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Publication 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 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 multidisciplinary clinical approach to facioscapulohumeral muscular dystrophy orthopedic surgery in facioscapulohumeral dystrophy(Literatura Medica, 2018) N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Çakmak, Özgür Öztop; Eren, İlker; Aslanger, Ayça Dilruba; Günerbüyük, Caner; Kayserili, Hülya; Oflazer, Piraye; Şar, Cüneyt; Demirhan, Mehmet; Özdemir, Yasemin Gürsoy; Faculty Member; Faculty Member; Doctor; Teaching Faculty; Faculty Member; Faculty Member; Doctor; Faculty Member; Faculty Member; School of Medicine; School of Medicine; N/A; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Koc University Hospital; 107818; 168021; N/A; 380939; 7945; N/A; N/A; 9882; 170592Background - Impaired shoulder function is the most disabling problem for daily life of Fascioscapulohumeral muscular dystrophy (FSHD) patients. Scapulothoracic arthrodesis can give a high impact to the functionality of patients. Here we report our experience with scapulothoracic arthrodesis and spinal stenosis surgery in FSHD patients. Patients and methods - 32 FSHD patients were collected between 2015-2016. Demographical and clinical features were documented. All the patients were neurologically examined. The Medical Research Council (MRC) and the FSHD evaluation scale was used to assess muscle involvement(1). Scapulothoracic arthrodesis and spinal stenosis surgeries were performed in eligible patients. Results - There were 16 male and 16 female (mean age 34.4 years; range 12-73) patients. 6 shoulders of 4 patients aged between 2132 years underwent scapulothoracic arthrodesis (two bilateral, one left and one right sided). Only one 63 years old female patient with severe hyperlordosis had spinal fusion surgery. All of the patients undergoing these corrective surgeries have better functionality in daily life, as well as superior shoulder elevation. Conclusion - Until the emergence and clinical use of novel therapeutics, surgical interventions are indicated in carefully selected patients with FSHD to improve arm movements, the posture and the quality of life of patients in general. Scapulothorosic arthrodesis is a management with good clinical results and patient satisfaction. In selected cases other corrective orthopedic surgeries like spinal fusion may also be considered.Publication Metadata only A new lumbar fixation device alternative to pedicle-based stabilization for lumbar spine: in vitro cadaver investigation(Taylor & Francis, 2020) Gomleksiz, Cengiz; Erbulut, Deniz Ufuk; Can, Halil; Kodigudla, Manoj Kumar; Kelkar, Amey, V; Kasapoglu, Eser; Ozer, Ali Fahir; Goel, Vijay K.; Özer, Ali Fahir; Faculty Member; School of Medicine; 1022Context: To evaluate the stability provided by a new bilateral fixation technique using an in vitro investigation for posterior lumbar segmental instrumentation. Design: Experimental cadaver study. In this study, we propose an alternative technique for a posterior lumbar fixation technique called "inferior-oblique transdiscal fixation" (IOTF). Setting: Study performed at Engineering Center for Orthopedic Research Exellence (ECORE) in Toledo University-Ohio. Participants: Six human lumbar cadaveric specimen used in this study. Interventions: In this study, we propose an alternative technique for a posterior lumbar fixation technique called "inferior-oblique transdiscal fixation" (IOTF). As a novel contribution to the classical technique, the entry point of the screw is the supero-lateral point of the intersecting line drawn between the corpus and the pedicle of the upper vertebra. This approach enables the fixation of two adjacent vertebrae using a single screw on each side without utilizing connecting rods. Outcome Measures: Flexion (Flex), extension (Ext), right and left lateral bending (LB & RB), and right and left axial rotation (LR & RR), and the position data were captured at each load step using the Optotrak motion measurement system and compared for IOTF and posterior transpedicular stabilization. Results: The Posterior stabilization system (PSS) and IOTF significantly reduced the ROM of L4-L5 segment compared to intact segment's ROM. During axial rotation (AR) IOTF fused index segment more than PSS. Besides