Genetic investigation of Leukodystrophy in Iran

How to Cite This Article: Houshmand M. Genetic investigation of Lukodystrophy in Iran. Iran J Child Neurol.Autumn 2014;8;4(Suppl.1):11-12

Mitochondrial Genetics, Disease and Inheritance

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Investigation of mutations in exon 14 of SH3TC2 gene and exon 7 of NDRG1 gene in Iranian Charcot Marie Tooth type 4 patient

CMT4 is an autosomal recessive form of Charcot-Marie-tooth disease which has shown more severity and earlier age of onset compared to other types of it, furthermore; CMT4C andCMT4D are the more prevalent types in Mediterranean countries due to higher incidence of consanguineous marriages. The most important aim of this study is to illuminate the rate of p.R148X mutation in NDRG1 gene and p.R1109X in SH3TC2 gene which are responsible genes for CMT4D and CMT4C respectively in Iranian population, Furthermore; this study investigated the probable other nucleotide changes in exon 14 of SH3TC2 gene and exon 7 of NDRG1 gene. In order to study this disease, 24 CMT4 affected individuals that they referred to Iran Special Medical Center, were clinically and electrophysiologically evaluated and selected for this study. The patients’ DNA was extracted from blood samples and after PCR, the products were sequenced and analyzed by Finch TV software. None of the founder mutations we were searching for were seen in this study. Sequencing of SH3TC2 gene showed SNP rs1025476 (g.57975C>T) in 21 patients (87.5%) that 7 individuals were homozygous and 14 individuals were heterozygous for this variant. Despite of high rate of considered mutations in some specific populations it seems that these mutations are very rare in Iranian CMT4 affected individuals. To clarify the association of SNP rs1025476 with CMT4, further assesments are needed and it could be helpful in knowing the Iranian population genetic markers and their genetic features

Occurrence of large-scale mitochondrial DNA deletions in human colorectal cancer

Introduction: The aim of this study was to determine the mutation patterns of colon cancers through screening of different regions of mitochondrial DNA (mtDNA) in colon cancer patients. Material and methods: In order to investigate whether deletions exist in the mitochondrial DNA of colon cancer patients, we used a PCR assay to assess the presence of large-scale deletions. We screened four regions of the mitochondrial genome by PCR amplification and Southern blot analysis followed by DNA sequencing. Previously, deficiency in mitochondrial complex I has been reported; therefore we focused on the region of mtDNA that encodes the genes of this complex. Results: In 11 out of 90 patients, we found an 8.7 kb deletion. Large-scale deletions of mtDNA are common events that have been found to occur in human ageing and in patients with mitochondrial myopathies. Based on our results the mtDNA 8.7 kb deletion occurs in 12.2% of the colorectal cancer (CRC) samples. Conclusions: As reactive oxygen species (ROS) are continuously generated by the respiratory chain, they may cause significant oxidative damage to mtDNA (for example mtDNA deletions or mutations) if not efficiently eliminated. Defective respiratory enzymes containing protein subunits encoded by the deleted mtDNA may further enhance free radical production, resulting in more profound oxidative damage in CRC patients. Copyright © 2008 Termedia & Banach

Novel Mutation in FRDA Gene among Iranian Patients with Friedreich's Ataxia

Introduction: Friedrich Ataxia’s diagnosis is typically based on clinical symptoms and extended GAA repeats. However, in some rare cases the disease is caused as a result of the mutation in the exons of the FRDA (Friedreich's ataxia) gene. The current study aimed to examine point mutations in exon 1 of the FRDA gene with the goal of finding a better way for diagnosing people suspected of this disease. Materials and Methods: In this study, 30 suspected patients of Friedrich Ataxia underwent PCR molecular test. Subsequently, sequencing and long PCR were utilized to assess exon 1 in five patients with extended repeats. Results: In total, 25 participants who had extended repeats were diagnosed with Friedrich Ataxia. In one out of the five patients, the nucleotide change from G to T was observed in the nucleotide number 815324. Conclusion: Since the change had a heterozygous nature, it did not cause any deficiency in Frataxin protein. Given that family marriages are prevalent in Iran, there is a possibility of homozygosity with this mutation or other mutations. It is thus recommended that gene sequencing should be performed for individuals with suspected Friedrich Ataxia

L-2-Hydroxyglutaric Aciduria is a Diagnostic Indicator of Leukodystrophy: A Case Report

