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AIM: To evaluate early dystonic features in children and adolescents with SGCE-myoclonus-dystonia. METHOD: In this cross-sectional study, 49 patients (26 females and 23 males) with SGCE-myoclonus-dystonia (aged 15y 2mo, SD 12y) with childhood-onset (2y 10mo, SD 1y 10mo) dystonia were examined using a standardized video recorded protocol. Dystonia was rated using the Writer's Cramp and Gait Dystonia Rating Scales. Disability and impairment for handwriting and walking were also rated. RESULTS: Dystonia was present at rest (n=1), posture (n=12), and during specific motor tasks (n=45) such as writing (n=35), walking (n=23), and running (n=20). Most children reported disability while performing these tasks. Early dystonic patterns were identified for writer's cramp and gait dystonia, the latter named the 'circular shaking leg', 'dragging leg', and 'hobby-horse gait' patterns. Sensory tricks were used by five and eight children to improve dystonia and myoclonus during writing and walking respectively. The rating scales accurately measured the severity of action dystonia and correlated with self-reported disability. INTERPRETATION: Children with SGCE-myoclonus-dystonia show recognizable dystonic patterns and sensory tricks that may lead to an early diagnosis and timely therapeutic approach. Isolated writer's cramp is a key feature in childhood and should prompt SCGE analysis. The proposed action dystonia scales could be used to monitor disease course and response to treatment. WHAT THIS PAPER ADDS: Most children with SGCE-myoclonus-dystonia got writer's cramp and had walking and running dystonia. Writer's cramp was a key feature and should prompt SGCE genetic investigation. 'Circular shaking leg', 'dragging leg', and 'hobby-horse gait' were recognized as early gait patterns. Children used sensory tricks to improve myoclonus and dystonia, suggesting common pathophysiological mechanisms. Action dystonia rating scales are valid tools to assess severity in children.
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Distonía , Trastornos Distónicos , Trastornos del Movimiento , Mioclonía , Niño , Femenino , Humanos , Masculino , Estudios Transversales , Distonía/diagnóstico , Trastornos Distónicos/diagnóstico , Mioclonía/diagnóstico , Mioclonía/genética , Sarcoglicanos/genéticaRESUMEN
OBJECTIVE: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. METHODS: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp. RESULTS: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits. SIGNIFICANCE: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.
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Epilepsia , Trastornos del Neurodesarrollo , Humanos , Epilepsia/genética , Mutación/genética , Convulsiones/genética , Canal de Potasio Kv1.6/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. RESULTS: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. CONCLUSIONS: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Corea , Distonía , Trastornos Distónicos , Trastornos del Movimiento , Niño , Humanos , Hipercinesia , Trastornos del Movimiento/genética , Trastornos del Movimiento/diagnóstico , Trastornos Distónicos/genética , Corea/diagnóstico , Corea/genética , Proteínas del Tejido Nervioso , Factores de Transcripción Forkhead , Hidrolasas Diéster Fosfóricas , ATPasa Intercambiadora de Sodio-Potasio , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genéticaRESUMEN
AIM: To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition. METHOD: Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis. RESULTS: We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome. INTERPRETATION: Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.
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Enfermedades de los Ganglios Basales , Enfermedades Mitocondriales , Enfermedades Autoinmunes del Sistema Nervioso , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/genética , Niño , Preescolar , ADN Mitocondrial , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación , Malformaciones del Sistema Nervioso , Estudios ProspectivosRESUMEN
Dravet syndrome (DS) is a severe infantile-onset epilepsy syndrome featuring drug resistant epilepsy, global developmental delay and intellectual disability. In addition to ataxia and progressive crouch gait, Parkinsonism has recently been reported as characteristic in young adults with DS. We describe 5 patients out of a series of 23 patients with DS who present between 12 and 24 months of age with repetitive episodes of eyelid closure, sometimes as fast as eye blinking or flickering. Consistent lack of any EEG correlate in serial video-EEG ruled out an epileptic origin. We propose that this movement disorder, namely 'eyelid stereotypies', might be an early motor trait of SCN1A-associated DS.
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Epilepsias Mioclónicas , Espasmos Infantiles , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/genética , Párpados , Humanos , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genética , Adulto JovenRESUMEN
Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.
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Alelos , Variación Genética/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Antígenos de Histocompatibilidad Menor/genética , Trastornos del Neurodesarrollo/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Humanos , Lactante , Recién Nacido , Leucocitos Mononucleares/fisiología , Masculino , Trastornos del Neurodesarrollo/diagnóstico por imagen , LinajeRESUMEN
De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). NDD show great locus heterogeneity and for many of the associated genes, there is substantial phenotypic diversity, including epilepsy, intellectual disability, autism spectrum disorder, movement disorders, and combinations thereof. We report two unrelated patients, a young girl with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio-based whole-exome sequencing analysis uncovered de novo missense variants in CHRM1. Biochemical analyses of one of the NDD-associated variants proved that it caused a reduction in protein levels and impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signaling pathways. Our data strengthen the concept that brain-reduced muscarinic signaling lowers the seizure threshold and severely impairs neurodevelopment.
