122 research outputs found
Childhood-onset mitochondrial diseases : with emphasis on molecular diagnostics of neurological disorders
No full textChildhood-onset mitochondrial diseases comprise a heterogeneous group of disorders, which may manifest with almost any symptom and affect any tissue or organ. Due to challenging diagnostics, most children still lack a specific aetiological diagnosis.
The aim of this thesis was to find molecular causes for childhood-onset mitochondrial disorders in Finland. We identified the underlying cause for 25 children, and found three new diseases, which had not been diagnosed in Finland before. These diseases caused severe progressive infantile-onset encephalomyopathies, and were due to defects in mitochondrial DNA (mtDNA) maintenance. Furthermore, the thesis provides the molecular background of Finnish patients with ‘leukoencephalopathy with brain stem and spinal cord involvement and elevated brain lactate’ (LBSL).
A new phenotype was identified to be due to mutations in Twinkle, resembling ‘infantile onset spinocerebellar ataxia’ (IOSCA). These mutations caused mtDNA depletion in the liver, thus confirming the essential role of Twinkle in mtDNA maintenance, and expanding the molecular background of mtDNA depletion syndromes.
The major aetiology for infantile mitochondrial myopathy in Finland was discovered to be due to mutations in thymidine kinase 2 (TK2). A novel mutation with Finnish ancestry was identified, and a genotype-phenotype correlation with mutation-specific distribution of tissue involvement was found, thus proving that deficient TK2 may cause multi-tissue depletion and impair neuronal function.
This work established the molecular diagnosis and advanced the knowledge of phenotypes among paediatric patients with polymerase gamma (POLG) mutations. The patients showed severe early-onset encephalopathy with intractable epilepsy. POLG mutations are not a prevalent cause of children’s ataxias, although ataxia is a major presenting symptom among adults. Our findings indicate that POLG mutations should be investigated even if typical MRI, histochemical or biochemical abnormalities are lacking.
LBSL patients showed considerable variation in phenotype despite identical mutations. A common, most likely European, ancestry, and a relative high carrier frequency of these mutations in Finland were discovered; suggesting that LBSL may be a quite common leukoencephalopathy in other populations as well. The results suggest that MRI findings are so unique that the diagnosis of LBSL is possible to make without genetic studies.
This thesis work has resulted in identification of new mitochondrial disorders in Finland, enhancing the understanding of the clinical variability and the importance of tissue-specificity of these disorders. In addition to providing specific diagnosis to the patients, these findings give light to the underlying pathogenetic mechanisms of childhood-onset mitochondrial disorders.Uusia lapsuuden mitokondriotauteja tunnistettu Suomessa
Mitokondriotaudit ovat perinnöllisiä sairauksia, jotka johtuvat häiriöistä solujen mitokondrioissa tapahtuvassa energiantuotannossa. Sairauden oireet voivat ilmetä lähes missä tahansa elimessä ja missä tahansa iässä. Aivo-, lihas-, maksa- ja sydänoireet ovat tyypillisiä. Lapsuudessa alkavat mitokondriotaudit ovat usein vaikeasti tunnistettavia ja niiden diagnostiikka on haastavaa, minkä vuoksi tarkka diagnoosi puuttuu useimmilta mitokondriotautia sairastavilta lapsilta.
Tutkimukseni tarkoituksena oli selvittää suomalaislasten mitokondriotautien molekyyligeneettista taustaa ja karakterisoida tämän tautiryhmän suomalaisia erityispiirteitä. Tutkimuksen myötä 25 lasta sai tarkan diagnoosin ja tunnistimme kolme mitokondrioiden toimintahäiriöistä johtuvaa sairautta, joita ei aiemmin ollut Suomessa todettu.
Nämä Suomessa nyt tunnistetut sairaudet ovat harvinaisia aivo- ja/tai lihassairauksia, jotka alkavat vauvaiässä tai varhaislapsuudessa ja johtavat yleensä kuolemaan jo lapsuusiässä. Sairaudet periytyvät peittyvästi, eli sairastuakseen lapsen on perittävä sairauden aiheuttava gee-nivirhe molemmilta vanhemmiltaan. Nämä sairaudet johtuvat perimän muutoksista tymidiinikinaasi 2 (TK2)-, twinkle- ja polymeraasi gamma (POLG)- proteiineja koodaavissa geeneissä. Nämä proteiinit ovat tärkeitä mitokondrioiden oman perimän, mitokondriaalisen DNAn, ylläpidossa. Häiriöt mitokondrioiden perimän ylläpidossa aiheuttavat solujen energia-aineenvaihdunnan häiriön.
Näiden sairauksien lisäksi tutkimuksessa selvitettiin LBSL-taudin (aivojen valkean aineen tauti) molekyyligenettinen tausta Suomessa. LBSL-tauti on uusi, äskettäin mitokondriotauteihin luokiteltu ataksiasairaus, joka johtuu häiriöstä mitokondrioiden proteiinisynteesissä. Sairauden alkamisikä vaihtelee varhaislapsuudesta nuoruusikään, ja sairaus on hitaasti etenevä. Huolimatta samanlaisista geenivirheistä potilaiden oirekuva ja sairauden vaikeusaste vaihtelevat, mikä viittaa muiden, vielä tuntemattomien, tekijöiden vaikutukseen sairaudenkulkuun.
