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KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.
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Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Animales , Ratones , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Encéfalo/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Cognición , Proteínas de Microfilamentos/genéticaRESUMEN
Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population.
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Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25-24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders.
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PURPOSE: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. METHODS: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. RESULTS: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. CONCLUSION: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.
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Trastornos de la Motilidad Ciliar , Ciliopatías , Proteínas del Citoesqueleto , Animales , Humanos , Ratones , Axonema/genética , Cilios/metabolismo , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/metabolismo , Trastornos de la Motilidad Ciliar/patología , Ciliopatías/genética , Ciliopatías/metabolismo , Ciliopatías/patología , Proteínas del Citoesqueleto/genética , Mutación , Proteínas/genética , Pez Cebra/genéticaRESUMEN
Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent 'missing heritability' in OCA is well described, with ~25-30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans. We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25-50%.
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PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants. RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein. CONCLUSION: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.
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Labio Leporino , Fisura del Paladar , Alelos , Animales , Moléculas de Adhesión Celular/genética , Labio Leporino/genética , Fisura del Paladar/genética , Proteínas Ligadas a GPI/genética , Estudios de Asociación Genética , Humanos , Hialuronoglucosaminidasa/genética , Ratones , FenotipoRESUMEN
SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-ß signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.
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Alelos , Amish/genética , Trastornos del Neurodesarrollo/genética , Proteínas de Unión al ARN/genética , Expresión Génica/genética , Genes Recesivos , HumanosRESUMEN
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
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Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Atresia Intestinal/genética , Antígenos de Histocompatibilidad Menor/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Femenino , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE: To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. METHODS: Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. RESULTS: Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. CONCLUSION: Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.
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Trasplante de Hígado , Acidemia Propiónica , Biomarcadores , Humanos , Laboratorios , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/genéticaRESUMEN
OBJECTIVES: The Holmes County Amish have low vaccination rates, an increasingly diverse population, and have an increased incidence of certain inherited diseases. The objectives were to evaluate; the rate and influences of vaccine hesitancy compared to a decade ago, vaccination patterns between Amish affiliations, vaccine practices of Amish special needs children, and the Amish's acceptance of a COVID-19 vaccine. STUDY DESIGN: In April of 2020, a survey assessing vaccination patterns and beliefs were mailed to 1000 Amish families, including ultra-conservative Amish sects and special needs families. RESULTS: The response rate was 39%. Among 391 respondents, 59% did not vaccinate their children, compared to only 14% that refused all vaccinations reported by Wenger et al in the same community only a decade ago. The ultra-conservative Amish rejected vaccines more often. Amish special needs children were more likely to receive vaccines than healthy Amish children. 75% responded they would reject a COVID-19 vaccine. Fear of adverse effects was the most common reason to reject vaccines. Families that accepted vaccines were more likely to cite a healthcare worker as the primary influence to vaccinate. Wives were more likely to cite their spouse as the primary influence to vaccinate. Families that rejected vaccines were more likely to state their bishop was the most influential person on vaccination. CONCLUSION: The Holmes County Amish have decreasing vaccine acceptance. Efforts to improve vaccination will require a targeted focus on the primary influences and beliefs of sub-populations within the Amish. Physician advocacy, peer mentorship, father-directed education, and close partnership with Church leadership will be needed to limit vaccine-preventable disease. The Amish may be at risk for low uptake of a COVID-19 vaccine.
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Amish , COVID-19/prevención & control , Aceptación de la Atención de Salud/estadística & datos numéricos , Negativa a la Vacunación/estadística & datos numéricos , Vacunación/estadística & datos numéricos , Vacunas contra la COVID-19 , Niño , Conocimientos, Actitudes y Práctica en Salud , Humanos , Ohio , Vacunación/psicologíaRESUMEN
Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.
