Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

[Myasthenia gravis. Update on diagnosis and therapy]. / Miastenia gravis. Actualización diagnóstica y terapéutica.

Myasthenia gravis is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction, and is clinically characterized by the presence of fatigueable muscle weakness. In the etiopathogenesis plays a central role the thymus and the most frequently detected pathogenic autoantibodies are targeted to the acetylcholine receptor. The increase in the knowledge of the immunological components of the neuromuscular junction in the last two decades has been fundamental to identify new pathogenic antibodies, reduce the percentage of patients with seronegative myasthenia, and propose a classification of patients into subgroups with clinical-therapeutic interest. In addition, in recent years, new drugs have been developed for the treatment of patients with myasthenia gravis that are refractory to conventional immunosuppressive treatment.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

Glucose metabolism in lean patients with mild type 2 diabetes mellitus: evidence for insulin-sensitive and insulin-resistant variants.

Obesity and type 2 diabetes mellitus (DM2) are 2 closely related syndromes, with obesity occurring in 70% to 80% of DM2 patients. Both syndromes are characterized by insulin resistance (IR). However, the metabolic characteristics of lean DM2 patients are not clearly defined, a fact attributed to the heterogeneity of the diabetes syndrome. Our objective was to study glucose metabolism in lean DM2 patients, in terms both of the basal and the insulin-stimulated states, and particularly, to investigate whether 2 subpopulations of diabetic patients are identifiable on the basis of degree of IR. Sixteen nonobese (body mass index [BMI] less than 27 kg. m(-2)) DM2 subjects with light to moderate fasting hyperglycemia were studied. Ten healthy subjects were used as a control group, with no family history of DM2 and matched by age, sex, and BMI in the diabetic group. All participants underwent an intravenous glucose tolerance test with frequent sampling over 180 minutes. Insulin sensitivity (IS) and glucose effectiveness at zero insulin (GEZI) were calculated using Bergman's minimal model. Non-insulin-mediated glucose uptakes (NIMGU) and insulin-mediated glucose uptakes (IMGU) were calculated for the basal (F) and insulin-stimulated states at 11.1 mmol/L of glucose (11.1). The beta-cell function was calculated via the acute insulin response to glucose (AIRg). Clustering techniques were used to identify subpopulations of DM2 patients on the basis of insulin sensitivity. The group of DM2 patients was characterized by both IR (IS index, 6.23 +/- 4.68 v 12.75 +/- 7.74 x 10(-5). min(-1). (pmol. L(-1))(-1), P <.01) and insulin secretion abnormalities (AIRg, 336 +/- 456 v 1,912 +/- 1,293 pmol/L. min, P <.0001), but showed similar values for GEZI (0.011 +/- 0.005 v 0.011 +/- 0.007 min(-1), not significant [NS]) in comparison to the control group. For the basal state, no differences were found between the DM2 patients and control subjects for NIMGU(F) (0.13 +/- 0.07 v 0.08 +/- 0.05 mmol/kg. min, NS) or for IMGU(F) (0.05 +/- 0.04 v 0.05 +/- 0.02 mmol/kg. min, NS). For the insulin-stimulated state, the DM2 patients showed a reduction of approximately 50% in the IMGU(11.1) value (0.20 +/- 0.17 v 0.38 +/- 0.24 mmol/kg. min, P <.05), but no significant differences were found for NIMGU(11.1) (0.19 +/- 0.09 v 0.20 +/- 0.12 mmol/kg. min, NS) in relation to the control group. Using the clustering technique, it was possible to identify 2 subpopulations of DM2 patients, a DM-IS group (n = 6) that was insulin sensitive (IS index, 11.70 +/- 2.40 x 10(-5). min(-1). (pmol. L(-1))(-1)) and a DM-IR group (n = 10) that was insulin resistant (IS index, 3.02 +/- 1.60 x 10(-5). min(-1). (pmol. L(-1))(-1)). The DM-IS group was characterized by an absence of IR, diminished GEZI, and a reduction in AIRg; whereas the DM-IR group was characterized by IR and a reduction in AIRg, but normal GEZI. We conclude that (1) as a group, DM2 patients are characterized by IR and beta-cell dysfunction, but normal NIMGU; (2) two subpopulations of DM2 patients can be identified on the basis of insulin sensitivity, with the DM-IS group further characterized by diminished GEZI; and finally, (3) deterioration in the pancreatic response to glucose stimulus is a sine qua non condition for a profound alteration in glucose metabolism in DM2 patients.

[CADASIL: brief report on a family with a new p.G296C mutation in exon 6 of the Notch-3 gene]. / CADASIL: comunicación de una familia con una nueva mutación p.G296C en el exón 6 del gen Notch-3.

