A 78-year-old Oklahoma woman who was diagnosed with polio as a child and was the last American to rely on an iron lung to live has died.
Martha Lillard found out she had the once-feared disease when she was 5 years old, which left her paralyzed from the neck down, and required her to use the machine to help her breathe while she slept.
Lillard contracted COVID-19 twice during the pandemic, which left her in the machine nearly 24 hours a day.
"They told her she wasn't supposed to live past 20 years old," her younger sister, Cindy McVey, told The Associated Press on Friday. "She had the enthusiasm and the drive to continue living and make the best of her life."
Despite having polio, Lillard was able to go to school two hours a day as a child, and she had tutors the rest of the time. She also used an intercom phone system that allowed her to interact with her teachers and classmates from home.
Lillard was even able to take road trips as a child because of a custom trailer that could accommodate the iron lung and her father making sure their hotels had wide enough doors for the machine.
An iron lung is a negative-pressure ventilator that helps a patient with paralyzed lung muscles breathe.
The disease once caused thousands of cases of paralysis in children during outbreaks each year in the first part of the 20th century before a vaccine became available in 1955.
By 1979, polio was considered eliminated in the U.S.
Later, Lillard was able to regain the use of her left arm and legs through therapy and was even able to drive for a time.
She lived independently for many years, even getting married earlier this year to a man from Egypt she corresponded with for two decades after he was able to obtain a visa.
"They were really soul mates," McVey said. "He's extremely brokenhearted."
Lillard, who wrote poetry and volunteered with the Humane Society, according to her sister, had just 25% lung capacity before she was diagnosed with COVID.
https://www.foxnews.com/health/last-american-use-iron-lung-dies-78-years-old-childhood-polio-diagnosis
Sunday, July 12, 2026
Riboflavin transporter deficiency and energy dysmetabolism
Colasuonno F, Marioli C, Tartaglia M, Bertini E, Compagnucci C, Moreno S. New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement. Biomedicines. 2022 Jun 6;10(6):1329. doi: 10.3390/biomedicines10061329. PMID: 35740351; PMCID: PMC9219947.
Abstract
Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.
Marioli C, Magliocca V, Petrini S, Niceforo A, Borghi R, Petrillo S, La Rosa P, Colasuonno F, Persichini T, Piemonte F, Massey K, Tartaglia M, Moreno S, Bertini E, Compagnucci C. Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells. Int J Mol Sci. 2020 Oct 7;21(19):7402. doi: 10.3390/ijms21197402. PMID: 33036493; PMCID: PMC7582490.
Abstract
Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.
Colasuonno F, Niceforo A, Marioli C, Fracassi A, Stregapede F, Massey K, Tartaglia M, Bertini E, Compagnucci C, Moreno S. Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency. Oxid Med Cell Longev. 2020 Aug 12;2020:6821247. doi: 10.1155/2020/6821247. PMID: 32855765; PMCID: PMC7443020.
Abstract
Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl β-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.
Abstract
Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.
Marioli C, Magliocca V, Petrini S, Niceforo A, Borghi R, Petrillo S, La Rosa P, Colasuonno F, Persichini T, Piemonte F, Massey K, Tartaglia M, Moreno S, Bertini E, Compagnucci C. Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells. Int J Mol Sci. 2020 Oct 7;21(19):7402. doi: 10.3390/ijms21197402. PMID: 33036493; PMCID: PMC7582490.
Abstract
Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.
Colasuonno F, Niceforo A, Marioli C, Fracassi A, Stregapede F, Massey K, Tartaglia M, Bertini E, Compagnucci C, Moreno S. Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency. Oxid Med Cell Longev. 2020 Aug 12;2020:6821247. doi: 10.1155/2020/6821247. PMID: 32855765; PMCID: PMC7443020.
Abstract
Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl β-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.
Wednesday, July 8, 2026
Shades of Questcor 8
I hold my nose and prescribe.
How much money does the manufacturer of Valtoco make?
The manufacturer of Valtoco, Neurelis, Inc., generated an estimated $295 million to $300 million in net sales for the full year of 2025. Because Valtoco is their flagship commercial product, it drives the vast majority of this revenue.
A breakdown of Neurelis' financial performance highlights their latest earnings structure:
Net Sales Growth: The $295–$300 million figure for 2025 represents an immense jump, more than doubling their 2024 net sales figures.
Profitability: The company reported an EBITDA margin of 30%+, meaning their core operating profitability is roughly $90 million or more before accounting for interest, taxes, depreciation, and amortization.Cash Reserves: As of December 31, 2025, Neurelis held $175+ million in cash with zero bank debt.
Growth Catalysts: Sales spiked dramatically following the FDA indication expansion allowing children ages 2 to 5 to be prescribed the nasal spray.
