Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies, where mutations in genes involved in RNA metabolism or characterized by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle MRI, with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterized by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although inter-individual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganization. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V ß = -1.06, P < 0.001; lobules VI-VII ß = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.

The CAPN3 p.Lys 254del variant is not always associated with dominant CAPN3-related muscular dystrophy.

INTRODUCTION/AIMS: Limb-girdle muscular dystrophy R1 (LGMDR1) calpain 3-related usually presents as a recessively transmitted weakness of proximal limb-girdle muscles due to pathogenic variants in the CAPN3 gene. Pathogenic variants in this gene have also been found in patients with an autosomal dominantly inherited transmission pattern (LGMDD4). The mechanism underlying this difference in transmission patterns has not yet been elucidated. Camptocormia, progressive limb weakness, myalgia, back pain, and increased CK levels are common clinical features associated with dominant forms. The p.Lys254del pathogenic variant was associated with camptocormia in two LGMDD4 families. This study aimed to present carriers found in recessively transmitted LGMDR1 families bearing the p.Lys254del variant that do not show muscle weakness. METHODS: DNA sequencing was performed on exon 5 of CAPN3 in family members to establish the carrier status of the pathogenic variant. They were evaluated clinically and MRI was performed when available. RESULTS: Two families presented with the p.Lys254del pathogenic variant in a homozygous or compound heterozygous state. Family members carrying only the pathogenic variant in the heterozygous state did not demonstrate the myopathic characteristics described in dominant patients. Camptocormia and other severe clinical symptoms were not observed. DISCUSSION: We conclude that the p.Lys254del pathogenic variant per se cannot be solely responsible for camptocormia in dominant patients. Other undisclosed factors may regulate the phenotype associated with the dominant inheritance pattern in CAPN3 pathogenic variant carriers.

CNS involvement in myotonic dystrophy type 1: does sex play a role?

Introduction: Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient's and disease-transmitting parent's sex) with a focus on CNS outcomes. Methods: Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions. Results: Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion. Discussion: This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinic-molecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis.

Oocyte electroporation prior to in vitro fertilization is an efficient method to generate single, double, and multiple knockout porcine embryos of interest in biomedicine and animal production.

Genetically modified pigs play a critical role in mimicking human diseases, xenotransplantation, and the development of pigs resistant to viral diseases. The use of programmable endonucleases, including the CRISPR/Cas9 system, has revolutionized the generation of genetically modified pigs. This study evaluates the efficiency of electroporation of oocytes prior to fertilization in generating edited gene embryos for different models. For single gene editing, phospholipase C zeta (PLC ζ) and fused in sarcoma (FUS) genes were used, and the concentration of sgRNA and Cas9 complexes was optimized. The results showed that increasing the concentration resulted in higher mutation rates without affecting the blastocyst rate. Electroporation produced double knockouts for the TPC1/TPC2 genes with high efficiency (79 %). In addition, resistance to viral diseases such as PRRS and swine influenza was achieved by electroporation, allowing the generation of double knockout embryo pigs (63 %). The study also demonstrated the potential for multiple gene editing in a single step using electroporation, which is relevant for xenotransplantation. The technique resulted in the simultaneous mutation of 5 genes (GGTA1, B4GALNT2, pseudo B4GALNT2, CMAH and GHR). Overall, electroporation proved to be an efficient and versatile method to generate genetically modified embryonic pigs, offering significant advances in biomedical and agricultural research, xenotransplantation, and disease resistance. Electroporation led to the processing of numerous oocytes in a single session using less expensive equipment. We confirmed the generation of gene-edited porcine embryos for single, double, or quintuple genes simultaneously without altering embryo development to the blastocyst stage. The results provide valuable insights into the optimization of gene editing protocols for different models, opening new avenues for research and applications in this field.

A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.

Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCß pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.

Encefalomielitis extensa por Borrelia: una forma atípica de neuroborreliosis / Extensive encephalomyelitis due to Borrelia: an atypical form of neuroborreliosis

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Registro español de la enfermedad de Pompe: análisis de los primeros 49 pacientes con enfermedad de Pompe del adulto / Spanish Pompe registry: Baseline characteristics of first 49 patients with adult onset of Pompe disease

