A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.

Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

Headache as the sole presentation of cerebral venous thrombosis: a prospective study.

Headache is the most frequent presenting symptom of cerebral venous thrombosis (CVT), most commonly associated with other manifestations. It has been described as its only clinical presentation in 15 % of patients. There is no typical pattern of headache in CVT. The objective of this study was to study the characteristics of headache as the sole manifestation of CVT. From a prospective study of 30 consecutive patients diagnosed with CVT over 18 months, we selected those who presented with headache only: they had a normal neurological examination, no papilloedema and no blood or any parenchymal lesion on CT scan. All were submitted to a systematic etiological workup and a structured questionnaire about the characteristics of headache was provided. Headache was the sole manifestation of CVT in 12 patients; it was diffuse or bilateral in the majority. Seven patients referred worsening with sleep/lying down, Valsalva maneuvers or straining. There was no association between the characteristics of headache and extension of CVT. Time from onset to diagnosis was significantly delayed in these patients presenting only with headache. In our series, 40 % of patients presented only with headache. There was no uniform pattern of headache apart from being bilateral. There was a significant delay of diagnosis in these patients. Some characteristics of headache should raise the suspicion of CVT: recent persistent headache, thunderclap headache or pain worsening with straining, sleep/lying down or Valsalva maneuvers even in the absence of papilloedema or focal signs.

Posterior Reversible Encephalopathy Syndrome and Anti-Angiogenic Agents: A Case Report.

Posterior reversible encephalopathy syndrome is an increasingly recognised clinico-radiological entity, associated with several medical conditions (such as systemic arterial hypertension) and characterised by seizures, altered mental status, headaches, and visual symptoms. Magnetic resonance imaging is a key component in this diagnosis, with hyperintense foci in T2-weighted images, corresponding to vasogenic oedema. The pathophysiology is not fully understood but probably involves loss of auto-regulation of cerebral vasculature or endothelial dysfunction or both. A 56-year-old male, suffering from a gastro-intestinal stromal tumour with hepatic metastasis resistant to imatinib, on therapy with sunitinib, came to the Emergency Department because of headaches, hallucinations, and loss of vision. There was no previous history of high blood pressure. A hypertensive crisis was diagnosed; ophthalmological examination on admission showed no light perception bilaterally. Brain imaging displayed bilateral parieto-occipital and frontal vasogenic oedema, consistent with the clinical diagnosis of posterior reversible encephalopathy syndrome. After treatment of hypertension and suspension of sunitinib, the patient recovered from his symptoms. Control imaging showed no oedema. Angiogenesis inhibitors, such as sunitinib and bevacizumab, can cause hypertension, one of the many medical conditions associated with the posterior reversible encephalopathy syndrome. This syndrome should be considered in cases of acute visual loss, particularly in view of its reversible nature when diagnosed and treated promptly.

Multiple Sclerosis Patient Management During the COVID-19 Pandemic: Practical Recommendations From the Portuguese Multiple Sclerosis Study Group (GEEM).

The spread of the COVID-19 pandemic has imposed significant challenges on healthcare provision, requiring changes in the conventional patient management, particularly in chronic diseases like multiple sclerosis (MS). To increase patient safety and reduce the risk of infection, while ensuring an appropriate and regular follow-up, tele-medicine gained prominence as a valid alternative to face-to-face appointments. However, the urgency of the implementation and the lack of experience in most MS centers led to "ad hoc" and extremely diverse approaches, which now merit to be standardized and refined. Indeed, while tele-consultation cannot fully replace face-to-face visits, it certainly can, and will, be incorporated as part of the routine care of MS patients in the near future. Bearing this in mind, the Portuguese Multiple Sclerosis Study Group (GEEM) has developed a set of recommendations for the usage of tele-medicine in the management of MS patients, both during the pandemic and in the future. The consensus was obtained through a two-step modified Delphi methodology, resulting in 15 recommendations, which are detailed in the manuscript.