Google AI
______________________________________________________
Why is Valtoco so expensive?
AI Overview
Valtoco is expensive because it is a brand-name medication with no generic alternative. Its high cost reflects the years of research and clinical trials required to develop its specialized, needle-free nasal delivery system, alongside the proprietary Intravail absorption technology.
Because it is a patented pharmaceutical manufactured by Neurelis, there are no competitors to drive down the retail price, which can easily exceed $380 to $1,000+ depending on the prescribed dosage. However, according to discussion on the r/Epilepsy Reddit Forum, users agree that the prohibitive retail prices can be bypassed using manufacturer savings programs and patient assistance programs, often bringing costs down significantly.
Patients prescribed Valtoco can utilize several tools to reduce their out-of-pocket costs:
Manufacturer Co-Pay Cards: Patients with commercial insurance can often pay as little as $20 through the VALTOCO Co-Pay Card Program.
Patient Assistance Programs: Uninsured or underinsured patients may qualify to receive the medication at no cost through the myNEURELIS Support Program.
Discount Cards: Using tools like the GoodRx Valtoco Page can also provide pharmacy coupons that drop the cash price well below retail.
Google AI
____________________________________________________________
ZNF292 neurodevelopmental disorder
Inspired by a patient
Kaushik K, Chapman G, Prakasam R, Batool F, Saleh M, Determan J, Huettner JE, Kroll KL. Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function. Cell Rep. 2025 May 27;44(5):115597. doi: 10.1016/j.celrep.2025.115597. Epub 2025 Apr 20. PMID: 40257863; PMCID: PMC12283078.
Abstract
Pathogenic mutation of the zinc-finger transcription factor ZNF292 is a recently defined contributor to human neurodevelopmental disorders (NDDs). However, the gene's roles in cortical development and regulatory networks under its control were previously undefined. Here, human stem cell models of ZNF292 deficiency, resembling pathogenic haploinsufficiency, are used to derive cortical inhibitory neuron progenitors and neurons. ZNF292-deficient progenitors undergo precocious differentiation but subsequently exhibit compromised interneuron maturation and function. In progenitors, genome-wide occupancy and transcriptomic analyses identify direct target genes controlling neuronal differentiation and synapse formation that are upregulated upon ZNF292 deficiency. By contrast, deficiency in interneurons compromises ZNF292 genome-wide association with and causes downregulation of direct target genes promoting interneuron maturation and function, including other NDD genes. ZNF292-deficient interneurons also exhibit altered channel activities, elevated GABA responsiveness, and hallmarks of neuronal hyperactivity. Together, the results of this work define neurodevelopmental requirements for ZNF292, some of which may contribute to pathogenic ZNF292 mutation-related NDDs.
Mirzaa GM, Chong JX, Piton A, Popp B, Foss K, Guo H, Harripaul R, Xia K, Scheck J, Aldinger KA, Sajan SA, Tang S, Bonneau D, Beck A, White J, Mahida S, Harris J, Smith-Hicks C, Hoyer J, Zweier C, Reis A, Thiel CT, Jamra RA, Zeid N, Yang A, Farach LS, Walsh L, Payne K, Rohena L, Velinov M, Ziegler A, Schaefer E, Gatinois V, Geneviève D, Simon MEH, Kohler J, Rotenberg J, Wheeler P, Larson A, Ernst ME, Akman CI, Westman R, Blanchet P, Schillaci LA, Vincent-Delorme C, Gripp KW, Mattioli F, Guyader GL, Gerard B, Mathieu-Dramard M, Morin G, Sasanfar R, Ayub M, Vasli N, Yang S, Person R, Monaghan KG, Nickerson DA, van Binsbergen E, Enns GM, Dries AM, Rowe LJ, Tsai ACH, Svihovec S, Friedman J, Agha Z, Qamar R, Rodan LH, Martinez-Agosto J, Ockeloen CW, Vincent M, Sunderland WJ, Bernstein JA; Undiagnosed Diseases Network,; Eichler EE, Vincent JB; University of Washington Center for Mendelian Genomics (UW-CMG),; Bamshad MJ. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet Med. 2020 Mar;22(3):538-546. doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14. PMID: 31723249; PMCID: PMC7060121.
Abstract
Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).
Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.
Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.
Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Dongxue L, Ruen Y, Ying Y, Liting C, Jie W, Chunjiao L, Wei L, Rikun C, Cuiyun L. Short Stature and Developmental Delay Associated With a Novel Frame-Shift Mutation in ZNF292: Case Report and Literature Review. Clin Case Rep. 2025 Aug 7;13(8):e70747. doi: 10.1002/ccr3.70747. PMID: 40777882; PMCID: PMC12329236.