INTRODUCCIÓN Y OBJETIVOS: La enfermedad de Pompe es una enfermedad rara con herencia autosómica recesiva por un déficit de maltasa ácida. Este déficit produce un acúmulo de glucógeno en los tejidos. Desde una perspectiva clínica, se caracteriza principalmente por una debilidad de cinturas y una afectación de la musculatura respiratoria. En 2013 se creó el registro español de enfermedad de Pompe. El objetivo de este artículo es analizar las características de los primeros 49 pacientes y divulgar la existencia de este registro dentro de la comunidad médica. MATERIAL Y MÉTODOS: Se realizó un estudio observacional en el que se analizaron las variables de los pacientes incluidos en el registro español de enfermedad de Pompe desde mayo de 2013 hasta octubre de 2018. RESULTADOS: Los 49 pacientes proceden de 7 hospitales españoles. Veintiséis pacientes son mujeres y 23, hombres. La edad media en el momento del análisis fue de 47,2 años. Diez pacientes estaban asintomáticos. La edad media de inicio de los síntomas fue 29 años; la debilidad de cintura pélvica fue el síntoma inicial más frecuente. El 49% de los pacientes tenían afectación respiratoria, el 70,8% necesitaba ventilación mecánica no invasiva. El análisis genético encontró la mutación IVS1−13T>G en el 85,3% de los pacientes. Todos los pacientes sintomáticos recibían tratamiento con ERT. CONCLUSIONES: Este registro permite conocer las características clínico-genéticas de pacientes adultos con enfermedad de Pompe en España, además de ser la base de futuros estudios de historia natural y del impacto de la ERT en el curso de la enfermedad

INTRODUCTION AND OBJECTIVES: Pompe disease is a rare autosomal recessive disorder produced by a deficiency of acid maltase. This deficit produces an accumulation of glycogen in tissues. Clinically it is mainly characterized by limb girdle and respiratory muscle weakness. In 2013, we developed the Spanish Pompe Registry. The objective of this article was to analyse the characteristics of the first 49 patients and disclose the existence of this registry within the medical community. MATERIAL AND METHODS: An observational retrospective study was undertaken. We analysed the 49 patients included in the Spanish Registry of Pompe Disease from May 2013 to October 2018. RESULTS: Patients were visited at 7 different Spanish hospitals. Twenty-six patients were women and 23 were men. The average age at the time of the analysis was 47.2 years. Ten patients were asymptomatic. The mean age of onset of symptoms was 29, and low limb girdle weakness was the most frequent initial symptom. Of the patients, 49% had respiratory involvement, and 70.8% of them required non-invasive mechanical ventilation. The most common mutation found was IVS1−13T>G in 85.3% of the patients. All symptomatic patients received treatment with ERT. CONCLUSIONS: This registry allows us to know the clinical and genetic characteristics of adult patients with Pompe disease in Spain. Moreover, it can be the basis for future studies of natural history to understand the impact of ERT in the course of the disease

Asociaciones de pacientes y autorización de nuevos fármacos en Estados Unidos. El caso del eteplirseno para la distrofia muscular de Duchenne / Patients organizations and new drug approval in the US. Eteplirsen and Duchenne muscular dystrophy case

Introducción. En 2016, la Agencia de Medicamentos y Alimentos (FDA) estadounidense autorizó la comercialización del eteplirseno para el tratamiento de la distrofia muscular de Duchenne. Este hecho ha sido muy controvertido, por cuanto la autorización se produjo tras una evaluación negativa por parte del comité asesor de la FDA y de sus propios técnicos. Fue la directora del Centro de Investigación y Evaluación de Fármacos quien autorizó el medicamento, decisión que no revocó el director de la FDA. Objetivo. Informar sobre los acontecimientos más relevantes que han conducido a la autorización del eteplirseno por la FDA. Desarrollo. En el artículo se exponen pormenorizadamente los hechos relevantes que acontecieron durante el desarrollo clínico y la evaluación reguladora del eteplirseno siguiendo la vía de la ‘autorización acelerada’. Se comentan las razones por las que los técnicos de la FDA entienden que este medicamento no ha mostrado producir beneficio clínico, la actitud de las asociaciones de pacientes y las exigencias postautorización que la FDA ha impuesto a la compañía propietaria del medicamento. Por último, se reflexiona sobre la situación en que quedan los pacientes españoles una vez que el eteplirseno está comercializado en Estados Unidos. Conclusiones. Este caso, único en la historia de autorización de medicamentos en el mundo occidental, pone de manifiesto las dificultades que las regulaciones actuales de autorización acelerada de nuevos medicamentos pueden tener en la interpretación de datos del desarrollo clínico, cuando éstos son escasos y de poca calidad, y cuando se trata de enfermedades raras sin terapias disponibles (AU)

