Search

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. This article is protected by copyright. All rights reserved.

Objectives: Several large-scale genome association studies have shown that variants in the “Clusterin”' (CLU) gene are important risk factors for Alzheimer's disease (AD). It has also been shown that plasma CLU levels were elevated in patients with AD and associated with disease severity and progression. In this study, we aimed to investigate whether the CLU rs11136000 polymorphism was associated with AD in our cohort of Turkish patients. We also evaluated the association of serum CLU levels and rs11136000 genotypes between patients and controls. Materials and Methods: Genotyping was performed in 327 patients who were diagnosed as having AD (mean age: 67.2 ± 10.8 years) and 344 controls (mean age: 57.7 ± 13.1 years). The rs11136000 genotypes were determined using quantitative real-time polymerase chain reaction with hydrolysis probes. Serum CLU levels were assessed in 25 patients with AD and 10 controls using enzyme-linked immunosorbent assay. Results: Our results showed no significant difference in genotype and allele frequencies of CLU rs11136000 polymorphisms between patients with AD and controls. Serum CLU levels in patients with AD did not differ from those of the controls. Furthermore, serum CLU levels showed no major difference between carriers of CC and TT + CT genotypes in the controls and patients with AD. Conclusion: Our results suggest that the CLU rs11136000 polymorphism is not associated with AD in our Turkish patients, and rs11136000 genotypes may not have an effect on serum CLU levels.

Objective: The etiology of Alzheimer's disease (AD) is affected via oxidative stress. Antioxidant enzymes are extremely important in preventing reactive oxygen species (ROS) causing damage in the cell. The changes in expression levels of oxidant and antioxidant genes are key factors in cell response to oxidative stress. As a result, this study investigated the change in expression levels of specif-ic oxidative stress related genes (solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), catalase (CAT ) and acyl-coa synthetase long chain family member 4 (ACSL4)) in peripheral blood of AD patients. Material and Method: Quantitative reverse-transcription poly-merase chain reaction (qRT-PCR) was used to assess the expression levels of oxidative stress-related genes in 25 AD patients and 22 controls, and the findings were statistically evaluated. Results:SLC7A11, GPX4, CAT, and ACSL4 gene expression levels did not vary significantly between AD patients and controls. The re-sults also showed significant negative correlation between age of onset and ACSL4 expression.Conclusion: This is the first study that evaluated mRNA expression levels of SLC7A11, GPX4 and ACSL4 genes in AD. The results sug-gested that the peripheral blood expression of above-mentioned genes did not alter in AD. However, due to the small number of subjects, this findings are preliminary and should be validated with a larger number of subjects., Amaç: Oksidatif stres, Alzheimer hastalığının (AH) etiyolojisinde önemli bir rol oynamaktadır. Antioksidan enzimler reaktif oksijen türevlerinin (ROS) hücreye zarar vermesini önlemek için çok önemlidir. Oksidan ve antioksidan enzimleri kodlayan genlerin anlatım seviyelerindeki değişimler hücrenin oksidatif strese karşı verdiği yanıtta anahtar faktördür. Bu nedenle çalışmamızda, AH hastalarının periferik kanlarında spesifik oksidatif stres ile ilişkili genlerin (solut taşıyıcı aile 7 üye 11 (SLC7A11), glutatyon peroksidaz 4 (GPX4), katalaz (CAT ) ve açil koA sentetaz uzun zincir aile üyesi 4 (ACSL4)) anlatım düzeylerindeki değişimin araştırılması amaçlanmıştır.Gereç ve Yöntem: Periferik kan lökositlerinde oksidatif stresle ilgili genlerin ekspresyon düzeylerindeki değişiklikler 25 AH hastası ve 22 kontrolde kantitatif ters transkripsiyon polimeraz zincir reaksiyonu (qRT-PCR) ile belirlenmiş ve sonuçlar istatistiksel olarak değerlendirilmiştir.Bulgular:SLC7A11, GPX4, CAT ve ACSL4 genlerinin anlatım düzeyleri, AH hastaları ve kontroller arasında istatistiksel olarak bir farklılık göstermemiştir. Ayrıca, sonuçlarımız başlangıç yaşı ile ACSL4 ekspresyonu arasında anlamlı negatif bir korelasyon olduğunu göstermiştir.Sonuç: Araştırmamız, AH hastalarının periferik kanlarında SLC7A11, GPX4 ve ACSL4 genlerinin anlatım düzeylerini değerlendiren ilk çalışma olup, sonuçlarımız söz konusu genlerin periferik kandaki an-latımlarının AH'de değişmediğini göstermiştir. Bununla birlikte, az sayıda hasta ve kontrol nedeniyle, bu bulgular başlangıç niteliğindedir ve daha geniş çalışma gruplarında doğrulanması gerekmektedir.

