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Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

AIM: To identify the copy number variations that are specific to myxopapillary ependymomas (MPEs) of the cauda equina. MATERIAL and METHODS: The patient cohort included five patients who underwent resection of histologically confirmed MPEs. Tumor samples collected during surgery and stored in liquid nitrogen as well as corresponding blood samples collected were analyzed. Genomic DNA from the venous blood and tumor samples was obtained using standard techniques and hybridized to a Cytoscan 750K Array in accordance with the manufacturer's introductions. RESULTS: As a novel finding, amplification on chromosome 14q32.33 was detected in all tumor and blood samples, except one tumor sample. All tumor tissues also showed amplification on chromosomes 5, 7, 9, and 16. CONCLUSION: Although further studies with larger cohorts are required to identify genes involved in MPE tumorigenesis and to validate our results, these findings provide a basis for advanced molecular biological and genetic studies of MPEs.

We report a 45 years old female patient with a left temporal grade II oligodendroglioma that recurred on the wall of the fourth ventricle at grade II oligodendroglioma.

WOS: 000358382400025, PubMed ID: 26005079, Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.

WOS: 000306664500011, PubMed ID: 22797413, Background: Restless legs syndrome (RLS) is a sensorimotor disorder in which affected individuals suffer from uncomfortable sensations and an urge to move their lower limbs; it occurs mainly in resting situations during the evening or at night. Multiple chromosomal loci have been mapped for RLS through family-based linkage analysis, and genome-wide association studies but causative mutations have not been identified yet. Method: We identified an RLS family from the eastern part of central Turkey which has 10 patients suffering from this syndrome. Whole genome linkage analysis was performed in family members who consented for study (9 affected and 2 unaffected). Results: A theoretical maximum logarithm of the odds score of 3.29 was identified at chromosome 13q32.3-33.2. This result shows strong genetic linkage to this locus. Conclusions: We demonstrated a genetic linkage at chromosome 13 in a RLS family. Further investigation in this linkage area may reveal a causative gene leading to RLS phenotype and may illuminate the pathogenesis of this disease. This study supports the genetic heterogeneity in the pathogenesis of this syndrome. Copyright (C) 2012 S. Karger AG, Basel, Scientific Research Project Fund of Cumhuriyet University [T-455], This work is supported by the Scientific Research Project Fund of Cumhuriyet University under project No. T-455.

A Patient With Duchenne Muscular Dystrophy and Autism Demonstrates a Hemizygous Deletion Affecting Dystrophin Ozdem Erturk, Kaya Bilguvar, Baris Korkmaz, Yasar Bayri, Fatih Bayrakli, Zulfikar Arlier, Ali K. Ozturk, Cengiz Yalcinkaya, Beyhan Tuysuz, Matthew W. State, and Murat Gunel* Division of Child Neurology, Department of Neurology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut Division of Genetics, Department of Pediatrics, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey Department of Genetics, Yale University, New Haven, Connecticut Child Study Center, Yale University School of Medicine, New Haven, Connecticut Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut

✓ Primary meningeal osteosarcomas are rare tumors, with only 19 reported cases in the literature; only 4 of these, including the present case, are in pediatric patients. In this report, the authors present the case of an 8-year-old boy with a history of generalized tonic–clonic seizures who was found to harbor a meningeal osteosarcoma within the sylvian fissure. Initial working diagnoses included meningioma and glioma. After tumor enlargement and progressive symptoms, the patient underwent a large frontotemporal craniotomy and complete resection of the lesion, which recurred 6 and 12 months after the initial surgery and was surgically treated after each recurrence. The rarity of primary meningeal osteosarcomas can make their diagnosis difficult, and histopathological evaluation is mandatory for diagnosis. Because of their fast progression, they must be treated aggressively by means of surgery, chemotherapy, and radiotherapy.

