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Several heterozygous variants of the glucocerebrosidase gene (GBA1) have been reported to increase the risk of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD has been reported to be more severe than idiopathic PD, and more deleterious variants are associated with more severe clinical phenotypes. We report a family with a heterozygous p.Pro454Leu variant in GBA1. The variant was associated with a severe and rapidly progressive neurodegenerative disease with Lewy bodies that were clinically and pathologically diverse. Pathogenicity prediction algorithms and evolutionary analyses suggested that p.Pro454Leu is deleterious.

Background and Purpose: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. Methods: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. Results: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%–3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40–48 years and their disease course had been unremarkable apart from the early onset. Conclusions: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.

Background: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset. Methods: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres. Results: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%). Conclusion: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

Introduction: The biallelic repeat expansion (AAGGG)exp in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson’s disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. Objective: We hypothesized that the biallelic (AAGGG)exp is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. Methods: Clinical data on nine patients with biallelic (AAGGG)exp were reviewed and 564 patients with Alzheimer’s disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)exp. Results: Five patients with biallelic (AAGGG)exp were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)exp was not detected among patients with Alzheimer’s disease or FTD. Conclusions: Cognitive impairment is a feature in patients with the biallelic (AAGGG)exp, but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.

Background: Leber’s hereditary optic neuropathy (LHON) is a common form of mitochondrial disease. The typical clinical presentation of LHON is subacute, painless loss of vision resulting from bilateral optic nerve atrophy. Moreover, extra-ocular manifestations such as cardiac conduction abnormalities and neurological manifestations such as multiple sclerosis (MS) like disease or parkinsonism are encountered in some patients. Abnormal findings in spinal cord MR imaging or in the cerebrospinal fluid (CSF) have been observed in previous cases of LHON-associated myelopathy. Case presentation: We report a male patient with LHON who developed symptoms of myelopathy including gait unsteadiness, enhanced deep tendon reflexes and sensory loss of the lower extremities. Imaging of the brain and spinal cord, CSF analysis, as well as neurography and electromyography did not disclose any abnormalities. The somatosensory evoked potential (SEP) findings were suggestive of dorsal column dysfunction. Conclusions: The patient case demonstrates that myelopathy associated with LHON can present without abnormal findings in central nervous system MR imaging or in the CSF, and without evidence suggestive of multiple sclerosis or MS-like disease. The dorsal column seems to be particularly vulnerable to myelopathy changes in LHON. Evoked potential investigations may assist in confirming the diagnosis, when clinical features are in line with myelopathy but findings in CSF analysis and central nervous system imaging are normal.

Background: Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. Methods: Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput ¹H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. Results: The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. Conclusions: The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory cha

An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson’s disease without ataxia suggesting that RFC1-related disorders include Parkinson’s disease as well.