Objective: Inflammation and associated microRNAs (miRNA) both play essential roles in the pathogenesis of Alzheimer’s disease (AD). The expression profile of miRNA’s in an AD brain, also reflected in the peripheral blood mononuclear cells, may give support to the inflammatory changes seen in the course of AD. We aimed to investigate the expression levels of specific inflammatory miRNAs (mir-146a, mir-144, mir-34a) in both blood leukocytes and plasma of AD patients and to evaluate their potential usability as biomarkers in AD diagnosis and to also demonstrate whether the expression of these miRNAs differ between early and late-onset AD patients. Methods: We investigated the expression levels of miRNAs in 16 early-onset and 26 late-onset AD patients and in their respective controls by using qRT-PCR. Results: Plasma mir-144 levels were significantly different between EOAD and LOAD patients (p=0.015). In addition, levels of leukocyte mir-34a were significantly down-regulated in EOAD compared to LOAD patients (p=0.027). Our results also showed significant positive correlations between age and plasma mir- 144 and leukocyte mir-34a expressions. Conclusion: The differential expression of plasma mir-144 and leukocyte mir-34a between EOAD and LOAD patients might reflect age-dependent changes in miRNA expression and might be independent of the disease status., Amaç: Enflamasyon ve ilişkili mikro RNA’lar (miRNA), Alzheimer hastalığının (AH) patogenezinde önemli rol oynamaktadırlar. AH beyininde görülen miRNA’ların anlatım profilindeki değişikliklerin periferal kan mononükleer hücrelerine de yansımış olması, AH sırasında görülen enflamatuar değişikliklerin bir göstergesi olabilir. Bu çalışmada, Alzheimer hastalarının hem periferal lökositlerinde hem de plazmalarında belirli enflamatuvar miRNA’ların (mir-146a, mir-144, mir-34a) anlatım düzeylerindeki değişiklikleri araştırmayı ve ve AH tanısında biyobelirteç olarak potansiyel kullanılabilirliklerini değerlendirmek. Ayrıca, bu miRNA’ların anlatımlarının erken ve geç başlangıçlı AH arasında farklılık gösterip göstermediğini belirlemeyi amaçladık. Gereç ve Yöntem: Gerçek zamanlı polimeraz zincir reaksiyonu yöntemini kullanarak 16 erken başlangıçlı ve 26 geç başlangıçlı AH hastası ve yaş-uyumlu kontrollerinde miRNA’ların anlatım düzeylerini araştırdık. Bulgular: Plazma mir-144 anlatım düzeyinin erken ve geç başlangıçlı AH hastaları arasında anlamlı farklılık gösterdiğini saptadık (p = 0.015). Ek olarak, lökosit mir-34a anlatım düzeyi erken başlangıçlı AH’de geç başlangıçlı AH hastalarına göre anlamlı derecede düşük bulundu (p = 0.027). Sonuçlarımız ayrıca, yaş ve plazma mir-144 (r=0.319, p=0.02) ile lökosit mir-34a (r=0.414, p=0.001) anlatım düzeyleri arasında anlamlı pozitif korelasyon olduğunu gösterdi. Sonuç: Bulgularımız erken ve geç başlangıçlı AH hastaları arasında plazma mir-144 ve lökosit mir-34a anlatımlarında görülen farklılığın miRNA ekspresyonundaki yaşa bağlı değişiklikleri yansıttığını ve hastalık durumundan bağımsız olabileceğini düşündürmektedir.

International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

'Triggering receptor expressed on myeloid cells 2' (TREM2) gene is involved in Alzheimer's disease (AD) and TREM2 mRNA expression is known to be increased in the peripheral blood cells of AD patients. In this study, we examined the expression levels of TREM2 mRNA in peripheral leukocytes of early and late-onset AD patients. We have also investigated the effect of the presence of APOE ε4 allele on TREM2 expression. TREM2 mRNA expression was analyzed in 30 early-onset AD (EOAD) patients, 38 late-onset AD (LOAD) patients, and in their age-matched controls by using quantitative real-time polymerase chain reaction. TREM2 levels in LOAD patients were higher than EOAD. Also, in elderly controls significantly higher TREM2 levels were found compared with young controls. Moreover, APOE ε4 carriers in LOAD patients exhibited significantly higher TREM2 expression levels than APOE ε4 non-carriers and elderly controls. Also, correlation analysis showed that TREM2 mRNA expression was increased by age. The differential expression of TREM2 mRNA levels between EOAD and LOAD patients might be independent of the AD disease status and results from an age-related increase in TREM2 expression. In LOAD patients, increased age and the presence of APOE ε4 allele further increase TREM2 expression. Taken together, we can suggest that age is a factor that increases TREM2 expression, and TREM2 and APOE ε4 may interact together in the pathogenesis of LOAD.

