A3243G Mutation Research Articles

Analysis of mitochondrial A1555G mutation in infants with hearing impairment.

Mutations in the mitochondrial 12S ribosomal RNA gene have been identified to be associated with deafness. Among these, the A to G transition at position 1555 is one of the most common pathogenic mutations associated with hearing loss. In order to evaluate the allele frequency of this mutation in infants with hearing loss, the A1555G mutation was screened in 300 deaf children and 100 age- and sex-matched healthy subjects. Consequently, 5 patients with this mutation were identified, whereas the mutation was absent in healthy controls. Among the patients with the mutation, only one had an obvious family history of hearing impairment. Notably, this pedigree manifested a high penetrance of deafness. In particular, the penetrance of deafness was 80 and 40%, when the aminoglycoside antibiotics (AmAn) was included or excluded, respectively. Clinical evaluation of this family exhibited a wide degree of hearing loss. Furthermore, screening for the complete mitochondrial genes revealed the occurrence of A1555G and transfer (t)RNAThr T15943C mutations, together with other genetic variations belonging to East Asian haplogroup C. Notably, the T15943C mutation, located at the T arm of tRNAThr, could disrupt the 63T-55A base-pairing and impair tRNA metabolism. Therefore, it was hypothesized that the combination of A1555G and T15943C mutations may result in mitochondrial dysfunction that is responsible for deafness. Screening for A1555G, as well as other potential pathogenic mutations in the mitochondrial genome, is critical for clinical diagnosis and prevention of hearing impairment.

Longterm Reversal of Severe Visual Loss by Mitochondrial Gene Transfer in a Mouse Model of Leber Hereditary Optic Neuropathy

In many human disorders mitochondrial dysfunction is central to degeneration of retinal ganglion cells. As these cells do not regenerate, vision is irreversibly lost. Here we show reversal of visual dysfunction by a mitochondrially targeted adeno associated virus in transgenic mice harboring a G11778A mutation in the ND4 subunit of complex I persists longterm and it is associated with reduced loss of RGCs and their axons, improved oxidative phosphorylation, persistence of transferred ND4 DNA and transcription of ND4 mRNA.

ATOH1/RFX1/RFX3 transcription factors facilitate the differentiation and characterisation of inner ear hair cell-like cells from patient-specific induced pluripotent stem cells harbouring A8344G mutation of mitochondrial DNA

Degeneration or loss of inner ear hair cells (HCs) is irreversible and results in sensorineural hearing loss (SHL). Human-induced pluripotent stem cells (hiPSCs) have been employed in disease modelling and cell therapy. Here, we propose a transcription factor (TF)-driven approach using ATOH1 and regulatory factor of x-box (RFX) genes to generate HC-like cells from hiPSCs. Our results suggest that ATOH1/RFX1/RFX3 could significantly increase the differentiation capacity of iPSCs into MYO7AmCherry-positive cells, upregulate the mRNA expression levels of HC-related genes and promote the differentiation of HCs with more mature stereociliary bundles. To model the molecular and stereociliary structural changes involved in HC dysfunction in SHL, we further used ATOH1/RFX1/RFX3 to differentiate HC-like cells from the iPSCs from patients with myoclonus epilepsy associated with ragged-red fibres (MERRF) syndrome, which is caused by A8344G mutation of mitochondrial DNA (mtDNA), and characterised by myoclonus epilepsy, ataxia and SHL. Compared with isogenic iPSCs, MERRF-iPSCs possessed ~42–44% mtDNA with A8344G mutation and exhibited significantly elevated reactive oxygen species (ROS) production and CAT gene expression. Furthermore, MERRF-iPSC-differentiated HC-like cells exhibited significantly elevated ROS levels and MnSOD and CAT gene expression. These MERRF-HCs that had more single cilia with a shorter length could be observed only by using a non-TF method, but those with fewer stereociliary bundle-like protrusions than isogenic iPSCs-differentiated-HC-like cells could be further observed using ATOH1/RFX1/RFX3 TFs. We further analysed and compared the whole transcriptome of M1ctrl-HCs and M1-HCs after treatment with ATOH1 or ATOH1/RFX1/RFX3. We revealed that the HC-related gene transcripts in M1ctrl-iPSCs had a significantly higher tendency to be activated by ATOH1/RFX1/RFX3 than M1-iPSCs. The ATOH1/RFX1/RFX3 TF-driven approach for the differentiation of HC-like cells from iPSCs is an efficient and promising strategy for the disease modelling of SHL and can be employed in future therapeutic strategies to treat SHL patients.