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis from deinnervated sweat glands, and delayed mental and motor development. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1), a receptor in the neurotrophin signaling pathway phosphorylated in response to nerve growth factor, are associated with this disorder. We identified six families from Northern Central Turkey with HSAN IV. We screened the NTRK1 gene for mutations in these families. Microsatellite and single nucleotide polymorphism (SNP) markers on the Affymetrix 250K chip platform were used to determine the haplotypes for three families harboring the same mutation. Screening for mutations in the NTRK1 gene demonstrated one novel frameshift mutation, two novel nonsense mutations, and three unrelated kindreds with the same splice-site mutation. Genotyping of the three families with the identical splice-site mutation revealed that they share the same haplotype. This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population.

Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay.The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million-bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure. RESULTS. Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion.A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister-Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

Trigeminal nerve schwannomas account for 0.07%-0.28% of all intracranial tumours. Advances in skull base surgery have led to more aggressive resection of these tumours, but surgery may associated with development of new neurological deficits.In this report, we analyse the long-term results 15 patients with newly diagnosed or residual/recurrent trigeminal schwannoma who underwent gamma-knife treatment.During a mean 61 months of follow-up, MRI revealed reduction of tumour size in 13 and no size change in 2 patients. The tumour growth control rate was 100% and only 1 patient had transient facial numbness and diplopia.For patients with small to moderate size trigeminal schwannomas, gamma-knife radiosurgery is associated with good tumour control and a minimal risk of adverse radiation effects.

Despite advances in the treatment of intracranial aneurysms (IA) in recent years, the overall outcome of patients with aneurysmal subarachnoid hemorrhage has shown only modest improvement. Given this poor prognosis, diagnosis of IA before rupture is of paramount importance. Currently, there are no reliable methods other than screening imaging studies of high-risk individuals to diagnose asymptomatic patients. Multiple levels of evidence suggest that environmental factors acting in concert with genetic susceptibilities lead to the formation, growth, and rupture of aneurysms in these patients. Epidemiological studies have already identified aneurysm-specific risk factors such as size and location, as well as patient-specific risk factors, such as age, sex, and presence of medical comorbidities, such as hypertension. In addition, exposure to certain environmental factors such as smoking have been shown to be important in the formation of IA. Furthermore, substantial evidence proves that certain loci contribute genetically to IA pathogenesis. Genome-wide linkage studies using relative pairs or rare families that are affected with the Mendelian forms of IA have already shown genetic heterogeneity of IA, suggesting that multiple genes, alone or in combination, are important in the disease pathophysiology. The linkage results, along with association studies, will ultimately lead to the identification of IA susceptibility genes. Identification of the genes important in IA pathogenesis will not only provide novel insights into the primary determinants of IA, but will also result in new opportunities for early diagnosis in the preclinical setting. Ultimately, novel therapeutic strategies based on biology will be developed, which will target these newly elucidated genetic susceptibilities.

We report on an apparently new syndrome in a consanguineous family with seven members, three of whom have cerebral anomalies including pachygyria and arachnoid cysts along with mental retardation and seizures. The two patients with seizure disorders also had multiple enlarged perivascular spaces seen in the white matter of the centrum semiovale. Our data provide a contribution to the accumulating knowledge on familial cerebral anomalies including arachnoid cysts and lissencephaly. Given the lack of mutation in known lissencephaly genes such as LIS1, 14-3-3epsilon, and DCX, this syndrome may constitute a new phenotype with autosomal recessive inheritance.

Pantothenate kinase-associated neurodegeneration (PKAN) syndrome is an autosomal-recessive neurodegenerative disease that causes progressive generalized dystonia. Currently, the disorder remains pharmacologically intractable. Herein we report the first case in which deep brain stimulation helped to relieve dystonic storm in a patient with PKAN syndrome who had homozygous c.628 2 T > G mutation of the PANK2 gene. A 10-year-old boy with PKAN disease presented with dystonic storm and was admitted to the emergency department. Examination revealed generalized dystonia and impaired breathing due to involvement of the respiratory muscles. The patient underwent surgery for bilateral globus pallidus internus deep brain stimulation. The patient showed marked response to treatment.