Charcot-Marie-Tooth (CMT) disease is probably the most common inherited neuromuscular disorder with prevalence estimates of 10–82/100,000. CMT is a clinically and genetically heterogeneous group of disorders that can be classified based on their histological, clinical, electrodiagnostic, and genetic features. Reduced or absent tendon reflexes, foot deformities, distal predominance of limb muscle weakness, wasting, and sensory loss are common clinical features. Pathogenic variants have been discovered in more than 100 genes in patients with CMT. In the present study we investigated the epidemiology of CMT and the frequency of its molecular etiologies in Northern Ostrobothnia, Finland. The patient registries at Oulu University Hospital were searched for possible CMT patients. Blood samples were requested from patients fulfilling the diagnostic criteria, and DNA was then subjected to molecular diagnostics. Selected families were examined clinically. We found 107 patients with CMT, suggesting a prevalence 34.6/100,000 in Northern Ostrobothnia. The dominantly inherited pathogenic variant p.His123Arg in ganglioside induced differentiation associated protein 1 (GDAP1) was found in 31.5% while peripheral myelin protein 22 (PMP22) duplication in 16.9% of the patients. In addition, we found a novel variant, p.His106Arg, in myelin protein zero (MPZ) that was described in affected members of two families and that was found to cause dominantly inherited, late-onset, relatively mild, predominantly axonal motor and sensory polyneuropathy. In addition, 23 patients with p.His123Arg in GDAP1 were examined clinically and electrodiagnostically. Remarkable proximal muscle weakness of the legs and asymmetry of symptoms and findings were defining features in these patients. Prevalence of CMT in Northern Ostrobothnia appears to be two-fold higher than the average in European populations. One reason could be the high portion of patients with heterozygous point mutation p.His123Arg, Tiivistelmä Charcot-Marie-Toothin tauti (CMT) on todennäköisesti yleisin periytyvä neuromuskulaarisairaus, sen esiintyvyydeksi on arvioitu 10–82⁄100 000. CMT on sekä kliinisesti että geneettisesti monimuotoinen ryhmä sairauksia, jotka voidaan luokitella histologisten, kliinisten, neurofysiologisten ja geneettisten ominaisuuksiensa mukaan. Vaimentuneet tai puuttuvat jännevenytysheijasteet, jalkaterien epämuodostumat, distaalisesti painottunut lihasheikkous ja atrofia sekä sensoriset puutosoireet ovat tavallisia kliinisiä löydöksiä. CMT:a aiheuttavia haitallisia muutoksia on löydetty yli 100 geenissä. Tämän tutkimuksen tarkoituksena oli selvittää CMT:n esiintyvyyttä ja molekulaarista etiologiaa Pohjois-Pohjanmaalla. Mahdolliset CMT potilaat valikoitiin sairauskertomusmerkintöjen perusteella Oulun yliopistollisen sairaalan potilasrekistereistä. Diagnoosikriteerit täyttäviltä potilaita pyydettiin verinäyte, josta eristetystä DNA:sta tutkittiin CMT:a aiheuttavia haitallisia muutoksia. Valikoidut perheet tutkittiin kliinisesti. Tunnistimme 107 CMT-potilasta, minkä perusteella CMT:n esiintyvyys Pohjois-Pohjanmaalla on 34,6⁄100,000. Autosomissa vallitsevasti periytyvä p.His123Arg-mutaatio GDAP1-geenissä (ganglioside induced differentiation associated protein 1) löytyi 31,5 %:lta ja PMP22-geenin (peripheral myelin protein 22) duplikaatio 16,9 %:lta potilasta. MPZ-geenissä (myelin protein zero) löysimme uuden muutoksen p.Arg106Cys kahdessa perheessä, joista toisessa tautialleeli segregoitui täysin polyneuropatian kanssa ja oli löydettävissä kahdessa sukupolvessa. P.Arg106Cys muutos aiheuttaa autosomissa vallitsevasti periytyvää, myöhään alkavaa ja kohtalaisen lievää, aksonaalisesti painottuvaa sensomotorista polyneuropatiaa. Lisäksi tutkimme 23 potilasta, joilla oli haitallinen muutos p.His123Arg GDAP1-geenissä. Merkittävällä osalla potilaista oli lihasheikkouden ja neurofysiologisten löydösten epäsymmetriaa sekä alaraajojen proksimaalista lihasheikkoutta. Verratt