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Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Epilepsia/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Mutación , Trastornos del Neurodesarrollo/genética , Receptor Muscarínico M1/genética , Receptores Muscarínicos/genéticaRESUMEN
Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.
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Malformación de Arnold-Chiari/genética , Colágeno Tipo I/genética , Colágeno Tipo VII/genética , Colágeno Tipo VI/genética , Adulto , Niño , Comorbilidad , Salud de la Familia , Femenino , Variación Genética , Humanos , Masculino , Secuenciación del ExomaRESUMEN
Myoclonus-dystonia (MD) is a rare childhood-onset movement disorder, with an estimated prevalence of about 2 per 1,000,.000 in Europe, characterized by myoclonic jerks in combination with focal or segmental dystonia. Pathogenic variants in the gene encoding ε-sarcoglycan (SGCE), a maternally imprinted gene, are the most frequent genetic cause of MD. To date, the exact role of ε-sarcoglycan and the pathogenic mechanisms that lead to MD are still unknown. However, there are more than 40 reported isoforms of human ε-sarcoglycan, pointing to a complex biology of this protein. Additionally, some of these are brain-specific isoforms, which may suggest an important role within the central nervous system. In the present review, we aim to provide an overview of the current state of knowledge of ε-sarcoglycan. We will focus on the genetic landscape of SGCE and the presence and plausible role of ε-sarcoglycan in the brain. Finally, we discuss the importance of the brain-specific isoforms and hypothesize that SGCE may play essential roles in normal synaptic functioning and their alteration will be strongly related to MD.
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Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Sarcoglicanos/genética , Sarcoglicanos/metabolismo , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Trastornos Distónicos/diagnóstico , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sinapsis/genética , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
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Anomalías Múltiples/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Distonía/genética , Enoil-CoA Hidratasa/genética , Enfermedad de Leigh/genética , Tioléster Hidrolasas/deficiencia , Valina/metabolismo , Encéfalo/diagnóstico por imagen , Preescolar , Distonía/diagnóstico , Enoil-CoA Hidratasa/deficiencia , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Internacionalidad , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/metabolismo , Imagen por Resonancia Magnética , Masculino , Redes y Vías Metabólicas/genética , Mutación , Fenotipo , Tasa de Supervivencia , Tioléster Hidrolasas/genéticaRESUMEN
OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.
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Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , Destreza Motora/fisiología , Sarcoglicanos/genética , Adolescente , Adulto , Niño , Desarrollo Infantil/fisiología , Preescolar , Trastornos Distónicos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.
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Proteínas F-Box/genética , Trastornos del Metabolismo del Hierro , Distrofias Neuroaxonales , Trastornos Parkinsonianos , Complejo de la Endopetidasa Proteasomal/metabolismo , Adulto , Consanguinidad , Epilepsia/enzimología , Epilepsia/genética , Epilepsia/patología , Epilepsia/fisiopatología , Femenino , Humanos , Trastornos del Metabolismo del Hierro/enzimología , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Trastornos del Metabolismo del Hierro/fisiopatología , Distrofias Neuroaxonales/enzimología , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/patología , Distrofias Neuroaxonales/fisiopatología , Paraplejía/enzimología , Paraplejía/genética , Paraplejía/patología , Paraplejía/fisiopatología , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Degeneraciones Espinocerebelosas/enzimología , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/patología , Degeneraciones Espinocerebelosas/fisiopatología , Síndrome , Adulto JovenRESUMEN
BACKGROUND: GRP94 is a glucose-regulated protein critical for survival in endoplasmic reticulum stress. Expression of GRP94 is associated with cellular transformation and increased tumorigenicity in breast cancer. Specifically, overexpression of GRP94 predicts brain metastasis (BM) in breast carcinoma patients with either triple negative or ErbB2 positive tumors. The aim of this study was to understand if microenvironmental regulation of GRP94 expression might be a hinge orchestrating BM progression. METHODS: GRP94 ablation was performed in a BM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a dataset of 29 metastases in diverse organs from human breast carcinomas and in BM tissue from tumors of different primary origin. BM patient-derived xenografts (PDXs) were used to test sensitivity to the therapeutic approach. RESULTS: BMs that overexpress GRP94 as well as tumor necrosis factor receptor-associated factor 2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (B-cell lymphoma 2 and inhibitors of apoptosis proteins) and engagement of pro-survival autophagy. GRP94 ablation downregulated autophagy in tumor cells, resulting in increased BM survival in vivo. These results were validated in a metastasis dataset from human patients, suggesting that targeting autophagy might be strategic for BM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BM from PDX exerts preventive inhibition of tumor growth (P < 0.001). CONCLUSIONS: We show that GRP94 is directly implicated in BM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.
