their injury and subsequent deterioration.”

Black was convicted after a nine-day trial in Dane County Circuit Court. Turnbill refused to testify for the prosecution. “I still believe that something happened to him at school,” she said.

Black, now 32, won’t get out of prison until 2045. Then, he faces 21 more years of community supervision, finishing his sentence at age 76.

‘It was the scariest thing ever’

Joshua Gehde said he never minded watching his girlfriend’s daughter, who he described as “very bubbly, happy, always smiling.”

The three had lived together for six months in an apartment near Madison’s Reindahl Park. They loved to visit the city’s botanical garden and just get outside together, he said.

“It felt like we were becoming a family, like everything was coming into place,” Gehde said during a phone interview from Stanley Correctional Institution.

On the morning the 2-year-old collapsed, his girlfriend went to work, and Gehde took the toddler to the park. He snapped a photo of the girl with a pacifier in her mouth, wisps of blond hair surrounding her face beneath the hood of her pink coat, and sent it to her mother.

After about an hour at the park, they went back home for lunch. He broke up some Ritz crackers on the highchair tray and put it on the floor where she could reach. He heard her cough a few times while he was in the bathroom but “didn’t think anything of it,” he told police. He thought she was fine. Minutes later, she wasn’t.

A paramedic who arrived at the scene said the girl’s lips were blue, and a firefighter reported using forceps to remove regurgitated food from her airway. A police officer who arrived on the scene originally concluded the event was a “tragic accident,” according to court documents.

Two days later, the girl died at the UW. Doctors reported the girl had brain and eye bleeding and brain swelling. Knox documented multiple bruises, including on the back of the girl’s head, and a large red mark on the girl’s left buttock she described as a “handprint.” Citing the brain and eye findings as a “constellation” of injuries, and marks she labeled as bruises, Knox declared the girl suffered “definite abusive head trauma.”

The day after the toddler died, Gehde, shackled at the wrists and ankles and wearing blue prison scrubs, shuffled into a Dane County Sheriff’s Office interrogation room. The then-25-year-old and two Madison police detectives sat on upholstered furniture, a coffee table between them, while he recounted the events leading up to the girl’s collapse.

At the request of detectives, he reenacted how he gave her back blows to dislodge the food from her throat on a toddler-sized mannequin.

“It was the scariest thing ever . . . she was lifeless,” he told the Madison detectives, as he sat back on the couch and reached for tissues to dry his eyes.

But detectives rejected his story based on what Knox told them. “We know for sure the doctors are going to say she didn’t choke on anything,” Detective Maya Krajcinovic said.

Since Gehde was the last one with her, he was the only one who could tell them what happened, they said.

“I’m not going to admit to something I didn’t do,” Gehde said, dissolving into tears. “I f***ing loved that girl.”

Later in the interview, Krajcinovic picked up the mannequin to demonstrate what she thought could cause the girl’s injuries. “If somebody grabs a kid and gets upset,” she said, shaking the dummy, its head flailing back and forth, then strikes its head on a couch, “ … that’s what causes bruises.”

Gehde looked at her confused and asked, “Who does that though?”

Defense offers other causes

Three medical specialists hired by the defense testified the girl died after blood clots in her brain caused a seizure, starving her brain and heart of oxygen. A neuroradiologist said small seizures can mimic a choking incident. And the girl’s autopsy report revealed she had bitten her tongue, a common occurrence in children having seizures.

Pediatric neurologist Dr. Joseph Scheller, said he could not determine if the clots were hours or days old. Regarding her bruises, he wrote 2-year-olds “can easily become bruised while engaging in play activities.”

In her medical report, Knox acknowledged the girl’s brain scan showed blood clots and bleeding throughout her brain, but, coupled with the child’s multiple bruises, concluded the girl’s brain injury was due to abusive head trauma.

During a cross-examination at trial, Gehde’s attorney asked Knox if she’s ever made a mistake.

“I am not aware that I have ever had a mistaken diagnosis,” she answered.

Gehde and other members of his family independently told Wisconsin Watch that the day after his defense team’s experts testified, some of the girl’s family members, including the child’s mother, switched sides and sat near Gehde’s parents and his defense attorneys.

If he had pleaded guilty, Gehde said both families would have “never heard any of this, they would have never heard the evidence to let them know I didn’t do anything — for them to support my innocence.”

The girl’s mother did not respond to interview requests, and attempts to interview other family members were unsuccessful. Private messages shared with Wisconsin Watch between the Gehde family and some of the girl’s family members, as recently as 2020, revealed they believed Gehde is innocent.

However, the jury did not.

Gehde’s 20-year prison sentence ends in 2039, followed by 15 years of probation. He unsuccessfully appealed in 2019.

He wrote in an email from prison: “My whole life was stripped from me for something I didn’t do.”

Separated — but still close

Less than one year after Brayden died, a consultant hired by the Sun Prairie School District inventoried the district’s playground equipment. The study listed — in poor condition and as a high priority for replacement — three district play structures, one of which was the monkey bars from which the girl said she saw Brayden fall.

A spokeswoman for the school district refused to answer questions about Brayden’s reported fall from the Royal Oaks Elementary School playground structure and the timing of the consultant’s hiring.

Black and Turnbill remain close and are trying to raise their two sons together, although the prison has banned her from visiting him because he was convicted of killing her son.

Black talks to his sons several times a week on Turnbill’s phone. The boys, who are now 9 and 8, know their father is in prison because of something that happened to their brother, but she has spared them the details.

She tells them, “The police don’t always tell the truth . . . the lawyers, the judges; the news doesn’t always tell you the truth.”

After Brayden died, Shannon and the boys lived with Black’s mother for three years, but have since moved from one living situation to the next. She now works as a housekeeper in a Madison hotel and rents a room there for her and the boys while she tries to get subsidized housing.

She hopes in sharing her story she can uncover the truth of what happened to her son that day — and find some justice for Black.

“Someday, I hope they figure out what really happened, and let him go.”

The Fund for Investigative Journalism provided financial support for this story. The nonprofit Wisconsin Watch (www.WisconsinWatch.org) collaborates with WPR, PBS Wisconsin, other news media and the University of Wisconsin-Madison School of Journalism and Mass Communication. All works created, published, posted or disseminated by Wisconsin Watch do not necessarily reflect the views or opinions of UW-Madison or any of its affiliates.

https://wnanews.com/2022/05/02/a-controversial-doctor-a-disputed-abuse-diagnosis-two-convicted-wisconsin-men-say-they-are-innocent/