Spinocerebellar Ataxia Type 2

1. Introduction: The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of neurodegenerative disorders caused by degeneration of cerebellum and its afferent and efferent connections. The degenerative process may additionally involves the ponto- medullar systems, pyramidal tracts, basal ganglia, cerebral cortex, peripheral nerves (ADCA I) and the retina (ADCA II), or can be limited to the cerebellum (ADCA III) (Harding et al., 1993). The most common of these dominantly inherited autosomal ataxias, ADCA I, includes many Spinocerebellar Ataxias (SCA) subtypes, some of which are caused by pathological CAG trinucleotide repeat expansion in the coding region on the mutated gene. Such is the case for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA17 and Dentatorubral-pallidoluysian atrophy (DRPLA) (Matilla et al., 2006). Among the almost 30 SCAs, the variant SCA2 is the second most prevalent subtype worldwide, only surpassed by SCA3 (Schöls et al., 2004; Matilla et al., 2006; Auburger, 2011)..

Mapping the gene for autosomal dominant restless legs syndrome in an Irish family

Restless Legs Syndrome (RLS) is a common neurological disorder affecting nearly 15% of the general population. Ironically, RLS can be described as the most common condition one has never heard of. It is usually characterised by uncomfortable, unpleasant sensations in the lower limbs inducing an uncontrollable desire to move the legs. RLS exhibits a circadian pattern with symptoms present predominantly in the evening or at night, thus leading to sleep disruption and daytime somnolence. RLS is generally classified into primary (idiopathic) and secondary (symptomatic) forms. Primary RLS includes sporadic and familial cases of which the age of onset is usually less than 45 years and progresses slowly with a female to male ratio of 2:1. Secondary forms often occur as a complication of another health condition, such as iron deficiency or thyroid dysfunction. The age of onset is usually over 45 years, with an equal male to female ratio and more rapid progression. Ekbom described the familial component of the disorder in 1945 and since then many studies have been published on the familial forms of the disorder. Molecular genetic studies have so far identified ten loci (5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p). No specific gene within these loci has been identified thus far. Association mapping has highlighted a further five areas of interest. RLS6 has been found to be associated with SNPs in the BTBD9 gene. Four other variants were found within intronic and intergenic regions of MEIS1, MAP2K5/LBXCOR1, PTPRD and NOS1. The pathophysiology of RLS is complex and remains to be fully elucidated. Conditions associated with secondary RLS, such as pregnancy or end-stage renal disease, are characterised by iron deficiency, which suggests that disturbed iron homeostasis plays a role. Dopaminergic dysfunction in subcortical systems also appears to play a central role. An ongoing study within the Department of Pathology (University College Cork) is investigating the genetic characteristics of RLS in Irish families. A three generation RLS pedigree RLS3002 consisting of 11 affected and 7 unaffected living family members was recruited. The family had been examined for four of the known loci (5q, 12q, 14p and 9p) (Abdulrahim 2008). The aim of this study was to continue examining this Irish RLS pedigree for possible linkage to the previously described loci and associated regions. Using informative microsatellite markers linkage was excluded to the loci on 5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p and also within the regions reported to be associated with RLS. This suggested the presence of a new unidentified locus. A genome-wide scan was performed using two microsatellite marker screening sets (Research Genetics Inc. Mapping set and the Applied Biosystems Linkage mapping set version 2.5). Linkage analysis was conducted under an autosomal dominant model with a penetrance of 95% and an allele frequency of 0.01. A maximum LOD score of 3.59 at θ=0.00 for marker D19S878 indicated significant linkage on chromosome 19p. Haplotype analysis defined a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to 2.5 Mb. There are approximately 100 genes annotated within the critical region. Sequencing of two candidate genes, KLF16 and GAMT, selected on the assumed pathophysiology of RLS, did not identify any sequence variant. This study provides evidence of a novel RLS locus in an Irish pedigree, thus supporting the picture of RLS as a genetically heterogeneous trait

Genetics of Restless Legs Syndrome

The genetically complex restless legs syndrome (RLS) was tested for associations with genes using rare variant ExomeChip genotypes of 9,192 cases/controls. Candidate genes were sequenced together with candidate genes from a meta-GWAS using MIPseq in 1,456 cases/controls. A list of potential RLS genes was obtained. Furthermore, 843 individuals from 79 RLS families were genotyped/imputed for RLS risk SNPs. They were associated with RLS in 15 families and explained 17% to 100% of the phenotypic variance. « Übersetzte Kurzfassung: Das komplex-genetische Restless Legs Syndrom (RLS) wurde unter der Verwendung seltener Varianten aus dem ExomeChip von 9.192 Fällen/Kontrollen auf Assoziationen mit Genen getestet. Die resultierenden Kandidatengene und weitere Kandidatengene aus einer Meta-GWAS wurden mittels MIPseq in 1.456 Fällen/Kontrollen sequenziert. Eine Liste potentieller RLS Gene wurde erhalten. Auch wurden bekannte RLS-Risiko-SNPs in 843 Personen aus 79 RLS-Familien typisiert. Die SNPs waren mit RLS in 15 Familien assoziiert und erklärten 17 % bis 100 % der phänotypischen Varianz