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis. .

Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants inTSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile- onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer’s disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257 AD patients (mean age: 75.9 years ± 10.4) and 414 controls (mean age: 62.2 years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the ‘TT’ genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p

DOI: 10.26650/experimed.2018.18004Objectives: Alzheimer’s disease (AD) is anirreversible, neurodegenerative disease with an increasing worldwideprevalence. Several different factors are known to play a role in itspathogenesis and genetic predisposition. MicroRNAs (miRNAs), which are involvedin several biological processes such as cell proliferation, celldifferentiation, and metabolism, are also believed to play a role in thepathogenesis of AD. These miRNAs present new areas of interest to researchersin terms of their broad range of target genes, the association with differentdiseases that appear to be unrelated to each other at the molecular level, andthe identification of commonalities between different diseases. Therefore, weaimed at investigating the expression levels of specific miRNAs related tocholesterol metabolism in peripheral blood. Material and Method: Considering theimportant role of lipid and cholesterol transport in the pathogenesis of AD andthe effect of miRNAs on this transport, we intended to investigate theexpression levels of miR-155 and -758 in patients with AD and controls usingthe real-time polymerase chain reaction method. Results: Our results demonstrated that theexpression of miR-155 was significantly decreased in patients with AD comparedto that in controls. However, there was no significant difference in theexpression of miR-758 between patients with AD and controls. Conclusion: A decreased miR-155 expressionin the peripheral blood of patients with AD suggests that this miRNA isinvolved in the pathogenesis of AD through its target genes. However, thisrelationship between the changes in miR-155 expression and AD need to bereinforced by functional studies., DOI: 10.26650/experimed.2018.18004Amaç: Alzheimer hastalığı (AH), dünyagenelinde prevalansı gittikçe artış gösteren, geri dönüşümsüz, nörodejeneratifbir hastalıktır ve patogenezinde genetik yatkınlığın yanında çok sayıda farklıfaktör etken rol oynamaktadır. Hücreproliferasyonu, hücre farklılaşması ve metabolizma gibi birçok biyolojiksüreçte görev alan mikro RNA’ların (miRNA), AH patogenezinde de rol oynadıklarıdüşünülmektedir. miRNA’ların hedef gen yelpazelerinin çok geniş olması, birbiriile ilişkisiz görünen farklı hastalıkları moleküler düzeyde ilişkilendirmek vefarklı hastalıkların ortak noktalarını tanımlamak açısından araştırmacılarayeni alanlar sunmaktadır. Bu nedenle çalışmamızda, belirli miRNA’larınperiferik kandaki anlatım düzeylerini incelemeyi amaçladık. Gereç ve Yöntem: Lipid ve kolesteroltransportunun AH patogenezinde oynadığı önemli rol ve miRNA’ların bu transportüzerindeki etkisini göz önünde bulundurarak, Alzheimer hasta grubu ve kontrolgrubunda, miR-155 ve miR-758’in periferik kandaki anlatım düzeylerini gerçekzamanlı polimeraz zincir reaksiyonu yöntemi ile incelemeyi amaçladık. Bulgular: Çalışmamızın sonucunda, miR-155anlatımının Alzheimer hasta grubunda, kontrol grubuna göre anlamlı düzeydeazaldığı, ancak miR-758 anlatımı açısından Alzheimer hasta grubu ve kontrolgrubu arasında anlamlı bir farklılığın olmadığı belirlendi. Sonuç: Alzheimer hastalarının periferikkanlarındaki azalmış miR-155 anlatımı, bu miRNA’nın hedef genleri aracılığıylaAH patogenezine etki edebileceğini düşündürmektedir. Ancak miR-155 anlatımdüzeyindeki değişim ile AH arasında gösterdiğimiz bu ilişkinin fonksiyonelçalışmalar ile desteklenmesi gerekmektedir.&nbsp

Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. Methods: We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders: the Department of Neurology, Faculty of Medicine, Istanbul University, and the Department of Neurology, Faculty of Medicine, Mersin University. Results: All patients were diagnosed with CTX after neurological symptom development, and their mean age at diagnosis was 38.7 ± 9.6 years, despite a mean onset age of 12.4 ± 10.6 years. The mean follow-up period was 28 months (range: 3–60 months). The most common initial clinical abnormalities in our cohort were unexplained chronic diarrhea (42%), febrile convulsion (42%), juvenile cataract (85%), childhood depression and autism (14%), parkinsonism (14%), and intellectual disability (100%). The most prominent neurological findings were the pyramidal-cerebellar syndrome (85%) and extrapyramidal signs (42%). All patients were genetically confirmed. Serum cholestanol levels were elevated in all patients and decreased after chenodeoxycholic acid (CDCA) treatment in 6 patients. Conclusion: This cohort is the largest CTX case series in Turkey. All cases showed improvement in gastrointestinal symptoms as a response to CDCA treatment and stabilization on neurological symptoms, i.e., no further progression of neurological abnormalities were noted during this treatment. Therefore, early diagnosis and treatment is crucial in preventing clinical deterioration.