Abstract
Pathogenic mutations in the ZNF292 gene are a significant genetic cause of Intellectual Developmental Disorder (IDD) in individuals, manifesting with a spectrum of clinical features including mild to severe intellectual impairment, speech delay, and co-occurring autism spectrum disorder (ASD). In this study, we present a novel clinical phenotype associated with a newly identified variant of ZNF292 and conduct a thorough review of relevant literature. A 4-year-old female patient displayed language developmental delays, short stature, and skeletal abnormalities. Trio whole-exome sequencing revealed a novel de novo heterozygous frameshift variant in exon 8 of the ZNF292 gene, c.5977_5978del, p.Gln1993fs. According to the ACMG guidelines, this variant is expected to be pathogenic. Our research unveils a novel variant in ZNF292-related disorders and expands the associated phenotypic spectrum. This study highlights the significance of employing next-generation sequencing for timely patient diagnosis, while further clinical phenotypic and genotypic investigations could improve the understanding of ZNF292-linked conditions.
Wang F, Qi N, Gao Y, Wu D, Zhang M, Zhang Q, Yang K, Peng H, Lei X, Liao S. [Genetic analysis of two children with developmental delay and intellectual disability]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Jul 10;40(7):876-880. Chinese. doi: 10.3760/cma.j.cn511374-20220318-00181. PMID: 37368394.
Abstract
Objective: To explore the genetic etiology of two patients with developmental delay and intellectual disability.
Methods: Two children who were respectively admitted to Henan Provincial People's Hospital on August 29, 2021 and August 5, 2019 were selected as the study subjects. Clinical data were collected, and array comparative genomic hybridization (aCGH) was carried out on the children and their parents for the detection of chromosomal microduplication/microdeletions.
Results: Patient 1 was a 2-year-and-10-month female and patient 2 was a 3-year-old female. Both children had featured developmental delay, intellectual disability, and abnormal findings on cranial MRI. aCGH revealed that patient 1 has harbored arr[hg19] 6q14.2q15(84621837_90815662)×1, a 6.19 Mb deletion at 6q14.2q15, which encompassed ZNF292, the pathogenic gene for Autosomal dominant intellectual developmental disorder 64. Patient 2 has harbored arr[hg19] 22q13.31q13.33(46294326_51178264)×1, a 4.88 Mb deletion at 22q13.31q13.33 encompassing the SHANK3 gene, haploinsufficiency of which can lead to Phelan-McDermid syndrome. Both deletions were classified as pathogenic CNVs based on the guidelines of American College of Medical Genetics and Genomics (ACMG) and were not found in their parents.
Conclusion: The 6q14.2q15 deletion and 22q13-31q13.33 deletion probably underlay the developmental delay and intellectual disability in the two children, respectively. Haploinsufficiency of the ZNF292 gene may account for the key clinical features of the 6q14.2q15 deletion.
Kaushik K, Chapman G, Prakasam R, Batool F, Saleh M, Determan J, Huettner JE, Kroll KL. Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function. Cell Rep. 2025 May 27;44(5):115597. doi: 10.1016/j.celrep.2025.115597. Epub 2025 Apr 20. PMID: 40257863; PMCID: PMC12283078.
Abstract
Pathogenic mutation of the zinc-finger transcription factor ZNF292 is a recently defined contributor to human neurodevelopmental disorders (NDDs). However, the gene's roles in cortical development and regulatory networks under its control were previously undefined. Here, human stem cell models of ZNF292 deficiency, resembling pathogenic haploinsufficiency, are used to derive cortical inhibitory neuron progenitors and neurons. ZNF292-deficient progenitors undergo precocious differentiation but subsequently exhibit compromised interneuron maturation and function. In progenitors, genome-wide occupancy and transcriptomic analyses identify direct target genes controlling neuronal differentiation and synapse formation that are upregulated upon ZNF292 deficiency. By contrast, deficiency in interneurons compromises ZNF292 genome-wide association with and causes downregulation of direct target genes promoting interneuron maturation and function, including other NDD genes. ZNF292-deficient interneurons also exhibit altered channel activities, elevated GABA responsiveness, and hallmarks of neuronal hyperactivity. Together, the results of this work define neurodevelopmental requirements for ZNF292, some of which may contribute to pathogenic ZNF292 mutation-related NDDs.