Introduction. In 2016 the US Food and Drug Administration (FDA) granted the marketing authorization for eteplirsen for Duchenne muscular dystrophy. This has been a very controversial decision since it happened after a negative assessment from both the Advisory Committee and the technical FDA evaluation team. The FDA’s Center for Drug Evaluation and Research (CDER) director was who ultimately approved the product, while the FDA Commissioner did not overrule that decision. Aim. To report about the most relevant events regarding the approval of eteplirsen by the US FDA. Development. All relevant facts that occurred during the clinical development and evaluation phase following "accelerated approval" procedure of eteplirsen are discussed in detail. The technical FDA evaluation team reasons supporting that the drug has not proven clinical benefit, the attitude of patient advocacy groups and the post-approval FDA requirements to the marketing authorization holder are discussed. Finally, we reflect on what is the situation Spanish patients face once eteplirsen is on the US market. Conclusions. This is a unique case in the history of drug authorizations in western countries, that shows the difficulties thatcurrent regulations on accelerated approval of new medicines could have when interpreting scarce and low quality clinical development data, when dealing with rare diseases with no available therapies (AU)

Guía para el seguimiento de la enfermedad de Pompe de inicio tardío / Guidelines for monitoring late-onset Pompe disease

Aunque el tratamiento con alglucosidasa alfa ha contribuido a mejorar el pronóstico de los pacientes con enfermedad de Pompe de inicio tardío, es necesario hacer un seguimiento periódico de la evolución de la enfermedad y de la eficacia del tratamiento. Por este motivo, un comité de expertos españoles ha elaborado una guía para el seguimiento de estos pacientes. El comité propone un modelo de pruebas de seguimiento para la enfermedad de Pompe de inicio tardío. En primer lugar, ha de valorarse el estado nutricional y la función deglutoria. En segundo lugar, y debido a la variabilidad del cuadro clínico, el comité recomienda el uso simultáneo de varias escalas que midan distintas funciones y pará- metros. De este modo, la fuerza muscular se evalúa con la escala del Medical Research Council; la función motora, con la prueba de la marcha en seis minutos y pruebas cronometradas; la discapacidad, con la escala de actividad específica de la enfermedad de Pompe construida según el análisis de Rasch; la función respiratoria, con la medida de la capacidad vital forzada y la saturación de oxígeno; y la fatiga, con la escala de intensidad de la fatiga. Por último, la seguridad y la tolerabilidad del tratamiento enzimático sustitutivo se controlan con el registro y tratamiento de los potenciales efectos adversos y la medición de los anticuerpos antialglucosidasa alfa. Se incluyen también diversas recomendaciones generales (AU)

Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included (AU)

Necrosis retiniana aguda por virus herpes simple tipo 1 a los tres años de una encefalitis herpética / Acute herpes simplex virus type 1 retinal necrosis three years after herpes simplex encephalitis

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Dolor y distensión abdominal como manifestación inicial de la neuroborreliosis / Abdominal pain and wall distension as the onset form of neuroborreliosis

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Hepatitis autoinmune en un paciente con esclerosis múltiple en tratamiento con acetato de glatiramero / Autoimmune hepatitis in a patient with multiple sclerosis under treatment with glatiramer acetate

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Guía clínica de la enfermedad de Pompe de inicio tardío / Clinical guidelines for late-onset Pompe disease

Resumen. Hasta 2006, la enfermedad de Pompe o glucogenosis tipo II era una enfermedad incurable y con tratamiento meramente paliativo. El desarrollo de la terapia de sustitución con la enzima α-glucosidasa recombinante humana ha constituido el primer tratamiento específico para esta enfermedad. El objetivo de esta guía es servir de referencia en el manejo de la variedad de inicio tardío de la enfermedad de Pompe, es decir, la que aparece después del primer año de vida. En la guía, un grupo de expertos españoles hace recomendaciones específicas en cuanto a diagnóstico, seguimiento y tratamiento de esta enfermedad. En cuanto al diagnóstico, el método de la muestra en sangre seca es imprescindible como primer paso para el diagnóstico de la enfermedad de Pompe, y el diagnóstico de confirmación de la enfermedad de Pompe debe realizarse mediante un estudio de la actividad enzimática en muestra líquida en linfocitos aislados o mediante el análisis mutacional del gen de la alfa-glucosidasa. En cuanto al tratamiento de la enfermedad con terapia de sustitución enzimática, los expertos afirman que es eficaz en la mejoría o estabilización de la función motora y pulmonar, y debe iniciarse cuando aparezcan los síntomas atribuibles a la enfermedad de Pompe (AU)

