Salpietro, V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, Maroofian R, Heimer G, Burglen L, Valence S et al..
2019.
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders, 2019. Nature Communications. 10(1)
AbstractAMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
Akinyemi, RO, Sarfo FS, Akinyemi J, Singh A, Onoja Akpa M, Akpalu A, Owolabi L, Adeoye AM, Obiako R, Wahab K, Sanya E, Komolafe M, Ogbole G, Fawale M, Adebayo P, Osaigbovo G, Sunmonu T, Olowoyo P, Chukwuonye I, Obiabo Y, Adeniji O, Fakunle G, Melikam E, Saulson R, Yaria J, Uwanruochi K, Ibinaiye P, Amusa GA, Yahaya IS, Dambatta AH, Faniyan M, Olowoniyi P, Bock-Oruma A, Joseph OC, Oguntade A, Kolo P, Laryea R, Lakoh S, Uvere E, Farombi T, Akpalu J, Oyinloye O, Appiah L, Calys-Tagoe B, Shidali V, Tabari NA, Adebayo O, Efidi R, Adeleye O, Owusu D, Ogunjimi L, Aridegbe O, Imoh CL, Sanni T, Gebreziabher M, Hemant T, Arulogun O, Ogunniyi A, Jenkins C, Owolabi M, Ovbiagele B.
2019.
Knowledge, attitudes and practices of West Africans on genetic studies of stroke: Evidence from the SIREN Study, 2019. International Journal of Stroke. 14(1)
AbstractBackground: It is crucial to assess genomic literacy related to stroke among Africans in preparation for the ethical, legal and societal implications of the genetic revolution which has begun in Africa. Objective: To assess the knowledge, attitudes and practices (KAP) of West Africans about stroke genetic studies. Methods: A comparative cross-sectional study was conducted among stroke patients and stroke-free controls recruited across 15 sites in Ghana and Nigeria. Participants' knowledge of heritability of stroke, willingness to undergo genetic testing and perception of the potential benefits of stroke genetic research were assessed using interviewer-administered questionnaire. Descriptive, frequency distribution and multiple regression analyses were performed. Results: Only 49% of 2029 stroke patients and 57% of 2603 stroke-free individuals knew that stroke was a heritable disorder. Among those who knew, 90% were willing to undergo genetic testing. Knowledge of stroke heritability was associated with having at least post-secondary education (OR 1.51, 1.25–1.81) and a family history of stroke (OR 1.20, 1.03–1.39) while Islamic religion (OR=0.82, CI: 0.72–0.94), being currently unmarried (OR = 0.81, CI: 0.70–0.92), and alcohol use (OR = 0.78, CI: 0.67–0.91) were associated with lower odds of awareness of stroke as a heritable disorder. Willingness to undergo genetic testing for stroke was associated with having a family history of stroke (OR 1.34, 1.03–1.74) but inversely associated with a medical history of high blood pressure (OR = 0.79, 0.65–0.96). Conclusion: To further improve knowledge of stroke heritability and willingness to embrace genetic testing for stroke, individuals with less formal education, history of high blood pressure and no family history of stroke require targeted interventions.
Chelban, V, Wilson MP, Warman Chardon J, Vandrovcova J, Zanetti MN, Zamba-Papanicolaou E, Efthymiou S, Pope S, Conte MR, Abis G et al..
2019.
PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation, 2019. Annals of Neurology. 86(2)
AbstractObjective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.
Sharma, A, Alatise O, Adisa A, Arowolo O, Olasehinde O, Famurewa O, Omisore A, Komolafe A, Olaofe O, Katung A, Ibikunle D, Egberongbe A, Olatoke S, Agodirin O, Adesiyun A, Adeyeye A, Ibrahim K, Kolawole O, Idris O, Kingham T.
2019.
Treatment of colorectal cancer in Sub‐Saharan Africa: Results from a prospective Nigerian hospital registry, 11. Journal of Surgical Oncology. 121
Abstractn/a
Olanrewaju, F.O., Oripelaye, M.M., Akinboro, A.O., Oninla, O. A., Echekwube, P.O., Olasode, O.A., Onayemi EO.
2019.
Frequency and Clinical Variants of Pigmentary Dermarcation Lines in Pregnancy in a Tertiary Health Facility, South Western Nigeria. . Nigerian Journal of Dermatology. 9(1):14-20.