We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853\_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease.

PubMed ID: 16256845, Background: Oncological treatment of a neoplasm is more than surgical removal of the tumor. Probably, this truth is the reason for the ongoing discussion on cavernous sinus meningiomas in the last decade. Debate on optimal management of cavernous sinus meningiomas aims to compare the different treatment strategies: (a) radical surgical resection and (b) conservative surgical resection complemented with radiosurgical treatment. Materials and Methods: Natural history of the change in the management strategy of cavernous sinus meningiomas in our department before and after GK facility became available in 1997 allowed us to compare the 2 aforementioned strategies. Before installation of a Leksell GK unit at the hospital in 1997, the neurosurgical team at Marmara University Institute of Neurological Sciences and Faculty of Medicine (Istanbul, Turkey) treated patients with cavernous sinus meningioma using radical resection (radical strategy, group A, 10 patients). After 1997, the same neurosurgical team used understanding of surgical removal of the extracavernous sinus tumor component with GK irradiation of the intracavernous part (conservative strategy, group B, 12 patients). Another group of patients, who were treated with GK as a first-step treatment, was analyzed (GK group, group C, 26 patients). Results: At the end of the third year, more stable tumor volume control was achieved in groups B and C; after the second year, an incline in the tumor volume-time graph was detected. Group B resulted in less cranial nerve-related complications; a certain degree of improvement in cranial nerve deficits was observed. Conclusion: Comparing 2 different management strategies for cavernous sinus meningiomas in the same hospital setting using the same neurosurgical group, we conclude that extracavernous resection followed by GK is as effective as radical surgery. Considering cranial nerve complications and third-year tumor volume control achievement, conservative approach yielded better results. Longer follow-up with larger series is necessary. © 2005 Elsevier Inc. All rights reserved., Scientific activities of Türker Kılıç, MD, PhD, have been financially supported by Turkish Academy of Sciences.

The fact that BRCA genes operate as tumor suppressors is evident from the genetics of the different human disorders caused by inherited mutations. Germline mutations affecting 1 allele of either BRCA1 or BRCA2 confer susceptibility to different types of cancers such as breast cancer and medulloblastoma. A family with a history of cancer was identified in Eastern Turkey in which one of the family members (a 13-year-old boy) had medulloblastoma. Venous blood was collected from available family members. The BRCA1 and BRCA2 genes were sequenced in the patient with medulloblastoma and the healthy father. An Asn372His homozygous variation was noted in the BRCA2 gene in the patient with medulloblastoma whereas the variation was heterozygous in the healthy father. A biallelic homozygous variation was demonstrated in the BRCA2 gene, which is important in medulloblastoma suppression, and may have caused medulloblastoma formation in the 13-year-old boy. Further investigations in large human populations with medulloblastoma are necessary for further delineation of BRCA gene malfunctions and their relationship to medulloblastoma formation, and to clarify the therapeutic implications of these malfunctions.

Perineural cysts are believed to be asymptomatic; however, they rarely cause symptoms related to nerve root compression. Cervical symptomatic perineural cysts are in fact exceedingly rare. There are no reported cervical perineural cysts in the literature that present like cubital tunnel syndrome. A patient with motor weakness of the abductor and adductor muscles of the fingers of the left hand and hypoesthesia in the hypothenar region of the left hand presented at our clinic. A neurological examination, and neuroradiological and electrophysiological evaluations supported the finding that the patient’s clinical condition was caused by a perineural cyst located around the C8 neural root. The neurological symptoms of the patient markedly improved after medical treatment. We reported the first cervical perineural cyst as presenting like cubital tunnel syndrome patient in the literature. The visualization of perineural cyst may need extra magnetic resonance imaging (MRI) sections in order to view the nerve root through the neural foramen or extraforaminal area. These lesions are benign, and the appropriate treatment is curative.

