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Publication Metadata only A biallelic mutation links myorg to autosomal-recessive primary familial brain calcification(Oxford University Press (OUP), 2019) Forouhideh, Yalda; Mueller, Kathrin; Ruf, Wolfgang; Assi, Muhannad; Seker, Tuncay; Knehr, Antje; Strom, Tim M.; Gorges, Martin; Schradt, Falk; Meitinger, Thomas; Ludolph, Albert C.; Pinkhardt, Elmar H.; Kassubek, Jan; Uttner, Ingo; Weishaupt, Jochen H.; N/A; Tunca, Ceren; Başak, Ayşe Nazlı; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; School of Medicine; N/A; 1512N/APublication Metadata only A combined clinical and computational approach to understand the sod1a4t-mediated pathogenesis of rapidly progressive familial amyotrophic lateral sclerosis(Wiley, 2019) Gelener, P.; Diker, S.; Ergoren, M. C.; Terali, K.; Tan, E.; N/A; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512Here, we aim to provide a comprehensive clinical and biomolecular description of familial amyotrophic lateral sclerosis (fALS) in a 25-year-old female patient with respect to the SOD1A4T genotype. The clinical diagnosis of the disease was based on family history, neurological examination, electroneurophysiological studies, and revised El Escorial criteria. The heterozygous presence of the A4T mutation in the proband was confrmed by PCR coupled with Sanger sequencing of exon 1 of the SOD1 gene. The mutation was introduced in silico into the three-dimensional structure of the native protein. After energy minimization and quality assessment, non-covalent interactions around threonine-4 and changes in protein stability were calculated computationally. The patient difered widely in age at onset, initial neurological symptoms and fndings, and survival time from her kindred, in which several members are afected. SOD1A4T-linked fALS in this case had bulbar involvement at onset, a combination of lower and upper motor neuron signs and showed rapid progression. Unlike alanine-4, threonine-4 failed to engage in hydrophobic interactions with the vicinal non-polar amino acids. The overall fold of the modeled SOD1A4T mutant remained intact, but unfolding free energy estimations disclosed a decrease in the protein’s stability. We report a phenotypically distinct patient with fALS due to the SOD1A4T mutation and further expand the largest pedigree ever published for SOD1A4T-linked fALS. Genotype‒phenotype correlation in fALS is complex, and it demands detailed clinical investigation and advanced scientifc research. Awareness of the broadened phenotypic spectrum might potentially enhance the diagnosis and genetic counseling of fALS.Publication Metadata only A family from Turkey with congenital myasthenia and hereditary(Wiley, 2023) Tezen, D.; Gündüz, A.; Demirbilek, V.; Khojakulov, Zakhiriddin; Başak, Ayşe Nazlı; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of MedicinePublication Metadata only A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the Covid-19 pandemic(Springer Science and Business Media Deutschland GmbH, 2024) Lal, Anoushka P.; Foong, Yi Chao; Sanfilippo, Paul G.; Spelman, Tim; Rath, Louise; Levitz, David; Fabis-Pedrini, Marzena; Foschi, Matteo; Habek, Mario; Kalincik, Tomas; Roos, Izanne; Lechner-Scott, Jeannette; John, Nevin; Soysal, Aysun; D’Amico, Emanuele; Gouider, Riadh; Mrabet, Saloua; Gross-Paju, Katrin; Cárdenas-Robledo, Simón; Moghadasi, Abdorreza Naser; Sa, Maria Jose; Gray, Orla; Oh, Jiwon; Reddel, Stephen; Ramanathan, Sudarshini; Al-Harbi, Talal; Hardy, Todd A.; Ozakbas, Serkan; Alroughani, Raed; Kermode, Allan G.; Surcinelli, Andrea; Laureys, Guy; Eichau, Sara; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Hodgkinson, Suzanne; Ramo-Tello, Cristina; Maimone, Davide; McCombe, Pamela; Spitaleri, Daniele; Sanchez-Menoyo, Jose Luis; Yetkin, Mehmet Fatih; Baghbanian, Seyed Mohammad; Karabudak, Rana; Al-Asmi, Abdullah; Jakob, Gregor Brecl; Khoury, Samia J.; Etemadifar, Masoud; van Pesch, Vincent; Buzzard, Katherine; Taylor, Bruce; Butzkueven, Helmut; Van der Walt, Anneke; Altıntaş, Ayşe; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicineBackground: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. Methods: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018–March 10 2020) and post-pandemic onset (March 11 2020–11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. Results: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39–2.13;switching: OR 1.66, 95% CI 1.40–1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09–1.87;switching: OR 1.67, 95% CI 1.41–1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06–1.49;Switching: OR 1.15, 95% CI 1.02–1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41–0.73;switching: OR 0.49, 95% CI 0.41–0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41–0.57;switching: OR 0.78, 95% CI 0.62–0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15–0.48;switching: OR 0.27, 95% CI 0.17–0.44)]. Conclusions: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges. © The Author(s) 2024.Publication Metadata only A multicenter international study to evaluate different aspects of relationship between MS and pregnancy(Sage, 2019) Zakaria, M.; Alroughani, R.; Moghadasi, A. N.; Terzi, M.; Sen, S.; Koseoglu, M.; Efendi, H.; Soysal, A.; Gozubatik-Celik, G.; Ozturk, M.; Sahraian, M.; Akinci, Y.; Kaya, Z. E.; Saip, S.; Siva, A.; N/A; Department of Industrial Engineering; Department of Industrial Engineering; Altıntaş, Ayşe; Gönen, Mehmet; Faculty Member; Faculty Member; School of Medicine; College of Engineering; 11611; 237468N/APublication Metadata only A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans(Oxford University Press (OUP), 2014) Pellegrino, Renata; Goel, Namni; Cardinale, Christopher J.; Dinges, David F.; Kuna, Samuel T.; Maislin, Greg; Van Dongen, Hans P. A.; Tufik, Sergio; Hogenesch, John B.; Hakonarson, Hakon; Pack, Allan I.; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Kavaklı, İbrahim Halil; Faculty Member; College of Engineering; 40319Study Objectives: Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loop-helix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Design: Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. Results: We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. Conclusions: There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis.Publication Metadata only Adjuvant versus on-progression Gamma Knife radiosurgery for residual nonfunctioning pituitary adenomas: A matched-cohort analysis(Amer Assoc Neurological Surgeons, 2023) Mantziaris, Georgios; Pikis, Stylianos; Chytka, Tomas; Liscak, Roman; Sheehan, Kimball; Sheehan, Darrah; Bindal, Shray K.; Niranjan, Ajay; Lunsford, L. Dade; Kaur, Rupinder; Madan, Renu; Tripathi, Manjul; Pangal, Dhiraj J.; Strickland, Ben A.; Zada, Gabriel; Langlois, Anne-Marie; Mathieu, David; Warnick, Ronald E.; Patel, Samir; Minier, Zayda; Speckter, Herwin; Xu, Zhiyuan; Anand, Rithika Kormath; Sheehan, Jason P.; Peker, Selçuk; Samancı, Mustafa Yavuz; School of MedicineOBJECTIVE Radiological progression occurs in 50%-60% of residual nonfunctioning pituitary adenomas (NFPAs). Stereotactic radiosurgery (SRS) is a safe and effective management option for residual NFPAs, but there is no consen-sus on its optimal timing. This study aims to define the optimal timing of SRS for residual NFPAs. METHODS This retrospective, multicenter study involved 375 patients with residual NFPAs managed with SRS. The patients were divided into adjuvant (ADJ;treated for stable residual NFPA within 6 months of resection) and progression (PRG) cohorts (treated for residual NFPA progression). Factors associated with tumor progression and clinical deteriora-tion were analyzed.RESULTS Following propensity-score matching, each cohort consisted of 130 patients. At last follow-up, tumor con-trol was achieved in 93.1% of patients in the ADJ cohort and in 96.2% of patients in the PRG cohort (HR 1.6, 95% CI 0.55-4.9, p = 0.37). Hypopituitarism was associated with a maximum point dose of > 8 Gy to the pituitary stalk (HR 4.5, 95% CI 1.6-12.6, p = 0.004). No statistically significant difference was noted in crude new-onset hypopituitarism rates (risk difference [RD] = -0.8%, p > 0.99) or visual deficits (RD = -2.3%, p = 0.21) between the two cohorts at the last follow-up. The median time from resection to new hypopituitarism was longer in the PRG cohort (58.9 vs 29.7 months, p = 0.01).CONCLUSIONS SRS at residual NFPA progression does not appear to alter the probability of tumor control or hormon-al/visual deficits compared with adjuvant SRS. Deferral of radiosurgical management to the time of radiological progres- sion could significantly prolong the time to radiosurgically induced pituitary dysfunction. A lower maximum point dose (< 8 Gy) to the pituitary stalk portended a more favorable chance of preserving pituitary function after SRS. https://thejns.org/doi/abs/10.3171/2022.10.JNS221873Publication Metadata only Alexithymia and depression may predict treatment failure in patients undergoing Gamma Knife radiosurgery for trigeminal neuralgia: the potential contribution of colored pain drawings(American Association of Neurological Surgeons, 2023) Samancı, Mustafa