Mirzaa GM, Chong JX, Piton A, Popp B, Foss K, Guo H, Harripaul R, Xia K, Scheck J, Aldinger KA, Sajan SA, Tang S, Bonneau D, Beck A, White J, Mahida S, Harris J, Smith-Hicks C, Hoyer J, Zweier C, Reis A, Thiel CT, Jamra RA, Zeid N, Yang A, Farach LS, Walsh L, Payne K, Rohena L, Velinov M, Ziegler A, Schaefer E, Gatinois V, Geneviève D, Simon MEH, Kohler J, Rotenberg J, Wheeler P, Larson A, Ernst ME, Akman CI, Westman R, Blanchet P, Schillaci LA, Vincent-Delorme C, Gripp KW, Mattioli F, Guyader GL, Gerard B, Mathieu-Dramard M, Morin G, Sasanfar R, Ayub M, Vasli N, Yang S, Person R, Monaghan KG, Nickerson DA, van Binsbergen E, Enns GM, Dries AM, Rowe LJ, Tsai ACH, Svihovec S, Friedman J, Agha Z, Qamar R, Rodan LH, Martinez-Agosto J, Ockeloen CW, Vincent M, Sunderland WJ, Bernstein JA; Undiagnosed Diseases Network,; Eichler EE, Vincent JB; University of Washington Center for Mendelian Genomics (UW-CMG),; Bamshad MJ. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet Med. 2020 Mar;22(3):538-546. doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14. PMID: 31723249; PMCID: PMC7060121.
Abstract
Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).
Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.
Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.
Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Dongxue L, Ruen Y, Ying Y, Liting C, Jie W, Chunjiao L, Wei L, Rikun C, Cuiyun L. Short Stature and Developmental Delay Associated With a Novel Frame-Shift Mutation in ZNF292: Case Report and Literature Review. Clin Case Rep. 2025 Aug 7;13(8):e70747. doi: 10.1002/ccr3.70747. PMID: 40777882; PMCID: PMC12329236.
Abstract
Pathogenic mutations in the ZNF292 gene are a significant genetic cause of Intellectual Developmental Disorder (IDD) in individuals, manifesting with a spectrum of clinical features including mild to severe intellectual impairment, speech delay, and co-occurring autism spectrum disorder (ASD). In this study, we present a novel clinical phenotype associated with a newly identified variant of ZNF292 and conduct a thorough review of relevant literature. A 4-year-old female patient displayed language developmental delays, short stature, and skeletal abnormalities. Trio whole-exome sequencing revealed a novel de novo heterozygous frameshift variant in exon 8 of the ZNF292 gene, c.5977_5978del, p.Gln1993fs. According to the ACMG guidelines, this variant is expected to be pathogenic. Our research unveils a novel variant in ZNF292-related disorders and expands the associated phenotypic spectrum. This study highlights the significance of employing next-generation sequencing for timely patient diagnosis, while further clinical phenotypic and genotypic investigations could improve the understanding of ZNF292-linked conditions.
Wang F, Qi N, Gao Y, Wu D, Zhang M, Zhang Q, Yang K, Peng H, Lei X, Liao S. [Genetic analysis of two children with developmental delay and intellectual disability]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Jul 10;40(7):876-880. Chinese. doi: 10.3760/cma.j.cn511374-20220318-00181. PMID: 37368394.
Abstract
Objective: To explore the genetic etiology of two patients with developmental delay and intellectual disability.
Methods: Two children who were respectively admitted to Henan Provincial People's Hospital on August 29, 2021 and August 5, 2019 were selected as the study subjects. Clinical data were collected, and array comparative genomic hybridization (aCGH) was carried out on the children and their parents for the detection of chromosomal microduplication/microdeletions.
Results: Patient 1 was a 2-year-and-10-month female and patient 2 was a 3-year-old female. Both children had featured developmental delay, intellectual disability, and abnormal findings on cranial MRI. aCGH revealed that patient 1 has harbored arr[hg19] 6q14.2q15(84621837_90815662)×1, a 6.19 Mb deletion at 6q14.2q15, which encompassed ZNF292, the pathogenic gene for Autosomal dominant intellectual developmental disorder 64. Patient 2 has harbored arr[hg19] 22q13.31q13.33(46294326_51178264)×1, a 4.88 Mb deletion at 22q13.31q13.33 encompassing the SHANK3 gene, haploinsufficiency of which can lead to Phelan-McDermid syndrome. Both deletions were classified as pathogenic CNVs based on the guidelines of American College of Medical Genetics and Genomics (ACMG) and were not found in their parents.
Conclusion: The 6q14.2q15 deletion and 22q13-31q13.33 deletion probably underlay the developmental delay and intellectual disability in the two children, respectively. Haploinsufficiency of the ZNF292 gene may account for the key clinical features of the 6q14.2q15 deletion.