Qualities of Restless Legs Syndrome and Periodic Limb Movements

ABSTRACT The two disorders of Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLM) are well recognised as fairly common neurological disorders. The presentation is of a sensory and motor component suggestive of a state of hyperexcitability of the nervous system. The underlying abnormality is believed to involve a dopamine deficiency but many of characteristics of the disorders have not been adequately described or quantified. I investigated, firstly, the possible reasons for the gender bias in the prevalence studies and found that women were more likely to have some associated conditions which may be related to RLS as well as a higher symptom load when compared to men subjects with RLS. I then looked at the problems of analysing the sensations occurring in RLS. Due to the lack of an adequate measuring tool and the possibility of a relationship between the sensations of RLS and those of pain, I used a validated descriptive pain questionnaire (the McGill pain questionnaire) to measure the sensations of RLS. Subjects with RLS were able to describe the sensations with the pain questionnaire and severity indices calculated from the McGill correlated well with measures of RLS severity but not with other intensity measures for pain. In the area of motor events I investigated the possibility of creating a classification system for the muscle activations documented as PLM. I recorded multiple muscle groups in the legs during sleep and devised a classification using sequence of activation and timing of activations from the different muscles. I also used the classification to show subtle changes in the leg activation patterns associated with change in sleep stage

Spinocerebellar Ataxia

The purpose of this book has been to depict as many biochemical, genetic and molecular advances as possible, in the vast field of the spinocerebellar ataxias

Fibromiyalji sendromu ve huzursuz bacak sendromu birlikteliği: Yaşam ve uyku kalitesi analizi

Fibromyalji Sendromu (FMS) ve Huzursuz Bacak Sendromu (HBS) toplumda oldukça sık görülen ve tanıları klinik olarak konulan hastalıklardır. FMS’li hastalarda HBS daha sık görülmekte ve bu durumun nedeni tam olarak bilinmemektedir. HBS farkındalığı istenilen düzeyde değildir. FMS’li hastalarda HBS eşlik etmesi durumunda HBS’ye tanı konmaması ve tedavi edilmemesi FMS tedavisini güçleştirir ve hastaların yaşam kalitesini olumsuz etkiler. Bu çalışmada FMS’li hastalarda HBS sıklığının ve şiddetinin bulunması, FMS ve HBS birlikteliğinin yaşam kalitesi ve uyku kalitesi üzerine etkisinin belirlenmesi amaçlanmıştır. Araştırmada FMS tanısıyla takip edilen veya FMS tanısı yeni konulan hastalarda yüz yüze görüşme yöntemi ile HBS varlığı ve şiddeti belirlendi ve tüm hastaların Pittsburg Uyku Kalitesi İndeksi (PUKİ), Epworth Uykuluk Skalası (EUA) ve Fibromyalji Etki Anketi (FEA) skorları bulundu. Ayrıca tam kan sayımı, ferritin, kreatinin, TSH düzeyleri ölçüldü. Araştırmaya ortanca yaşları 49.0(39.0-57.0) [ortanca(%25-75)] 115 kadın hasta katıldı. Hastaların %42.6’sında FMS’ye eşlik eden HBS olduğu bulundu. HBS hastaların %20.4’ünde şiddetli, %18.3’ünde orta şiddetli olarak sınıflandırıldı. FMS’li hastaların %91.3’ü kendilerinde uyku bozukluğu olduğunu belirtti ve % 76.5’inde PUKİ ile uyku bozukluğu olduğu saptandı. HBS’si olan ve olmayan FMS hastalarının PUKİ skorları 9.0±4.4vs7.8±4.3,p=0.003; EUS skorları 5.0(3.0- 7.5)vs3.0(1.0-4.3),p=0.036 ve FEA skorları 68.1±9.8vs59.4±16.9,p=0.027 olarak bulundu. HBS’si olan hastalarda uyku kalitesi bozukluğu ve anemi sıklıkları daha fazlaydı. HBS’si şiddetli ve çok şiddetli olan grubun FEA skorları hafif ve orta olanlardan yüksekti. Araştırmamızda FMS’de HBS sıklığının normal toplumdan fazla olduğu, HBS’si olan olan FMS hastalarının uyku ve yaşam kalitelerinin daha kötü olduğu bulundu. Bu sonuçlara dayanarak FMS tanısı konulan her hastada HBS varlığının araştırılması ve varsa bu hastalığa yönelik tedavilerin planlanması gerektiği söylenebilir. FMS ve HBS birlikteliğini daha iyi açıklayabilecek prospektif kohort çalışmaları yapılmalıdır

Next‐generation sequencing in the diagnosis of Dementia and Huntington’s disease Phenocopy Syndromes

