RESUMEN
Several neurodegenerative diseases and neuropsychiatric disorders display aberrant posttranslational modifications (PTMs) of one, or many, proteins. Lithium treatment has been used for mood stabilization for many decades, and is highly effective for large subsets of patients with diverse neurological conditions. However, the differential effectiveness and mode of action are not fully understood. In recent years, studies have shown that lithium alters several protein PTMs, altering their function, and consequently neuronal physiology. The impetus for this review is to outline the links between lithium's therapeutic mode of action and PTM homeostasis. We first provide an overview of the principal PTMs affected by lithium. We then describe several neuropsychiatric disorders in which PTMs have been implicated as pathogenic. For each of these conditions, we discuss lithium's clinical use and explore the putative mechanism of how it restores PTM homeostasis, and thereby cellular physiology. Evidence suggests that determining specific PTM patterns could be a promising strategy to develop biomarkers for disease and lithium responsiveness.
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Trastorno Bipolar , Enfermedades Neurodegenerativas , Biomarcadores , Trastorno Bipolar/tratamiento farmacológico , Humanos , Litio/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Procesamiento Proteico-PostraduccionalRESUMEN
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (nâ¯=â¯648) and controls (nâ¯=â¯317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85⯵mol/l/h versus 3.12⯵mol/l/h, pâ¯=â¯0.018; after controlling for batch effect, pâ¯=â¯0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89⯵mol/l/h versus 3.10⯵mol/l/h, pâ¯=â¯0.040; after controlling for batch effect, pâ¯=â¯0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, nâ¯=â¯155; control, nâ¯=â¯194), alpha galactosidase A activity was lower in PD compared to controls (2.77⯵mol/l/h versus 3.10⯵mol/l/h, pâ¯=â¯0.044; after controlling for a batch effect, pâ¯=â¯0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (ORâ¯=â¯0.54; 95% CI:0.31-0.95; pâ¯=â¯0.032). When LRRK2 G2019S PD carriers (nâ¯=â¯37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.
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Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , Anciano , Estudios de Cohortes , Activación Enzimática/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnósticoRESUMEN
Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.
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Trastorno Bipolar/metabolismo , Diferenciación Celular/fisiología , Neuronas/efectos de los fármacos , Adulto , Antimaníacos/uso terapéutico , Antipsicóticos/uso terapéutico , Biomarcadores Farmacológicos/metabolismo , Trastorno Bipolar/genética , Estudios de Casos y Controles , Giro Dentado/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Litio/uso terapéutico , Compuestos de Litio/uso terapéutico , Masculino , Técnicas de Placa-ClampRESUMEN
Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well-characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets. Furthermore, we showed targeted downstream GPCR dysregulation for some of the variants that may contribute to disease pathology. Particularly interesting was the finding of a rare and functionally relevant nonsense mutation in the corticotropin-releasing hormone receptor 2 (CRHR2) gene that tracked with affected status in one family. By focusing on rare variants in informative families, we identified key biochemical pathways likely implicated in this complex disorder.
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Trastorno Bipolar/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Trastorno Bipolar/metabolismo , Estudios de Casos y Controles , Familia , Femenino , Frecuencia de los Genes/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Receptores de Hormona Liberadora de Corticotropina/genética , Secuenciación del ExomaRESUMEN
Dominant mutations in PIEZO2, which codes for the principal mechanotransduction channel for proprioception and touch sensation, have been found to cause different forms of distal arthrogryposis. Some observations suggest that these dominant mutations induce a gain-of-function effect on the channel. Here, we report a consanguineous family with three siblings who showed short stature, scoliosis, gross motor impairment, and a progressive form of contractures involving the distal joints that is distinct from that found in patients with dominant mutations in PIEZO2. These siblings also displayed deficits in proprioception and touch sensation. Whole-exome sequencing performed in the three affected siblings revealed the presence of a rare homozygous variant (c.2708C>G; p.S903*) in PIEZO2. This variant is predicted to disrupt PIEZO2 function by abolishing the pore domain. Sanger sequencing confirmed that all three siblings are homozygous whereas their parents and an unaffected sibling are heterozygous for this variant. Recessive mutations in PIEZO2 thus appear to cause a progressive phenotype that overlaps with, while being mostly distinct from that associated with dominant mutations in the same gene.
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Artrogriposis/genética , Contractura/genética , Canales Iónicos/genética , Propiocepción/genética , Adulto , Artrogriposis/fisiopatología , Bangladesh , Consanguinidad , Contractura/fisiopatología , Femenino , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Escoliosis/genética , Escoliosis/fisiopatología , Hermanos , Tacto/genéticaRESUMEN
Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.
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Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Proteína 2 de Unión a Metil-CpG/genética , Mutación Missense , Adolescente , Adulto , Secuencia de Aminoácidos , Sitios de Unión/genética , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Discapacidad Intelectual/patología , Masculino , Fenotipo , Síndrome de Rett/genética , Síndrome de Rett/patología , Homología de Secuencia de AminoácidoRESUMEN
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
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Exoma , Genes , Enfermedades Genéticas Congénitas/diagnóstico , Mutación , Análisis de Secuencia de ADN , Canadá , Niño , Enfermedades Genéticas Congénitas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.
