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We present an infant referred to Developmental Paediatrics for delays, slow growth, hypotonia, esotropia and spasticity. Over the course of 2 months, the infant's exam progressed, demonstrating worsening spasticity and tonal changes in the setting of a normal brain MRI with acquired microcephaly. Genetic testing demonstrated a pathogenic CTNNB1 nonsense mutation. Following the discovery of the underlying cause for the child's clinical picture, the child was evaluated by therapeutic services and neurology, which was initially only available via asynchronous telehealth, due to a resource limited area. Cerebral palsy is a nonprogressive neurodevelopmental disorder and, when associated with developmental delay, qualifies for further genetic investigation into the underlying aetiology. Genetic testing recommendations exist for developmental delay, but there is no current algorithm regarding testing for cerebral palsy. Education and clear guidelines on genetic testing allow for better prognostication and potential treatment in cases of cerebral palsy, especially when associated with other disorders.
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Parálisis Cerebral , Discapacidades del Desarrollo , Espasticidad Muscular , beta Catenina , Humanos , Espasticidad Muscular/genética , Espasticidad Muscular/diagnóstico , Lactante , Discapacidades del Desarrollo/genética , Parálisis Cerebral/genética , beta Catenina/genética , Masculino , Codón sin Sentido , Femenino , Imagen por Resonancia Magnética , Pruebas GenéticasAsunto(s)
Síndrome de Down , Adolescente , Niño , Síndrome de Down/terapia , Promoción de la Salud , HumanosRESUMEN
PURPOSE: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. METHODS: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. RESULTS: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. CONCLUSION: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.
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ADN Helicasas , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Trastornos del Neurodesarrollo , ADN Helicasas/genética , Heterocigoto , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , SíndromeRESUMEN
Primary ciliopathies are heterogenous disorders resulting from perturbations in primary cilia form and/or function. Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar/brain stem malformation, hypotonia, and developmental delays. At least 35 genes are associated with Joubert syndrome, including the gene KIAA0753, which is part of a complex required for primary ciliogenesis. The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized. We describe four individuals with biallelic pathogenic KIAA0753 variants, including five novel variants. We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis. Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity. Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation. Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants.
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Anomalías Múltiples , Ciliopatías , Anomalías del Ojo , Enfermedades Renales Quísticas , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cerebelo/anomalías , Cilios/genética , Cilios/patología , Ciliopatías/genética , Ciliopatías/patología , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/patología , Proteínas Asociadas a Microtúbulos , Retina/anomalíasRESUMEN
BACKGROUND: Long QT3 syndrome type 3 (LQT3) is a gain of function mutation of the SCN5A gene that is inherited in an autosomal dominant fashion. Long QT3 syndrome type 3 results in an increase in arrhythmic events during rest, sleep, and bradycardia by extending the QT interval and inducing Torsades de pointes and sudden cardiac death. Attempting to block the sodium channel with Class I anti-arrhythmics or blocking adrenergic tone with beta-blockers especially in women has shown to be beneficial. There have been few large-scale studies on treating patients with LQT3 due to its lethality and underreported number of cases. Specifically, the safety and efficacy of pharmacologic treatment in pregnant LQT3 patients are unknown. CASE SUMMARY: This case demonstrates the safe use of Mexiletine and Propranolol in a 3rd-trimester pregnant LQT3 patient after a presumed ventricular arrhythmia and device-lead electrical short from therapy rendered her implantable cardioverter defibrillator inoperable in a VVI mode (venticular demand pacing). With appropriate medications, the patient was safely monitored through the remainder of her pregnancy and safely delivered at 36 weeks of pregnancy a healthy baby girl. The daughter, heterozygous for LQT3, showed no evidence of intrauterine growth restriction or other side effects from the medications. DISCUSSION: There are many variants of the SCN5A gene mutations that can lead to different phenotypes and not all mutations are responsive to the same medications. In this case, Mexiletine and Propranolol, both of which have only recently shown to benefit certain variants or LQT3 respectively, were safely started during the 3rd trimester of pregnancy without harming the foetus.
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TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.