Objective To investigate cognitive functions in non-demented patients with early-onset Parkinson's disease (PD), and to compare PARK2 gene mutation carriers and non-carriers by means of event-related brain potentials (ERPs). Methods The participants comprised patients with early-onset PD (EOPD) and healthy controls (HC). Patients with EOPD were divided into two groups as carriers of known pathogenic variants of PARK2 gene (EOPD-PC) and non-carriers of genes involved in familial PD (EOPD-NC). ERP data were collected during auditory oddball and visual continuous performance test (CPT). Results Both EOPD groups (EOPD-PC and EOPD-NC) displayed reduced and delayed P3 in response to oddball target and CPT NoGo. CPT Go P3 was reduced in EOPD-NC but not in EOPD-PC. Oddball target N1 was reduced and P2 was enhanced in both EOPD-PC and EOPD-NC. In both cognitive tasks, RTs were prolonged and accuracy was lower in EOPD-PC and EOPD-NC. Conclusions We found several EOPD-related neurophysiologic changes, implying impairments in cognitive functions. Pairwise comparisons between EOPD-PC and EOPD-NC revealed no significant ERP marker. Significance In this study, the confounding effect of normative aging was somewhat excluded compared with many previous studies. In contrast with the many oddball studies in non-demented PD, we clearly observed reduced and prolonged P3 in early-onset PD. Our NoGo P3 findings also contribute to the limited ERP research concerning response inhibition.

Objective DJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS). Methods The family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis. Results The index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor-dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation. Conclusions This is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex.

Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a significant proportion of patients with early-onset disease. However, no large multicentre studies of known recessive Parkinson's disease-linked genes have been performed, to guide genetic testing according to age at onset, family history, ethnic origin, or phenotype. We aimed to evaluate the relative frequencies of mutations in genes causing recessive Parkinson's disease and their associated phenotypes in a large series of European and North African cases. Methods: Clinical data for 1664 patients were collected between 1990 and 2018 from 511 families with recessive Parkinson's disease and/or with consanguinity, and 1098 isolated cases. All the recessively inherited genes were screened by Sanger and/or targeted next-generation sequencing and gene dosage methods. Clinical features were compared between patients with PRKN and those without mutations, by regression analyses adjusted for sex, age at onset, disease duration and levodopa medication. Findings: Biallelic mutations of genes known to cause recessive Parkinson's disease were found in 246 of the 1609 index cases (15·3%): 150 familial (29·4%) and 96 (8·7%) isolated cases. The most frequently mutated genes were PRKN, in 199 cases (12·4%), PINK1, in 23 (1·8%), and DJ-1, in two (0·16%). We screened 675 index cases by targeted sequencing, and 22 were found to have mutations in genes known to cause atypical parkinsonism (3·3%). PRKN and PINK1 mutation frequencies were higher in early-onset (≤40 years) than late-onset Parkinson's disease. The frequency of PRKN mutations in the 1609 index cases decreased with increasing age at onset, from 38% in cases ≤20 years to 4·4% in those with onset at 41 to 60 years. No mutation of PRKN or another recessive Parkinson's disease gene was found in patients with onset above 60. PRKN mutations were more frequent in Caucasians (13·4%) than in North Africans (7·4%). Conversely, PINK1 mutations were more frequent in North Africans (6·3%) than in Caucasians (0·9%). PRKN patients had an earlier age at onset, lower levels of asymmetry, akinesia, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. Interpretation: This is a large study providing information about the frequency of recessive Parkinson's disease genes according to age at onset, family history, ethnic origin, and associated phenotype. Its findings will be useful for genetic testing and counselling. Funding Statement: Fondation de France, France-Parkinson Association, la Federation pour la Recherche sur le Cerveau, the French program "Investissements d'avenir", National Institute for Health Research. Declaration of Interests: SL reports grants from Fondation de France, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), both outside the scope of the submitted work. MA reports grants and personal fees from Abbvie, Teva, Aguettant, Actelion Pharmaceuticals, personal fees from Johnson and Johnson, Merz, Orkyn, all outside the scope of the submitted work. ER reports grants, personal fees and non-financial support from Orkyn, Aguettant, Merz pharma, Everpharma, personal fees and non-financial support from Movement Disorders Society, grants and non-financial support from Elivie, non-financial support from Merck, Dystonia Coalition, Dystonia Medical Research Foundation, grants from Ipsen, Fondation Desmarest, Fonds de dotation Brou de Lauriere, Agence Nationale de la Recherche, AMADYS, personal fees from Medday pharma, Retrophin, European Academy of Neurology, International Association of Parkinsonism and related Disorders, all outside the submitted work. CT received fees from ALLERGAN and from MERZ. J-CC reports grants from Sanofi, personal fees from EverPharma, Denali, BrainEver, Theranexus, Air Liquide, all outside the scope of this work. EB reports grants from Medtronic France, Abbvie, UCB, and Aguettant laboratories but no conflict of interest nor financial concerns about the present research paper submitted for publication. AB reports grants from ANR - Agence nationale de recherche, ARNN - Association pour la Recherche en Neuro-imagerie et Neuropsychologie, France Parkinson, AP-HP, FMR - Fondation Maladies Rares (ex GIS), France Parkinson + FRC (Federation pour la Recherche sur le Cerveau), Universite Mohammed V - Rabat, Prix Allianz Institut de France, RDS (Roger de Spoelberch Foundation), FDF -Fondation de France-, all outside the submitted work. All other authors have no competing interests to declare. Ethics Approval Statement: Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (INSERM, CCPPRB du Groupe Hospitalier Pitie-Salpetriere, Paris, France).

Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD.

Alzheimer's disease (EOAD, LOAD), mild cognitive impairment (MCI), Parkinson's disease (PD) and healthy controls were included to determine the serum interleukin-1s (IL-1α, IL-1β), IL-6 and alpha-2-macroglobulin (α2M) levels using ELISA. IL-6 might be a significant contributor to the inflammatory response in LOAD. The MCI data indicate that IL-1s, α2M and BDNF are somehow related, and this relationship might allow MCI patients to be more similar to the healthy controls. A correlation analysis of multiple biomarkers in different neurodegenerative disorders might be more useful than determining the levels of a single cytokine in a single disorder.

Background Recessive mutations in the F-box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian-pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations. Methods Whole exome and targeted Sanger sequencing were performed for genetic analysis in a family with two members affected by Parkinson's disease (PD). All family members underwent detailed clinical, mental, and neurological examination. Results The new p.L34R (c.101 T>G) FBXO7 mutation was detected in a homozygous state in two Turkish sibs with typical levodopa-responsive PD. Conclusion This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety.

Ataxia-telangiectasia (A-T) is an autosomal recessive inherited disease characterized by progressive childhood-onset cerebellar ataxia, oculomotor apraxia, choreoathetosis and telangiectasias of the conjunctivae. Further symptoms may be immunodeficiency and frequent infections, and an increased risk of malignancy. As well as this classic manifestation, several other non-classic forms exist, including milder or incomplete A-T phenotypes caused by homozygous or compound heterozygous mutations in the ATM gene. Recently, ATM mutations have been found in 13 Canadian Mennonites with early-onset, isolated, predominantly cervical dystonia, in a French family with generalized dystonia and in an Indian family with dopa-responsive cervical dystonia. In this article, we will describe a Turkish family with three affected sibs. Their phenotypes range from pure cervical dystonia associated with hand tremor to truncal and more generalized dystonic postures. Exome sequencing has revealed the potentially pathogenic compound heterozygous variants p.V2716A and p.G301VfsX19 in the ATM gene. The variants segregated perfectly with the phenotypes within the family. Both mutations detected in ATM have been shown to be pathogenic, and the α-fetoprotein, a marker of ataxia telangiectasia, was found to be increased. This report supports recent literature showing that ATM mutations are not exclusively associated with A-T but may also cause a more, even intra-familial variable phenotype in particular in association with dystonia.

Introduction Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well-established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey. Methods We performed Sanger sequencing of all coding LRRK2 and SNCA exons in a sample of 91 patients with Parkinsonism. Copy number variations in SNCA, PRKN, PINK1, DJ1 and ATP13A2 were assessed using the MLPA method. All patients had a positive family history compatible with autosomal dominant inheritance. Results Known mutations in LRRK2 and SNCA were found in 3.3% of cases: one patient harbored the LRRK2 G2019S mutation, and two patients carried a SNCA gene duplication. Furthermore, we found a heterozygous deletion of PRKN exon 2 in one patient, and four rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I; SNCA: T72T). Genetic testing in one affected family identified the LRRK2 R1067Q variant as a possibly pathogenic substitution. Conclusion Point mutations in LRRK2 and SNCA are a rare cause of autosomal dominant PD in Turkey. However, copy number variations should be considered. The unclassified variants, especially LRRK2 R1067Q, demand further investigation.