Monday, July 6, 2026
MOGAD — An emerging disease: Q&A
MOGAD — An Emerging Disease: Q&A with a Pediatric Neurologist
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neuroimmune condition that affects the brain, eyes and spine. Though it shares similarities with other diseases, it was recently classified as its own disease after information distinguishing it from other conditions was discovered.
Brenda Banwell, M.D., a pediatric neurologist and pediatrician-in-chief at Johns Hopkins Children’s Center, has studied the disease for years, and co-created the Pediatric Multiple Sclerosis, MOGAD and Neuroimmune Disorders Program. She answers common questions about the condition.
Key Points
MOGAD is a rare condition that occurs when the immune system attacks the brain, the nerves connected to the eyes and the spinal cord.
It's unclear how prevalent MOGAD is because diagnostic criteria were recently established.
Children or adults with a diagnosis of MOGAD should be referred to a neurologist with understanding of the condition.
Johns Hopkins has a team of internationally recognized leaders in pediatric neuroimmunology and an established program for treating MOGAD.
What is MOGAD?
Myelin oligodendrocyte glycoprotein antibody-associated disease, more commonly called MOGAD, is a condition that affects children and adults in which the immune system attacks the brain, the nerves connected to the eyes and the spinal cord.
What are the common symptoms of MOGAD?
Vision loss is the most common symptom. A person will also have some pain during eye movement.
Spinal cord attack is another common symptom. This involves numbness, tingling or weakness in the arms and legs, depending on the level of the spinal cord involvement. If the lower part of the spinal cord is involved, patients may have difficulty passing urine and have symptoms of loss of bladder control.
Acute disseminated encephalomyelitis (ADEM) is the third-most common symptom. With ADEM, a person experiences confusion, often along with:
confusion, lack of awareness or, in extreme cases, coma
limb weakness
visual impairment
lack of balance while walking
What are the differences between the symptoms in MOGAD and Multiple Sclerosis (MS)?
To the best of our knowledge, MOGAD shows no symptoms before the first attack. Patients I speak with don’t have any symptoms that occur in the weeks leading up to their first attack.
MS is different. People who don’t know they have MS until their first attack will often tell me they are more tired than their friends, or that their hand went numb for a couple of days, or they couldn’t see well in one eye, but it got better over a week or two.
These observations tell me that MS starts way before the first attack, whereas MOGAD seems to start near the time of attack.
How common is MOGAD?
We don't know yet how common MOGAD is. That’s because the criteria for making a MOGAD diagnosis were published in 2023, and many clinicians around the world are just now applying them and identifying children and adults who meet them.
Also, the diagnosis of MOGAD requires the detection of antibodies or proteins in the bloodstream that target myelin oligodendrocyte glycoprotein (MOG). This testing has become reliably available in only about the last five years, and it's still not easily accessible in many parts of the world.
What treatment options are available for MOGAD?
The treatment of MOGAD depends on whether it is a patient’s first symptomatic event or a relapse.
First Event: This is when we treat the patient immediately when they come in with the first event of visual loss, confusion or spinal cord symptoms.
Treatment with high-dose corticosteroids typically works quickly and reduces inflammation in the brain, the optic nerves or the spinal cord.
If that's not enough, we move to other therapies, often using plasma exchange. In this therapy, we take those MOG antibodies we believe are contributing to the symptoms out of blood circulation — like a dialysis for the bloodstream.
We also use intravenous immunoglobulin (IVIG), which introduces antibodies from healthy donors into the blood through IV and can help neutralize the MOG antibodies and reduce inflammation while suppressing the immune system.
In addition to that, we can also use tocilizumab or a similar medicine, which is an immunosuppressant that can be lifesaving for someone having a severe MOGAD attack.
Relapsing MOGAD: The second treatment instance is for people who experience relapsing MOGAD, and we want to prevent those relapses.
We can use IVIG, but in a monthly dose.
Sometimes, we use rituximab, an antibody therapy that blocks one particular part of the immune system that triggers the relapse.
At this point, there are no specific treatments for MOGAD that have been approved through the typical regulatory process — by the Food and Drug Administration in the United States, and by the European Medicines Agency in Europe. All therapies right now are guided by specialists that have worked as a community to provide guidelines for the treatment of MOGAD.
Will all people with MOGAD have a relapse?
Not all patients will have a relapsing form of MOGAD. Some people will have one attack, and that appears to be the entire experience they have with MOGAD.
Is MOGAD more commonly seen in children or adults?
MOGAD is probably more common in children. That might change as more adult care providers start to recognize more people with MOGAD because we now have the ability to test for the antibody and use the diagnostic criteria.
What kind of doctor should a person diagnosed with MOGAD see for care?