Polyadenylation and degradation of structurally abnormal mitochondrial tRNAs in human cells.

RNA 3′ polyadenylation is known to serve diverse purposes in biology, in particular, regulating mRNA stability and translation. Here we determined that, upon exposure to high levels of the intercalating agent ethidium bromide (EtBr), greater than those required to suppress mitochondrial transcription, mitochondrial tRNAs in human cells became polyadenylated. Relaxation of the inducing stress led to rapid turnover of the polyadenylated tRNAs. The extent, kinetics and duration of tRNA polyadenylation were EtBr dose-dependent, with mitochondrial tRNAs differentially sensitive to the stress. RNA interference and inhibitor studies indicated that ongoing mitochondrial ATP synthesis, plus the mitochondrial poly(A) polymerase and SUV3 helicase were required for tRNA polyadenylation, while polynucleotide phosphorylase counteracted the process and was needed, along with SUV3, for degradation of the polyadenylated tRNAs. Doxycycline treatment inhibited both tRNA polyadenylation and turnover, suggesting a possible involvement of the mitoribosome, although other translational inhibitors had only minor effects. The dysfunctional tRNALeu(UUR) bearing the pathological A3243G mutation was constitutively polyadenylated at a low level, but this was markedly enhanced after doxycycline treatment. We propose that polyadenylation of structurally and functionally abnormal mitochondrial tRNAs entrains their PNPase/SUV3-mediated destruction, and that this pathway could play an important role in mitochondrial diseases associated with tRNA mutations.

Promoter analysis and transcriptional regulation of human carbonic anhydrase VIII gene in a MERRF disease cell model

Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial neuromuscular disease. We previously reported a significant decrease of mRNA and protein levels of nuclear DNA-encoded carbonic anhydrase VIII (CA8) in MERRF cybrids harboring A8344G mutation in mitochondrial DNA (mtDNA). In this study, we established a reporter construct of luciferase gene-carrying hCA8 promoter containing several putative transcription factor-binding sites, including GC-box, AP-2 and TATA-binding element in the 5'flanking region of the hCA8 gene. Using a series of mutated hCA8 promoter constructs, we demonstrated that a proximal GC-box, recognized by Sp1 and other Sp family members, may be a key cis-element functioning at the promoter. Additionally, a significant increase of the hCA8 promoter activity was observed in the wild-type and mutant cybrids with over-expression of eGFP-Sp1, but no detectable increase in the CA8 protein expression. In contrast, over-expression of Flag-Sp1 and Flag-Sp4 significantly increased the hCA8 promoter activity as well as endogenous CA8 protein expression in neuron-like HEK-293 T cells. However, down-regulation of Sp1, but not Sp4, in 293 T cells revealed a significant reduction of CA8 expression, suggesting that Sp1 is a predominant transcription factor for regulation of CA8 activity. Furthermore, our data indicate that chromatin structure may be involved in the expression of hCA8 gene in MERRF cybrids. Taken together, these results suggest that Sp1 transactivates hCA8 gene through the proximal GC box element in the promoter region. The key modulator-responsive factor to the mtDNA mutation and how it may affect nuclear hCA8 gene transcription need further investigations.

Mitochondrial A3243G mutation results in corneal endothelial polymegathism.