Summary. Before 2006, Pompe disease or glycogenosis storage disease type II was an incurable disease whose treatment was merely palliative. The development of a recombinant human alpha-glucosidase enzymatic replacement therapy has become the first specific treatment for this illness. The aim of this guide is to serve as reference for the management of the late-onset Pompe disease, the type of Pompe disease that develops after one year of age. In the guide a group of Spanish experts make specific recommendations about diagnosis, follow-up and treatment of this illness. With regard to diagnosis, the dried blood spots method is essential as the first step for the diagnosis of Pompe disease. The confirmation of the diagnosis of Pompe disease must be made by means of an study of enzymatic activity in isolated lymphocytes or a mutation analysis of the alpha-glucosidase gene. With regard to treatment with enzymatic replacement therapy, the experts say that is effective improving or stabilizating the motor function and the respiratory function and it must be introduced when the first symptoms attributable to Pompe disease appear (AU)

Parkinsonismo inducido por sulpiride y veralipride: dos historias diferentes / Parkinsonism induced by sulpiride and veralipride: two different stories

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HLA-DRB1 en pacientes caucásicos con neuromielitis óptica / HLA-DRB1 typing in Caucasians patients with neuromyelitis optica

Introducción. Los anticuerpos contra la aquaporina-4 (Ac-AQP-4) permitieron identificar como enfermedades diferentes a la neuromielitis óptica (NMO) y la esclerosis múltiple (EM). Estudios recientes sugieren que los alelos HLA-DRB1 contribuyen de forma diferente en la NMO y la EM en poblaciones no caucásicas. Nuestro objetivo fue analizar la distribución HLA-DRB1 en pacientes con NMO de origen caucásico. Sujetos y métodos. Se incluyó una cohorte de 22 pacientes con NMO (el 73% con Ac-AQP-4), 228 con EM y 225 controles sanos de origen español, y se genotipificó el locus HLA-DRB1. Posteriormente, los resultados se combinaron con los descritos en una población caucásica francesa: 45 pacientes con NMO (el 53% con Ac-AQP-4), 156 con EM y 310 controles sanos. Resultados. En la cohorte española, la NMO, en comparación con la EM, se asociaba a una mayor frecuencia del alelo DRB1*10 (odds ratio, OR = 15,1; intervalo de confianza del 95%, IC 95% = 3,26-69,84; p = 0,012). En el análisis combinado, y comparado con controles sanos, la NMO se asociaba a una mayor frecuencia del alelo DRB1*03 (OR = 2,27; IC 95% = 1,44-3,58; p < 0,0008), y esto se relacionaba con tener Ac-AQP-4 (OR = 2,74; IC 95% = 1,58-4,77; p < 0,0008). Por el contrario, la EM se asociaba a una mayor frecuencia del alelo DRB1*15 (OR = 2,09; IC 95% = 1,62-2,68; p < 0,0008) y a una menor frecuencia del alelo DRB1*07 (OR = 0,58; IC 95% = 0,44-0,78; p < 0,0008). Conclusiones. Los pacientes caucásicos con NMO y EM presentan una distribución alélica HLA-DRB1 diferente. El alelo DRB1*03 parece contribuir a ser IgG-NMO seropositivo. Son necesarios estudios multicéntricos colaborativos para conocer mejor la contribución genética en la susceptibilidad a padecer NMO (AU)

Introduction. The existence of antibodies to aquaporin-4 (AQP-4-ab) has identified neuromyelitis optica (NMO) and multiple sclerosis (MS) as different diseases. Although HLA-DRB1 alleles contribute to MS risk, recent studies suggest that HLA background differs between patients with NMO or MS in non-Caucasians populations. Our study was aimed to analyze HLA-DRB1 distribution in Caucasians NMO patients. Subjects and methods. We recruited a cohort of 22 NMO patients (73% were AQP-4-ab positive), 228 MS patients and 225 healthy controls from Spain and we genotyped the HLA-DRB1 locus. Then, we performed a pool analysis using reported data from 45 NMO patients (53% were AQP-4-ab positive), 156 MS patients and 310 healthy controls from Caucasian French population. Results. In the Spanish cohort, NMO was associated with increased frequency of DRB1*10 allele compared with MS (odds ratio, OR = 15.1; 95% confidence interval, 95% CI = 3.26-69.84; p = 0.012). In the pooled analysis, by comparison with healthy controls, NMO was associated with increased frequency of DRB1*03 allele (OR = 2.27; 95% CI = 1.44-3.58; p < 0.0008) which was related to AQP-4-ab seropositivity (OR = 2.74; 95% CI = 1.58-4.77; p < 0.0008). By contrast, MS as associated with increased frequency of DRB1*15 allele (OR = 2.09; 95% CI = 1.62-2.68; p < 0.0008) and decreased frequency of DRB1*07 allele (OR = 0.58; 95% CI = 0.44-0.78; p < 0.0008). Conclusions. Caucasian patients with NMO and MS have a different HLA-DRB1 allelic distribution. DRB1*03 allele seems to contribute to NMO seropositivity. Multicenter collaborative efforts are needed to adequately address the genetic contribution to NMO susceptibility (AU)

