Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies

ICAR: endoscopic skull‐base surgery

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A Cross-Sectional Retrospective Study Assessing Potentially Inappropriate Medications for Elderly Diabetic Patients in a Tertiary Care Hospital in Saudi Arabia

Haifa A Fadil,1 Ziyad S Alrehaili,2 Khaled M Alharbi,3 Abdulaziz F Almuzaini,4 Raed Hamed Alharbi,4 Hindi S Alharbi,4 Hossein M Elbadawy,5,6 Yaser M Alahmadi1 1Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia; 2Medical and Pharmaceutical Services, Pharmacy Department, General Directorate of Medical Services Ministry of Interior, Riyadh, Kingdom of Saudi Arabia; 3Ambulatory Care Pharmacy Department, Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia; 4Pharmaceutical Care Department, King Salman Bin Abdulaziz Medical City, Madinah, Kingdom of Saudi Arabia; 5Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia; 6Health and Life Research Center, Taibah University, Madinah, Saudi ArabiaCorrespondence: Haifa A Fadil, Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia, Email [email protected]: The aging global population presents challenges in medication management, particularly among diabetic elderly patients vulnerable to potentially inappropriate medications (PIM). PIM can lead to adverse outcomes like hypoglycemia, falls, cognitive decline, and hospitalizations, affecting quality of life and survival. This study aimed to assess PIM prevalence among diabetic elderly patients in a tertiary care hospital in Saudi Arabia, using the American Geriatrics Society 2023 Updated Beers Criteria.Methods: A cross-sectional retrospective study was conducted among 480 diabetic adults aged 60 years or older at a tertiary care hospital over 3 months. Data, including demographics, comorbidities, and medication use, were extracted from Electronic Health Records. 2023 AGS Updated Beers Criteria® was followed.Results: The median age was 66 years with a male predominance (62.7%). Peripheral vascular disease (42.7%) and prior myocardial infarction (22.7%) were prevalent comorbidities. Inappropriate insulin use was observed in 17.7% of insulin users, mainly short-acting insulin without basal/long-acting insulin. Approximately 39.2% of patients were prescribed antidiabetic drugs deemed inappropriate by Beers Criteria, with Gliclazide being the most common (35.6%). Despite potential drug–disease interactions, such as urogenital infections, half of the patients received cautioned drugs, while only 4.2% experienced such infections.Conclusion: The study highlights the prevalence of PIMs among diabetic elderly patients in Madinah, Saudi Arabia. Adherence to Beers Criteria guidelines is crucial to optimize therapy for this population. Age and congestive heart failure were significant predictors of PIM use.Keywords: beers criteria, elderly, diabetes, insulin, PIM, Saudi Arabi