DYTCA is a syndrome that is characterized by predominant dystonia and mild cerebellar ataxia. We examined two affected siblings with healthy, consanguineous, Turkish parents. Both patients presented with a combination of childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Routine diagnostic investigations excluded known genetic causes. Biochemical analyses revealed a mitochondrial respiratory chain complex IV and a coenzyme Q10 deficiency in a muscle biopsy. By exome sequencing, we identified a homozygous missense mutation (c.154A >C; p.Thr52Pro) in both patients in exon 2 of the COX20 (FAM36A) gene, which encodes a complex IV assembly factor. This variant was confirmed by Sanger sequencing, was heterozygous in both parents, and was absent from 427 healthy controls. The exact same mutation was recently reported in a patient with ataxia and muscle hypotonia. Among 128 early-onset dystonia and/or ataxia patients, we did not detect any other patient with a COX20 mutation. cDNA sequencing and semi-quantitative analysis were performed in fibroblasts from one of our homozygous mutation carriers and six controls. In addition to the exchange of an amino acid, the mutation led to a shift in splicing. In conclusion, we extend the phenotypic spectrum of a recently identified mutation in COX20 to a recessively inherited, early-onset dystonia-ataxia syndrome that is characterized by reduced complex IV activity. Further, we confirm a pathogenic role of this mutation in cerebellar ataxia, but this mutation seems to be a rather rare cause.

SUMMARY It has been generally recognized that, in most cases of Parkinson’s disease (PD), the causes are a result of the complex interaction of genetic and environmental factors. Only approximately 10–15% of PD cases appear to be rare forms with a Mendelian genetic cause. There has been an increasing need and demand in daily clinical work to look for a molecular diagnosis, although a number of neurologists feel uneasy when dealing with the growing number of possible genes and risk factors related to PD that are accessible for diagnosis. Research has highlighted the consequences not only for hereditary but also sporadic forms of PD. This review will provide an overview of the principal aspects of the genetics of PD. It will focus on their differences and similarities, and discuss several useful tools for clinicians, and the role and importance of a neurogeneticist.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10−4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer's disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort.

INTRODUCTION Cerebral white matter hyperintensities (WMHs) detected on magnetic resonance imaging scans are frequently seen in both Alzheimer's disease (AD) and depression patients and believed to play an important role in cognition and mood. Depressive symptoms and depression may accompany AD in all stages of the disease. The aim of the study was to evaluate the relationship of regional WMHs with depressive symptoms, cognitive status, medial temporal lobe atrophy, and daily living activities in early-stage AD patients. METHOD Forty-five patients with very mild or mild AD were examined. All subjects underwent MRI and were assessed by the Geriatric Depression Scale (GDS) and the Addenbrooke's Cognitive Examination-Revised (ACE-R) for the evaluation of depressive symptom severity and cognitive status, respectively. The patients were divided into two groups based on the selected cut-off point in the GDS. CDR sum of the boxes (CDR-sb) scores were calculated as a measure of activities of daily living (ADLs). MRI T2-FLAIR slices were used to rate the white-matter lesions according to the Age-Related White Matter Changes Rating Scale, assessing the WMHs in frontal, parietooccipital, temporal, infratentorial and basal ganglia areas individually. Medial temporal lobe atrophy was assessed with high-resolution T1 images using visual rating scale. RESULTS In the depressive group, frontal WMH scores were found to be higher than in the non-depressive group (p=0.006). ACE-r, CDR-sb and medial temporal lobe atrophy scores did not differ among the groups. CDR-sb scores showed a significant correlation with frontal WMH scores (left frontal WMH r=0.439, p=0.003, right frontal AMH r=0.459, p=0.001). Linear regression models revealed the effect of WMHs on depressive symptoms among the other factors including age, functionality and atrophy in the medial temporal areas. DISCUSSION Our findings underscore the potential role of regional, particularly frontal AMHs in depressive symptoms and functionality of the early AD patients.

Vitamin D is a secosteroid hormone that shares a synthetic pathway with cholesterol. ApoE, which is involved in the transport of cholesterol, is the most significant genetic risk factor for sporadic Alzheimer's disease (AD). Surprisingly, recent studies have indicated the presence of an evolutionary juncture between these two molecules. To demonstrate this possible relationship, we investigated serum levels of 25-hydroxyvitamin-D3 (25OHD) in patients with early onset-AD (EOAD; n:22), late onset-AD (LOAD; n:72), mild cognitive impairment (MCI; n:32) and in healthy subjects (n:70). We then analyzed the correlation between 25OHD and cytokines, BDNF and Hsp90 with respect to ApoE alleles, as these molecules were investigated in our previous studies. The LOAD patients had low levels of 25OHD, but these low levels originated only from ApoEɛ4 non-carrier patients. Negative correlations were observed between serum 25OHD and TNFα, IL-1β or IL-6 levels in healthy subjects or MCI patients, but these same correlations were positive in LOAD patients. ApoE alleles indicated that these positive correlations exist only in ɛ4 carrier LOAD patients. Consequently, our results indicate that vitamin D deficiency presents a greater risk for ApoEɛ4 non-carrier AD patients than for ɛ4 carriers. Therefore, it might be beneficial to monitor the vitamin D status of ApoEɛ4 allele non-carrier AD patients.