Chronic subdural hematoma (CSDH) is a common disease in neurosurgical practice affecting mainly elderly people. CSDH grows slowly within the dural border cell (DBC) layer, which is continuous with the dura and the arachnoid. Inflammatory mechanisms involving the dura mater have an acknowledged role in the progression of CSDH. Also, subarachnoid hemorrhage (SAH) induces an inflammatory cascade and yet, a fibroproliferative reaction, which reflects increased collagen synthesis in the arachnoid. Meninges are a site for active collagen synthesis in normal conditions. In this study, we aimed to evaluate the contribution of meningeal extracellular matrix synthesis, namely collagen and glycosaminoglycans, in slowly growing chronic subdural collections after head injury. The protein content of CSDH fluid was characterized in order to evaluate proteins putatively involved in CSDH pathogenesis. Altogether, 39 patients with CSDH or effusion were included in the study. The age of the hematoma was determined and subdural fluid and serum samples were assayed for the concentrations of procollagen propeptides (PICP, PIIINP, ICTP) by radioimmunoassays and of glycosaminoglycans by colorimetric methods. The proteome of CSDH fluid and serum of five patients was investigated with two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The results indicated that meningeal ECM synthesis is induced after cleavage of the DBC layer. Concentrations of procollagen propeptides in subdural fluid increased rapidly after head injury and remained high for at least three months. High, although variable, concentrations of glycosaminoglycans were also found. However, proteomic studies showed that CSDH proteins originate mainly from blood and the results implied the involvement of coagulation and fibrinolysis cascades in CSDH pathology. The increase of procollagen propeptides in subdural fluid may be regarded as a sign of sustained dural collagen synthesis after cleavage of the, Tiivistelmä Krooninen subduraalihematooma (pitkäaikainen kovakalvon alainen verenpurkauma) on tavallinen neurokirurgista hoitoa vaativa sairaus, jota esiintyy yleisimmin iäkkäillä potilailla. Krooninen subduraalihematooma syntyy kovakalvon rajasolukerroksen repeämisen seurauksena. Repeäminen aiheuttaa kovakalvolla inflammatorisen vasteen, mikä vaikuttaa taudin etenemiseen. Myös lukinkalvonalainen verenvuoto (subaraknoidaalivuoto) aiheuttaa lukinkalvolla inflammatorisen vasteen ja kollageenituotannon lisääntymisen. Aivokalvojen solut tuottavat kollageenia, mutta rajasolukerroksessa kollageenia ei ole. Tässä työssä tutkimme soluväliaineen, erityisesti kollageenien ja glykosaminoglykaanien, tuotantoa kroonisissa subduraalihematoomissa pään vamman jälkeen. Lisäksi tutkimme hematoomanesteen sisältämiä proteiineja ja arvioimme niiden osuutta taudin kehityksessä. Tutkimuksessa oli 39 potilasta. Subduraalihematooman iäksi määritettiin aika pään vammasta subduraalihematooman leikkaushoitoon. Prokollageenien propeptidien (PICP, PIIINP, ICTP) konsentraatio määritettiin radioimmunologisella menetelmällä ja glykosaminoglykaanien konsentraatio kolorimetrisillä menetelmillä. Hematoomanesteen ja seerumin proteomi karakterisoitiin viideltä potilaalta käyttäen kaksiulotteista elektroforeesia (2-DE) ja massaspektrometriaa (MS). Tutkimustulokset osoittivat, että rajasolukerroksen repeämän jälkeen kovakalvossa käynnistyy soluväliaineen tuotantoa. Prokollageenien propeptidien konsentraatio subduraalihematoomanesteessä lisääntyi nopeasti pään vamman jälkeen ja pysyi korkeana ainakin kolme kuukautta. Lisäksi glykosaminoglykaanien konsentraatio oli korkea, joskin vaihteleva. Proteomin analysointi osoitti, että subduraalihematoomanesteen proteiinit ovat suurimmalta osin peräisin verestä ja että subduraalihematooman laajenemiseen vaikuttavat koagulaatio- ja fibrinolyysimekanismit. Propeptidien lisääntymistä voidaan pitää merkkinä kovakalvon pitkäkestoisesta kollageenin tuotannosta rajasoluker