Background Intraventricular hemorrhage, which has a poor prognosis, is an extremely rare presenting symptom of central nervous system vasculitis. Sneddon syndrome, which is a systemic vasculitic disease, generally presents with ischemic stroke and livedo reticularis. Intraventricular hemorrhage is extremely rare in Sneddon syndrome and has not been reported as the presenting complaint. Methods We report a 37-year-old woman who presented with acute intraventricular hemorrhage, and on further evaluation her condition was diagnosed as Sneddon syndrome. Results Patient underwent ventriculoperitoneal shunting operation for hydrocephalus and her condition markedly improved 6 months later; she was independent in her activities of daily living. Conclusions In this report, we emphasize the importance of multisystemic evaluation of patients, especially those with obscure angiography findings.

S. Karger AG, Background: Cerebellar hypoplasia (CH) is a rare malformation caused by various etiologies, usually manifesting clinically as nonprogressive cerebellar ataxia with or without mental retardation. The molecular pathogenesis of the autosomal recessive cerebellar ataxias has a wide range of mechanisms. Differential diagnosis and categorization of the recessive cerebellar ataxias, however, need more specific, biochemical and genetic investigation. Methods: This study applied whole-genome linkage analysis to study a family with nonprogressive cerebellar ataxia and additional mental retardation, epilepsy, and facial dysmorphic features. Genotyping and linkage analysis was done using the GeneChip Mapping 250K NspI Array (Affymetrix Inc., Santa Clara, Calif., USA) for genome-wide linkage analysis of the genotyping data from the affected children and their parents. Results: Allegro software version 1.2 was used for multipoint linkage analysis. We assumed an autosomal recessive inheritance pattern and assigned a penetrance of 0.999. Single-nucleotide polymorphism allele frequencies were estimated from the Affymetrix data of the Caucasian family studied. Using these parameters, a theoretical maximum logarithm of the odds score of 2.69 was identified at chromosome 20p11.21-q11.23. Conclusions: This chromosomal locus is unprecedented in autosomal recessive and nonprogressive ataxia disorder. Further investigation might reveal a new causative gene generating the CH phenotype. © 2014 S. Karger AG, Basel., Bayrakli, F.; Department of Neurosurgery, Cumhuriyet University School of Medicine, Kampus Merkez, TR-58140 Sivas, Turkey; email: fbayrakli@cumhuriyet.edu.tr

Study design A case of lumbar spinal epidural hemangioma is presented. Objective To present the first reported lumbar spinal epidural hemangioma patient clinically mimicking the lumbar disc herniation disease. Summary of background data Capillary hemangiomas are benign endothelial cell neoplasms that are believed to be hamartomatous proliferations of vascular endothelial cells. The occurrence of spinal epidural capillary hemangiomas is exceedingly rare. There are only 3 reported epidurally located cases of capillary hemangiomas in the spinal channel in literature. Lumbar spinal epidural capillary hemangioma in a patient has not been previously reported. Methods Radiologic features, pathology, and clinical course were documented. Results L4 hypoesthesia and back pain of the patient was caused by an epidurally located capillary hemangioma. The neurologic symptoms of the patient were markedly improved after surgery. Conclusion We have reported for the first lumbar epidural capillary hemangioma patient in literature. These lesions are benign and surgical treatment is curative.