Mitokondriotauteihin ei toistaiseksi ole parantavaa hoitoa, mutta diagnoosin löytyminen lopettaa raskaat tutkimukset sekä ohjaa oireenmukaista hoitoa ja kuntoutusta. POLG- ja twinkle-geenivirheiden tunnistaminen on erityisen tärkeää, koska epilepsialääke valproaatti voi laukaista vaikean maksavaurion näille potilaille. Tarkka diagnoosi mahdollistaa perheille myös perinnöllisyysneuvonnan. Tutkimuksen myötä mitokondriotautien diagnostiikka on Suomessa parantunut, ja tutkimuksessa saatiin uutta tietoa lasten mitokondriotautien oirekuvasta, mitokondrioiden perimän ylläpitoon vaikuttavista tekijöistä ja häiriöiden vaikutuksista. Sairauksien mekanismien tunteminen on edellytys hoitomahdollisuuksien kehittämiselle
Estimating excess hazard ratios and net survival when covariate data are missing: strategies for multiple imputation.
No full textBACKGROUND: Net survival is the survival probability we would observe if the disease under study were the only cause of death. When estimated from routinely collected population-based cancer registry data, this indicator is a key metric for cancer control. Unfortunately, such data typically contain a non-negligible proportion of missing values on important prognostic factors (eg, tumor stage). METHODS: We carried out an empirical study to compare the performance of complete records analysis and several multiple imputation strategies when net survival is estimated via a flexible parametric proportional hazards model that includes stage, a partially observed categorical covariate. Starting from fully observed cancer registry data, we induced missingness on stage under three scenarios. For each of these scenarios, we simulated 100 incomplete datasets and evaluated the performance of the different strategies. RESULTS: Ordinal logistic models are not suitable for the imputation of tumor stage. Complete records analysis may lead to grossly misleading estimates of net survival, even when the missing data mechanism is conditionally independent of survival time given the covariates and the bias on the excess hazard ratios estimates is negligible. CONCLUSIONS: As key covariates are unlikely missing completely at random, studies estimating net survival should not use complete records. When the missingness can be inferred from available data, appropriate multiple imputation should be performed. In the context of flexible parametric proportional hazards models with a partially observed stage covariate, a multinomial logistic imputation model for stage should be used and should include the Nelson-Aalen cumulative hazard estimate and the event indicator
The relationship between quality of research and citation frequency.
No full textBACKGROUND: Citation counts are often regarded as a measure of the utilization and contribution of published articles. The objective of this study is to assess whether statistical reporting and statistical errors in the analysis of the primary outcome are associated with the number of citations received. METHODS: We evaluated all original research articles published in 1996 in four psychiatric journals. The statistical and reporting quality of each paper was assessed and the number of citations received up to 2005 was obtained from the Web of Science database. We then examined whether the number of citations was associated with the quality of the statistical analysis and reporting. RESULTS: A total of 448 research papers were included in the citation analysis. Unclear or inadequate reporting of the research question and primary outcome were not statistically significantly associated with the citation counts. After adjusting for journal, extended description of statistical procedures had a positive effect on the number of citations received. Inappropriate statistical analysis did not affect the number of citations received. Adequate reporting of the primary research question, statistical methods and primary findings were all associated with the journal visibility and prestige. CONCLUSION: In this cohort of published research, measures of reporting quality and appropriate statistical analysis were not associated with the number of citations. The journal in which a study is published appears to be as important as the statistical reporting quality in ensuring dissemination of published medical science
Lapsuuden mitokondriotaudit - yhden soluelimen toimintaviasta kymmeniä erilaisia sairauksia
No full textLapsuudessa alkavat mitokondriotaudit ovat useimmiten eteneviä aivo- tai lihastauteja, joihin voi liittyä muiden elimien, kuten maksan, sydämen, munuaisten ja aistinelinten toiminnanhäiriöitä. Mitokondriotaudit ovat yksi yleisimmistä periytyvistä aineenvaihduntatautiryhmistä, ja niiden mahdollisuus tulisi pitää mielessä, kun lapsella on tunnistamaton, etenevä sairaus. Diagnosointi on vaativaa kliinisen kuvan monimuotoisuuden, laboratoriotutkimusten epäspesifisyyden ja joidenkin tarkennettujen tutkimusten, kuten lapsilta nukutuksessa otettavan lihaskudosnäytteen, kajoavan luonteen vuoksi. Uudet genominlaajuiset tutkimusmenetelmät ovat osoittautuneet arvokkaiksi lasten mitokondriotautien diagnostiikassa. Vain yksittäisiin mitokondriotauteihin on toistaiseksi täsmähoitoja. Kaikki potilaat tarvitsevat kuitenkin yksilöllistä hoitoa, kuntoutusta ja pysyviä hoitosuhteita, perheet puolestaan sekä perinnöllisyysneuvontaa että pitkäjänteistä tukea.Peer reviewe
Without ENMG, detecting pediatric vincristine neuropathy is a challenge
No full textObjective: Vincristine, a widely used anticancer chemotherapy drug, may cause polyneuropathy (PNP), potentially resulting in permanent functional impairment. We characterized the occurrence and development of vincristine-induced neuropathy (VIPN) in early treatment of childhood leukemia. Methods: This prospective study of 35 pediatric acute lymphoblastic leukemia (ALL) patients comprised systematic clinical and electrophysiological studies at both the time of diagnosis and at least one time point during the first months of treatment. Results: After vincristine treatment, all patients had axonal sensorimotor PNP on electroneuromyography (ENMG) In 34/35 patients, the motor and in 24/35 the sensory responses were decreased. Interestingly, in 3 patients PNP was most prominent in the upper limb. However, some children had no PNP symptoms despite moderate ENMG findings, and not all clinical symptoms were correlated with abnormal ENMG. Conclusions: Pediatric VIPN is a sensorimotor, predominantly motor axonal neuropathy. VIPN can be detected even in its early phase by ENMG, but it is difficult to detect by symptoms and clinical examination only. Significance: Pediatric ALL patients treated with vincristine are at risk of developing VIPN. Since the clinical signs of PNP in acutely ill children are difficult to identify, VIPN can easily be overlooked if ENMG is not performed.Peer reviewe
- …