Dementia is a major cause of disability worldwide, especially in the elderly. While Mendelian causes of dementia only account for a small proportion of cases, their role in elucidating the pathophysiology has been paramount. Genetically defined cohorts also offer opportunities for trials of disease‐modifying treatments, even before the onset of symptoms. Previously, only a small number of genes could be selected for genetic testing because of cost‐restrictions, but the advent of next‐generation sequencing has enabled its more widespread use. This thesis explored the use of next‐generation sequencing in patients living with dementia and HD phenocopy (HDPC) syndromes, who include patients with mixed presentations of dementia and motor symptoms. Using a validated 17 gene Dementia Gene panel supplemented by C9orf72 expansion testing and Apolipoprotein (ApoE) genotyping in over 3000 patients and controls, I determined the success rate of genetic panel testing in dementia; I developed an algorithm for the selection of patients for genetic testing based on the clinical presentation and common predictors of genetic causes of dementia. A detailed analysis of the ApoE data in the frontotemporal dementia cohort revealed strong effects of ApoE4 on age at onset in the subset with proven or suspected tau neuropathology, as well as opposite effects of amyloid‐beta pathology. In order to improve the definition and diagnostic rate of HDPC syndromes, patients who were referred for HD testing from two clinics were compared based on their clinical presentation; patients could not be distinguished based on clinical presentation alone, even if analysed as patterns. Given the low success rate of dementia gene panel testing in the HDPC cohort, 50 patients were selected for whole‐genome sequencing based on their HD‐likeness and their likelihood of harbouring a Mendelian variant. The results revealed a number of variants of interest but require replication

Molecular mechanisms of congenital limb malformations

Congenital limb malformations occur in 1 in 500 to 1 in 1000 human live births and are diverse in their epidemiology, aetiology and anatomy. The molecular analysis of disturbed gene function in inherited limb malformations provides essential information for the understanding of physiological and pathophysiological limb development in humans as well as in other vertebrates. The following Ph.D thesis focussed on the identification and molecular characterisation of disease causing genes and their pathophysiological mechanism for selected human limb defects such as Cenani-Lenz syndrome (CLS), Werner mesomelic syndrome (WMS), Bardet-Biedl syndrome (BBS), Split hand/ foot malformation (SHFM) and Temtamy preaxial brachydactyly syndrome (TPBS). In this context, we were able to identify novel limb specific genes and causative mutations in different components of evolutionary highly conserved pathways and, furthermore, to elucidate their role in physiological as well as in pathophysiological limb development. In detail, we found (i) alterations in the low-density-lipoprotein-related protein 4 (LRP4), an antagonistic receptor of Wnt signalling, causing the rare autosomal recessive CLS, (ii) specific mutations in the cis-acting limb-specific enhancer of the sonic hedgehog (SHH) gene being causative for WMS, and (iii) mutations in CHSY1 to be responsible for TPBS. Furthermore, we could show that mutations in the ciliary protein BBS12 can cause a very mild BBS phenotype. Moreover, we used in vitro studies to obtain insights into the molecular pathogenesis of these limb malformations. We studied the effect of five LRP4 mutants on the transduction and activation of canonical Wnt signalling by using a Dual-Luciferase Reporter Assay and showed that co-expression of each of the five missense mutations with LRP6 and WNT1 abolish the known antagonistic effect of LRP4 on LRP6-mediated activation of Wnt/ß-catenin signalling and thus conclude that homozygous LRP4 mutations in CLS cause a loss of protein function. Additionally, we functionally characterized the first autosomal recessive p.R332W mutation in the WNT10b gene causing SHFM6 and rise evidence that p.R332W causes loss of function of Lrp6-mediated Wnt signalling. In this regard we examined the role of the SHFM3 candidate gene Fgf8 in altering Wnt signalling and demonstrated that Fgf8 is a novel putative Wnt signalling antagonist which functions by direct interaction with Wnt10b. Hence, we present the first direct cross-talk between Fgf and Wnt signalling pathways and, therefore, physically link two important signalling pathways involved in limb initiation and outgrowth

Frontotemporal Dementia in the Netherlands

__Abstract__ In 1892, Arnold Pick described the first patients with a clinical syndrome that is currently named frontotemporal dementia (FTD). He emphasised the focal aspect of cortical atrophy in his patients, to this day the hallmark of this disorder. Following a detailed description of the neuropathological changes by Alois Alzheimer in 1911, including the argyrophilic neuronal inclusions later known as Pick bodies, the term Pick’s disease was introduced in 1926. Over the years, many different names have been used to describe this clinical and pathological entity: frontal lobe dementia, dementia of non-Alzheimer type, dementia of frontal lobe type, Pick’s disease, and others. In 1994, the term FTD was introduced to describe the clinical syndrome associated with focal frontotemporal degeneration, with semantic dementia and primary progressive aphasia being recognised as clinical variants of FTD. Typical features of this syndrome, which often presents with a presenile onset, are progressive behavioural changes and language disturbances. FTD can be caused by a number of neuropathological substrates, including Pick’s disease, which is currently defined by the presence of argyrophilic Pick bodies. In 1994, a genetic-epidemiological study on FTD was started at the Erasmus MC of Rotterdam. The main research questions addressed in this study are the estimation of the prevalence of FTD in the Netherlands, the clinical aspects of the temporal variant of FTD, and further elucidation of the genetic and other risk factors involved in the aetiology of FTD