Background: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. Methods: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. Results: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency

The authors would like to thank all the patients their families and the normal volunteers for their contribution and Prof Nihan Unaltuna-Erginel for her help in DNA management. The authors also thank Sedat Aydın for his help in MRI acquisition, Huseyin Bulut, MD for the psychiatric advice, and Geetika Kalloo for the helpful suggestions on the manuscript. Background: Parkin (PARK2) gene mutations are the predominant cause of autosomal recessive parkinsonism. Characteristic features include: early onset symptoms with slow clinical course, good response to low doses of levodopa, and frequently treatment-induced dyskinesia. Studies using a voxel-based morphometry approach showed a decrease in the gray matter volume of the basal ganglia in mutation carriers during the symptomatic stages. A bilateral, presumably compensatory increase of basal ganglia gray matter value was recently demonstrated in asymptomatic Parkin mutation carriers. Behavioral disorders including: anxiety, psychosis, panic attacks, depression, disturbed sexual, behavioral and obsessive-compulsive disorders have been reported in these patients. Method: A total of 28 Parkinson’s Disease (PD) patients consisting of 10 Young-Onset without Parkin mutations (YOPD), 9 Young-Onset with Parkin mutations (YOPD-p), 9 Late-Onset without Parkin mutations (LOPD) and 32 healthy control subjects were studied with an automated volumetric assessment method to quantify subcortical atrophy. Patients but not controls also underwent a neuropsychological and neuropsychiatric assessment. Results: Results revealed a reduction of bilateral caudate nuclei volumes in YOPD-p patients compared to the YOPD patients while there were no statistically significant differences between other groups. YOPD-p patients showed similar results to other patient groups on neuropsychiatric and neuropsychological evaluation measures. Conclusion: YOPD-p and YOPD patients showed a different pattern of volume changes in basal ganglia. Despite its relatively benign clinical course, carrying the Parkin mutation seems to be associated with greater atrophy in subcortical structures. Failure of compensatory mechanisms, different mutation types and pathophysiologic processes may underlie this diverse pattern of subcortical brain changes. This studywas supported by Istanbul University Research Funds and Istanbul Neuropsychiatry Hospital Research Support Program.

Background and purpose: To evaluate the phenotype and the frequencies of mutations in PRKN, DJ1 and PINK1 genes in patients with Parkinson disease (PD) in Turkey. Methods: Eighty-six patients from 77 PD families participated in the study. Seventy-four families were originating from Turkey, two families from Greece and one family from Bulgaria. All patients underwent detailed neurological examination. PRKN, PINK1 and DJ1 genes were sequenced, and dosage analysis was performed by multiplex ligation-dependent probe amplification. Results: Sixteen patients with PD were found to carry homozygous (n = 14) or compound heterozygous (n = 2) PRKN mutations. We identified exon rearrangements, three point mutations and one new point mutation in exon 2 (p.K27del). In two families, two new PINK1 point mutations (L31X and P416L) were identified. No pathogenic mutations were found in DJ1 gene. Clinical phenotypes of PRKN patients were comparable to previously described features, but only in four of 13 families, the pedigree structure was clearly consistent with an autosomal recessive (AR) mode of inheritance in comparison with nine families where also different pattern of transmission could have been possible. Conclusions: Our data suggest that the PRKN gene mutation is the most frequent form of ARPD in Turkey. The proportion of mutations with regard to the age of onset in our population is in the range of those previously described, but our pedigrees are characterized by high rate of consanguinity, which might explain the high proportion of families with homozygous mutations and of patients in more than one generation. Pathogenic DJ1 mutations do not seem to play a major role in Turkey.

Parkin gene mutations cause a juvenile parkinsonism. Patients with these mutations may commonly exhibit REM sleep behaviour disorders, but other sleep problems (insomnia, sleepiness, restless legs syndrome) have not been studied. The aim of this study was to evaluate the sleep-wake phenotype in patients with two parkin mutations, compared with patients with idiopathic Parkinson's disease (iPD). Sleep interview and overnight video-polysomnography, followed by multiple sleep latency tests, were assessed in 11 consecutive patients with two parkin mutations (aged 35-60 years, from seven families) and 11 sex-matched patients with iPD (aged 51-65 years). Sleep complaints in the parkin group included insomnia (73% patients versus 45% in the iPD group), restless legs syndrome (45%, versus none in the iPD group, P = 0.04), and daytime sleepiness (45%, versus 54% in the iPD group). Of the parkin patients, 45% had REM sleep without atonia, but only 9% had a definite REM sleep behavior disorder. All sleep measures were similar in the parkin and iPD groups. Two parkin siblings had a central hypersomnia, characterized by mean daytime sleep latencies of 3 min, no sleep onset REM periods, and normal nighttime sleep. Although the patients with two parkin mutations were young, their sleep phenotype paralleled the clinical and polygraphic sleep recording abnormalities reported in iPD, except that restless legs syndrome was more prevalent and secondary narcolepsy was absent.