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Ligasas de Carbono-Carbono/genética , Corazón/fisiopatología , Trastornos del Neurodesarrollo/genética , Acidemia Propiónica/genética , Ácidos/sangre , Ácidos/orina , Adolescente , Adulto , Aminoácidos/sangre , Aminoácidos/orina , Biomarcadores/sangre , Biomarcadores/orina , Ligasas de Carbono-Carbono/sangre , Ligasas de Carbono-Carbono/orina , Carnitina/sangre , Carnitina/orina , Niño , Preescolar , Ecocardiografía , Femenino , Corazón/diagnóstico por imagen , Humanos , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación/genética , Trastornos del Neurodesarrollo/sangre , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/orina , Compuestos Orgánicos/sangre , Compuestos Orgánicos/orina , Fenotipo , Acidemia Propiónica/sangre , Acidemia Propiónica/diagnóstico por imagen , Acidemia Propiónica/orina , Adulto JovenRESUMEN
An 11-week-old unvaccinated, term Amish boy initially presented with poor feeding, microcephaly, failure to thrive, and developmental delays. His physical examination was significant for both weight and head circumference being less than the third percentile, and he was noted to have micrognathia, truncal hypotonia, and head lag. He was admitted to the pediatric hospital medicine service for further diagnostic evaluation. Laboratory studies assessing for endocrinological and metabolic etiologies yielded negative results, and imaging studies (including a chest radiograph, echocardiogram, and abdominal ultrasound) were normal. However, intracranial calcifications were noted on a head ultrasound. The etiology of his constellation of symptoms was initially thought to be infectious, but the ultimate diagnosis was not made until after discharge from the pediatric hospital medicine service.
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Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Microcefalia/diagnóstico por imagen , Hipotonía Muscular/diagnóstico por imagen , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Calcinosis/sangre , Calcinosis/complicaciones , Cefalometría/métodos , Humanos , Lactante , Masculino , Microcefalia/sangre , Microcefalia/complicaciones , Hipotonía Muscular/sangre , Hipotonía Muscular/complicaciones , Malformaciones del Sistema Nervioso/sangre , Malformaciones del Sistema Nervioso/complicacionesRESUMEN
Cartilage-hair hypoplasia (CHH) is an autosomal recessive, short limb skeletal dysplasia with a variable immunologic phenotype. The spectrum of immune function ranges from clinically normal to severe combined immunodeficiency (SCID). Multiple studies have shown that abnormal immune parameters may not predict severe outcomes. Newborn screening (NBS) using T cell receptor excision circle (TREC) assay can now effectively identify infants with severe T cell deficiency who are at risk for SCID. NBS has allowed for cost-effective identification of patients with SCID and improved outcomes with hematopoietic stem cell transplant (HSCT). Ohio reports two abnormal TREC results: decreased and absent TREC. This study evaluated the laboratory and clinical differences in eight Amish patients with CHH with an abnormal TREC result on the NBS. There were four patients with absent TREC and four patients with decreased TREC. The absent TREC patients had lower CD3, CD4, naïve CD4, CD8 cells, and phytohemagglutinin (PHA)-induced lymphocyte proliferation. Three patients with absent TREC were diagnosed with SCID and two underwent successful HSCT. Patients with absent TREC experienced more CHH-related morbidity including anemia requiring transfusion, Hirschsprung's disease, and failure to thrive. No patients with decreased TREC required HSCT. Our study indicates that CHH patients with absent TREC tend to have more severe immunological and clinical phenotype than patients with decreased TREC. Confirmation of these trends in a larger group would guide providers and parents in a timely referral for HSCT, or cost-effective surveillance monitoring of children with a life-threatening illness.
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Amish , Patología Molecular/métodos , Receptores de Antígenos de Linfocitos T/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Linfocitos T/inmunología , Síndromes de Tricotiodistrofia/diagnóstico , Células Cultivadas , Preescolar , Estudios de Cohortes , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Activación de Linfocitos , Tamizaje Neonatal , Pronóstico , Inmunodeficiencia Combinada Grave/genética , Resultado del Tratamiento , Síndromes de Tricotiodistrofia/genéticaAsunto(s)
Proteínas Portadoras/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Fenotipo , Adolescente , Adulto , Niño , Consanguinidad , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
The centrosomal protein 55 kDa (CEP55 (OMIM 610000)) plays a fundamental role in cell cycle regulation and cytokinesis. However, the precise role of CEP55 in human embryonic growth and development is yet to be fully defined. Here we identified a novel homozygous founder frameshift variant in CEP55, present at low frequency in the Amish community, in two siblings presenting with a lethal foetal disorder. The features of the condition are reminiscent of a Meckel-like syndrome comprising of Potter sequence, hydranencephaly, and cystic dysplastic kidneys. These findings, considered alongside two recent studies of single families reporting loss of function candidate variants in CEP55, confirm disruption of CEP55 function as a cause of this clinical spectrum and enable us to delineate the cardinal clinical features of this disorder, providing important new insights into early human development.