this, addition of transforaminal lumbar interbody fusion (TLIF) cage improved the stabilization of IOTF system during flexion, extension and lateral bending. Whereas, PSS yielded better fusion results during extension compared to IOTF with and without interbody fusion cages. Conclusions: We hypothesized that the new posterior bilateral system would significantly decrease motion compared to the intact spine. This cadaver study showed that the proposed new posterior fusion technique IOTF fused the index segment in a similar fashion to the classical pedicle screw fusion technique.Publication 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 Open Access A novel modular dynamic stabilization system for the treatment of degenerative spinal pathologies(Turkish Neurosurgical Society, 2019) Çevik, Orhun Mete; Erbulut, Deniz Ufuk; Goel, Vijay; N/A; Özer, Ali Fahir; Yaman, Onur; Şentürk, Salim; Öktenoğlu, Bekir Tunç; Sasani, Mehdi; Süzer, Süleyman Tuncer; Faculty Member; Doctor; Doctor; Faculty Member; School of Medicine; 1022; N/A; N/A; N/A; N/A; 221691Aim: to show the preliminary clinical results of the Orthrus modular dynamic stabilization system that is a new instrumentation system intended for degenerative diseases of the lumbar spine. Material and methods: the system utilizes two different types of screws that can be used in conjunction with different types of rods such as titanium, carbon fiber or PEEK. The first type of screw is a double headed screw to interconnect to the upper and lower level with independent rods. The second type of screw is a sliding screw to be used on a immovable vertebrae that allows movement in two planes on the tip. Results: the system has been used on 36 patients with pathology varying from degenerative disc disease to degenerative lumbar scoliosis. Satisfactory results have been obtained in a all 36 patients in the 12-month follow-up period. Conclusion: the Orthrus dynamic system shows better clinical results than the available dynamic systems on the market. It also proves to provide similar fusion with considerably less postoperative morbidity which makes it a better method to treat adult degenerative spine diseases for carefully chosen patients.Publication Metadata only A novel pathogenic variant in the 3ʹ end of the AGTPBP1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype?(Springer, 2021) Turay, Sevim; Eroz, Recep; 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; 1512Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a recently described form of the large group of infantile hereditary lower motor neuron diseases (Teoh et al. 2017), resulting from biallelic damaging variants in the AGTPBP1 gene, first described by Shashi et al. in EMBO J 37(23):e100540, 2018. AGTPBP-related neurodegeneration is a severe neurodevelopmental disorder that progresses with global developmental delay and intellectual disability, often accompanied with peripheral nerve damage and lower motor degeneration and a fatal course in the early years of life. The encoded protein is ATP/GTP-Binding Protein1, also known as cytosolic carboxypeptidase 1 (CCP1) or nervous system nuclear protein induced by axotomy (NNA1). Here we report a consanguineous family with four offspring, two of whom are affected. The index patient is a 21-month-old male with global developmental delay and hypotonia. The proband's 17-year-old sister, diagnosed with cerebral palsy, had severe hypotonia accompanied by motor and cognitive retardation. WES analysis revealed a novel homozygous c.3293G > A variant in the AGTPBP1 gene with high pathogenicity scores. Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents. The affected siblings present with hypotonia and motor and cognitive retardation, in line with the studies previously reported. However, in our patients, no signs of cerebellar atrophy in cranial MRI were present, so the acronym CONDCA is not applicable; lower motor neuron findings were also absent. The matching and distinguishing aspects of our patients will add to the present literature and expand our understanding of this rare genetic neurodegenerative disease of early childhood.Publication Metadata only A novel PNPLA6 mutation in a Turkish family with intractable holmes tremor and spastic ataxia(Springer-Verlag Italia Srl, 2021) Emekli, Ahmed S.; Samancı, Bedia; Şimşir, Gülşah; Hanagasi, Haşmet