Matrices de ADN: visión general y aplicaciones específicas / ADN arrays: a general overview and specific applications

Las dificultades derivadas de la gran complejidad del genoma humano, debido a la gran cantidad de genes que lo constituyen, y las dificultades a la hora de realizar un correcto diagnóstico molecular han requerido la utilización de tecnologías avanzadas, como las matrices de ADN. Por medio de esta tecnología es posible analizar en un solo experimento grandes secuencias de regiones genómicas, detectar mutaciones o polimorfismos característicos de cada individuo, así como analizar variaciones de expresión de genes implicados en diferentes enfermedades o en la utilización de fármacos. Del mismo modo, la información derivada de las matrices de ADN permite un gran avance en la medicina personalizada aplicada a cada paciente, pues se evitan los efectos adversos no deseados y se obtiene el mejor rendimiento para cada fármaco utilizado

Difficulties derived from the big complexity of the human genome (because of the great amount of genes) and difficulties at the time of performing a correct molecular diagnosis have led to the utilization of advanced technologies such as DNA arrays. By this technique, it is possible to analyze in a single experiment great sequences of genomic regions, to detect mutations or polymorphisms (characteristic of each individual), and to analyze variations in the expression of genes implicated in different disorders or in the utilization of drugs. Similarly, the use of DNA arrays-derived information has led to a considerable advance in the personalized medicine that is applied to every patient, avoiding unwanted adverse effects and the consecution of the best performance effectiveness for each drug

Análisis de la marcha en la enfermedad de Parkinson y su respuesta al tratamiento dopaminérgico / Gait analysis in Parkinson’s disease and response to dopaminergic treatment

FUNDAMENTO Y OBJETIVO: Analizar objetivamente las alteraciones de la marcha en pacientes con enfermedad de Parkinson (EP)y los cambios observados tras la administración de medicación dopaminérgica. PACIENTES Y MÉTODO: Se incluyó a 15 pacientes con enfermedad de Parkinson para la comparación de la marcha con un grupo de 15 individuos sanos de la misma edad y a24 pacientes para la comparación antes y después de la administración de la medicación. Se realizó el análisis con un nuevosistema de fotogrametría tridimensional. RESULTADOS: Los pacientes presentaron de forma significativa una menor velocidad, longitud de zancada, de paso y menores amplitudes articulares de cadera y rodillaque el grupo control, sin diferencias en la cadencia, base de sustentación ni en los tiempos relativos del ciclo de la marcha. No se encontraron diferencias significativasen la comparación de la marcha antes y después de la administración de la medicación dopaminérgica. CONCLUSIONES: El análisis de la marcha permite cuantificar las alteraciones de la marcha en pacientes con enfermedad de Parkinson y el potencial efecto de intervenciones terapéuticas. Los resultados indican un cierto grado de resistencia a la levodopa en la marcha de estos pacientes

BACKGROUND AND OBJECTIVE: The objective of this study was to analyze the gait abnormalities in patients with idiopathic Parkinson’s disease(PD), and their response to dopaminergic treatment. PATIENTS AND METHOD: 15 patients and 15 healthyage-matched subjects were included for comparison between pathologic and «normal» gait, and 24 PD patients were included to assess the effects of treatment. Gait analysis was achieved with a new 3D-photogramme try system. RESULTS: Patients had significative lower velocity, stride length, step length and hip and knee ranges when compared with control subjects. There were no differences in cadence, step width and relative times of gait-cycle. There were no differences in the patients’ gait variables after administration of a dopaminergic medication. CONCLUSIONS: Gait analysis allows quantification of gait disturbances in patients with PD and the potential effects of treatment. The results of this study suggest a certain degree of«levodopa-resistance» in gait in these patients