Proper mitochondrial function is a key determinant of endurance performance. Mitochondria are cell organelles which are responsible for cellular energy production through oxidative phosphorylation (OXPHOS). The subunits of OXPHOS complexes are encoded in part by mitochondrial DNA (mtDNA). Previous research has indicated that variation in mtDNA affects endurance performance and a paucity of mtDNA haplogroup J and K has been detected among Finnish endurance athletes. Such a finding suggests that these mtDNA lineages are “uncoupling genomes” which favor heat generation instead of adenosine triphosphate (ATP). Here, the objective was to explore differences in mtDNA variants between elite endurance athletes, sprint athletes and controls. For this purpose, the rate of functional variants and the mutational load in mtDNA of Finnish athletes (n=141) and controls (n=77) was determined. The complete sequences enabled us to search for possible uncoupling variants within haplogroups J and K. Furthermore, the association of haplogroups J and K with physical performance was determined in a population-based cohort of 1,036 healthy Finnish men undergoing compulsory military service. Physical performance was evaluated by means of a 12-minute Cooper running test and muscle fitness index, both at the beginning and end of service. Additionally, the effects of long-term exercise intervention on branched-chain amino acid (BCAA) catabolism was evaluated. BCAAs are the major group of amino acids which are catabolized in skeletal muscle and their oxidation mainly takes place in mitochondria. Rare mtDNA variants were more common among endurance athletes than sprinters or controls (p=0.04), suggesting that rare variation may contribute to endurance performance. The fact that two of the sprinters harbored disease-causing mtDNA variants may indicate that sprinters have a better tolerance for deleterious mutations than endurance athletes. The association of mtDNA haploplogroups J and K, Tiivistelmä Mitokondriot ovat soluelimiä, jotka tuottavat oksidatiivisessa fosforylaatiossa valtaosan elimistön tarvitsemasta energiasta. Tämän vuoksi mitokondrioiden toiminta vaikuttaa olennaisesti kestävyysurheilusuoritukseen. Mitokondrioilla on oma DNA (mtDNA) ja osa hengitysketjun alayksiköistä rakennetaan siinä olevan ohjeen mukaisesti. Aiemmissa tutkimuksissa on havaittu, että mtDNA:n geneettinen muuntelu voi vaikuttaa energian tuotantoon ja mtDNA:n haploryhmät J ja K ovat harvinaisia suomalaisilla kestävyysurheilijoilla. On mahdollista, että näihin haploryhmiin liittyy mitokondrion hengitysketjun toiminnan irtikytkeytyminen energian tuotannosta, jolloin muodostuu adenosiinitrifosfaatin (ATP) sijasta lämpöä. Tässä tutkimuksessa määritettiin mtDNA:n muuntelun suuruus suomalaisilla kestävyys- ja nopeusurheilijoilla (n=141) sekä terveillä kontrolleilla (n=77). Lisäksi tunnistettiin funktionaaliset variantit eli geenimuutokset, jotka voivat vaikuttaa syntyvän proteiinin toimintaan. Haploryhmien J ja K sekvensseistä tunnistettiin hengitysketjun irtikytkentään myötävaikuttavat variantit. Näiden haploryhmien vaikutusta fyysisen kunnon kehitykseen arvioitiin tutkimalla varusmiespalvelusta suorittavista nuorista miehistä koostuvaa väestöotosta (n=1,036). Varusmiesaineistoa käyttämällä tutkittiin myös pitkäkestoisen liikuntaharjoittelun vaikutusta haaraketjuisten aminohappojen (BCAA) aineenvaihduntaan. BCAA:t ovat aerobisessa liikuntasuorituksessa aminohapoista tärkeimpiä energianlähteitä ja niiden metabolia tapahtuu mitokondrioissa. Tutkimuksen perusteella harvinaiset funktionaaliset variantit olivat kestävyysurheilijoilla tavallisempia kuin nopeusurheilijoilla tai kontrolleilla (p=0.04). Tämä voi viitata siihen, että mtDNA:n harvinainen variaatio parantaa hengitysketjun toimintaa ja edesauttaa kestävyysurheilusuoritusta. Kahdella tutkituista nopeusurheilijoista todettiin mitokondriotaudille altistava geenivirhe. On mahdollista, että nopeusurheilijat sietävät paremmin

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

Background: The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. Patients and methods: All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. Results: A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. Conclusions: Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuro

Background: We have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts. Results: Following a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001). Conclusions: These results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.