INTRODUCTION: CADASIL is a dominant autosomal inborn systemic arteriopathy, whose genetic anomaly is located in the Notch-3 gene of chromosome 19. It is clinically characterised by migraine with aura, recurrent stroke and cognitive deterioration, and is one of the causes of strokes among the young. CASE REPORT: The propositus was a 57-year-old male who presented a clinical picture of dysarthria, loss of strength in the left extremities and alterations affecting balance with dysmetry in the left extremities, related with an acute ischaemic stroke in the cerebellar peduncle. An ultrastructural study of a biopsy specimen of the skin revealed the electron-dense deposits that characterise CADASIL. The genetic analysis identified a new mutation for this disease in codon 296 of exon 6 in the Notch-3 gene that produces a change of amino acid, from glycine to cysteine in protein (p.G296C). CONCLUSIONS: This communication reports the case of a family with CADASIL that was a carrier of a new p.G296C mutation located in exon 6 of the Notch-3 gene.

Trombosis venosa cerebral en adultos en el Complejo Hospitalario-Universitario De A Coruña España: revisión clínico-radiológica de 48 casos diagnosticados entre 1995 Y 2005 / Cerebral vein thrombosis in adults in the Hospital-University of A Coruña Spain: clinico-radiological review of 48 cases diagnosed between 1995 and 2005

Introducción. La trombosis venosa cerebral es una patología del sistema nervioso central cuya incidencia es aún desconocida. El diagnostico es difícil, teniendo en cuenta que las manifestaciones neurológicas así como su etiología pueden ser extremadamente variables. Objetivos: conocer la etiología, clínica y pronóstico de las trombosis de los senos venosos cerebrales en el Complejo Hospitalario Universitario Juan Canalejo de A Coruna. Pacientes y métodos: se revisaron de forma retrospectiva los casos diagnosticados de TVC desde 1995 a 2005. Se registro la etiología, las manifestaciones clínicas, los signos radiológicos en la TAC en el momento del ingreso, el tratamiento aplicado y el pronóstico a los 6 meses empleando la escala modificada de Rankin. Resultados: se registraron 48 casos de los cuales 27 eran mujeres y 21 hombres; el rango de edad fue de 21 a 88 años, con una mediana de 43 años. La etiología infecciosa estuvo presente en cinco casos equivalente al 10,4%). En pacientes jóvenes (<43 años) los trastornos de la coagulación y/o la toma de anticonceptivos hormonales se constato en el 66,7% de los casos, mientras que en los mayores de 43 años la etiología neoplásica se encontró en el 29% y no pudo identificarse en el 45,8%. El síntoma más frecuente fue la cefalea en el 72,9%. En la tomografía axial computarizada el signo radiológico mas frecuente fue la hiperdensidad de uno o varios senos venosos (62,5%), pero fue estrictamente normal en el 20% de los casos. Treinta y cuatro pacientes recibieron tratamiento anticoagulante con buena evolución, así el 75% presento puntuación en la escala modificada de Rankin ≤1 a los seis meses. Ocho pacientes (16,7%) fallecieron, pero la mortalidad estuvo fuertemente relacionada con la patología de base de los mismos (50% cáncer). Conclusiones: en pacientes jóvenes predomina la etiología por anticonceptivos y los trastornos de la coagulación, en cambio, a partir de la sexta década dominan las neoplasias subyacentes y causas indeterminadas. El tratamiento anticoagulante es eficaz y seguro. El pronóstico es excelente en la mayoría de los casos...

Introduction. Cerebral venous thrombosis is a pathology of the central nervous system which incident is still unknown. The diagnosis is difficult because the neurological manifestations and its etiology may be extremely varied. Objectives. The aim of our study was to ascertain the etiology, the clinical manifestations and the prognosis of the cases of Cerebral venous thrombosis diagnosed at our Hospital. Patients and Methods. It was reviewed retrospectively all histories of the patients who were diagnosed of cerebral venous thrombosis from 1995 to 2005. It was recorded the etiological factors, the clinical manifestations, the radiological signs in the computed tomography scan at admission, the treatment administered and the prognosis at six months was classified in accordance with the modified Rankin scale (mRS). Results. We reviewed 48 cases (27 females; 21 males). The age range was 21 to 88 years old, with a median at 43 years. The infectious etiology was present in five patients (10,4%). In the young group (<43years), coagulation diseases and/or oral hormone contraceptives were involved in 66,7% of the cases, whereas in the age group (≥43 years), an underlying neoplasm was identified in 29% of the cases and no etiological factor in 45,8%. Headache was the most frequent symptom (72,9%). The most frequently observed radiological sign in the computed tomography scan was hyperdensity in one or more venous sinuses (62.5%), but it was normal in 20% of the cases. 34 patients received anticoagulant treatment with a good evolution, so 75% presented mRS ≤1 at six months. Death occurred in 8 patients (16,7%), although it was closely related to their basic condition (50% neoplasm). Conclusions. In young population, the most frequently etiologies are contraceptives and coagulation disease and in people older than 60 years, the underlying neoplasm and cases of unknown etiology prevail. The anticoagulant treatment is effective and safe. The prognosis was excellent in the most of the cases...