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.

The epidemiology of multiple sclerosis in the entre Douro e Vouga region of northern Portugal: a multisource population-based study.

BACKGROUND: The prevalence of Multiple Sclerosis (MS) has been increasing worldwide and the north-south gradient of prevalence may be disappearing in the Northern hemisphere. The few previous prevalence studies performed in Portugal have reported a lower prevalence than the average for Western Europe. The aim of this study is to estimate the prevalence of MS in the Entre Douro e Vouga region, in Northern Portugal. METHODS: Multiple overlapping sources were used to ascertain all cases from the reference population: records from hospitals in the region and neighbouring regions; diagnostic databases of primary care physicians; and applications for disability benefits. The prevalence date was set at 1 January 2014. The reference population was 274,859 inhabitants. Patients' neurologists were contacted to retrieve clinical information and confirm the diagnosis based. RESULTS: A total of 177 patients were identified after eliminating duplicates from different sources. The female to male ratio was 1.9 and the mean age at disease onset was 33.5 (standard deviation: 10.3). Clinically isolated syndrome accounted for 9.0% of patients, relapsing remitting for 58.8%, secondary progressive for 20.3% and primary progressive for 11.8%. The prevalence was estimated in 64.4 patients per 100,000 (95% confidence interval: 54.9;73.9). CONCLUSIONS: In this study we report a higher point prevalence of MS than had been previously described in Portugal, but still far from the higher values recently reported in other Southern European countries.

Intracerebral abscess: a rare complication of Deep Brain Stimulation.

INTRODUCTION: Deep Brain Stimulation (DBS) is a therapeutic option for some forms of Parkinson's disease (PD). The main adverse effects of this surgery are: infection (2-9%), haemorrhage (1-4%) and seizures (1-3%). We report a rare complication of DBS: an intracranial abscess. CASE REPORT: A 59-year-old male who had suffered PD for 19 years was submitted to bilateral subthalamic nucleus DBS in September 2003, when he was 52. One month later, he developed an inflammatory reaction of the skin and subcutaneous tissue surrounding the area of the subcutaneous DBS system. No infectious agent was isolated. In the following 12 months he required 5 major surgeries due to a process of systematic inflammation/infection throughout different locations of the DBS system. A few days after removal of the DBS device, he developed a right oculomotor nerve paresis and mild left hemiparesis. A CT scan revealed an abscess in the right thalamo-mesencephalic area. Both the new neurological deficits and the previous tremor and rigidity improved after surgical drainage and medical treatment. CONCLUSION: This case report illustrates a rare complication of DBS surgery. Nevertheless, Parkinsonism improved, probably because the abscess acted like a subthalomotomy.

Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations.

PURPOSE: Hereditary spastic paraplegias compose a group of neurodegenerative disorders with a large clinical and genetic heterogeneity. Among the autosomal recessive forms, spastic paraplegia type 11 is the most common. METHODS: To better understand the spastic paraplegia type 11 mutation spectrum, we studied a group of 54 patients with hereditary spastic paraplegia. Mutation screening was performed by PCR amplification of SPG11 coding regions and intron boundaries, followed by sequencing. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification. RESULTS: We report 13 families with spastic paraplegia type 11 carrying either novel or previously identified mutations. We describe a complex entire SPG11 rearrangement and show that large gene rearrangements are frequent among patients with spastic paraplegia type 11. Moreover, we mapped the deletion breakpoints of three different large SPG11 deletions and provide evidence for Alu microhomology-mediated exon deletion. CONCLUSION: Our analysis shows that the high number of repeated elements in SPG11 together with the presence of recombination hotspots and the high intrinsic instability of the 15q locus all contribute toward making this genomic region more prone to large gene rearrangements. These findings enlarge the amount of data relating repeated elements with neurodegenerative disorders and highlight their importance in human disease and genome evolution.

Determinants of age at onset in a Portuguese cohort of autosomal dominant spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegias present a high variability of age at onset, ranging from childhood to older age. Our objective was to identify the determinants of age at onset in autosomal dominant HSP (AD-HSP) in a large cohort of patients and families. METHODS: We included 239 patients from 89 families identified in the Portuguese multisource population-based survey of hereditary ataxias and spastic paraplegias. Patients were systematically examined by a team of neurologists, admitted for complete clinical workup and tested for SPG3, SPG4 and SPG31. RESULTS: Average age at onset was 38.2 years in the first generation, 32.3 years in the second and 17.5 years in the third, with a significant decrease of average age at onset between generations (p < .001). A decrease in the average age at onset was seen in all genotypes (SPG4: p < .001; SPG3: p = .15; SPG31: p < .001). In families with more than one generation (n = 38), this decrease was observed in 78.9%. In multivariate linear regression model, the independent effect of generation in anticipation of age at onset was confirmed (p < .001), adjusting for family, genotype and mutation. We also observed a significant lower age at onset in patients with missense versus truncating mutations (p = .015) in patients with SPG4. CONCLUSION: These results confirm the impact of missense mutations in an earlier age at onset in SPG4 patients. Even though the age at onset could be affected by subjectivity, our results are consistent with the presence of an anticipation phenomenon in AD-HSP.

Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40-70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS.

Anterior biopercular syndrome caused by unilateral infarction.

The anterior biopercular syndrome is characterized by facio-pharyngo-glosso-masticatory diplegia, with automatic dissociation of movements. It generally translates bilateral opercular lesion, often of vascular etiology. There are very few cases described with unilateral lesions. We present the case of a patient with a bilateral anterior opercular syndrome caused by unilateral infarction.

A síndrome biopercular anterior caracteriza-se por diplegia facio-faringo-glosso-mastigatória, com dissociação dos movimentos automáticos. Traduz geralmente lesão opercular bilateral, frequentemente de etiologia vascular. Há casos raros descritos de lesão unilateral. Apresentamos o caso de uma doente com uma síndrome opercular anterior bilateral causada por um enfarte unilateral.

Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey.

IMPORTANCE: Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This study is a systematic review of families with HSP resulting from a population-based survey. Novel genotype-phenotype correlations were established. OBJECTIVE: To describe the clinical, genetic, and epidemiological features of Portuguese AD-HSP families. DESIGN: Retrospective medical record review. SETTING: A population-based systematic survey of hereditary ataxias and spastic paraplegias conducted in Portugal from 1993 to 2004. PARTICIPANTS: Families with AD-HSP. MAIN OUTCOME MEASURE: Mutation detection in the most prevalent genes. RESULTS: We identified 239 patients belonging to 89 AD-HSP families. The prevalence was 2.4 in 100 000. Thirty-one distinct mutations (26 in SPG4, 4 in SPG3, and 1 in SPG31) segregated in 41% of the families (33.7%, 6.2%, and 1.2% had SPG4, SPG3 and SPG31 mutations, respectively). Seven of the SPG4 mutations were novel, and 7% of all SPG4 mutations were deletions. When disease onset was before the first decade, 31% had SPG4 mutations and 27% had SPG3 mutations. In patients with SPG4 mutations, those with large deletions had the earliest disease onset, followed by those with missense, frameshift, nonsense, and alternative-splicing mutations. Rate of disease progression was not significantly different among patients with SPG3 and SPG4 mutations in a multivariate analysis. For patients with SPG4 mutations, disease progression was worst in patients with later-onset disease. CONCLUSIONS AND RELEVANCE: The prevalence of AD-HSP and frequency of SPG3 and SPG4 mutations in the current study were similar to what has been described in other studies except that the frequency of SPG4 deletions was lower. In contrast, the frequency of SPG31 mutations in the current study was rare compared with other studies. The most interesting aspects of this study are that even in patients with early-onset disease the probability of finding a SPG4 mutation was higher than for patients with SPG3 mutations; there was no difference in disease progression with genotype but an association with the age at onset; 7 new SPG4 mutations were identified; and for the first time, to our knowledge, the nature of the SPG4 mutations was found to predict the age at onset.

Absceso intracerebral: una rara complicación de la estimulación cerebral profunda / No disponible

Introducción La estimulación cerebral profunda (DBS) es una opción terapéutica en algunas formas de la enfermedad de Parkinson (PD). Sus complicaciones principales son las infecciónes (2–9%), las hemorragias (1–4%) y las convulsiones (1–3%). Se presenta una complicación rara de la DBS: un absceso intracraneal. Caso clínico Un paciente de 59 años fue enviado para estimulación bilateral del núcleo subtalámico en setiembre del 2003 tras 19 años de enfermedad. Un mes más tarde desarrolló una reacción inflamatoria de la piel y tejido subcutáneo en las zonas adyacentes al sistema de DBS, no se consiguiendo aislar ningún microorganismo. Durante los 12 meses siguientes fueron necesarios cinco drenajes quirúrgicas por infecciones o inflamaciones en diferentes localizaciones del sistema. Finalmente se decidió retirar todo el sistema, pero unos días más tarde desarrolló una paresia del III par derecho y una discreta hemiparesia izquierda. Un TAC cerebral reveló la presencia de un absceso en la región talamo-mesencefalica. Tanto estos últimos déficits, como el temblor y la rigidez previos, mejoraron después del drenaje quirúrgico y del tratamiento médico. Conclusión Este caso, ilustra una complicación rara de la cirugía de DBS. Sin embargo el paciente mejoró de su Parkinson ya que el absceso se “comportó” como una subtalamotomía (AU)