How to Cite this Article: Ashrafi MR, Nikkhah A, Houshmand M, Aryani O. L-2-Hydroxyglutaric Aciduria is a Diagnostic Indicator of Leukodystrophy: A CaseReport Iranian Journal of Child Neurology 2011;5(4):37-38. L-2-Hydroxyglutaric aciduria is a rare autosomal recessive inherited neurometabolic disorder.It is characterized by slow progressive neurological dysfunction with cerebellar ataxia, pyramidal and extrapyramidal signs, intellectual decline, and seizures. Herein, we report a case of a 7-year-old boy from Tehran whose symptoms and signs indicated leukoencephalopathy with macrocephaly and motor delay. References 1. Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, et al. L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992;32(1):66-71. 2. Duran M, Kamerling JP, Bakker HD, Van Gennip AH, Wadman S. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 1980;3(4):109-12. 3. Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, et al. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics  2008;39(2):119-22. 4. De Klerk JB, Huijmans JG, Stroink H, Robben SG, Jakobs C, Duran M. L-2-hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics 1997;28(6):314-7. 5. Fenichel GM. Clinical pediatric neurology: a signs and symptoms approach. Saunders:Elsevier, 2009. 6. Diogo L, Fineza I, Canha J, Borges L, Cardoso ML, Vilarinho L. Macrocephaly as the presenting feature of L-2-hydroxyglutaric aciduria in a 5-month-old boy. J Inherit Metab Dis 1996;19(3):369-70. 7. Rzem R, Van Schaftingen E, Veiga-da-Cunha M. The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 2006;88(1):113-6. 8. Shafeghati Y, Vakili G, Entezari A. L-2-hydroxyglutaric aciduria: A report of six cases and Review of the Literature. Arch Iran Med 2006;9(2):165-9.

No Hot Spot Mutations CHRNE c.1327 delG, CHAT c.914T>C, and RAPSN c.264C>A in Iranian Patients with Congenital Myasthenic Syndrome

 AbstractObjectivesWe aimed to perform genetic testing and clinical data of patients with Congenital Myasthenic Syndrome, a rare disorder caused by mutations in genes encoding molecules expressed in the neuromuscular junction and constitutes fatigable muscle weakness. MethodsSixteen patients were screened in Taban Clinic, Tehran, Iran from 2014 to 2015 for the hot spot mutations in known CMSs genes (CHRNE, CHAT, RAPSN) based on clinical data. PCR was performed and then direct DNA sequencing was done for mutation identification.ResultsMost patients represented the criteria of Congenital Myasthenic Syndrome in view of early ptosis, motor delay, normal mental development, easy fatigability, decrement in repetitive nerve stimulation test of EMG-NCV and a negative result for antibody against of acetylcholine receptor. No variations were found in the mutational analysis of the CHRNE gene. Analysis of CHAT gene revealed c.358G>A (P. A120T) variation in 9 patients. In the gene RAPSN, polymorphism c.456T>C )P.Y152Y) and polymorphism c.193-15C>T (IVS1-15C>T) were identified in 11 and one patients, respectively.ConclusionThe common founder mutations of involved genes in CMSs could be very rare among ethnic Iranian. Screening of the entire genes would be efficient to distinguish the specific mutations in specific ethnicity

Increased Prevalence 12308 A > G mutation in Mitochondrial tRNALeu (CUN) Gene Associated with earlier Age of Onset in Friedreich Ataxia

How to Cite this Article: Heidari MM, Khatami M, Houshmand M, Mahmoudi E, Nafissi Sh .Increased Prevalence 12308 A > G mutation in MitochondrialtRNALeu (CUN) Gene Associated with earlier Age of Onset in Friedreich Ataxia. Iranian Journal of Child Neurology 2011;5(4):25-31.Objective Friedreich ataxia (FRDA) is an inherited recessive disorder. Mitochondrial DNA is a candidate modifying factor for FRDA.The purpose of this study was to investigate the relationship between the tRNALeu (CUN) 12308 A> G mutation and age of onset in Friedreich ataxia.Materials & Methods The 12308 A> G substitution in mitochondrial tRNALeu (CUN) was examined in DNA samples from 30 Friedreich ataxia patients and 48 control subjects by temporal temperature gradient gel electrophoresis (TTGE) and sequencing. Logistic regression was used to determine of cutoff age of onset.ResultsTwenty-two patients had the 12308 A> G mutation, and we found that its overall prevalence was significantly higher in 20 patients aged 17 years or younger than in 2 patients aged over 17 years (90% versus 10%). The 12308 A> G mutation lies in a region that has been highly conserved between species.Conclusion Our results show that the 12308 A > G mutation is associated with earlier age of onset in Friedreich ataxia. Thus, this mutation might cause the younger age of onset in FRDA.References Grabczyk E, Usdin K. The GAA*TTC triplet repeat expanded in Friedreich ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner. Nucleic Acids Res 2000;28(14):2815-22.Sakamoto N, Chastain PD, Parniewski P, Ohshima K, Pandolfo M, Griffith JD, et al. Sticky DNA: self association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich ataxia. 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A Novel Mutation of GDAP1 Associated with Charcot-Marie-Tooth Disease in An Iranian Family

As a result of higher distributed consanguinity in the Mediterranean region and the Middle East, autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) are more common in these areas. CMT disease caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene is a severe autosomal recessive neuropathy resulting in either demyelinating CMT4A neuropathy or axonal neuropathy with vocal cord paresis. The patient was an 8-year-old boy with AR inheritance that showed some delayed achievement of motor milestones, including walking, also bilateral foot drop, wasting of distal muscles in the legs, pes cavus and marked weakness of the foot dorsiflexors. He had no hoarseness or vocal cord paralysis. Total genomic DNA was extracted from whole peripheral blood of the patient and his family by using standard procedures. PCR- sequencing method were used to analysis the whole coding regions of the GDAP1 gene. A novel homozygote insertion of T nucleotide in codon 34 was detected (c.100_101insT) that probably led to an early stop codon. This mutation may be associated with a common haplotype, suggesting a common ancestor that needs further investigation in the Iranian population