Altitude sickness on Mount Whitney

A California teen, who was placed in a coma after he hallucinated and walked off a cliff while hiking, is now breathing on his own, according to his family

Zane Wach, 14, had his "breathing tube removed" after he was placed in a medically induced coma two weeks ago

The teen began experiencing altitude sickness as he and his father were hiking Mount Whitney in Northern California, causing him to "experience some hallucinations," his father previously said

A California teen, who was placed in a coma after he hallucinated and walked off a cliff while hiking, is breathing on his own, according to his family.

On Thursday, June 26, the father of 14-year-old Zane Wach shared an update on the teen's health following an incident two weeks ago, in which Zane began experiencing hallucinations due to what doctors believe was altitude sickness.

Zane’s father, Ryan Wach, wrote in a Facebook post shared on the teen’s grandmother Lisa Hinrichsen-Wach's page that Zane had reached his first "giant milestone" since being placed in a medically induced coma.

"I'll be brief today as it was a big day but very hard," Ryan began. "Zane had the breathing tube removed and taken off the [ventilator]. This was a giant milestone and opens the door to many new steps forward. He's not doing much else at the moment, the largest focus is watching closely so that he does well breathing on his own as well and being able to cough and swallow."

"The hard part is that he is well into feeling the effects of withdrawal," the dad continued. "He's been on a lot of heavy drugs for a while and getting off those is extremely hard and painful. As parents, it's terrible to watch. We hope he gets through this with the least possible suffering."

Ryan previously said he and his 14-year-old son were climbing Mount Whitney in Northern California on June 10 when the incident occurred, according to The Independent and SFGATE.

During their 19-hour hike, Ryan said his son began showing signs of altitude sickness, according to NBC affiliate KSNV. The duo started heading back down the mountain, but things progressively worsened as they continued descending.

Ryan said his son started feeling “considerably better” about six miles from the trailhead, but his condition worsened about an hour later, and Zane “started to doubt reality.”

A short time later, Ryan said his son thought they had “finished the hike multiple times over,” but they still had not reached the trailhead. 

“He started to experience some hallucinations,” Ryan told SFGATE. “He knew he was hallucinating. He said he saw things like snowmen and Kermit the Frog.”

“He told me he couldn’t tell if he was dreaming or not,” the dad further recalled, “and he would shake his head in disbelief, like, ‘This is not real.’ Like he was in the movie Inception or something.”

Eventually, another group of hikers helped the pair call for help, according to SFGATE and The Independent, but Zane, still experiencing hallucinations, walked off a cliff and fell 120 feet.

“I didn’t see how there would be a way for him to survive it, so I screamed,” Ryan recalled to The Independent. He told the outlet that he quickly raced over to his son after the fall and found him “still breathing.”

Rescue teams arrived about six hours later, and Zane was flown to Southern Inyo Hospital in Lone Pine before being transported to Sunrise Children’s Hospital in Las Vegas, according to SFGATE.

Zane sustained several injuries from the fall, including head trauma, a broken ankle, a broken finger and a partially broken pelvis.

“It’s going to be a survival story in the end, but right now we’re still in the middle of it,” Ryan said.

The teen's family has raised nearly $30,000 through a GoFundMe campaign to support him following the incident.

“We believe in the power of community to lift each other up, and we thank you for your prayers and support,” wrote Heather Riggen, who organized the online fundraiser. “Together we are stronger. Team Zane all the way! We believe in you, buddy; continue to fight.”

https://people.com/teen-taken-off-ventilator-after-hallucinating-and-walking-off-cliff-11763200

Outcomes in early-treated guanidinoacetate methyltransferase deficiency

Caspi L, Hayeems R, Schulze A. Outcomes in Early-Treated Guanidinoacetate Methyltransferase Deficiency: A Sibling Cohort Study. Neurol Genet. 2025 May 30;11(3):e200262. doi: 10.1212/NXG.0000000000200262. PMID: 40469081; PMCID: PMC12135069.

Abstract

Background and objectives: Guanidinoacetate methyltransferase deficiency (GAMT-D), a rare inborn error of creatine metabolism, is a disabling neurodevelopmental disorder due to the combined effect of cerebral creatine depletion and guanidinoacetate accumulation. Existing therapies efficiently improve both of the biochemical abnormalities. The goal of this study was to provide evidence for the crucial role of age at treatment initiation in clinical outcomes in affected individuals.