Opinions, beliefs and knowledge of people with multiple sclerosis on COVID-19 pandemic and vaccine.

BACKGROUND: Considering the potential COVID-19 impact on pwMS health and the importance of vaccination for this population, we decided to assess: (a) pwMS' beliefs and knowledge on COVID-19 pandemic; (b) their acceptance towards COVID-19 vaccination and (c) pwMS' opinions on general vaccination. METHODS: Observational study, based on a cross-sectional (10-20th September 2020) online survey, conducted in a cohort of pwMS' followed at two Portuguese hospitals. The survey included measures to characterize the sample and a questionnaire designed to assess the topics defined for this study. RESULTS: 270 respondents completed the full survey (response rate 58.2%). pwMS greatest concern during the pandemic was an aggravation of MS, especially by patients older than 50 years old. Almost 40% of the patients older than 50 felt that the pandemic negatively affected their MS related medical assistance. Most patients believed they would recover from COVID-19 infection. More than half of the responders feared a MS aggravation if they got COVID-19; this was more pronounced in patients with progressive MS. About 12% of the participants did not want to be vaccinated and almost 40% was unsure. Regarding vaccines in general, almost a third of the participants feared their side effects or MS related complications. CONCLUSION: Having knowledge of pwMS' opinions on COVID-19 pandemic impact and vaccination is useful to better address these issues. Fears and expectations towards vaccination must be discussed with pwMS.

Neuromyelitis optica spectrum disorders: A nationwide Portuguese clinical epidemiological study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits. OBJECTIVE: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics. METHODS: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included. RESULTS: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome. CONCLUSION: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries.

Schwannoma of the Fourth Ventricle: The Eighth Case Report.

OBJECTIVE: We report an uncommon case of a surgical resection of a fourth ventricle tumor in an adult that proved to be a schwannoma. METHODS: A 53-year-old man presented with a 1.5-year history of gait unsteadiness and vertigo and a few-week history of headache, emesis, and neurogenic dysphagia. A brain magnetic resonance imaging revealed a large, heterogeneously contrast enhancing mass located within the fourth ventricle, compressing the brainstem and causing supratentorial ventricle enlargement. A suboccipital craniotomy and a telovelar approach were performed to resect the tumor. The ventricular system was repermeabilized at the end of the operation. RESULTS: A postoperative magnetic resonance imaging confirmed complete tumor removal. There was an initial worsening of the preoperative deficits, which progressively improved. The tumor was classified as a fourth ventricle schwannoma. There has been no evidence of tumor recurrence during the 6 years of follow-up. At present, the patient is ambulatory and reports an intermittent diplopia on conjugated gaze. CONCLUSION: This case report intends to reveal the eighth case of a fourth ventricle schwannoma since 1957. Schwannomas of the fourth ventricle are infrequent but should be accounted in the differential diagnosis of space-occupying lesions in this location. Gross total resection might be the definite treatment of these tumors if deemed possible.

Multiple sclerosis and motherhood choice: an observational study in Portuguese women patients.

INTRODUCTION. Multiple sclerosis (MS) is a disabling disease occurring mainly in women of childbearing age. MS may interfere with family planning and motherhood decision. AIM. To study the influence of MS diagnosis and course of the disease on motherhood decision. PATIENTS AND METHODS. The cohort of 35 to 45-year-old female patients diagnosed with MS for at least ten years was selected from six Portuguese MS centers. A structured questionnaire was applied to all patients in consecutive consultation days. Clinical records were reviewed to characterize and collect information about the disease and pregnancies. RESULTS. One hundred women were included; mean age at MS diagnosis was 26.3 ± 5.0 years; 90% of the participants presented with a relapsing-remitting MS; 57% had no pregnancies after the diagnosis. MS type and number of relapses were not significantly different between women with or without pregnancies after the diagnosis (p = 0.39 and p = 0.50, respectively). Seventy-seven percent of the patients did not have the intended number of pregnancies. Main reasons given were fear of future disability and the possibility of having relapses. Forty-three women considered that pregnancy might worsen MS. CONCLUSION. In our population, motherhood choice was unrelated to the MS type and the number of relapses. However, a relevant number of women had fewer pregnancies than those intended before MS diagnosis and believed that pregnancy could worsen the disease. An effort to better inform the patients should be made to minimize the impact of MS diagnosis on motherhood decision.

