Farmakogenetiikka saapuu klinikkaan

English summaryPeer reviewe

Kystisen fibroosin uudistuva lääkehoito

Vertaisarvioitu. English summary.• Kystinen fibroosi on harvinainen, huonoennusteinen monielinsairaus. • Sairauden aiheuttava mutaatio CFTR-geenissä johtaa kloridikanavan poikkeavaan toimintaan. Tämä ¬vahingoittaa eniten keuhkoja, mutta myös mm. haimaa, maksaa ja suolistoa. • Hoito on ollut oireenmukaista, mutta tehokkaimmallakin hoidolla potilaiden elinajan odote on ollut selvästi lyhempi kuin normaaliväestössä. • Kymmenen viime vuoden aikana markkinoille on tullut mutaatiospesifisiä lääkkeitä, jotka vaikuttavat ¬sairauden perussyyhyn. Niiden ansiosta hoito ja elinajan odote paranevat.Peer reviewe

Two novel mutations in the DNAH11 gene in primary ciliary dyskinesia (CILD7) with considerable variety in the clinical and beating cilia phenotype

Background Diagnosis of primary ciliary dyskinesia (PCD) still remains a challenge, especially with mutations in the Dynein Arm Heavy Chain 11 (DNAH11) gene. Classical diagnostic measures like Transmission Electron Microscopy (TEM) are not applicable for mutations in the DNAH11 gene since ultrastructural defects of the ciliary apparatus are absent. Novel mutations encoding for PCD appear all the time with considerable variation in the clinical picture, making it necessary to update data bases and guidelines for PCD diagnostics. Methods In this study we examined two unrelated, Finnish families with symptoms of PCD applying the clinical scoring system: Primary ciliary dyskinesia Rule (PICADAR), high speed video microscopy analysis (HSVMA) for ciliary movement, a commercially available gene panel analysis and nasal Nitric Oxide (nNO) measurements if applicable. Results Two, likely pathogenic variants in the DNAH11 gene (c.2341G > A, p. (Glu781Lys) ja c.7645 + 5G > A) were detected. In the first family, compound heterozygous mutations led to disease manifestation in two of 4 children, which showed a similar phenotype of cilia beating pattern but marked differences in disease severity. In the second family, all three children were homozygotes for the c.2341G > A p.(Glu781Lys) mutation and showed a similar degree of disease severity. However, the phenotype of cilia beating pattern was different ranging from stiff, static cilia to a hyperkinetic movement in one of these children. Conclusions In this study we describe two Finnish families with PCD, revealing two novel mutations in the DNAH11 gene which show considerable variety in the clinical and beating cilia phenotype. The results of this study show the clinician that PCD can be much milder than generally expected and diagnosis demands a combination of measures which are only successful in experienced hands. Chronic and repeatedly treated wet cough should raise suspicion of PCD, referring the patient for further diagnostics to a specialised PCD centre

Food allergy in a child with de novo KAT6A mutation

Crying combined with miscellaneous gastrointestinal symptoms are typical symptoms of infant with food allergy, but are also common among children with abnormal neurological development. Mutations in KAT6A gene is known to cause a syndrome characterized by developmental delay, hypotonia, cardiac defects, microcephaly, specific facial features and early feeding problems. However, these feeding problems have not earlier been specified. We present the first reported case of a DBPCFC confirmed food allergy in a child with KAT6A mutation whose feeding problems resolved with elimination diet. The present case does not establish proof of cause, but highlights the importance of careful clinical diagnostics despite other possible causes for feeding problems. Recognizing that early feeding problems these patients regularly have might be caused by food allergy is important for outcome and quality of life for these patients

Flunssaisen vauvan uloshengitys vinkuu - mistä taudista on kyse?

Bronkioliitti on viruksen aiheuttama pienten hengitysteiden tulehdussairaus, joka johtaa ensimmäiseen uloshengitysvaikeuskohtaukseen tiukan määritelmän mukaisesti alle 6 kuukauden ikäisellä ja laajan määritelmän mukaisesti alle 2-vuotiaalla lapsella. RSV-bronkioliitti ja ”rinovirus-atopiavinkuna” ovat erilaiset sairaudet, joiden riskitekijät, patogeneesi, taudinkulku, hoito ja ennuste eroavat toisistaan

Cut-off values to evaluate exercise-induced asthma in eucapnic voluntary hyperventilation test for children