WOS: 000329598700009, PubMed ID: 24310458, AIM:To evaluate the effectiveness of invasive procedures in medically intractable genitofemoral and ilioingunal neuralgia. MATERIAL and METHODS: This is a prospective study of 20 patients with genitofemoral and ilioinguinal neuralgias who were treated at our medical center between 2007 and 2011. Genitofemoral and ilioinguinal nerve blocks were performed in all cases after medical treatment had failed to alleviate the patients' pain. Neurectomy was performed for the patients whose pain did not improve. Patient histories, physical examinations and visual analogue scale scores before and after treatments were analyzed. RESULTS: Fourteen (70%) of the patients were treated with nerve blocks and six (30%) of the patients whose pain did not improve with nerve block application underwent neurectomy which resulted in pain relief. CONCLUSION: For patients with medically intractable genitofemoral and ilioinguinal neuralgias, nerve blocks and neurectomies can be applied safely for pain control.

WOS: 000331663300014, PubMed ID: 24535794, AIM: To show the mutation in HTRA1 gene in a patient suffering from CARASIL syndrome with degenerated spine as a component of the disease. MATERIAL and METHODS: We identified a family that one of the members had CARASIL syndrome in eastern Turkey and collected venous blood from available persons. The HTRA1 gene sequenced in all family members. RESULTS: C to T transition at position 1108 (c.1108 C>T) in exon 6, causing stop codon formation (R370X) was seen in the HTRA1 gene in a homozygous state in the CARASIL patient whereas it was heterozygous in other healthy family members. CONCLUSION: We demonstrated homozygous c.1108 C>T mutation in the HTRA1 gene causing a very rare syndrome, especially in the non-Japanese population, called CARASIL. Patients with degenerated spine and progressive clinical symptoms must be evaluated or reevaluated for other central nervous system symptoms and signs to rule out other diseases or syndromes., Scientific Research Project Fund of Cumhuriyet University [T-447], This work is supported by a Scientific Research Project Fund of Cumhuriyet University under project number T-447.

WOS: 000311780000025, PubMed ID: 22526707, To investigate the effect of an anti-TNF-alpha agent (etanercept) on recovery processes in a partial spinal cord injury (SCI) model using clinical and electrophysiological tests. Twenty-four New Zealand rabbits were divided into three groups: group 1 [SCI + 2 ml saline intramuscular (i.m.), n = 8], group 2 (SCI + 2.5 mg/kg etanercept, i.m., 2-4 h after SCI, n = 8) and group 3 (SCI + 2.5 mg/kg etanercept, i.m., 12-24 h after SCI, n = 8). Rabbits were evaluated before SCI, immediately after SCI, 1 week after, and 2 weeks after SCI, clinically by Tarlov scale and electrophysiologically by SEP. Tarlov scores of groups 2 and 3 were significantly better than group 1, 2 weeks after SCI. SEP recovery was significantly better in groups 2 and 3 than group 1, 2 weeks after SCI. These results show that blocking TNF-alpha mediated inflammation pathway by an anti-TNF-alpha agent enhances clinical and electrophysiological recovery processes in partial SCI model., Cumhuriyet University [T-475], This work is supported by the Scientific Research Project Fund of the Cumhuriyet University under project number T-475.

WOS: 000305677700028, PubMed ID: 22389037, Arachnoid cysts are congenital fluid-filled compartments within the cerebrospinal fluid cisterns and cerebral fissures. They most commonly occur sporadically, and familial occurrence has rarely been reported. In this study, we showed the first genetic linkage in the literature in a pure intracranial arachnoid cyst family with autosomal recessive trait. We identified an intracranial arachnoid cyst family in southern Turkey whose six of seven offspring had intracranial arachnoid cysts in different localizations, and collected venous blood from seven offspring of the family. Whole-genome linkage analysis was performed in all offspring. A theorical maximum logarithm of the odds score of 4.6 was identified at chromosome 6q22.31-23.2. This result shows strong genetic linkage to this locus. We present the first genetic linkage analysis result in a pure intracranial arachnoid cyst family in literature. Further investigation of this linkage area can reveal a causative gene causing the intracranial arachnoid cyst phenotype and can illuminate the pathogenesis of this disease., Cumhuriyet University [T-455], This work was supported by the Scientific Research Project Fund of Cumhuriyet University under project number T-455.