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Neoplasias Encefálicas , Proteínas de la Membrana , Animales , Autofagia , Proteínas HSP70 de Choque Térmico , Humanos , Proteínas de la Membrana/genética , Trasplante de NeoplasiasRESUMEN
Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis and high morbidity due to the difficulty in identifying biomarkers that allow a more targeted therapy. Previously, we performed transcriptomic analysis of human breast cancer patient samples and evaluated the differential expression of genes in brain metastasis (BrM) compared to lung, bone and liver metastasis. Our network approach identified upregulation of glucose-regulated protein 94 (GRP94) as well as proteins related to synthesis of fatty acids (FA) in BrM. Here we report that BrM cells show an increase in FA content and decreased saturation with regard to parental cells measured by Raman spectroscopy that differentiate BrM from other metastases. Moreover, BrM cells exerted a high ability to oxidize FA and compensate hypoglycemic stress due to an overexpression of proteins involved in FA synthesis and degradation (SREBP-1, LXRα, ACOT7). GRP94 ablation restored glucose dependence, down-regulated ACOT7 and SREBP-1 and decreased tumorigenicity in vivo. In conclusion, GRP94 is required for the metabolic stress survival of BrM cells, and it might act as a modulator of lipid metabolism to favor BrM progression.
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Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Ácidos Grasos/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Ácidos Grasos/análisis , Femenino , Proteínas HSP70 de Choque Térmico/análisis , Humanos , Proteínas de la Membrana/análisis , Ratones DesnudosRESUMEN
Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free-thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free-thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.
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Proteínas de Transporte de Membrana/deficiencia , Deficiencia de Tiamina/genética , Tiamina/metabolismo , Anemia Megaloblástica , Transporte Biológico , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Diabetes Mellitus , Pérdida Auditiva Sensorineural , Humanos , Enfermedad de Leigh , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Mutación , Fenotipo , Tiamina/líquido cefalorraquídeo , Tiamina/uso terapéutico , Deficiencia de Tiamina/congénito , Deficiencia de Tiamina/tratamiento farmacológico , Tiamina Pirofosfato/metabolismoRESUMEN
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
Asunto(s)
Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , Neuronas/metabolismo , Sinapsis/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/genética , Adolescente , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Epilepsia/metabolismo , Exocitosis , Femenino , Heterocigoto , Humanos , Lípidos/química , Imagen por Resonancia Magnética , Masculino , Fusión de Membrana , Trastornos del Movimiento/genética , Mutación , Trastornos del Neurodesarrollo/metabolismo , Neurotransmisores/metabolismo , Fenotipo , Dominios Proteicos , Proteínas R-SNARE/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/fisiologíaRESUMEN
OBJECTIVE: Non-progressive genetic disorders may present with motor dysfunction resembling cerebral palsy (CP). Such patients are often characterized as CP mimics. The purpose of this work was to delineate the clinical manifestations and molecular findings of CP mimic patients, with the ultimate goal to offer specific disease-modifying therapy and genetic counseling. METHODS: Retrospective study of 47 patients diagnosed with CP and no acquired etiology. Chart review of clinical, neuroradiological, biochemical and molecular data was performed. RESULTS: 31,91% of patients manifested with features resembling dyskinetic CP, 19,14% spastic CP, 10,63% ataxic CP and 38,30% mixed CP. In 23 patients molecular diagnosis was reached and included 5 hereditary spastic paraplegia genes (SPG) in spastic CP mimics; HPRT1, TH, QDPR, DDC in dystonic CP mimics; ADCY5 and NIKX2-1 in choreic CP mimics; CANA1A in ataxic CP mimics; and SPG, PDHA1, NIKX2-1, AT, SLC2A1 and SPR in mixed CP mimics. In 14 patients, the etiological diagnosis led to specific treatment. CONCLUSIONS: CP mimics show a number of features that differ from classic CP and can be used as diagnostic clues, including presence of mixed motor features, minor dysmorphic features, oculogyric movements, multiple features of autonomic dysfunction, and acquired microcephaly. A more stringent use of the concept of CP focused on acquired lesions during the perinatal and infancy periods, and excluding disorders that could be of genetic origin, could contribute to a purer use of the term. Identification of a specific genetic cause for CP mimics may in certain cases lead to etiologic treatment.