Methods: In a mixed-method interview-based and questionnaire-based cohort study, 4 sibling pairs with GAMT-D (case group) and 8 healthy, age-matched sibling pairs (control group) were enrolled. In the case group, each younger sibling was diagnosed and treated earlier than their older sibling. Interviews with parents in the case group were performed to ascertain major perceived differences between the siblings and to construct a questionnaire that was completed by the parents for each child in both groups.

Results: In the case group, all younger, earlier treated siblings had distinctly better outcomes in all ascertained domains compared with their older siblings, including development, cognition, school level, motor skills, coordination, adaptive functioning, behavior, needs or supportive measures, and seizures. Remarkably, in the case group, the outcomes in 2 children treated as neonates were not different from the healthy controls; the outcomes in 2 other children treated since infancy were better compared with those treated after the age of 2 years.

Discussion: The favorable outcome observed in patients with GAMT-D when treatment is initiated in the presymptomatic period or early infancy should serve as a compelling argument for those programs that have not already implemented newborn screening of GAMT-D.

Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E. Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology. 2006 Aug 22;67(4):719-21. doi: 10.1212/01.wnl.0000230152.25203.01. PMID: 16924036.

Abstract

Prospective observation in a neonate with guanidinoacetate methyltransferase deficiency (GAMT-D), a severe neurometabolic disorder, revealed increased guanidinoacetate levels at birth. After 14-month treatment with creatine, high-dose ornithine, benzoate, and an arginine-restricted diet, the patient's development is normal and she does not present any symptoms of GAMT-D. The authors' observation indicates that early detection of GAMT-D is possible in the neonatal period, and presymptomatic treatment may prevent its manifestation.

Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araújo HC, Coskun T, Diogo L, Geraghty M, Haliloglu G, Konstantopoulou V, Leuzzi V, Levtova A, Mackenzie J, Maranda B, Mhanni AA, Mitchell G, Morris A, Newlove T, Renaud D, Scaglia F, Valayannopoulos V, van Spronsen FJ, Verbruggen KT, Yuskiv N, Nyhan W, Schulze A. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2014 Jan;111(1):16-25. doi: 10.1016/j.ymgme.2013.10.018. Epub 2013 Nov 7. PMID: 24268530.

Abstract

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.

Do seizures damage the brain?

Klein P, Carrazana E, Glauser T, et al. Do Seizures Damage the Brain? Cumulative Effects of Seizures and Epilepsy: A 2025 Perspective. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251331927

Abstract

In 1885, William Gowers proposed that epilepsy is a progressive disease, based on clinical evidence before any effective treatments were available. His long-standing hypothesis has been summarized with the statement “seizures beget seizures.” Whether this is the case and related questions about seizure-induced modification and damage of brain circuits are of fundamental importance for neurobiological understanding of epilepsy, development of effective treatment strategies, clinical management, and prognostication. Consensus about progression and seizure-induced damage has remained controversial. Here, we critically review these long-standing questions, incorporating perspectives about perceived inconsistencies in past studies, potential implications of recent longitudinal imaging and cognitive studies, and emphasize experimental and clinical gaps that have proved challenging. Answers to these questions are important for development of management strategies to achieve prompt effective acute control of seizures and prevention of their potential recurrence and long-term comorbidities.

From the article:

Consensus Points in 2025?
The long-standing controversies about progressive brain damage in chronic epilepsy remain difficult to conclusively resolve, but recent longitudinal human studies demonstrating progressive cortical thinning associated with continuing seizures and cognitive studies revealing progressive declines over decades associated with neuronal loss and decreased neurogenesis provide new context to critically reevaluate Gower's progression hypothesis and the significance of seizure-induced neuronal loss observed in the most sensitive experimental studies. We conclude with a summary of potential consensus points across experimental and clinical perspectives in 2025:
1.
Epilepsy is not progressive in all patients
The >60% of patients achieving seizure control do not have progressive courses or cognitive decline, but a subset of patients with TLE and other focal epilepsies experience progressive decline without apparent progressive initial insults. The decline may include increasing frequency of seizures over time, with or without functional or cognitive declines. Typical absence seizures and other “benign” childhood epilepsies do not invariably lead to progressive decline, but in a subset of absence and “benign” epilepsy patients, attention, cognitive, behavioral, and psychiatric issues may emerge in adolescence after seizures abate, perhaps reflecting initial etiology or a consequence of seizures.
2.
Damage is greater with longer versus shorter seizures
Damage in SE has increased urgency for rapid treatment, with intervention thresholds shifting from 30 min of unremitting seizures to 5 min. Whether a single seizure or repeated brief seizures lead to significant structural or functional changes in the human brain remains controversial, but the most sensitive histologic methods in experimental animals demonstrate subtle, but cumulative, neuronal death with repeated brief seizures accompanied by functional deficits.
3.
Progressive cortical thinning occurs with recurring seizures in human longitudinal imaging studies
Cortical thinning increases with duration of epilepsy, appears to be related to seizures, and progresses in postsurgical patients whose seizures continue compared to postsurgical patients who are seizure free. These observations are consistent with seizure-induced cumulative cortical damage.
4.
Neuropsychological studies across epilepsy patients over decades demonstrate a declining cognitive trajectory not seen in age-matched people without epilepsy
Recent human studies associating cognitive declines with decades of epilepsy, neuronal loss, and reduced neurogenesis, as well as animal studies showing seizure-induced neuronal loss, potentially implicate continuing underestimated seizures as a contributing factor, but primary progressive etiological and/or effects of other factors such as ASMs cannot be excluded.
5.
Studies of progression in humans are significantly limited by the inaccuracy of seizure counts over long periods
Continuous scalp EEG recordings reveal seizures not detected clinically, and depth EEG recordings demonstrate that electrographic seizures are more frequent than detected in scalp recordings or clinical records, and may not be recognized as a clinically apparent seizure. Patient, family, and medical historical records are inadequate for resolution of questions about relationships of seizure burden to imaging patterns of damage and cumulative cognitive deficits. The insensitivity and inaccuracy of human seizure counts is a major impediment to resolving questions about progressive impact of uncontrolled seizures, but experimental studies offer the potential to determine seizure counts more accurately.
6.
Across both experimental and human domains, it remains difficult to separate progression caused by underlying primary etiologies from progression secondary to recurring seizures
Experimental studies that induce focal seizures without initial pathologic alterations offer the potential to separate these confounding processes. Transgenic animals with epilepsy secondary to genetic or epigenetic defects do not typically provide this opportunity, or resolve the question of initial etiological or secondary seizure-induced contributions to progressive damage.
These points derived from recent clinical, imaging, cognitive studies, and previous experimental observations may serve as guidelines and provide potential directions for investigations to address cumulative adverse consequences of recurring seizures. Concerns about progressive damage remain compelling for the ∼35% of patients who do not achieve control with current therapies and for those who lack access to adequate treatment. The available data about progressive adverse long-term effects of epilepsy provides a compelling need for more effective acute interventions to prevent recurring seizures and their potential consequences.

Lived experiences of multiple sulfatase deficiency-affected individuals and their families

Gavazzi F, Yu E, Tashnim Z, Woidill S, Sevagamoorthy A, Arnold K, Ammann-Schnell L, Groeschel S, Krägeloh-Mann I, Breitling V, Schlotawa L, Ahrens-Nicklas R, Adang LA. Exploration Into Lived Experiences of Multiple Sulfatase Deficiency-Affected Individuals and Their Families. J Child Neurol. 2025 May 14:8830738251339848. doi: 10.1177/08830738251339848. Epub ahead of print. PMID: 40368343.