A.; Gürvit, Hakan; Bilgiç, Başar; 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; 1512Autosomal recessive cerebellar ataxias are a group of rare neurological diseases with a genetic origin. Recently, the mutations in the PNPLA6 gene were suggested to lead to ataxia and also to other specific syndromes such as Boucher-Neuhauser (ataxia, hypogonadism, and chorioretinal dystrophy) or Gordon-Holmes Syndromes (ataxia, hypogonadism, and brisk reflexes) within a broad spectrum of neurodegenerative diseases. Here we report three patients from a single-family with a novel pathogenic mutation in the PNPLA6 gene which led to predominantly spastic-ataxia, and intractable Holmes tremor. The PNPLA6-related disease should be considered in the differential diagnosis of spastic-ataxias even in the absence of chorioretinal dystrophy, and hypogonadotropic hypogonadism. Further studies should unravel the factors which account for the phenotypic variability present in patients with PNPLA6 gene mutations.Publication Metadata only A variation of the cords of the brachial plexus on the right and a communication between the musculocutaneous and median nerves on the left upper limb: a unique case(Thieme Medical Publishers, 2013) Tatarli, Necati; Ceylan, Davut; Hacioglu, Husniye; Uygun, Seda; Seker, Askin; Çavdar, Safiye; Keleş, Güven Evren; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 1995; N/ADuring routine anatomical dissection of the upper extremity of a 64-year-old cadaver for educational purposes, we observed variations in the brachial plexus on each side. On the right an anomaly of cord formation was present and on the left there was a communication between the musculocutaneous nerve (MCN) and median nerve (MN). On the right side the brachial plexus showed two trunks, superior (C5 and C6) and inferior (C7, C8, and T1); the middle trunk was absent. The superior trunk bifurcated into anterior and posterior divisions, the anterior division continued as the lateral cord forming the MCN. The posterior division gave off the subscapular branch. The inferior trunk trifurcated into radial, median, and ulnar nerves. The radial nerve gave off the axillary and thoracodorsal nerves. The ulnar nerve gave off the median cutaneous nerves of the arm and forearm. The median nerve received a small ascending branch from the MCN. On the right side, there was a communicating branch from the MCN to the MN in the lower third of the arm region. This communicating branch also gave rise to a muscular branch to the brachialis muscle and the lateral cutaneous nerve of forearm. No additional heads of the biceps brachii muscle were observed in either upper limb. Knowledge of the variations of the brachial plexus in humans can be valuable for operations of the shoulder joint and its repair for providing an effective block or treatment for anesthetists and also for explaining otherwise incomprehensible clinical signs for neurologists.Publication Metadata only Abo and rh blood groups and risk of myelomeningocele(Turkish Neurosurgical Soc, 2020) Isik, Semra; Cevik, Serdar; Turhan, Ali Haydar; Hanimoglu, Hakan; N/A; Baygül, Arzu Eden; Faculty Member; School of Medicine; 272290AIM: To investigate the relationship between the distribution of ABO or Rhesus (Rh) blood group antigens and the incidence of myelomeningocele. MATERIAL and METHODS: A retrospective data was reviewed for all myelomeningocele patients operated at a tertiary academic hospital between years 2014 and 2019. Age, sex, delivery method, physical and neurological examination findings, and radiological findings alongside with blood type of each patient were recorded. The data of blood group distribution among the study patients was compared to the data of healthy individuals in the same region. RESULTS: Patients with group B and AB showed a higher chance of developing myelomeningocele. Rh-positive blood group was associated with high incidence of myelomeningocele (93.5%), whereas Rh-negative blood group showed least association (6.5%). Rh-positive blood group was also found to be more frequent in patients with myelomeningocele with hydrocephalus and Chiari malformation. CONCLUSION: The findings of this study show that ABO and Rh blood groups have an effect on the development of myelomeningocele under the influence of environmental or genetic factors.