The mitochondrial DNA point mutation A3243G leads to a spectrum of syndromes ranging from MIDD to MELAS. Ocular manifestations include pattern macular dystrophy and concentric perifoveal atrophy. Given the high metabolic demand of corneal endothelial cells, we performed specular biomicroscopy analysis in patients harboring the mitochondrial DNA point mutation A3243G to assess for the associated presence of corneal endothelial abnormalities. We present a case series with participants from two institutions. Patients diagnosed with macular dystrophy associated with MIDD or MELAS, and the mitochondrial DNA point mutation A3243G were recruited. Exclusion criteria included a prior diagnosis, or a positive family history, of endothelial corneal dystrophy. Slit-lamp corneal examination and specular biomicroscopy were performed. Corneal endothelial cell count, cell size and polymegathism, and central corneal thickness were assessed. Patients diagnosed with MIDD or MELAS based on clinical history and examination were genetically tested for the mitochondrial DNA point mutation A3243G using pyrosequencing. Five patients (two male and three female participants) from five different families, and with different ethnic backgrounds, met the inclusion criteria. Their ages ranged from 41 to 60years. Corneal endothelial changes observed using slit-lamp examination were primarily mild to rare guttata. Specular biomicroscopy displayed mainly polymegathism associated with guttata. The average endothelial cell count was 2358±456 cells per mm2, the average endothelial cell size was 442±103μm2 and the average central corneal thickness (CCT) was 551±33μm. These values were similar to that of the average population. The average coefficient of variation (COV), an index of heterogeneity in cell size, was 42.0 ± 4.1%. When compared to the average population, the average COV was significantly higher than predicted for the patients' age. None of the patients had signs of corneal edema. One patient had a pre-Descemet's opacity. In patients with the mitochondrial DNA point mutation A3243G, corneal endothelial polymegathism is present. This is mainly associated with mild guttata. The findings of corneal endothelial cell polymegathism may be a biomarker of mitochondrial disease, specifically in patients with the mitochondrial DNA A3243G mutation.

Analysis of mitochondrial function in human induced pluripotent stem cells from patients with mitochondrial diabetes due to the A3243G mutation

We previously established human induced pluripotent stem (iPS) cells in two diabetic patients from different families with the mitochondrial A3243G mutation and isolated isogenic iPS cell clones with either undetectable or high levels of the mutation in both patients. In the present study, we analyzed the mitochondrial functions of two mutation-undetectable and two mutation-high clones in each patient through four methods to assess complex I activity, mitochondrial membrane potential, mitochondrial respiration, and mitochondrial ATP production. In the first patient, complex I activity, mitochondrial respiration, and mitochondrial ATP production were decreased in the mutation-high clones compared with the mutation-undetectable clones, and mitochondrial membrane potential was decreased in a mutation-high clone compared with a mutation-undetectable clone. In the second patient, complex I activity was decreased in one mutation-high clone compared with the other clones. The other parameters showed no differences in any clones. In addition, the complex I activity and mitochondrial respiration of the mutation-undetectable clones from both patients were located in the range of those of iPS cells from healthy subjects. The present study suggests that the mitochondrial function of the mutation-undetectable iPS cell clones obtained from two patients with the A3243G mutation is comparable to the control iPS cells.

The Mitochondrial COI/tRNASER(UCN) G7444A Mutation may be Associated with Hearing Impairment in a Han Chinese Family.