Abstract

Despite their importance, rare diseases' impact on patients and families is understudied. This is particularly true for ultrarare disorders, such as multiple sulfatase deficiency (MSD), a pediatric neurodegenerative disorder. To address this gap, we captured caregiver perspectives on how multiple sulfatase deficiency affects their child, themselves, and their families regarding adaptive behaviors and health-related quality of life.Overall, 19 multiple sulfatase deficiency caregivers participated in assessments capturing health outcomes related to daily functional abilities (Vineland Adaptive Behavior Scale-Third Edition [VABS-3]: n = 19), child health-related quality of life (Caregiver Priorities and Child Health Index of Life with Disabilities: n = 12; Pediatric Quality of Life Inventory-generic core scales: n = 13), and caregiver health-related quality of life (Pediatric Quality of Life Inventory-family impact module: n = 12; Traumatic Brain Injury Caregiver Quality of Life: n = 15). The Pediatric Quality of Life Inventory-family impact module results were compared to a data set from metachromatic leukodystrophy (n = 30), a rare disease with an overlapping sulfatase deficiency.The Vineland Adaptive Behavior Scale-Third Edition captured global impairment across domains in multiple sulfatase deficiency. Despite these functional limitations, the Caregiver Priorities and Child Health Index of Life with Disabilities and Pediatric Quality of Life Inventory-generic core scales captured relative preservation of health-related quality of life, especially related to emotional well-being. Compared with the Pediatric Quality of Life Inventory-generic core scales, the Caregiver Priorities and Child Health Index of Life with Disabilities captured a broader spectrum of health-related quality of life across all domains and caregivers' top priorities in disease management and care coordination. The health-related quality of life of caregivers was severely impacted, with caregivers reporting profound feelings of grief and entrapment. Additionally, there was a similar caregiver burden between multiple sulfatase deficiency and metachromatic leukodystrophy.Our results will help inform psychosocial outcome measures for rare disease families and patient-centered endpoints in impending multiple sulfatase deficiency clinical trials.

Atidarsagene autotemcel for metachromatic leukodystrophy 2

Fumagalli F, Calbi V, Gallo V, Zambon AA, Recupero S, Ciotti F, Sarzana M, Fraschini M, Scarparo S, De Mattia F, Miglietta S, Pierini C, Soncini M, Morena F, Montini E, Barzaghi F, Consiglieri G, Ferrua F, Migliavacca M, Tucci F, Fratini ES, Ippolito A, Silvani P, Calvi MR, Clerici A, Corti A, Facchini M, Locatelli S, Sangalli M, Zancan S, Miotto F, Natali Sora MG, Baldoli C, Martino S, Córdoba-Claros A, Moro SL, Gollop ND, Abate J, Yarzi MN, Nutkins P, Shenker A, Calissano M, Brooks J, Richardson A, Campbell L, Filippi M, Naldini L, Cicalese MP, Ciceri F, Bernardo ME, Aiuti A. Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy. N Engl J Med. 2025 Apr 24;392(16):1609-1620. doi: 10.1056/NEJMoa2405727. PMID: 40267426. Clinical Trial

Abstract

Background: Metachromatic leukodystrophy (MLD) is an ultrarare, severe lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA).

Methods: We treated patients who had MLD with atidarsagene autotemcel (arsa-cel), a hematopoietic stem-cell-based gene therapy, in two prospective open-label clinical studies and expanded-access programs. We compared their outcomes with those of untreated patients (natural history cohort). The primary end point was survival free from severe motor impairment (the time from birth to the first occurrence of loss of locomotion and of sitting without support or death from any cause).

Results: A total of 39 treated patients and 49 untreated patients were included. The median follow-up was 6.76 years (range, 0.64 to 12.19). Arsa-cel resulted in a significantly lower risk of severe motor impairment or death than no treatment among patients with presymptomatic late-infantile MLD (P<0.001), those with presymptomatic early-juvenile MLD (P = 0.04), and those with early-symptomatic early-juvenile MLD (P<0.001). The estimated percentage of patients surviving without severe motor impairment at 6 years of age was 0% (95% confidence interval [CI], not evaluable) among untreated patients with late-infantile MLD and 100% (95% CI, 100 to 100) among treated patients with presymptomatic late-infantile MLD. The estimated percentage of patients surviving without severe motor impairment at 10 years of age was 11.2% (95% CI, 0.9 to 36.4) among untreated patients with early-juvenile MLD and 87.5% (95% CI, 38.7 to 98.1) and 80.0% (95% CI, 40.9 to 94.6) among treated patients with presymptomatic and early-symptomatic early-juvenile MLD, respectively. No evidence of insertional oncogenesis was found. The most common grade 3 or higher adverse event was febrile neutropenia. Anti-ARSA antibodies were detected transiently in 6 of 39 patients (15%). Three deaths occurred, all of which were considered by the investigators to be unrelated to arsa-cel.

Conclusions: Among patients with presymptomatic late-infantile or early-juvenile MLD and those with early-symptomatic early-juvenile MLD, the risk of severe motor impairment or death was significantly lower among those who received treatment with arsa-cel than in a natural history cohort that did not receive treatment.

