8 research outputs found

    Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere

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    4 pages 359-363 in the print version, additional 7 pages online.Peer reviewe

    Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

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    Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

    Down syndrome, health and disability:a population-based case record and follow-up study

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    Abstract The present study surveyed medical problems and mental health in an unselected population-based series of people with Down syndrome (DS). All people with DS identified in the Intellectual Disability Service Register in the Kainuu region (n=138) were included, and their health and disability case records in the public services were analysed. The severity of intellectual disability was related to age, gender, and recorded medical problems. Adaptive behaviour changes were assessed among adults repeatedly during ten years using the Adaptive Behaviour Scale - Residential and Community, Part I. The study evaluated health surveillance and practices were compared to the national Current Care guidelines. Numerous medical problems and behavioural symptoms were recorded in this population. Surgical treatments were used extensively. The number of medical problems varied to a great degree among participants. Health problems were extensive from birth to old age. Many health concerns were age-related. The degree of intellectual disability related to visual and neurological impairments. Depression, and among participants in their forties and older, Alzheimer’s disease were the most common underlying reasons for changes in adaptive behaviour. A gradual functional decline and dementia affected many participants at a relatively early age. Visual acuity and hearing should be regularly monitored in all individuals with DS because of a high prevalence of visual impairment and hearing loss in this population. There was a general lack of evidence that the health care guidelines initiated five years ago were being followed. This suggests that possibilities to enhance health have not been optimally implemented. Therefore, further efforts are needed to diagnose and treat medical problems in people with DS.Tiivistelmä Tutkimuksessa kuvattiin todettujen terveysongelmien yleisyyttä ja terveysseurannasta annettujen suositusten toteutumista Downin oireyhtymässä. Nykyisin Kainuussa elävien Down -henkilöiden tietojen lisäksi alueella aiemmin asuneiden saatavissa olevat sairaus- ja huoltokertomustiedot analysoitiin (n=138). Kehitysvammaisuuden vaikeusasteen, iän, sukupuolen ja todettujen sairauksien yhteyksiä selvitettiin. Aikuisten ja ikääntyvien Down -henkilöiden toimintakykyä seurattiin kymmenen vuoden ajan käyttäen Adaptiivisen käyttäytymisen asteikkoa. Käypä hoito -suosituksen toteutumista terveysseurannan osalta arvioitiin. Down -henkilöillä oli todettu lukuisia terveysongelmia ja käytösoireita kaikissa ikäryhmissä. Kirurgisia hoitoja oli tehty paljon. Yksilölliset erot sairastavuudessa ja toimintakyvyssä olivat erittäin huomattavat. Monet terveysongelmista liittyivät tiettyyn ikään. Vaikeasti kehitysvammaisilla todettiin enemmän silmäsairauksia ja näön ongelmia sekä neurologisia sairauksia kuin lievästi tai keskivaikeasti kehitysvammaisilla. Masennus ja yli 40 vuoden ikäisillä Alzheimerin tauti olivat yleisimmät toimintakyvyn heikentymisen syyt. Toimintakykvyn heikentyminen alkoi usein 40 ikävuoden jälkeen ja moni sairastui suhteellisen nuorena dementiaan. Kaikkien Down -henkilöiden kuuloa ja näköä tulisi seurata säännöllisesti, koska kuulon alentuminen ja näön ongelmat ovat yleisiä ja jäävät usein toteamatta. Hoitosuositukset eivät toteutuneet ainakaan säännöllisen kuulon ja kilpirauhasen toiminnan seurannan osalta viiden vuoden kuluessa suositusten antamisesta. Terveysseurannan parempi toimeenpano terveyden edistämiseksi on mahdollista. Down henkilöiden sairauksien toteamisen ja hoidon kehittäminen vaatii edelleen työtä

    Lower thoracic spine extension mobility is associated with higher intensity of thoracic spine pain

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    Abstract Objectives: To evaluate the association of thoracic spine (TS) posture and mobility with TS pain. Methods: Participants with TS pain reported maximum, average, and night pain in TS area, and pain summary score was calculated. Upright and sitting TS postures were evaluated by inspection. TS posture and mobility (flexion and extension) were recorded using an inclinometer and a tape measure, respectively. Correlations between posture and mobility assessments were calculated using Spearman rank correlation, the association of TS posture and mobility with TS pain by logistic regression analysis. Results: The participants’ (n = 73, 52 females, age range 22–56) TS pain duration was 12 weeks on average. The correlations for measurements of TS posture and flexion mobility were higher than correlations of other TS measurements being between 0.53 and 0.82. Decreased extension mobility of the upper (from 1st to 6th TS segments; Th1–Th6) TS was associated with higher worst pain (OR 1.04, 95% CI 1.00–1.07) and whole TS with pain sum score (OR 1.05, 95% CI 1.01–1.08). Less kyphotic whole TS was associated with lower pain sum score (OR 0.96, 95% CI 0.92–1.00). Greater flexion mobility of upper and lower (Th6–Th12) TS were associated with lower pain sum score (OR 0.96, 95% CI 0.91–1.00, and OR 0.96, 95% CI 0.91–1.00, respectively). Conclusions: Reduced thoracic extension mobility was associated with higher pain scores and the greater flexion mobility with lower pain scores. Future research is warranted to evaluate if treatments geared toward TS extension mobility improvements would result in lower TS pain

    Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

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    Abstract The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case

    Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

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    Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called “thin” lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

    Molecular understanding of sulphuric acid–amine particle nucleation in the atmosphere

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