Background and Aim The eucapnic voluntary hyperventilation (EVH) testing is a diagnostic tool for diagnostics of exercise-induced bronchoconstriction; while the testing has become more common among children, data on the test's feasibility among children remain limited. Our aim was to investigate EVH testing feasibility among children, diagnostic testing cut-off values, and which factors affect testing outcomes. Methods We recruited 134 patients aged 10-16 years with a history of exercise-induced dyspnoea and 100 healthy control children to undergo 6-min EVH testing. Testing feasibility was assessed by the children's ability to achieve >= 70% of the target minute ventilation of 30 times forced expiratory volume in 1 s (FEV1). Bronchoconstriction was assessed as a minimum of 8%, 10%, 12%, 15% or 20% fall in FEV1. Patient characteristics were correlated with EVH outcomes. Results Overall, 98% of the children reached >= 70%, 88% reached >= 80%, 79% reached >= 90% and 62% reached >= 100% of target ventilation in EVH testing; of children with a history of exercise-induced dyspnoea, the decline percentages were as follows: 24% (>= 8% fall), 17% (>= 10% fall), 10% (>= 12% fall), 6% (>= 15% fall) and 5% (>= 20% fall) in FEV1, compared to 11%, 4%, 3%, 1% and 0% among the healthy controls, respectively. Healthy controls and boys performed testing at higher ventilation rates (p <.05). Conclusion Eucapnic voluntary hyperventilation testing is feasible among children aged 10-16 years and has diagnostic value in evaluating exercise-induced dyspnoea among children. A minimum 10% fall in FEV1 is a good diagnostic cut-off value. Disease status appears to be important covariates.Peer reviewe

CFAP300 mutation causing primary ciliary dyskinesia in Finland

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.publishedVersionPeer reviewe

Uni- ja hengityskeskus yhtenäistää diagnostiikkaa ja hoitoa

Hengitysvajeen sekä uni- ja vireystilahäiriöiden hoidossa tarvitaan useiden erikoisalojen moniammatillista yhteistyötä. Kansallisella koordinaatiolla haetaan kustannustehokkuutta ja potilaiden yhdenvertaisuuden toteutumista. Sitä varten perustettiin TYKS:n Uni- ja hengityskeskus.</p

The relationship of serum vitamins A, D, E and LL-37 levels with allergic status, tonsillar virus detection and immune response

BackgroundTonsils have an active role in immune defence and inducing and maintaining tolerance to allergens. Vitamins A, D, and E, and antimicrobial peptide LL-37 may have immunomodulatory effects. We studied how their serum levels were associated with allergy status, intratonsillar/nasopharyngeal virus detection and intratonsillar expression of T cell-and innate immune response-specific cytokines, transcription factors and type I/II/III interferons in patients undergoing tonsillectomy.Methods110 elective tonsillectomy patients participated. Serum levels of vitamins A, 25(OH)D, and E, LL-37 and allergen-specific IgE as well as nasopharyngeal/intratonsillar respiratory viruses were analyzed. The mRNA expression of IFN-alpha, IFN-beta, IFN-gamma, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-beta, FOXP3, GATA3, RORC2 and Tbet in tonsils were analyzed by quantitative RT-PCR.ResultsThe median age of the patients was 16 years (range 3-60), 28% of subjects had atopy, and 57% carried >= 1 respiratory virus in nasopharynx. Detection of viruses decreased by age. Higher vitamin A levels showed borderline significance with less viral detection (P = 0.056). Higher 25(OH) D was associated with less allergic rhinitis and atopy (P < 0.05) and higher vitamin E with less self-reported allergy (P < 0.05). In gene expression analyses, 25(OH)D was associated with higher IL-37, vitamin A with higher IFN-gamma and vitamin E with less IL-28 (P < 0.05). LL-37 was associated with less FOXP3, RORC2 and IL-17 in tonsils (P < 0.05).ConclusionsVitamin D and E levels were associated with less allergic disorders. Vitamin A was linked to antiviral and vitamin D with anti-inflammatory activity. LL-37 and was linked to T regulatory cell effects

The relationship of serum vitamins A, D, E and LL-37 levels with allergic status, tonsillar virus detection and immune response

Background: Tonsils have an active role in immune defence and inducing and maintaining tolerance to allergens. Vitamins A, D, and E, and antimicrobial peptide LL-37 may have immunomodulatory effects. We studied how their serum levels were associated with allergy status, intratonsillar/nasopharyngeal virus detection and intratonsillar expression of T cell- and innate immune response-specific cytokines, transcription factors and type I/II/III interferons in patients undergoing tonsillectomy. Methods: 110 elective tonsillectomy patients participated. Serum levels of vitamins A, 25(OH)D, and E, LL-37 and allergen-specific IgE as well as nasopharyngeal/intratonsillar respiratory viruses were analyzed. The mRNA expression of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2 and Tbet in tonsils were analyzed by quantitative RT-PCR. Results: The median age of the patients was 16 years (range 3–60), 28% of subjects had atopy, and 57% carried ≥1 respiratory virus in nasopharynx. Detection of viruses decreased by age. Higher vitamin A levels showed borderline significance with less viral detection (P = 0.056). Higher 25(OH)D was associated with less allergic rhinitis and atopy (P < 0.05) and higher vitamin E with less self-reported allergy (P < 0.05). In gene expression analyses, 25(OH)D was associated with higher IL-37, vitamin A with higher IFN-γ and vitamin E with less IL-28 (P < 0.05). LL-37 was associated with less FOXP3, RORC2 and IL-17 in tonsils (P < 0.05). Conclusions: Vitamin D and E levels were associated with less allergic disorders. Vitamin A was linked to antiviral and vitamin D with anti-inflammatory activity. LL-37 and was linked to T regulatory cell effects