Anyone with a diagnosis of MOGAD should be referred to either a child or adult neurologist who understands this condition. MOGAD is rare and there are many doctors around the world who would not be familiar with its diagnosis and/or the different treatments and the strategies to manage the condition.
What is the long-term outlook for people diagnosed with MOGAD?
Most patients with MOGAD do well. I can also share that relapsing MOGAD is generally a much more serious condition than cases of one event. When you have relapsing MOGAD, you're most likely going to experience new attacks in the eye, leading to loss of vision. But with current therapies, we seem to be doing better at suppressing those attacks than we were 20 years ago.
With proper therapy, most of my patients are doing very well, but what I don't know is how they will be doing in 10 or 20 years. We’re going to need to work as a community to figure that out in this era of prompt diagnosis and available treatment.
https://www.hopkinsmedicine.org/health/expert-qa/mogad-q-and-a?
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neuroimmune condition that affects the brain, eyes and spine. Though it shares similarities with other diseases, it was recently classified as its own disease after information distinguishing it from other conditions was discovered.
Brenda Banwell, M.D., a pediatric neurologist and pediatrician-in-chief at Johns Hopkins Children’s Center, has studied the disease for years, and co-created the Pediatric Multiple Sclerosis, MOGAD and Neuroimmune Disorders Program. She answers common questions about the condition.
Key Points
MOGAD is a rare condition that occurs when the immune system attacks the brain, the nerves connected to the eyes and the spinal cord.
It's unclear how prevalent MOGAD is because diagnostic criteria were recently established.
Children or adults with a diagnosis of MOGAD should be referred to a neurologist with understanding of the condition.
Johns Hopkins has a team of internationally recognized leaders in pediatric neuroimmunology and an established program for treating MOGAD.
What is MOGAD?
Myelin oligodendrocyte glycoprotein antibody-associated disease, more commonly called MOGAD, is a condition that affects children and adults in which the immune system attacks the brain, the nerves connected to the eyes and the spinal cord.
What are the common symptoms of MOGAD?
Vision loss is the most common symptom. A person will also have some pain during eye movement.
Spinal cord attack is another common symptom. This involves numbness, tingling or weakness in the arms and legs, depending on the level of the spinal cord involvement. If the lower part of the spinal cord is involved, patients may have difficulty passing urine and have symptoms of loss of bladder control.
Acute disseminated encephalomyelitis (ADEM) is the third-most common symptom. With ADEM, a person experiences confusion, often along with:
confusion, lack of awareness or, in extreme cases, coma
limb weakness
visual impairment
lack of balance while walking
What are the differences between the symptoms in MOGAD and Multiple Sclerosis (MS)?
To the best of our knowledge, MOGAD shows no symptoms before the first attack. Patients I speak with don’t have any symptoms that occur in the weeks leading up to their first attack.
MS is different. People who don’t know they have MS until their first attack will often tell me they are more tired than their friends, or that their hand went numb for a couple of days, or they couldn’t see well in one eye, but it got better over a week or two.
These observations tell me that MS starts way before the first attack, whereas MOGAD seems to start near the time of attack.
How common is MOGAD?
We don't know yet how common MOGAD is. That’s because the criteria for making a MOGAD diagnosis were published in 2023, and many clinicians around the world are just now applying them and identifying children and adults who meet them.
Also, the diagnosis of MOGAD requires the detection of antibodies or proteins in the bloodstream that target myelin oligodendrocyte glycoprotein (MOG). This testing has become reliably available in only about the last five years, and it's still not easily accessible in many parts of the world.
What treatment options are available for MOGAD?
The treatment of MOGAD depends on whether it is a patient’s first symptomatic event or a relapse.
First Event: This is when we treat the patient immediately when they come in with the first event of visual loss, confusion or spinal cord symptoms.
Treatment with high-dose corticosteroids typically works quickly and reduces inflammation in the brain, the optic nerves or the spinal cord.
If that's not enough, we move to other therapies, often using plasma exchange. In this therapy, we take those MOG antibodies we believe are contributing to the symptoms out of blood circulation — like a dialysis for the bloodstream.
We also use intravenous immunoglobulin (IVIG), which introduces antibodies from healthy donors into the blood through IV and can help neutralize the MOG antibodies and reduce inflammation while suppressing the immune system.
In addition to that, we can also use tocilizumab or a similar medicine, which is an immunosuppressant that can be lifesaving for someone having a severe MOGAD attack.
Relapsing MOGAD: The second treatment instance is for people who experience relapsing MOGAD, and we want to prevent those relapses.
We can use IVIG, but in a monthly dose.
Sometimes, we use rituximab, an antibody therapy that blocks one particular part of the immune system that triggers the relapse.
