Filiz Koç

The distinct genetic pattern of ALS in Turkey and novel mutations

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey. No SOD1 mutations were detected in sALS patients; however, C9orf72 (3.1%) and UBQLN2 (0.6%) explained 3.7% of sALS in the population. Exome sequencing revealed mutations in OPTN, SPG11, DJ1, PLEKHG5, SYNE1, TRPM7, and SQSTM1 genes, many of them novel. The spectrum of mutations reflect both the distinct genetic background and the heterogeneous nature of the Turkish ALS population.

ATXN2 and Its Neighbouring Gene SH2B3 Are Associated with Increased ALS Risk in the Turkish Population

Expansions of the polyglutamine (polyQ) domain (≥34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27–33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1–4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re-assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31–32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p = 0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p = 0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway.

Thyrotoxic hypokalaemic periodic paralysis in a Turkish population: three new case reports and analysis of the case series

Objective  Thyrotoxic hypokalaemic periodic paralysis (THPP) is an uncommon condition with intermittent episodes of muscle weakness and occasionally severe paralysis. THPP is a common complication of hyperthyroidism in Asian populations, and has also been reported in other ethnic groups including Caucasians. This study aimed to conduct an analysis of THPP in a Turkish population, and is to our knowledge the first analysis of a homogeneous Caucasian group.

Neurofibromatosis Type 1 Association with Moyamoya Disease

The neurofibromatoses are genetic disorders of the nervous system that primarily affect the development and growth of neural (nerve) cell tissues. The neurofibromatoses are classified as neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1 is the more common type of the neurofibromatoses. The gene responsible for NF1 is located on the chromosome region 17q11.2 and for familial moyamoya disease on chromosome 17q25. This article reports on a 20-year-old female with neurofibromatosis-1 who developed moyamoya syndrome. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link in the near future.

Effects of sex and age on strength-duration properties.

OBJECTIVE To evaluate the possible effects of sex and age on strength-duration time constant (SDTC). METHODS The SDTC of 126 healthy volunteers was measured following stimulation of right median nerve at the wrist. Variations in values were evaluated according to sex and age. RESULTS The SDTC was 438.6+/-114.5 micros in women and 396.2+/-90.3 in men (P=.023). In men, as age increased, so did SDTC. However, this was not true in women. Comparing the values of women and men, aged below 40, demonstrated a difference in excitability, confined to younger patients. CONCLUSIONS As SDTC depends on the biophysical properties of the axonal membrane and can provide some information about Na(+) channel function, these data raise the possibility of a difference in Na(+) channel function between men and women and a difference in the conductance with age. SIGNIFICANCE The age- and sex-related differences shown in this study suggest a possible biochemical or hormonal influence on axonal excitability.

Genome-Wide Copy Number Variation in Sporadic Amyotrophic Lateral Sclerosis in the Turkish Population: Deletion of EPHA3 Is a Possible Protective Factor

The genome-wide presence of copy number variations (CNVs), which was shown to affect the expression and function of genes, has been recently suggested to confer risk for various human disorders, including Amyotrophic Lateral Sclerosis (ALS). We have performed a genome-wide CNV analysis using PennCNV tool and 733K GWAS data of 117 Turkish ALS patients and 109 matched healthy controls. Case-control association analyses have implicated the presence of both common (>5%) and rare (<5%) CNVs in the Turkish population. In the framework of this study, we identified several common and rare loci that may have an impact on ALS pathogenesis. None of the CNVs associated has been implicated in ALS before, but some have been reported in different types of cancers and autism. The most significant associations were shown for 41 kb and 15 kb intergenic heterozygous deletions (Chr11: 50,545,009–50,586,426 and Chr19: 20,860,930–20,875,787) both contributing to increased risk for ALS. CNVs in coding regions of the MAP4K3, HLA-B, EPHA3 and DPYD genes were detected however, after validation by Log R Ratio (LRR) values and TaqMan CNV genotyping, only EPHA3 deletion remained as a potential protective factor for ALS (p = 0.0065024). Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions.