The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Parkinson’s disease is the second most common neurodegenerative disease, affecting 1 % of the population at the age of 60 years in Finland. The latest studies estimate the heritablitity of PD to be around 27 %. Mendelian inheritance accounts for only a small proportion of PD and the majority of PD cases are thought to result from a complex mixture of risk factors. This is supported by the latest genome-wide association study (GWAS) meta-analysis that identified 90 risk loci, explaining 16–36 % of the heritability of PD. However, the majority of the variants underlying the loci, the pathomechanisms of PD and special characteristics of PD in Finland remain to be clarified. The present study investigated the genetics of PD, focusing especially on the Finnish population. We studied the role of the EIF4G1 gene in PD and identified a c.3513_3521del deletion preventing the translation of messenger-RNA in a Caucasian-American male. In a Finnish cohort, we did not find any significant association between variants in EIF4G1 and PD. We could not identify significant associations between established monogenic variants, risk variants and PD after correction for multiple testing. In GWAS single variant association (SVA) test, loci near genes GBA, SIPA1L2 and SNCA had almost significant associations to PD and the whole exome sequencing study (WES) identified a GBA variant rs2230288 with an altered allele frequency of 8.5 % in Finnish PD cases. Furthermore, the polygenic risk score (PRS) including variant rs2230288 in GBA and variant rs2291312 in TTN was associated with PD with an odds ratio (OR) of 2.7 (95% confidence interval 1.4–5.2; p < 2.56e-03). We identified several novel candidate variants and genes. In gene-level association analysis; some of the identified candidates included GPR126 with an OR of 1.056 and MPHOSPH10 with an OR of 1.53. In the SVA test, the most notable candidate variants included variant rs41289829 in NMBR, variant rs146727650 in GPR126 and va, Tiivistelmä Parkinsonin tauti (PT) on toiseksi yleisin hermostorappeumasairaus, jonka vallitsevuus Suomessa on noin 1 % yli 60-vuotiailla. Uusimmat kaksostutkimukset arvioivat PT:n perinnöllisyyden olevan noin 27%. Taudilla on harvinaisia monogeenisiä muotoja, mutta PT:n oletetaan olevan pääasiallisesti monitekijäinen tauti, jossa useiden riskitekijöiden yhteisvaikutus johtaa taudin puhkeamiseen. Viimeisin meta-analyysi genomin kattavista assosiaatiotutkimuksista (genome-wide association study; GWAS) tunnistaa 90 riskilokusta, jotka voisivat selittää 16–36% PT:n perinnöllisyydestä. Variantit riskilokusten taustalla, niihin liittyvät patomekanismit ja tuntemus PT:n mahdollisista geneettisistä erityispiirteistä suomalaisessa väestössä ovat pääosin selvittämättä. Väitöskirjatutkimuksessa selvitettiin PT:n genetiikkaa keskittyen erityisesti suomalaiseen väestöön. Tutkimme EIF4G1 geenin merkitystä PT:ssa ja löysimme yhdeltä amerikkalaiselta PT-potilaalta harvinaisen c.3513_3521del deleetion, joka estää lähetti-RNA:n translaation yhdessä 39:stä transkriptissa. Suomalaisessa kohortissa EIF4G1:n ja PT:n välillä ei ollut yhteyttä. Tunnettujen monogeenisten muotojen, riskivarianttien ja PT:n välille ei löytynyt yhteyttä monimuuttujakorjauksen jälkeen. GWAS tutkimuksessa lokukset geenien GBA, SIPA1L2 ja SNCA lähettyvillä olivat kuitenkin lähellä tilastollista merkitsevyyttä, ja eksomisekvensointiaineistossa (whole exome sequencing, WES) GBA:n variantin rs2230288 alleelifrekvenssi oli 8.5% potilailla ja 4.7% kontrolleilla. Lisäksi polygeeninen riskipisteytys (polygenic risk score, PRS) joka sisälsi GBA variantin rs2230288 ja TTN-geenin variantin rs2291312 oli yhteydessä PT:iin vetosuhteella 2.7 (95%:n luottamusväli 1.4–5.2; p < 2.56e-03). Tutkimuksessa tunnistettiin myös useita uusia ehdokasvariantteja ja -geenejä. Geenitason assosiaatioista vahvimpia kandidaatteja olivat GPR126 tulosuhteella (OR) 1.056 sekä MPHOSPH10 tulosuhteella 1.53. Yksittäisvarianteista puolestaan vahv

Cardiomyopathy and cardiac conduction defects are common manifestations of mitochondrial disease. Previous studies suggest that clinically asymptomatic individuals harbouring pathogenic mitochondrial DNA (mtDNA) mutations in the cardiac muscle may have sudden cardiac death (SCD) as the first manifestation of mitochondrial disease. We investigated the contribution of pathogenic mtDNA point mutations and mtDNA haplogroups in cardiac muscle in a cohort of 280 Finnish subjects that had died from non-ischaemic SCD with the median age of death at 59 years and in 537 population controls. We did not find any common or novel pathogenic mutations, but the frequency of haplogroup H1 was higher in the SCD subjects than that in 537 population controls (odds ratio: 1.76, confidence interval 95%: 1.02–3.04). We conclude that, at the population level, pathogenic point mutations in mtDNA do not contribute to non-ischaemic SCD, but natural variation may modify the risk.

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well‐documented evidence, rapidly advancing and cost‐effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases...

Variants associated with Parkinson’s disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4–5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD.