At this point, there are no specific treatments for MOGAD that have been approved through the typical regulatory process — by the Food and Drug Administration in the United States, and by the European Medicines Agency in Europe. All therapies right now are guided by specialists that have worked as a community to provide guidelines for the treatment of MOGAD.
Will all people with MOGAD have a relapse?
Not all patients will have a relapsing form of MOGAD. Some people will have one attack, and that appears to be the entire experience they have with MOGAD.
Is MOGAD more commonly seen in children or adults?
MOGAD is probably more common in children. That might change as more adult care providers start to recognize more people with MOGAD because we now have the ability to test for the antibody and use the diagnostic criteria.
What kind of doctor should a person diagnosed with MOGAD see for care?
Anyone with a diagnosis of MOGAD should be referred to either a child or adult neurologist who understands this condition. MOGAD is rare and there are many doctors around the world who would not be familiar with its diagnosis and/or the different treatments and the strategies to manage the condition.
What is the long-term outlook for people diagnosed with MOGAD?
Most patients with MOGAD do well. I can also share that relapsing MOGAD is generally a much more serious condition than cases of one event. When you have relapsing MOGAD, you're most likely going to experience new attacks in the eye, leading to loss of vision. But with current therapies, we seem to be doing better at suppressing those attacks than we were 20 years ago.
With proper therapy, most of my patients are doing very well, but what I don't know is how they will be doing in 10 or 20 years. We’re going to need to work as a community to figure that out in this era of prompt diagnosis and available treatment.
https://www.hopkinsmedicine.org/health/expert-qa/mogad-q-and-a?
Sunday, July 5, 2026
Is cardiac death death?
Arizona police have recommended felony child abuse charges against the parents of an 18-month-old boy who investigators say nearly drowned after they admitted using marijuana and failed to properly supervise him during a Super Bowl party earlier this year. The child later drew national attention after he was mistakenly declared dead before being found alive hours later in a hospital morgue.
The Maricopa County Attorney's Office is reviewing the Gilbert Police Department's recommendation that Vincent Fiordilino's parents face felony child abuse charges, according to AZFamily. No charges have been filed.
Investigators say Vincent disappeared from his parents' view during the gathering before guests found him floating face down in a backyard swimming pool. According to a police report obtained by AZFamily, both parents later admitted to smoking marijuana during the party. The report alleges Vincent's fall into the pool went unnoticed because both parents were impaired by marijuana and/or other mind-altering substances.
After Vincent was pulled from the water, first responders transported him to Mercy Gilbert Medical Center, where a doctor pronounced him dead that evening, according to police. The case took an extraordinary turn hours later when medical personnel discovered the toddler was alive and breathing after he had already been transferred to the hospital's morgue around 7:23 p.m., according to police. Vincent was immediately airlifted to Phoenix Children's Hospital for treatment.
The police report alleges responding officers and Vincent's parents questioned whether the toddler had actually died before he was pronounced dead, saying they believed he was still showing signs of life. Hospital staff reportedly told them Vincent was exhibiting agonal breathing, an involuntary reflex that can occur near death.
According to the report, a nurse later reported detecting a pulse after the child had been pronounced dead. Detectives allege the physician who made the initial determination maintained his assessment was correct and instructed hospital staff to stop lifesaving measures despite concerns from Vincent's parents and responding officers that the toddler still appeared to be breathing. Police did not recommend criminal charges against the physician, according to AZFamily.
According to AZFamily, a Dignity Health spokesperson said the hospital conducted a review following the incident.
"This is a heartbreaking situation. We immediately conducted a thorough review of all aspects of the care that was provided to learn what happened and to make meaningful changes to strengthen our care," the spokesperson said in a statement. "Out of respect for the patient's privacy, we cannot discuss details. We continue to work with the family and their representative. Patient safety and exceptional care is our highest priority."
A GoFundMe campaign created for the family described Vincent as a "miracle baby" after he survived the ordeal.
"Vincent was declared deceased," the fundraiser says. "His devastated parents were sent home in unimaginable grief. But God had other plans. A little after 11:30 p.m., the family received a call no one expected: the medical examiner had detected a faint heartbeat."
According to the fundraiser, Vincent's kidneys, lungs and liver began shutting down after he arrived at Phoenix Children's Hospital. An MRI initially identified two small areas of potential brain damage, but later testing reportedly found no brain damage. The fundraiser says Vincent continues to require extensive therapy, ongoing medical monitoring and treatment as he recovers.
Fox News Digital has reached out to the Maricopa County Attorney's Office, Gilbert Police Department, Mercy Gilbert Medical Center and Phoenix Children's Hospital for comment.