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Sitios Genéticos , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Trastorno de la Conducta del Sueño REM/genética , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Proteínas de Membrana de los Lisosomas/genética , Masculino , Persona de Mediana Edad , Receptores Depuradores/genética , Ubiquitina Tiolesterasa/genética , Proteínas tau/genéticaRESUMEN
We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.
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Sistema de Transporte de Aminoácidos ASC/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Mutación Missense , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Frecuencia de los Genes , Humanos , Lactante , Recién Nacido , Judíos/genética , Masculino , Datos de Secuencia Molecular , Linaje , HermanosRESUMEN
We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.
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Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , MicroARNs/genética , Farmacogenética/métodos , Estadística como Asunto/métodos , Adulto , Femenino , Genómica/instrumentación , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética/instrumentación , Estadística como Asunto/instrumentación , Resultado del Tratamiento , Adulto JovenRESUMEN
Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (ß-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3ß. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3ß inhibitor, and observed the enhanced expression of ß-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on ß-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/ß-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD.
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Cloruro de Litio/farmacología , Cloruro de Litio/uso terapéutico , Distrofia Muscular Oculofaríngea/tratamiento farmacológico , Distrofia Muscular Oculofaríngea/patología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Ratones , Distrofia Muscular Oculofaríngea/metabolismo , Proteínas Mutantes/metabolismo , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Mioblastos/patología , Proteína I de Unión a Poli(A)/genética , Proteína I de Unión a Poli(A)/metabolismo , Transporte de Proteínas/efectos de los fármacos , Expansión de Repetición de Trinucleótido/genética , beta Catenina/metabolismoAsunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Codón sin Sentido , Exoma , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Niño , Estudios de Asociación Genética , Pruebas Genéticas/métodos , Humanos , Discapacidad Intelectual/patología , Padres , Factor de Transcripción 4RESUMEN
We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.
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Predisposición Genética a la Enfermedad/genética , Proteínas del Choque Térmico HSP40/genética , Proteínas de la Membrana/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Lipofuscinosis Ceroideas Neuronales/epidemiología , Lipofuscinosis Ceroideas Neuronales/patología , Linaje , Polimorfismo Genético , Eliminación de SecuenciaRESUMEN
BACKGROUND AND PURPOSE: Although essential tremor (ET) has a genetic basis, specific genes have not been identified. Recently, in a large ET family (FET1) from Quebec, a non-sense mutation (p.Q290X) in the amyotrophic lateral sclerosis (ALS) gene fused in sarcoma/translated in liposarcoma (FUS/TLS) was identified by exome sequencing. No confirmatory studies have been published. METHODS: Two-hundred and fifty-nine ET cases and 262 controls were enrolled in a study at Columbia University. We performed a comprehensive analysis of the FUS/TLS gene by sequencing all exons in a subsample of 116 ET cases with early-onset (≤40 years) ET. We evaluated an association between ET and SNPs in the FUS/TLS gene by genotyping four haplotype tagging SNPs in all 259 ET cases and 262 controls. Additionally, seven variants associated with ALS, two variants of unknown pathogenicity detected in ALS cases, eight mis-sense variants predicted to be damaging, and six rare variants were genotyped in these 259 ET cases and 262 controls. RESULTS: FUS/TLS mutations previously reported in ALS, the FET1 family, or novel mutations were not found in any of the 116 early-onset ET cases. In the case-control analyses, although the power of the performed associations was limited, no significant association between tagging SNPs in FUS/TLS and ET was observed, and none of the analyzed SNPs showed evidence of association with ET. CONCLUSION: Our study suggests that pathogenic mutations in FUS/TLS are rare in a sample of early-onset ET cases in North America. We did not find evidence that the FUS/TLS gene is a risk factor for ET.
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Temblor Esencial/genética , Proteína FUS de Unión a ARN/genética , Adulto , Edad de Inicio , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS: We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS: We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS: The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.
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Esclerosis Amiotrófica Lateral/epidemiología , Recolección de Datos/métodos , Sistema de Registros/estadística & datos numéricos , Sistema de Registros/normas , Canadá/epidemiología , Recolección de Datos/estadística & datos numéricos , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Sistemas en LíneaRESUMEN
OBJECTIVE: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. METHODS: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. RESULTS: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). CONCLUSION: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
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Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Adulto , Edad de Inicio , Anciano , Esclerosis Amiotrófica Lateral/mortalidad , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Análisis de SupervivenciaAsunto(s)
Cobre/metabolismo , Neuropatía Hereditaria Motora y Sensorial/genética , Enfermedad de la Neurona Motora/genética , Neuronas Motoras/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Enfermedad de la Neurona Motora/metabolismoRESUMEN
Distal hereditary motor neuropathy (dHMN) is a sub-group of Charcot-Marie-Tooth disease (CMT), the most common peripheral neuropathy, that affects only motor neurons. The recent observation of ATP7A mutations in dHMN provides insight for a common disease mechanism that may involve copper homeostasis. Functionally, diverse proteins were previously shown to underlie dHMN and a convergent link is destined to unfold for some of these. We propose connections between copper and known dHMN genes that overlap also with the causative genes of other motor neuron disorders (MNDs).