Wolf NI, van der Knaap MS, Engelen M. Treatment of leukodystrophies: Advances and challenges. Eur J Paediatr Neurol. 2025 May;56:46-50. doi: 10.1016/j.ejpn.2025.03.016. Epub 2025 Apr 15. PMID: 40279833.

Abstract

Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and emerging treatments are shifting the field from therapeutic nihilism to cautious optimism. Allogenic haematopoietic stem cell transplantation (HSCT), used since the 1980s, has shown efficacy in specific leukodystrophies, such as adrenoleukodystrophy and metachromatic leukodystrophy, when administered early. Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD. Trials for gene replacement and antisense oligonucleotide therapies are ongoing for several leukodystrophies, including Canavan disease and Alexander disease. Certain treatments, such as guanabenz for Vanishing White Matter, target disease-specific dysregulated molecular pathways. Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies.

Zambon AA, Rancoita PMV, Quattrini A, Butera C, Gentile F, Facchini M, Mazza S, Recupero S, Gallo V, Shenker A, Gollop ND, Del Carro U, Calbi V, Di Serio C, Natali Sora MG, Filippi M, Aiuti A, Fumagalli F. Effects of atidarsagene autotemcel gene therapy on peripheral nerves in late-infantile metachromatic leukodystrophy. Brain. 2025 Apr 26:awaf157. doi: 10.1093/brain/awaf157. Epub ahead of print. PMID: 40286327.

Abstract

This study evaluates the efficacy of arsa-cel gene therapy (GT) in mitigating the severity and progression of peripheral neuropathy as assessed by nerve conduction velocity (NCV) in individuals affected by late-infantile metachromatic leukodystrophy (LI-MLD). This is a post-hoc analysis conducted on pre-symptomatic patients affected by LI-MLD treated with ex vivo autologous hematopoietic stem cell GT (atidarsagene autotemcel, "arsa-cel") in the context of prospective open-label, single-arm, interventional trials and expanded access programs. All patients were followed longitudinally with nerve conduction studies (NCSs) of peripheral motor (ulnar - UN, deep peroneal - DPN) and sensory (median - MN, sural - SN) nerves. These results were compared with those from a control group of untreated patients (NHx) studied with the same standardized protocol. We then analyzed the effects of baseline characteristics (age at treatment, severity of neuropathy pre-treatment expressed as age-matched NCV Z-scores) and arylsulfatase A (ARSA) enzyme activity (measured in peripheral blood myeloid CD15+ cells post treatment) on NCVs of treated patients. The primary endpoint of this post-hoc analysis was NCV, reflecting severity of demyelinating neuropathy. Changes in dermal nerve histopathology in skin biopsies were used as an exploratory outcome. Fifteen treated and 16 NHx patients were included in the analyses, with a median age (IQR) at treatment of 13 (9.1;14.5) months. At 36 months of age, treated patients showed higher estimated NCVs in all nerves compared to age-matched controls (∼15 m/s difference in motor nerves). Peripheral neuropathy was observed in the majority of treated patients at their pre-treatment examination (age range 7.3-17.4 months). Severity of pre-treatment neuropathy in treated patients did not have an effect on NCV values at 2 years post-GT, or on the rate of NCV slowing afterwards. A younger age at treatment was associated with higher NCVs of motor UN and sensory MN 2 years post-GT. Overall, ARSA levels in CD15+ cells correlated with NCVs of motor DPN at 2 years post-GT, and ARSA levels were associated with a slower decrease or a slight increase in NCVs of the DPN, UN and MN nerves afterwards. In summary, peripheral neuropathy assessed by NCV is significantly ameliorated in LI patients treated with arsa-cel compared to untreated patients of similar age. In addition to the potential role of early age at treatment in the preservation of myelin, supraphysiological ARSA levels may slow demyelination of the DPN and other peripheral nerves. Arsa-cel may exert a stronger effect on NCV than allogeneic hematopoietic stem cell transplantation due to its greater ARSA expression.

Lipid intolerance

Finley Ranson, 14, of England, and his mother speak about a "rare condition" in which his body rejects fat, requiring the teenager to receive twice weekly infusions in order to eat.