Brittany Miller
https://www.foxnews.com/us/toddler-declared-dead-after-near-drowning-found-alive-hospital-morgue-hours-later-police-say
Investigators say Vincent disappeared from his parents' view during the gathering before guests found him floating face down in a backyard swimming pool. According to a police report obtained by AZFamily, both parents later admitted to smoking marijuana during the party. The report alleges Vincent's fall into the pool went unnoticed because both parents were impaired by marijuana and/or other mind-altering substances.
After Vincent was pulled from the water, first responders transported him to Mercy Gilbert Medical Center, where a doctor pronounced him dead that evening, according to police. The case took an extraordinary turn hours later when medical personnel discovered the toddler was alive and breathing after he had already been transferred to the hospital's morgue around 7:23 p.m., according to police. Vincent was immediately airlifted to Phoenix Children's Hospital for treatment.
The police report alleges responding officers and Vincent's parents questioned whether the toddler had actually died before he was pronounced dead, saying they believed he was still showing signs of life. Hospital staff reportedly told them Vincent was exhibiting agonal breathing, an involuntary reflex that can occur near death.
According to the report, a nurse later reported detecting a pulse after the child had been pronounced dead. Detectives allege the physician who made the initial determination maintained his assessment was correct and instructed hospital staff to stop lifesaving measures despite concerns from Vincent's parents and responding officers that the toddler still appeared to be breathing. Police did not recommend criminal charges against the physician, according to AZFamily.
According to AZFamily, a Dignity Health spokesperson said the hospital conducted a review following the incident.
"This is a heartbreaking situation. We immediately conducted a thorough review of all aspects of the care that was provided to learn what happened and to make meaningful changes to strengthen our care," the spokesperson said in a statement. "Out of respect for the patient's privacy, we cannot discuss details. We continue to work with the family and their representative. Patient safety and exceptional care is our highest priority."
A GoFundMe campaign created for the family described Vincent as a "miracle baby" after he survived the ordeal.
"Vincent was declared deceased," the fundraiser says. "His devastated parents were sent home in unimaginable grief. But God had other plans. A little after 11:30 p.m., the family received a call no one expected: the medical examiner had detected a faint heartbeat."
According to the fundraiser, Vincent's kidneys, lungs and liver began shutting down after he arrived at Phoenix Children's Hospital. An MRI initially identified two small areas of potential brain damage, but later testing reportedly found no brain damage. The fundraiser says Vincent continues to require extensive therapy, ongoing medical monitoring and treatment as he recovers.
Fox News Digital has reached out to the Maricopa County Attorney's Office, Gilbert Police Department, Mercy Gilbert Medical Center and Phoenix Children's Hospital for comment.
Brittany Miller
https://www.foxnews.com/us/toddler-declared-dead-after-near-drowning-found-alive-hospital-morgue-hours-later-police-say
Thursday, July 2, 2026
Human rabies
An 11-year-old boy died of a rabies infection in Ontario, Canada, according to a medical journal article published Monday.
The Canadian Medical Association Journal did not identify the boy or his family but wrote that he was first brought to a hospital weeks after an encounter with a bat.
"The patient’s family reported that, during a visit to a cottage in northern Ontario 19 days before symptom onset, the boy had been awoken by a bat on his nose and mouth. He had swatted the bat off his face; his father had caught the bat in a cooking pot and released it outside," CMAJ wrote.
"The child had no visible lesions on his face, and his parents did not consider that the bat had behaved erratically. Therefore, they did not seek medical assessment," the journal noted.
The boy was ultimately admitted to a hospital 20 days after the encounter with the bat, when his parents brought him to an emergency room. He was first sent home but then brought back the following morning and admitted to the hospital.
Doctors noted that the boy's condition "rapidly worsened" by the evening, but he spent more than two weeks in the hospital before dying.
"By day 5 of admission, his brainstem reflexes were absent. Life-sustaining therapies were withdrawn on day 17 of admission, and he died peacefully with his family at his bedside," the journal article said.
Doctors who authored the article warned that any direct human contact with a bat, even in the absence of a visible bite or scratch, should be discussed with public health authorities.
Rabies is almost always fatal in humans if not treated quickly with postexposure prophylaxis, or PEP. The treatment is nearly always successful if administered promptly after exposure.
Anders Hagstrom
https://www.foxnews.com/world/11-year-old-dies-rabies-bat-landed-face-sleeping
Padmaja Sreeram, Neha Saini, Karen Choong, Ellery Cunan, Alan C. Jackson, Jeffrey M. Pernica
and Brian Hummel. Fatal rabies in a child. CMAJ June 29, 2026 198(25) E969-E972;
DOI: https://doi.org/10.1503/cmaj.251933
DOI: https://doi.org/10.1503/cmaj.251933
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