Contains fulltext : 167923.pdf (Publisher’s version ) (Open Access) Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Background: Mutations in the parkin gene cause autosomal recessive early-onset parkinsonism. The effect of single heterozygous mutations in parkin is still unclear. The aim of the present study was to evaluate the frequency of exonic parkin variants in a case-control study. Methods: The parkin gene was screened for both point mutations and exon rearrangements in 172 isolated French patients with Parkinson’s disease (PD) and 170 controls from the same population. Patients with single parkin variants were also screened for PINK1, DJ-1 and LRRK2 exon 41 mutations. Results: We identified 10 exonic sequence variations, including 3 known polymorphisms and 7 rare heterozygous variants, 2 of which were novel. There were significantly more rare heterozygous variants in patients (n=10) with early-onset parkinsonism than in controls (n=2). The screening of PINK1, DJ-1 and LRRK2 exon 41 in the 10 heterozygous parkin patients failed to identify a second causative mutation. Conclusion: Our results suggest that single parkin mutations increase the risk of early-onset PD, but we cannot exclude that a second parkin mutation has been missed.

Background: Mutations in the LRRK2 gene, the most frequent of which is the G2019S mutation in exon 41, cause familial and sporadic Parkinson’s disease (PD) with reduced penetrance. Objectives: To assess the frequency of the LRRK2 G2019S mutation in families thought to have autosomal recessive PD (siblings but not their parents were affected) and to determine the clinical features of LRRK2 mutation carriers. Methods: We sequenced both strands of exon 41 of the LRKK2 gene in 90 index cases from French and North African families in which PD might have been inherited as a recessive trait. Patients with mutations underwent detailed clinical evaluations. Results: We found heterozygous G2019S mutations in 1 Algerian and 1 French family (overall relative frequency = 2.2%). Four LRRK2-positive patients had typical PD, but their Mini Mental State Examination (MMSE) scores were lower than those of patients without this mutation. Conclusion: The LRRK2 G2019S mutation is as frequent in families with possible autosomal recessive PD (2.2%) as in the sporadic cases published elsewhere (1.9%). The clinical features in the LRRK2-positive patients were those of typical PD, except for lower MMSE scores.

Parkinson's disease is a frequent disorder caused primarily by the loss of dopaminergic neurons of the substantia nigra. Mutations in the PTEN-induced kinase (PINK1) gene, in addition to those in parkin and DJ-1, have been found in families with recessive early-onset Parkinson's disease. We screened for parkin and PINK1 mutations in a panel of 177 autosomal recessive Parkinson's disease families with ages at onset < or =60 years, mostly from Europe. In 7 unrelated families, we identified 10 pathogenic PINK1 mutations (5 missense, 2 nonsense and 3 frameshift deletion mutations), 8 of which were novel. All the mutations were in the homozygous or compound heterozygous states. Interestingly, pseudo-dominant inheritance was observed in a family with two different mutations. The clinical characteristics of 12 PINK1 patients and 114 parkin patients were similar, even for signs such as dystonia at onset and increased reflexes, which were thought to be specific to parkin. In contrast, onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations. These results suggest that PINK1 is the second most frequent causative gene in early-onset Parkinson's disease with a slowly progressive phenotype, indistinguishable from early-onset patients with parkin mutations.

Mutations in LRRK2 were recently identified in autosomal dominant Parkinson's disease (PD), including the G2019S mutation. To evaluate its frequency, we analyzed 198 probands with autosomal dominant PD, mostly from France and North Africa. Surprisingly, the frequency in North African families (7/17, 41%) was greater than those from Europe (5/174, 2.9%). The clinical features in 21 patients, including 1 with a homozygous mutation, were those of typical PD, with lower Mini-Mental State Examination scores. There were also 15 unaffected mutation carriers, aged 32 to 74 years. LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa.

Parkin gene mutations are reported to be a major cause of early-onset parkinsonism (age at onset < or = 45 years) in families with autosomal recessive inheritance and in isolated juvenile-onset parkinsonism (age at onset

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31 %). Remarkably, a recurrent de novo mutation, c. 959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity. Refereed/Peer-reviewed

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30–50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D.