The fact that BRCA genes operate as tumor suppressors is evident from the genetics of the different human disorders caused by inherited mutations. Germline mutations affecting 1 allele of either BRCA1 or BRCA2 confer susceptibility to different types of cancers such as breast cancer and medulloblastoma. A family with a history of cancer was identified in Eastern Turkey in which one of the family members (a 13-year-old boy) had medulloblastoma. Venous blood was collected from available family members. The BRCA1 and BRCA2 genes were sequenced in the patient with medulloblastoma and the healthy father. An Asn372His homozygous variation was noted in the BRCA2 gene in the patient with medulloblastoma whereas the variation was heterozygous in the healthy father. A biallelic homozygous variation was demonstrated in the BRCA2 gene, which is important in medulloblastoma suppression, and may have caused medulloblastoma formation in the 13-year-old boy. Further investigations in large human populations with medulloblastoma are necessary for further delineation of BRCA gene malfunctions and their relationship to medulloblastoma formation, and to clarify the therapeutic implications of these malfunctions.

Severe myoclonic epilepsy of infancy (SMEI) (OMIM #607208), also known as Dravet syndrome, is a rare genetic disorder characterized by frequent generalized, unilateral clonic or tonic-clonic seizures that begin during the first year of life. Heterozygous de novo mutations in the SCN1A gene, which encodes the neuronal voltage-gated sodium channel α subunit type 1 (Nav1.1), are responsible for Dravet syndrome, with a broad spectrum of mutations and rearrangements having been reported. In this study, the authors present 4 novel mutations and confirm 2 previously identified mutations in the SCN1A gene found in a cohort of Turkish patients with Dravet syndrome. Mutational analysis of other responsible genes, GABRG2 and PCDH19, were unrevealing. The authors’ findings add to the known spectrum of mutations responsible for this disease phenotype and once again reinforce our understanding of the allelic heterogeneity of this disease.

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.

Meningiomas are the most common benign intracranial neoplasms. Nearly 20% of all primary intracranial tumors are meningiomas. Primary intraosseous meningiomas are a subtype of the meningiomas that represents the most uncommon manifestation of meningiomas. Although rare, these tumors can be found to occur in unexpected areas of the head and neck. The patient was a 78- year-old male who was operated two times for urinary bladder cancer. During his routine oncology follow-ups, the PET scan demonstrated a hyperactive area in the right parietal bone. Preoperative diagnosis was a metastasis, but histological examination revealed an osteolytic interosseous meningioma. The possibility of an intraosseous meningioma mimicking a metastatic tumor should be kept in mind.

The appearance of a new lesion several years after radiation treatment for a primary brain tumor may represent different kind of pathologies. We present a 24-year-old patient who suffered from right-sided hemiparesis and ataxic gait with a history of an operation due to left frontoparieal grade II fibrillary astrocytoma and fractioned radiotherapy. His cranial MRI study showed heterogeneous signal intensity of brain stem radionecrosis in the pons spreading through the mesencephalon and left brachium pontis. The leading diagnosis was high-grade glial tumor. The patient underwent stereotaxic biopsy and histopathological examination revealed radionecrosis. Radiation necrosis has a radiological appearance similar to various important pathologies. Tissue sampling for histopathological examination is mandatory for definite diagnosis and correct treatment of the disease.

Paired box gene 6 (PAX6) is the causative gene of aniridia. it is a dominantly inherited eye abnormality characterized by partial or complete absence of the iris. The PAX6 gene is located on chromosome 11 p13 and contains 14 exons. It is expressed mainly in the developing eye and central nervous system. Submicroscopic copy number variations are common in the human genome. Submicroscopic deletions may cause several human diseases, either by disrupting coding sequences or by eliminating regulatory elements essential for expression of the gene in question. Over the past several years, array-based comparative genomic hybridization has become an increasingly useful too] for both identifying normal cytogenetic variations and characterizing chromosomal abnormalities associated with developmental delays and cancer. Our results support the notion that assessing copy number variation of the PAX6 gene itself and also of flanking regions, may contribute to the molecular diagnosis of aniridia. (C) 2009 Elsevier Ltd. All rights reserved.