TITLE: Esclerosis multiple y decision de la maternidad: estudio observacional en pacientes portuguesas.Introduccion. La esclerosis multiple (EM) es una enfermedad incapacitante que afecta mayoritariamente a mujeres en edad fertil. La EM puede alterar el deseo de crear una familia y concebir hijos. Objetivo. Estudiar la influencia del diagnostico de la EM y de su evolucion sobre la decision de ser madre. Pacientes y metodos. Se selecciono una cohorte integrada por pacientes de 35-45 años diagnosticadas de EM desde hacia por lo menos 10 años que eran atendidas en seis centros portugueses. Las participantes respondieron a un cuestionario estructurado en dias de consulta consecutivos. Se revisaron las historias clinicas para caracterizar y recabar informacion sobre la enfermedad y los embarazos. Resultados. Participaron 100 mujeres; la media de edad en el momento del diagnostico de la EM era de 26,3 ± 5,0 años; el 90% de las participantes presentaba la forma remitente recurrente; el 57% de las pacientes no se habian quedado embarazadas despues del diagnostico. El tipo de EM y el numero de recidivas no difirieron de manera significativa entre las mujeres que habian concebido despues del diagnostico y las que no (p = 0,39 y p = 0,50, respectivamente). El 77% no habia tenido el numero de hijos deseado. Los principales motivos aducidos fueron el temor a la incapacidad futura y la posibilidad de sufrir recidivas. Cuarenta y tres mujeres creian que el embarazo podia agravar la EM. Conclusion. En la poblacion del estudio, la decision de ser o no ser madre no guardo relacion con el tipo de EM ni con el numero de recidivas. No obstante, un numero relevante de mujeres tuvieron menos embarazos de los que habian deseado antes de ser diagnosticadas y pensaban que la gestacion podia empeorar la enfermedad. Seria conveniente mejorar la informacion que reciben estas pacientes a fin de minimizar el impacto del diagnostico de la EM en la decision de ser madre.

Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation.

Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.

Rapidly progressive corticobasal degeneration syndrome.

INTRODUCTION: Corticobasal syndrome (CBS) has a heterogeneous clinical presentation with no specific pathologic substratum. Its accurate diagnosis is a challenge for neurologists; in order to establish CBS definitively, postmortem confirmation is required. Some clinical and radiological features can help to distinguish it from other neurodegenerative conditions, such as Creutzfeldt-Jakob disease (CJD). CLINICAL CASE: A 74-year-old woman presented with language impairment, difficulty in walking and poor attentiveness that had begun 10 days before. Other symptoms, such as asymmetrical extra-pyramidal dysfunction, limb dystonia and 'alien limb' phenomena, were established over the next 2 months, with rapid progression. Death occurred 3 months after symptom onset. Laboratory results were normal. Initially, imaging only showed restricted diffusion with bilateral parieto-occipital gyri involvement on DWI-MRI, with unspecific EEG changes. An autopsy was performed. Brain neuropathology confirmed sporadic CJD (sCJD). CONCLUSIONS: CBS is a heterogeneous clinical syndrome whose differential diagnosis is extensive. CJD can occasionally present with clinical characteristics resembling CBS. MRI detection of abnormalities in some sequences (FLAIR, DWI), as previously reported, has high diagnostic utility for sCJD diagnosis - especially in early stages - when other tests can still appear normal. Abnormalities on DWI sequencing may not correlate with neuropathological findings, suggesting a functional basis to explain the changes found.