| 1. |
- Götz, Alexandra, et al.
(författare)
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Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy
- 2011
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 88:5, s. 635-642
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Tidskriftsartikel (refereegranskat)abstract
- Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.
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| 2. |
- Korkman, Marit, et al.
(författare)
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Neurocognitive test profiles of extremely low birth weight five-year-old children differ according to neuromotor status
- 2008
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Ingår i: Developmental Neuropsychology. - : Informa UK Limited. - 8756-5641 .- 1532-6942. ; 33:5, s. 637-655
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Tidskriftsartikel (refereegranskat)abstract
- The neurocognitive outcome of children born with extremely low birth weight (ELBW) is highly variable due to the complexity of morbidity. So far, no study has compared comprehensive neuropsychological test profiles in groups with different neuromotor status. In a national cohort of ELBW children neuropsychological test profiles were assessed in 4 groups defined according to a neurological examination at 5 years of age: normal neuromotor status (N = 56). motor coordination problems (N = 32), Multiple Subtle neuromotor signs including, both motor coordination problems and deviant reflexes (N = 20), and spastic diplegia (N = 12). The neurocognitive assessment included a test of intelligence. the Wechsler Primary and Preschool Scale of Intelligence-Revised (WPPSI-R) and 14 subtests of attention and executive functions, verbal functions, Manual motor functions, visuoconstructional functions and verbal learning (NEPSY). The children with normal neuromotor status performed within the average range: children with motor coordination problems had widespread impairment and children with spastic diplegia and children with multiple minor neuromotor(Or Signs had uneven test profiles with stronger verbal results but weaknesses in attention and executive functions, and in manual motor and visuoconstructional tasks. In conclusion, very preterm children with neuromotor signs, including motor coordination problems, are at risk for neurocognitive impairment. in spite of average intelligence. More impaired children have more irregular test profiles. Follow-up and neuropsychological assessment of very preterm children with minor neuromotor signs are therefore indicated.
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| 3. |
- Sjöblom, Liisa, et al.
(författare)
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Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.
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| 4. |
- Tommiska, Viena, et al.
(författare)
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Analysis of neurodevelopmental outcomes of preadolescents born with extremely low weight revealed impairments in multiple developmental domains despite absence of cognitive impairment
- 2020
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Ingår i: Health Science Reports. - : Wiley. - 2398-8835. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Children with extremely low-birth weight (ELBW) have a high risk for cognitive, motor, and attention impairments and learning disabilities. Longitudinal follow-up studies to a later age are needed in order to increase understanding of the changes in neurodevelopmental trajectories in targeting timely intervention. The aims of this study were to investigate cognitive and motor outcomes, attention-deficit hyperactivity (ADHD) behaviour, school performance, and overall outcomes in a national cohort of ELBW children at preadolescence, and minor neuromotor impairments in a subpopulation of these children and to compare the results with those of full-term controls. The additional aim was to report the overall outcome in all ELBW infants born at 22 to 26 gestational weeks. Methods: This longitudinal prospective national cohort study included all surviving ELBW (birth weight <1000 g) children born in Finland in 1996 to 1997. No children were excluded from the study. Perinatal, neonatal, and follow-up data up to the age of 5 years of these children were registered in the national birth register. According to birth register, the study population included all infants born at the age under 27 gestational weeks. At 11 years of age general cognitive ability was tested with the Wechsler Intelligence Scale for Children, ADHD behavior evaluated with a report from each child's own teacher (ADHD Rating Scale IV), and school performance with a parental questionnaire. An ELBW subpopulation consisting of a cohort representative children from the two university hospitals from two regions (n = 63) and the age-matched full-term born controls born in Helsinki university hospital (n = 30) underwent Movement Assessment Battery for Children and Touwen neurological examination comprising developmental coordination disorder (DCD) and minor neurological dysfunction (MND), respectively. Results: Of 206 ELBW survivors 122 (73% of eligible) children and 30 (100%) full-term control children participated in assessments. ELBW children had lower full-scale intellectual quotient than controls (t-test, 90 vs 112, P <.001), elevated teacher- reported inattention scores (median = 4.0 vs 1.0, P =.021, r =.20) and needed more educational support (47% vs 17%, OR 4.5, 95% CI 1.6-12.4, P =.02). In the subpopulation, the incidences of DCD were 30% in ELBW and 7% in control children (P =.012, OR 6.0 CI 1.3-27.9), and complex MND 12.5% and 0%, (P =.052; RR 1.1 95% CI 1.04-1.25), respectively. Of survivors born in 24 to 26 gestational weeks, 29% had normal outcome. Conclusion: As the majority of the extremely preterm born children had some problems, long-term follow-up is warranted to identify those with special needs and to design individual multidisciplinary support programs.
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| 5. |
- Tommiska, Viena, et al.
(författare)
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No improvement in outcome of nationwide extremely low birth weight infant populations between 1996-1997 and 1999-2000
- 2007
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Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 119:1, s. 29-36
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE. Our goal was to investigate whether outcome in extremely low birth weight infants changes over time in Finland. PATIENTS AND METHODS. All infants with a birth weight < 1000 g born in Finland in 1996 - 1997 and 1999 - 2000 were included in the study. Perinatal and follow-up data were collected in a national extremely low birth weight infant research register. Data concerning cerebral palsy and visual impairment were obtained from hospitals, the national discharge, and visual impairment registers. RESULTS. A total of 529 and 511 extremely low birth weight infants were born during 1996 - 1997 and 1999 - 2000. No changes were detected in prenatal, perinatal, neonatal, and postneonatal mortality rates between the periods. The survival rates including stillborn infants were 40% and 44%. The incidence of respiratory distress syndrome and septicemia increased from 1996 - 1997 to 1999 - 2000 (75% vs 83% and 23% vs 31%). The overall incidence of intraventricular hemorrhage increased (29% vs 37%), but the incidence of intraventricular hemorrhage grades 3 through 4 did not (16% vs 17%). The rates of oxygen dependency at the age corresponding with 36 gestational weeks, retinopathy of prematurity stages 3 to 5, cerebral palsy, and severe visual impairment did not change. Mortality remained higher in 1 university hospital area during both periods compared with the other 4 areas, but no regional differences in morbidity were detected during the later period. CONCLUSIONS. No significant changes were detected in birth or mortality rate in extremely low birth weight infants born in Finland during the late 1990s, but some neonatal morbidities seemed to increase. Regional differences in mortality were detected in both cohorts. Repeated long-term follow-up studies on geographically defined very preterm infant cohorts are needed for establishing reliable outcome data of current perinatal care. Regional differences warrant thorough audits to assess causalities.
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