Objective: To study genetic causes of the low frequency of Huntington disease (HD) in the Finnish population, we determined HTT haplogroups in the population and patients with HD and analyzed intergenerational Cytosine-Adenosine-Guanosine (CAG) stability. Methods: A national cohort of patients with HD was used to identify families with mutant HTT (mHTT). HTT haplogroups were determined in 225 archival samples from patients and from 292 population samples. CAG repeats were phased with HTT haplotypes using data from parent-offspring pairs and other mHTT carriers in the family. Results: The allele frequencies of HTT haplotypes in the Finnish population differed from those in 411 non-Finnish European subjects (p < 0.00001). The frequency of haplogroup A was lower than that in Europeans and haplogroup C was higher. Haplogroup A alleles were significantly more common in patients than in controls. Among patients with HD haplotypes A1 and A2 were more frequent than among the controls (p = 0.003). The mean size of the CAG repeat change was +1.38 units in paternal transmissions being larger than that (−0.17) in maternal transmissions (p = 0.008). CAG repeats on haplogroup A increased by 3.18 CAG units in paternal transmissions, but only by 0.11 units in maternal transmissions (p = 0.008), whereas haplogroup C repeat lengths decreased in both paternal and maternal transmissions. Conclusions: The low frequency of HD in Finland is partly explained by the low frequency of the HD-associated haplogroup A in the Finnish population. There were remarkable differences in intergenerational CAG repeat dynamics that depended on HTT haplotype and parent gender.

Background: We have previously reported on paucity of mitochondrial DNA (mtDNA) haplogroups J and K among Finnish endurance athletes. Here we aimed to further explore differences in mtDNA variants between elite endurance and sprint athletes. For this purpose, we determined the rate of functional variants and the mutational load in mtDNA of Finnish athletes (n = 141) and controls (n = 77) and determined the sequence variation in haplogroups. Results: The distribution of rare and common functional variants differed between endurance athletes, sprint athletes and the controls (p = 0.04) so that rare variants occurred at a higher frequency among endurance athletes. Furthermore, the ratio between rare and common functional variants in haplogroups J and K was 0.42 of that in the remaining haplogroups (p = 0.0005). The subjects with haplogroup J and K also showed a higher mean level of nonsynonymous mutational load attributed to common variants than subjects with the other haplogroups. Interestingly, two of the rare variants detected in the sprint athletes were the disease-causing mutations m.3243A > G in MT-TL1 and m.1555A > G in MT-RNR1. Conclusions: We propose that endurance athletes harbor an excess of rare mtDNA variants that may be beneficial for oxidative phosphorylation, while sprint athletes may tolerate deleterious mtDNA variants that have detrimental effect on oxidative phosphorylation system. Some of the nonsynonymous mutations defining haplogroup J and K may produce an uncoupling effect on oxidative phosphorylation thus favoring sprint rather than endurance performance.

Background: Thrombolysis improves stroke outcome, but efficacy of the treatment is limited by time. Therefore, recognition of stroke symptoms by dispatch centres and by emergency medical services (EMS) is crucial, as is minimization of pre-hospital delays. We investigated the pre-hospital delays in patients with stroke treated with thrombolysis and compared the delays between rural and urban patients. Methods: Patients that had received thrombolysis at Oulu University Hospital (OUH) between 1 January 2013 and 31 December 2015 were identified. Patients were divided into urban and rural based on the site of the EMS mission. Pre-hospital charts and medical records were reviewed. Onset-to-dispatch, dispatch-to-arrival of EMS, on-scene, transport and door-to-needle times were studied. Results: Three hundred one stroke patients were treated with thrombolysis at OUH, and 232 of them were included in the study. Positive Face Arm Speech Test (FAST) findings, priority dispatch code and transport code were associated with shorter transport delays. The priority dispatch was not used in 12.5% of stroke patients treated with thrombolysis. The rural patients had a four minutes longer dispatch-to-arrival delay and 50 (34, 74) minutes longer transport time. The door-to-needle time was 8 (5, 14) minutes shorter in rural patients than in urban patients. Conclusions: Positive FAST findings and the use of priority dispatch code and priority transport code were associated with shorter transport delays. There is room for improvement in door-to-needle time and in stroke recognition by the dispatch centre and EMS providers. For the rural population, helicopter transportation could reduce the long pre-hospital time.

Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detected., Tiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muua

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well-documented evidence, rapidly advancing and cost-effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases. Although the importance of genetics for diagnosis and genetic counseling is undisputed, the recent development of first genetargeted therapies entering clinical trial1,2 is adding an important new layer to the (re-)consideration of genetic testing in neurology. However, establishing accurate genotype– phenotype and genotype–treatment relationships requires large sample sizes. Systematic reviews can serve as instruments to combine information from several small samples, but unfortunately, this is often complicated by inconsistent and incomplete reporting of clinical and genetic data across studies. Thus, large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.