Publications by authors named "Marilena Christoforou"

3 Publications

  • Page 1 of 1

Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy.

Epilepsia 2021 Feb 7;62(2):e35-e41. Epub 2021 Jan 7.

Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.
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February 2021

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.

J Med Genet 2020 Nov 10. Epub 2020 Nov 10.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Background: Pathogenic variants of encoding the β subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.

Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of loss in mouse.

Results: We delineated a key role of in heart sinus conduction and showed that -inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. mice were smaller and had a smaller heart than and , but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in mice. In contrast, mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.

Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of signalling in the autonomic control of the heart will pave the way for future drug screening.
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November 2020

Energetic, antioxidant, inflammatory and cell death responses in the red muscle of thermally stressed Sparus aurata.

J Comp Physiol B 2020 07 25;190(4):403-418. Epub 2020 Apr 25.

Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.

For a comprehensive understanding of fish responses to increasing thermal stress in marine environments, we investigated tissue energetics, antioxidant levels, inflammatory and cell death responses in Sparus aurata (gilthead seabream) red muscle during exposure to elevated temperatures (24 °C, 26 °C, 30 °C) compared to the control temperature of 18 °C. Energetic aspects were assessed by determining lactate, glucose and lipids levels in blood plasma, ATP, ADP and AMP levels, and AMPK phosphorylation as an indicator of regulatory changes in energy metabolism, in tissue extracts. Oxidative defence was assessed by determining superoxide dismutase, catalase and glutathione reductase maximum activities. Moreover, xanthine levels were determined as an indicator of purine conversion to xanthine and associated ROS production. In the context of inflammatory response and cell death due to oxidative stress, pro-inflammatory cytokines (IkBα phosphorylation, IL-6 and TNFα) levels, and LC3 II/I ratio and SQSTM1/p62 as indicators of autophagic-lysosomal pathway were also determined. A recovery in the efficacy of ATP production after a marked decrease during the 1st day of exposure to 24 °C is observed. This biphasic pattern is paralleled by antioxidant enzymes' activities and inflammatory and autophagy responses, indicating a close correlation between ATP turnover and stress responses, which may benefit tissue function and survival. However, exposure beyond 24 °C caused tissue's antioxidant capacity loss, triggering the inflammatory and cell death response, leading to increased fish mortality. The results of the present study set the thermal limits of the gilthead seabream at 22-24 °C and establish the used cellular and metabolic indicators as tools for the definition of the extreme thermal limits in marine organisms.
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July 2020