| 31. |
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| 32. |
- Fellman, Vineta, et al.
(författare)
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Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause
- 2008
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 53:6, s. 554-558
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Tidskriftsartikel (refereegranskat)abstract
- The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III (CIII). A homozygous point mutation (232A -> G) has been found as the genetic etiology for fetal growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome (MIM 603358). Variable phenotypes have been found with other mutations. Our aim was to assess whether 232A -> G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder. A further aim was to confirm the GRACILE genotype-phenotype constancy (n = 8). Three new cases with homozygous 232A -> G mutation were identified; all had the primary GRACILE characteristics. No other mutations were found in the gene in other cases. All infants with GRACILE syndrome had the typical mutation. In conclusion, the rather homogenous population of Finns seems to have a specific BCS1L mutation that, as homozygous state, causes GRACILE syndrome, whereas other mutations are rare or not occurring. Thus, the novel clinical implication of this study is to screen for BCS1L mutations only if CIII is dysfunctioning or lacking Rieske protein, and to assess 232A -> G mutation in cases with GRACILE syndrome.
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| 33. |
- Fellman, Vineta, et al.
(författare)
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Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1
- 2022
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Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier BV. - 0925-4439. ; 1868:1
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Tidskriftsartikel (refereegranskat)abstract
- In the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome (3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy, and Leigh-like syndrome). The SERAC1 protein is located at the contact site between mitochondria and the endoplasmic reticulum (ER) and is crucial for cholesterol trafficking. Our aim was to investigate the effect of the homozygous truncating mutation on mitochondrial structure and function. In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial network was severely fragmented, and the cristae morphology was altered. Filipin staining showed uneven localization of unesterified cholesterol. The calcium buffer function between cytoplasm and mitochondria was deficient. In liver mitochondria, complexes I, III, and IV were clearly decreased. In transfected COS-1 cells the mutant protein with the a 45-amino acid C-terminal truncation was distributed throughout the cell, whereas wild-type SERAC1 partially colocalized with the mitochondrial marker MT-CO1. The structural and functional mitochondrial abnormalities, caused by the loss of SERAC1, suggest that the crucial disease mechanism is disrupted interplay between the ER and mitochondria leading to decreased influx of calcium to mitochondria and secondary respiratory chain deficiency.
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| 34. |
- Gram, Magnus, et al.
(författare)
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The radical-binding lipocalin A1M binds to a Complex I subunit and protects mitochondrial structure and function.
- 2013
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Ingår i: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 18:16, s. 2017-2028
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Tidskriftsartikel (refereegranskat)abstract
- Aims: During cell death, energy-consuming cell degradation and recycling programs are performed. Maintenance of energy-delivery during cell death is therefore crucial but the mechanisms to keep the mitochondrial functions intact during these processes are poorly understood. We have investigated the hypothesis that the heme- and radical-binding ubiquitous protein A1M (α1-microglobulin) is involved in protection of the mitochondria against oxidative insult during cell death. Results: Using blood cells, keratinocytes and liver cells, we show that A1M binds with high affinity to apoptosis-induced cells and is localized to mitochondria. The mitochondrial Complex I subunit NDUFAB1 was identified as a major molecular target of the A1M-binding. Furthermore, A1M was shown to inhibit the swelling of mitochondria, and to reverse the severely abrogated ATP-production of mitochondria when exposed to heme and ROS. Innovation: Import of the radical- and heme-binding protein A1M from the extracellular compartment confers protection of mitochondrial structure and function during cellular insult. Conclusion: A1M binds to a subunit of Complex I and has a role in assisting the mitochondria to maintain its energy delivery during cell death. A1M may also, at the same time, counteract and eliminate the ROS generated by the mitochondrial respiration to prevent oxidative damage to surrounding healthy tissue.
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| 35. |
- Haavisto, Anu, et al.
(författare)
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Latent class growth analysis identified different trajectories in cognitive development of extremely low birthweight children
- 2022
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Ingår i: BMJ Paediatrics Open. - : BMJ. - 2399-9772. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Recent longitudinal studies suggest stable cognitive development in preterm children, although with great individual variation. This prospective neurocognitive follow-up study of extremely low birthweight (ELBW, <1000 g) children aimed to characterise groups with different developmental trajectories from preschool to preteen age. Methods ELBW children (n=115) born in Finland in 1996-1997 participated in cognitive assessments at a median age of 5.0 years and 11.3 years. A standardised test of intelligence (Wechsler Preschool and Primary Scale of Intelligence-Revised or Wechsler Intelligence Scale for Children-third edition) was administered at both ages. Results Three ELBW groups with different developmental trajectories over time were identified with latent class growth analysis. Children with average (Full-Scale IQ (FSIQ): 85-115) and below average (FSIQ: <85) intelligence at 5 years of age had significant decreases in intelligence scores by 11 years of age (-11.7 points and -14.9 points, respectively, both p<0.001), while those with above average intelligence (FSIQ: >115) showed stable development (-3.2 points, p=0.250). Multiple linear regression showed that neonatal complications (intraventricular haemorrhage grade 3-4 and blood culture positive sepsis) and maternal education significantly predicted lower intelligence at the second assessment (F(3,106)=7.27, p<0.001, adjusted R 2 =0.147). Conclusions ELBW children represent a heterogeneous patient population in which groups with different cognitive trajectories can be detected. Deterioration may occur particularly in children with initial average or below average cognitive performance at 5 years of age, with neonatal complications and lower maternal education presenting as risk factors. Catch-up in cognitive functions seems more uncommon in the ELBW population, which should be noted in clinical work.