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Proteínas de Ciclo Celular/genética , Hidranencefalia/genética , Enfermedades Renales/genética , Riñón/fisiopatología , Amish/genética , Centrosoma/metabolismo , Consanguinidad , Citocinesis/genética , Femenino , Mutación del Sistema de Lectura/genética , Homocigoto , Humanos , Hidranencefalia/fisiopatología , Recién Nacido , Enfermedades Renales/fisiopatología , Masculino , Fosforilación/genética , GemelosRESUMEN
GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7-30.5â¯years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7⯱â¯2.0 (1â¯min) and 8.9⯱â¯0.5 (5â¯min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30â¯months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5â¯years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.
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Epilepsia/tratamiento farmacológico , Epilepsia/genética , Gangliósidos/fisiología , Sialiltransferasas/deficiencia , Adolescente , Adulto , Alelos , Puntaje de Apgar , Niño , Preescolar , Epilepsia/complicaciones , Femenino , Glicoesfingolípidos/sangre , Homocigoto , Humanos , Lactante , Masculino , Microcefalia , Estudios Retrospectivos , Convulsiones , Sialiltransferasas/sangre , Sialiltransferasas/genética , Estados Unidos , Adulto JovenRESUMEN
Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
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Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Mutación con Pérdida de Función/genética , Tirosina-ARNt Ligasa/genética , Adulto , Dominio Catalítico/genética , Preescolar , Femenino , Enfermedades Genéticas Congénitas/fisiopatología , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Heterocigoto , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Secuenciación del Exoma , Levaduras/genéticaRESUMEN
PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.
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Variación Biológica Poblacional/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Adolescente , Alelos , Antígenos Nucleares/genética , Proteínas Portadoras/genética , Niño , Preescolar , Estudios de Cohortes , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Exoma/genética , Femenino , Frecuencia de los Genes/genética , Heterogeneidad Genética , Humanos , Mutación INDEL/genética , Masculino , Mutación , Proteínas Nucleares/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas/genética , Estudios Retrospectivos , Secuenciación del Exoma/métodos , CohesinasRESUMEN
BACKGROUND: The Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Review included childhood immunizations among the 10 great public health achievements in the United States in the 20th century. Despite this acknowledged success, childhood immunization rates continue to be much lower in select populations. Amish communities have persistently lower immunization rates. Recent outbreaks in Amish communities include a 2014 measles outbreak in Ohio, resulting in 368 cases reported. A recent outbreak of pertussis in an Amish community in Ohio resulted in the death of a 6-week-old Amish baby. METHODS: A study was designed to determine the knowledge, beliefs, attitudes, and opinions of Amish parents relative to the immunization of Amish children. Data were collected through a questionnaire. Each potential participant was mailed a copy of a letter describing the proposed study. The questionnaire, a copy of the current immunization schedule, and a return stamped envelope were also included in the mailed packet. The study sample consisted of 84 Amish individuals who voluntarily filled out and returned questionnaires. RESULTS: The findings from the data analysis demonstrated that fear, especially concern over too many recommended immunizations and immunizations overwhelming the child's system, was the most frequent reported reasons for not having children immunized according to recommendations. CONCLUSIONS: Religious factors and access to care were not among reasons most reported. Designing an educational campaign for educating Amish parents on the risks and benefits of immunizations with focus on specific concerns may improve immunization rates.
Asunto(s)
Amish/psicología , Conocimientos, Actitudes y Práctica en Salud/etnología , Población Rural/estadística & datos numéricos , Cobertura de Vacunación/estadística & datos numéricos , Vacunación/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ohio , Padres/psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with α-, ß-, and γ-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with α- and ß-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.