A teenager who is unable to eat any food at all has a condition so rare that doctors said they haven't found anyone else with the same ailment.

Finley Ranson, age 14, was born with an extreme response to all food, with his body reacting as if it was a virus and causing him to bleed internally.

"I've got a rare condition where I can't have fat into my stomach," the boy told news agency SWNS. "It is impacting my life, as I've not been able to eat any food or drink other than water."

The boy's digestive system cannot tolerate lipids, which are fatty compounds or oils that are found in foods.

When Ranson, who is from England, was 4 years old, he was taken to a London hospital, "where a central line fed nutrients and minerals into his heart," his mother said. "It was a game-changer. He was happy, bouncing and starting to put on weight."

Finley now regularly receives the lipid infusions via a tube, which enters his chest and goes to the central vein in his heart.

He receives carbohydrates, proteins, vitamins and minerals three times a day into his stomach via a different tube.

He started undergoing the six-hour process every week when he was 4 years old.

For the past five years, it has been twice a week.

"We have to bypass the gastrointestinal tract completely," Dr. Manas Datta, a pediatrician who has treated Finley since birth, told the BBC.

Doctors tried introducing separate ingredients from the tube into the boy's stomach, but "as soon as they put the lipid in, we took 10 steps back," the boy's mother, Rhys Ranson, told SWNS.

Ranson's condition is so rare that it doesn't even have a name, although he has dubbed it "Finley-itis."

His condition has baffled medical professionals, who believe he may be one of the only people whose body reacts to lipids in this way.

"That's the unfortunate thing that we bump up against in medicine with rare diseases that confound doctors," Dr. Neeta Ogden, an allergist and immunologist in Edison, New Jersey, who is not involved in Ranson's care, told Fox News Digital.

Dr. Stephen Tilles, an allergy and immunology specialist in Seattle, told Fox News Digital that Ranson's condition is not the sort of thing typically associated with a food allergy.

"Obviously, it's an adverse reaction to the lipid component of food, but that's not on the list of things that allergists will encounter in their practices," said Tilles, who is also unaffiliated with Ranson's care.

Doctors originally believed Ranson might be allergic to breast milk, but after being fed hypoallergenic milk through a tube, he still failed to thrive, his mother reported.

"His stools were all blood and mucus, and he wouldn't put on weight" when he was a baby, Rhys Ranson told SWNS.

"We have to bypass the gastrointestinal tract completely."

She is now being trained to perform the lipid infusions at home, which she hopes will improve her son's quality of life.

"We're unsure what the future looks like," she said.

"We hope there's a day that comes [when] he can have a normal diet … but if not, as long as Finley's happy and healthy and thriving the way he is, we're happy to continue what life is like for us at the moment."

Peter Burke is a lifestyle editor with Fox News Digital.

https://www.foxnews.com/food-drink/teen-unnamed-condition-cant-eat-food-baffling-doctors-worldwide

CRNKL1 variants are associated with severe microcephaly and pontocerebellar hypoplasia with seizures

Ray Das, Sankalita et al. Recurrent de novo variants in the spliceosomal factor CRNKL1 are associated with severe microcephaly and pontocerebellar hypoplasia with seizures. The American Journal of Human Genetics. Published online June 18, 2025 DOI: 10.1016/j.ajhg.2025.05.013

Summary
Splicing is a complex process that is required to create the transcriptomic diversity needed for specialized functions in higher eukaryotes. The spliceosome contains more than 100 proteins and RNA molecules, which coordinate this dynamic process. Despite the ubiquity of splicing, pathogenic variants in spliceosomal components often cause a tissue-specific phenotype, hinting at further complexities that are not yet fully understood. We have identified a cohort of ten families with de novo missense variants in a spliceosomal component, CRNKL1, where nine individuals harbor one of two missense variants that both affect the same amino acid, Arg267. All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly, with pontocerebellar hypoplasia, seizures, and severe intellectual disability. Microinjection of mRNA encoding mutant Crnkl1 into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. Taking these results together, we have identified CRNKL1 as a disease-associated gene and demonstrate the requirement for this protein in brain development. Our findings contribute to a growing disease cluster, where associated components act at the same spliceosomal stage and cause a severe neurological phenotype, suggesting a more intricate role for these spliceosomal subcomplexes than previously thought.

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.

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

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

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

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.

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.

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.