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Enfermedad de Leigh/terapia , Fallo Hepático/terapia , Proteínas Mitocondriales/genética , Biosíntesis de Proteínas , ARNt Metiltransferasas/genética , Acetilcisteína/administración & dosificación , Acetilcisteína/metabolismo , Acidosis/genética , Acidosis/metabolismo , Cisteína/administración & dosificación , Cisteína/metabolismo , ADN Mitocondrial/genética , Femenino , Humanos , Lactante , Enfermedad de Leigh/genética , Enfermedad de Leigh/metabolismo , Enfermedad de Leigh/patología , Fallo Hepático/genética , Fallo Hepático/metabolismo , Fallo Hepático/patología , Trasplante de Hígado/métodos , Masculino , Mitocondrias/enzimología , Proteínas Mitocondriales/deficiencia , ARN de Transferencia/genética , ARNt Metiltransferasas/deficienciaRESUMEN
PURPOSE: Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. METHODS: We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. RESULTS: We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. CONCLUSION: Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.
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Anomalías Múltiples , Discapacidad Intelectual , Trastornos del Desarrollo del Lenguaje , Niño , Discapacidades del Desarrollo/genética , Factores de Transcripción Forkhead/genética , Heterocigoto , Humanos , Trastornos del Desarrollo del Lenguaje/genética , Mutación Missense , HablaRESUMEN
OBJECTIVE: To determine whether the Ghent Criteria (2010) can be reliably used in evaluating preadolescents and adolescents for Marfan syndrome by comparing aortic growth, systemic scores, and anthropometric features in individuals with and without Marfan syndrome. STUDY DESIGN: A retrospective chart review was completed for patients less than 15 years of age referred for Marfan syndrome. Comparisons were made between the first and last visit. Paired t tests were used to compare Ghent systemic scores. Wilcoxon rank-sum test were used to compare age, aortic root z scores, height z scores, and body mass index z scores. Recursive partitioning was used to identify combinations of factors to distinguish Marfan syndrome. RESULTS: In total, 53 individuals met inclusion criteria (29 Marfan syndrome and 24 non-Marfan syndrome). Ghent systemic score increased in the Marfan syndrome group and declined in the non-Marfan syndrome. The non-Marfan syndrome group did not develop progressive aortic root dilation with age. Individuals with Marfan syndrome had higher median height z scores than non-Marfan syndrome, with no difference in median body mass index z score between groups. A combination of aortic root z score above 0.95 and Ghent systemic score above 3 was highly indicative of a Marfan syndrome diagnosis in children less than 15 years of age. CONCLUSION: The Ghent criteria (2010) can be used to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age. Genetic testing should be used as an aide in confirming or excluding the diagnosis of Marfan syndrome in individuals with an aortic root z score above 0.95 in combination with a Ghent systemic score above 3 at initial visit.
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Aorta/diagnóstico por imagen , Síndrome de Marfan/diagnóstico , Adolescente , Estatura , Índice de Masa Corporal , Niño , Ecocardiografía , Fibrilina-1 , Estudios de Seguimiento , Pruebas Genéticas , Humanos , Imagen por Resonancia Cinemagnética , Síndrome de Marfan/genética , Mutación , Estudios RetrospectivosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Ensamble y Desensamble de Cromatina/genética , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Anomalías Musculoesqueléticas/genética , Mutación Missense/genética , Fenotipo , Síndrome , Factores de Transcripción/genéticaRESUMEN
PURPOSE: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. METHODS: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. RESULTS: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. CONCLUSION: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX.
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Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/farmacología , Inhibidores Enzimáticos/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Amino Alcoholes/química , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistema Libre de Células/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Femenino , Humanos , Hidrazinas/química , Ligandos , Ratones , Modelos Moleculares , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirazoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipids ceramide and sphingosine into the antiapoptotic lipid sphingosine-1-phosphate and activates the signal transduction pathways that lead to cell proliferation, migration, the activation of the inflammatory response, and the impairment of apoptosis. There is compelling evidence that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization, and metastatic spread. High levels of SK1 expression or activity have been associated with a poor prognosis in several human cancers. Recent studies using cancer cell and mouse models demonstrate a significant potential for SK1-targeting therapies to synergize with the effects of chemotherapy and radiotherapy; however, until recently the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. With the recent discovery of SK1 inhibiting properties of a clinically approved drug FTY720 (Fingolimod), SK1 has gained significant attention from both clinicians and the pharmaceutical industry and it is hoped that trials of newly developed SK1 inhibitors may follow soon. This review provides an overview of the SK1 signaling, its relevance to cancer progression, and the potential clinical significance of targeting SK1 for improved local or systemic control of human cancers.