Mehmet Seven

Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism

Background Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. Methods Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. Results PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20-years-old. Conclusions NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families.

Changes in the Antioxidant System in Epileptic Children Receiving Antiepileptic Drugs: Two-Year Prospective Studies

The aim of this study was to measure changes in the antioxidant systems of epileptic children who had been receiving either valproate or carbamazepine monotherapy for 2 years. For this purpose, levels of erythrocyte glutathione, glutathione peroxidase, superoxide dismutase, and serum lipid peroxidation in 25 healthy children and 27 children who had previously been diagnosed as having epilepsy but who had not, prior to the study, received antiepileptic drugs were tested. Of the 27 epileptic children, 14 were given valproate, and the remaining 13 were given carbamazepine; these tests were repeated in the 13th and 24th months of treatment. The results showed that, during valproate therapy, the lipid peroxidation levels of the epileptic children increased and the glutathione peroxidase levels decreased in comparison with those levels recorded in the control and pretreatment groups. In addition, the superoxide dismutase levels were found to be increased during the first year of valproate therapy when compared with those of the pretreatment group. However, during carbamazepine therapy, lipid peroxidation levels increased when compared with the control group only, not the pretreatment group. Furthermore, the results showed that during the second year of treatment, the superoxide dismutase levels of the children receiving carbamazapine monotherapy were found to be higher than those of both the control and pretreatment groups. From these results, it can be concluded that the antioxidant systems of the children who had been receiving valproate therapy during the 2 years were more significantly affected than those of the children who had been receiving carbamazepine. (J Child Neurol 2001;16:603-606).

Deficiency of selenium and zinc as a causative factor for idiopathic intractable epilepsy

PURPOSE The accumulation of free radicals may lead to seizures and increase the risk of their recurrence. Glutathione peroxidase and superoxide dismutase are 2 major enzymes that are involved in antioxidative defense mechanisms. Selenium (Se), zinc (Zn), and copper (Cu) are important trace elements that participate in the structure of these enzymes. The purpose of this study was to evaluate the possible associations between trace elements and idiopathic intractable epilepsy (IIE) by comparing the levels of Se, Zn, and Cu between patients with IIE and healthy children. METHODS Our study was designed as a case-control study with 70 IIE patients and 60 healthy children who were matched for age, ethnicity, and socioeconomic status. The levels of serum Se, Zn, and Cu were measured with an atomic absorption spectrophotometer. The results were statistically analyzed with SPSS version 16.0. KEY FINDINGS We found that the patients with IIE had significantly decreased levels of serum Se and Zn compared to those of the control group (p<0.05). SIGNIFICANCE We believe that this study presents the first reports of decreased levels of Se and Zn in patients with IIE. These results may provide new insights for delineating the etiological basis of IIE and its potential therapeutic options.

Polymorphisms of the DNA repair genes XPD and XRCC1 and the risk of age-related macular degeneration.

PURPOSE Oxidative stress seems to be an important factor in the development of age-related macular degeneration (AMD). The role of DNA repair mechanisms has also received attention recently in AMD pathogenesis. This case-control study was conducted to determine the frequency of polymorphisms in two DNA repair enzyme genes, xeroderma pigmentosum complementation group D (XPD), codons 312 and 751, and x-ray cross-complementing group 1 (XRCC1), codons 194 and 399, in patients with AMD and in disease-free control subjects. METHODS Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to analyze XPD Asp312Asn and Lys751Gln and XRCC1 Arg194Trp and Arg399Gln in 120 patients with AMD (65 with dry type and 55 with wet type) and in age-matched 205 disease-free control subjects. RESULTS Genotypic and allelic distributions of the polymorphisms were detected. For the XPD polymorphism, although the allele frequencies were not different between the patients and healthy control subjects, there was a significant difference between frequencies for the XPD751 Gln/Gln genotype in AMD patients (9%) and healthy control subjects (19%; P=0.02). The XPD751 Gln/Gln genotype seemed to have a protective effect against development of AMD (odds ratio, 0.41; 95% confidence interval, 0.19-0.88). Stratification by subtype of AMD revealed that the XPD751 Gln/Gln genotype was significantly lower only in the patients with dry type (P=0.02). These interactions remained nearly significant after Bonferroni correction (P<0.0125). Haplotype analysis for the two XPD polymorphisms revealed that the haplotype GC (312Asp-(751)Gln) was a protective haplotype against AMD. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the XRCC1 gene between the patients and the control subjects. CONCLUSIONS Polymorphism in XPD codon 751 may be associated with the development of AMD.