Strength–duration properties of sensory and motor axons in alcoholic polyneuropathy

Abstract Objective: The strength–duration time constant (SDTC) is a measure of axonal excitability and depends on the biophysical properties of the axonal membrane. The strength–duration time constant can provide information about Na+ channel function. We aimed to examine changes in the SDTCs of motor and sensory fibers in the median nerves in patients with alcoholic polyneuropathy. Methods and results: We measured the SDTCs of motor and sensory fibers in 17 patients with alcoholic polyneuropathy (15 men and two women) after stimulating the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects (six men and four women). In patients, the SDTC and rheobase for the motor fibers were 370.8 ± 97.4 μs and 3.9 ± 1.7 mA; for the sensory fibers, the SDTC and rheobase were 464.7 ± 104.3 μs and 3.3 ± 1.9 mA. In controls, the SDTC and rheobase for the motor fibers were 359.3 ± 103.5 μs and 3.5 ± 1.9 mA; for the sensory fibers, the SDTC and rheobase were 478.9 ± 113.9 μs and 2.1 ± 1.5 mA. Sensory fibers had significantly longer SDTCs and lower rheobase than motor fibers in patients and controls. However, when the values of the patients and controls were compared, a statistically significant difference was only found for the rheobase of sensory fibers (p=0.037). Conclusions: Although alcoholic neuropathy corresponds to the pattern of axonopathy, it did not act on the SDTC of the median nerve, which depends on the biophysical properties of the axonal membrane at the node of Ranvier. The process causing axonal degeneration in alcoholic neuropathy may affect internodal channels other than nodal channels or the Na+ –K+ ATP pump.

A large family with Charcot-Marie-Tooth Type 1a and Type 2 diabetes mellitus.

Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating peripheral neuropathy, and CMT Type 1A is the most common form. In most cases, CMT1A is usually caused by duplication at chromosome 17p11.2–12. Type 2 diabetes mellitus (Type 2 DM) is a common metabolic disorder, characterized by chronic hyperglycemia that can be associated with micro- and/or macrovascular complications. Only a few studies reported CMT1A duplication in association with Type 2 DM. This article explores the characteristics of a large family of 69 members with respect to CMT1A and Type 2 DM. CMT1A was detected in 28 of them. Molecular genetic study was performed in 22, and duplication was detected in all of them. Six of the 22 members with CMT1A also had Type 2 DM based on the American Diabetes Association diagnostic criteria. Association of these two conditions may be coincidental; however, the occurence of these two diseases in this large family may also suggest a genetic basis. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link.

Analysis of Altered Mental Status in Turkey

The aim of this study was to determine the frequency and etiology of altered mental status in adults at an Emergency Department. Medical records of 790 patients with altered mental status were reviewed. Out of 790 patients, 414 (52.3%) were male, 376 (47.7%) were female. Mean age was 45.65 ± 15.5 years. Etiologic factors were neurological (n = 566; 71.6%), head trauma (n = 82; 10.4%), endocrine/metabolic (n = 48; 6.1%), cardiovascular/pulmonary (n = 49; 6.2%), infectious (n = 30; 3.8%), gynecologic and obstetric (n = 2; 0. 4%), toxicologic (n = 12; 1.5%). Of patients, 40% were in deep coma, 11% were confused, 20% were in agitated confusion, 15% were lethargic, and 14% were in stupor. Eighteen percent of were hypertensive. Total mortality rate was 20.1% (n = 159). Common causes of death were cerebrovascular disease and trauma. Most patients presenting with altered mental status seem to be elderly with the most frequent cause being cerebrovascular accidents. Fatality rate is very high.

Macrodystrophia lipomatosa with multiple entrapment neuropathies: a case report.

Macrodystrophia lipomatosa is a rare nonhereditary congenital malformation that mainly affects mesenchymal structures. The pathology is associated with hypertrophic fibro-adipose tissues. One or more of the digits of the extremities are affected. This condition is previously described as macrodactyly, megalodactyly, or localized gigantism. This article describes a 48-year-old male patient who presented with the enlargement of unilateral (right) lower limb, especially of the first toe and tarsal tunnel syndrome. Although there is no clinically significant involvement of the upper extremities, bilateral cubital and unilateral carpal tunnel syndromes were also detected and macrodystrophia lipomatosa with multiple entrapment neuropathies was diagnosed in the patient.