Yavuz; Öner, Sanem Sultan Yörük; Peker, Selçuk; School of Medicine; Koç University HospitalOBJECTIVE Gamma Knife radiosurgery (GKRS) effectively achieves high rates of pain control in trigeminal neuralgia (TN); however, psychological factors can also impact how individuals perceive pain and respond to treatment. The authors aimed to measure the effects of alexithymia and depression on GKRS outcomes, as well as the potential role of colored pain drawings (CPDs) in identifying patients who require additional psychological support. METHODS Seventy-three medically intractable, typical patients with TN were included. Participants completed a visual analog scale (VAS), the Toronto Alexithymia Scale (TAS-20), and the Turkish version of the Beck Depression Inventory-II (BDI-II). Participants used colored pens to draw their pain patterns on standardized face charts and CPDs were categorized as expected or unexpected. Based on the Barrow Neurological Institute pain scale, patients were categorized as responders or nonresponders. RESULTS Most patients (63%) were female, and the median age was 60 (range 27–88) years. Of 73 patients, 56 (76.7%) were responders and 17 (23.3%) were nonresponders. Forty-nine patients (67.1%) had expected CPDs, whereas 24 (32.9%) had unexpected CPDs. Responder and nonresponder groups had similar ages, genders, education, comorbidities, and initial VAS scores. Both groups preferred the colors red and black to describe intense pain (79.2% vs 67.3%, p = 0.411). Significantly better pain relief was observed in patients with expected CPDs than in those with unexpected CPDs (87.8% vs 54.2%, p = 0.003). The unexpected CPD group had significantly more alexithymia (58.3% vs 32.7%, p = 0.045). The mean BDI-II score of the cohort was 26 (range 15–37) and was significantly higher in the unexpected group (28.3 vs 24.8, p = 0.028). Unexpected CPD (OR 12.540) and higher TAS-20 score (OR 3.22) increased treatment failure risk. CONCLUSIONS The outcomes of TN treatment can be influenced by psychological factors, and patients with TN with higher total TAS-20 and BDI-II scores, along with unexpected CPDs, had an increased likelihood of treatment failure. CPDs can be accessed quickly and may allow the physician to screen out most patients with unfavorable psychometrics and proceed with the necessary treatment with appropriate psychological support.Publication Metadata only Alterations in expressions of DNA base excision repair (BER) genes in unipolar and bipolar depression(N/A, 2022) Yılmaz, Selda; Akan, Pınar; Özerdem, Ayşegül; N/A; Ceylan, Deniz; Baysal, Kemal; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 137755; 119184N/APublication Metadata only An unusual familial dementia associated with G131V PRNP mutation(Wiley, 2021) Yetim, Ezgi; Saka, Esen; N/A; N/A; Gül, Tuğçe; Başak, Ayşe Nazlı; PhD Student; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; 1512Background Gerstmann-Struassler-Scheinker disease is one of the familial prion diseases secondary to mutations in the prion protein gene (PRNP). The clinical phenotype has a diverse spectrum and might show variation among cases with the same genotype. We report a patient with G131V mutation in thePRNPgene, who was initially considered to harbor familial Alzheimer's disease, based on the family history, clinical presentation and imaging findings. Methods A case with a G131V mutation in thePRNPgene is described, and the literature is reviewed. Results A 35-year-old man presented with personality changes, behavioral disturbances and cognitive complaints. A similar clinical phenotype was reported in the patient's father, a paternal uncle and a paternal aunt. In conjunction with the observation of mild cerebral atrophy on magnetic resonance imaging and hypometabolism in bilateral temporal and parietal lobes on positron-emission tomography studies, the diagnosis was initially considered as familial Alzheimer's disease. However, whole-exome sequencing of the index patient, confirmed with Sanger sequencing in his father and uncle, revealed the presence of a heterozygous G131V variant in thePRNPgene. Conclusion To the best of our knowledge, this is the third report of a G131V mutation in thePRNPgene in the literature. Although ataxia and extrapyramidal findings accompanied dementia in patients reported in the previous literature, the members of the family in the present case primarily reported cognitive impairment, underscoring the importance of genetic evaluation in familial early-onset dementia patients, regardless of clinical and imaging features suggestive of alternative pathologies.