Neuroimaging findings of four patients with Sandhoff disease.

Sandhoff disease is a severe form of GM2 gangliosidosis that is caused by the deficiency of both hexosaminidase A and B. Startle reaction, hypotonia, psychomotor retardation, and blindness are the main clinical features. Presented are computed tomography and magnetic resonance imaging findings of four patients with Sandhoff disease diagnosed by enzymatic analyses. Bilateral homogeneous thalamic hyperdensity was evident on computed tomography. Magnetic resonance imaging scans revealed mild cortical atrophy, a thin corpus callosum, and abnormal signal intensities in the caudate nucleus, globus pallidum, putamen, cerebellum, and brainstem. No correlation was evident between the severity of the central nervous system imaging findings and the clinical pictures. In this article the neuroimaging findings of four patients with Sandhoff disease are discussed.

The role of miRNAs in cancer: from pathogenesis to therapeutic implications.

Cancer is still one of the dominating causes of deaths worldwide, although there have been important enhancements for detection and diagnosis of cancer recently. miRNAs are shown to participate in carcinogenesis of several types of tumors and their aberrant expression of miRNAs has been detected in cell lines, xenografts and clinical samples. miRNAs are thought to target and modulate the expression of more than 60% of human genes, which makes the expressional regulation by miRNAs the most abundant post-transcriptional regulation mode. Here, we have reviewed the most current literature to shed a light on the functions of miRNAs on human carcinogenesis. Possible roles of miRNAs in oncogenesis through both genetic and epigenetic changes occurring during cancer initiation, progression, invasion or metastasis are summarized.

The drug-transporter gene MDR1 C3435T and G2677T/A polymorphisms and the risk of multidrug-resistant epilepsy in Turkish children

One-third of all individuals with epilepsy are resistant to antiepileptic drug (AED) treatment. Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters. Several polymorphic variants within the multidrug resistance 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein, have been proposed to be associated with AED resistance in epilepsy patients. The aim of this study was to evaluate the effect of C3435T and G2677T/A polymorphisms of MDR1 on AED resistance in Turkish children with epilepsy. MDR1 C3435T and G2677T/A were genotyped in 152 patients with epilepsy, classified as drug-resistant in 69 and drug-responsive in 83. Genotypes of the C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction followed by restriction fragment length polymorphism. Genotype and allele frequencies of C3435T and G2677T/A polymorphisms of the MDR1 gene did not differ between drug-resistant and drug-responsive epilepsy patients. Our results suggest that MDR1 C3435T and G2677T/A polymorphisms are not associated with AED resistance in Turkish epileptic patients. To clarify the exact clinical implication of the MDR1 polymorphisms on the multidrug resistance in epilepsy, further investigations in various ethnic populations would be necessary.

N-acetyl-β-glucosaminidase and β-galactosidase activity in children receiving antiepileptic drugs

To evaluate renal tubular function in children receiving antiepileptic drugs the urinary activity of two lysosomal enzymes, N-acetyl-β-glucosaminidase and β-galactosidase, were measured. The enzyme levels were determined before the administration of antiepileptic drugs and 8 months after. Fourteen epileptic children received valproate, and 17 received carbamazepine. The urinary activity of these enzymes in 25 healthy control patients also was examined. Increased N-acetyl-β-glucosaminidase activity was found in 50% of patients taking valproate and in 17.6% of patients taking carbamazepine. Increased β-galactosidase activity was found in 28.5% of patients taking valproate and 11.7% of patients taking carbamazepine compared with the results before treatment. On the basis of these results, it is suggested that patients taking antiepileptic drugs, especially valproate, may demonstrate minor signs of tubular dysfunction. In those patients who use these drugs at increased dosage levels or for long periods, the possibility of tubular dysfunction may be increased, and these dysfunctions may manifest in clinical symptoms.

Anophthalmia-Waardenburg syndrome: a report of three cases.

We report on 2 Turkish families with children who had bilateral anophthalmia, upper and lower limb abnormalities, mental retardation and consanguineous parents. We have evaluated the 2 cases in the first family and the only case in the second as anophthalmia-Waardenburg syndrome. This is an extremely rare autosomal recessive syndrome.