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| 36. |
- Hansen-Pupp, Ingrid, et al.
(författare)
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Postnatal Decrease in Circulating Insulin-Like Growth Factor-I and Low Brain Volumes in Very Preterm Infants.
- 2011
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96:4, s. 1129-1135
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Tidskriftsartikel (refereegranskat)abstract
- Context: IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. Objective: The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. Design: Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. Main Outcome Measures: We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. Results: Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. Conclusion: Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants.
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| 37. |
- Hikmat, O., et al.
(författare)
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Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:11, s. 2155-2165
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers. Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results: Thirty-three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation: The phenotypic spectrum of BCS1L-related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L-related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.
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| 38. |
- Huotilainen, Minna, et al.
(författare)
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Auditory magnetic responses of healthy newborns
- 2003
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Ingår i: NeuroReport. - 1473-558X. ; 14:14, s. 1871-1875
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Tidskriftsartikel (refereegranskat)abstract
- We recorded magnetic brain activity from healthy human newborns when they heard frequency changes in an otherwise repetitive sound stream. We were able to record the magnetic counterpart of the mismatch negativity (MMN) previously described only with electric recordings in infants. The results show that these recordings are possible, although still challenging due to the small head size and head movements. The modelling of the neural sources underlying the recorded responses suggests cortical sources in the temporal lobes.
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| 39. |
- Huotilainen, Minna, et al.
(författare)
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Could audiovisual training be used to improve cognition in extremely low birth weight children?
- 2011
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Ingår i: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 100, s. 1489-1494
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To study whether a dyslexia remediation programme, Audilex, improves cognition in extremely low birth (ELBW) children. Methods: Six-year-old ELBW children were allocated to a 5-week training with Audilex or playing control computer games. Before and after intervention, auditory event-related brain potentials (ERP) to sound changes were recorded and reading related skills assessed. Primary outcome was the mismatch negativity (MMN) component of ERP. Secondary outcomes were Audilex Test (ability to perform the Audilex games), the reading skills after the intervention and 2 years later. Of eligible children, 39 (54%) consented and 22 (30%) completed the protocol. Results: The MMN responses to the frequency (p = 0.02) and duration deviants (p < 0.01) increased after Audilex training (n = 11), but not after control game playing (n = 11). Audilex Test performance was similar in both groups. The reading skills were similar after intervention and 2 years later; word reading score 59.7, 66.8 and 74.9 and comprehensive reading score 8.1, 8.8 and 9.4 in Audilex, Control and healthy class-mate children, respectively. Conclusions: Although all children did not complete the protocol, the results suggest that training with Audilex dyslexia programme might be beneficial for enhancing neural-level sound discrimation and possibly reading skills in ELBW children. A larger trial is warranted.
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| 40. |
- Högberg, Ulf, 1949-, et al.
(författare)
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Difficult birth is the main contributor to birthrelated fracture and accidents to other neonatal fractures
- 2020
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 109:10, s. 2040-2048
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Specific birthrelated fractures have been studied; underestimates might be a problem. We aimed to assess all fractures diagnosed as birthrelated as well as other neonatal fractures.METHODS: A population-based study on all infants born in Sweden 1997-2014; data was retrieved from the Swedish Health Registers (10th version of International Classification of Diseases. Outcome measures were birthrelated fractures (ICD-10 P-codes) and other neonatal fractures (ICD-10 S-codes).RESULTS: The overall fracture incidence was 2.9 per 1,000 live birth (N=5,336); 92.6% had P-codes and 7.4% (S-codes). Some birthrelated fractures were diagnosed beyond the neonatal period. Other neonatal fractures could have been birthrelated. Clavicle fracture, (88.8%) was associated with adverse maternal- and infant anthropometrics and birth complications. The few neonates with rib fractures all had concomitant clavicle fracture. For skull fractures, a minor part was birthrelated, most were associated with accidents. Half of the long bone fractures were associated with accidents. Birthrelated femur fractures were associated with bone fragility risk factors. Five infants with abuse diagnoses had fractures: skull (4), long bone (2), and rib (1).CONCLUSION: Birthrelated and other neonatal fractures are rarely diagnosed. Difficult birth is the main contributor to birthrelated fracture, and accidents to other neonatal fractures.
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