Bayri, Yasar/0000-0003-1707-6055 WOS: 000251534700011 PubMed: 17676595 SNP and comparative genome hybridization arrays (aCGH) are powerful techniques for identifying genome rearrangements, deletions, and duplications. We hypothesized that current array-based detection of copy number variation (CNV) could complement parametric linkage analysis and allow the rapid identification of functional mutations in families with inherited disorders. Herein, we demonstrate the utility of this technique by rapidly identifying a disease causing microdeletion within the PARK2 gene in a family with autosomal recessive Parkinsonism. Hum Mutat 28(12), 1236-1240, 2007. (c) 2007 Wiley-Liss, Inc.

Background Chordomas are rare, slow growing, infiltrative tumors thought to arise from vestigial or ectopic notochord. Chordoma can occur along the axial skeleton, predominantly in the sphenooccipital, vertebral, and sacrococcygeal regions. Although most chordomas are sporadic, familial cases have also been reported. The most common molecular cytogenetic abnormalities in these tumors are monosomy of chromosome 1 and gain of chromosome 7. In addition, a variety of other chromosomal changes, which are associated with losses and gains of different chromosomes, have also been described in chordomas, such as 1q, 2p, 3p, 5q, 9p, 10, 12q, 13q, 17, and 20q. Methods In this study, using molecular cytogenetics (iFISH), we have studied 1p36, 1q25, 3p13-p14, 7q33, 17p13.1 ( p53 gene locus), 2p13 (TGF- α locus), 6p12 (VEGF locus), and 4q26-q27 (bFGF/FGF2 locus) loci in chordoma tissues from seven patients with 7 primary tumors and 11 recurrences. Results We found that chromosomes 1p36, 1q25, 2p13, and 7q33 are affected in primary chordomas, and these aberrations persist in recurrences. However, the chromosome 6p12 aberration was seen only in primary chordomas, but not in recurrences, indicating that this locus may be associated with chordoma genesis. Conclusions Our descriptive data from interphase FISH analyses suggest that future studies should incorporate a larger number of patients and should focus on identifying the candidate genes in chordoma pathogenesis. Such studies may use a whole-genomic approach, in addition to the regions identified in this study and others.

Background Multiple myeloma (MM) presentation with cerebral mass lesion is unusual. Gamma knife radiosurgery for plasmacytoma has not been reported so far. Case Report We report a 70-year-old female with a medical history of infiltrative ductal carcinoma of the breast. She developed cavernous sinus syndrome (CSS) 5 months before admission to the hospital. The magnetic resonance imaging revealed an isointense solitary mass in the left cavernous sinus in noncontrast T1-weighted images. The lesion was highly enhancing with gadolinium-diethylenetriaminopentaacetic acid. She was operated by using Dolenc technique, and the tumor was partially resected. The pathological examination of the tumor tissue revealed a plasmacytoma. Systemic evaluation was positive for the diagnosis of MM. She underwent gamma knife radiosurgery for the residual cavernous sinus tumor. Chemotherapy with prednisolone and melphalan was given. Follow-up magnetic resonance images 6 months after the treatment demonstrated complete tumor disappearance. However, she died of sepsis 26 months after the diagnosis. Conclusion This is an unusual MM case with a history of breast cancer, which had CSS and which demonstrated an excellent response to gamma knife radiosurgery.

WOS: 000325205700001, PubMed ID: 24073994, Background: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. Results: We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. Conclusions: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans., Cumhuriyet University [T-455, T-496], This work is supported by the Scientific Research Project Fund of Cumhuriyet University under project numbers T-455 and T-496.