Variations in mitochondrial genome have been found to be associated with hearing loss. Of these, the mitochondrial 12S rRNA and tRNASer(UCN) are the hot-spots for pathogenic variants associated with deafness. To understand the putative role of mitochondrial DNA (mtDNA) variants in hearing loss, we recently screened the variants in mitochondrial genomes in patients with deafness from the Hangzhou area of Zhejiang Province, People’s Republic of China (PRC). In this study, we describe a maternally-inherited Han Chinese family with high penetrance of hearing loss, notably, the penetrance of hearing loss in this family were 80.0 and 40.0%, when the aminoglycoside was included or excluded. Three matrilineal relatives in this pedigree exhibited different levels of hearing loss with different age at onset. In addition, sequence analysis of the complete mitochondrial genome showed the presence of the well-known C1494T pathogenic variant in the 12S rRNA gene and the G7444A pathogenic variant in the COI/ tRNASer(UCN). The C1494T anomaly had been reported to be a pathogenic mutation associated with aminoglycoside-induced and nonsyndromic hearing loss (AINHL), while the G7444A was considered as a secondary mutation associated with deafness. However, the lack of functional variants in GJB2 and TRMU genes suggested that nuclear modified genes may not play important roles in deafness expression. Thus, the combination of G7444A and C1494T pathogenic variants in the mitochondrial genome may account for the high penetrance of hearing loss in this Chinese family.

Generation of an induced pluripotent stem cell (iPSC) line from a 40-year-old patient with the A8344G mutation of mitochondrial DNA and MERRF (myoclonic epilepsy with ragged red fibers) syndrome

Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNALys gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers.

Generation of an induced pluripotent stem cell line from a 39-year-old female patient with severe-to-profound non-syndromic sensorineural hearing loss and a A1555G mutation in the mitochondrial MTRNR1 gene

Sensorineural hearing loss (SNHL) is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC) line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1). This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.

Detection of a new case harboring mitochondrial A3243G mutation of MELAS syndrome

Mitochondrial genome A3243G mutation in the tRNALeu(UUR) encodinggene (MTTL)is the main cause of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). This mutation exists in heteroplasmic form and severity of the disease is affected by many factors including heteroplasmy level.
 In this study, a pediatric proband (female, 8 years old) was found to carry A3243G mutation at 77.6% of heteroplasmy by using PCR-RFLP in combination with real-time PCR. The results of the A3243G mutation analysis of the proband’s family showed that her mother without any symptoms of encephalopathyalso carried the mutation at 7.9% of heteroplasmy whereas the mutation was not found in the proband’s healthy father and healthy sister, indicating that the proband received the A3243G mutation from her mother and the expression of MELAS syndromes depended on the level of heteroplasmy.

Prenatal diagnosis of mitochondrial disease: analysis of 28 pedigrees with mitochondrial DNA mutation

Objective To perform a prenatal diagnosis for the second fetuses from 28 pedigrees with proband of mitochondrial disease due to mitochondrial DNA (mtDNA) mutation. Methods From April 2011 to November 2015, peripheral blood samples of 28 probands and their parents, urine samples of these probands and their mothers as well as amniotic fluid samples of the second fetuses from the 28 pedigrees were collected in Peking University First Hospital. DNA sequencing was used to identify mtDNA mutations. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to verify mutation sites, calculate mutation loads, and further confirm the diagnosis after birth. Microsatellite maker analysis was also performed on five short tandem repeats located in nuclear genes to exclude maternal contamination. Statistical analysis was carried out using independent t-test. Results In the 15 pedigrees carrying A3243G mutation, 13 mothers and nine fetuses carried A3243G mutation. Neither the other two mothers nor their fetuses were positive for A3243G mutation. Among the 12 pedigrees with T8993G mutation, there were eight mothers carrying T8993G mutation and all of their fetuses carried the same mutation; and the other four mothers and their fetuses were negative for T8993G mutation. T10191C mutation was only found in one proband and the second fetus of that pedigree, but not in the mother. None of the fathers had mtDNA mutation. Results of PCR-RFLP were consistent with those of DNA sequencing. Short tandem repeat analysis demonstrated that amniocyte samples were from fetuses without maternal contamination. No mtDNA mutations were found in the six newborns who were negative for mtDNA mutations in prenatal diagnosis. The mean mutation load in urine samples of the six mothers without A3243G mutation in amniocytes was significantly lower than that of the nine mothers with A3243G mutation [(10.1±4.8) % vs (28.2±15.1) %, t=2.290, P=0.043]. Conclusions The lower the mtDNA mutation load in maternal urine samples, the less the possibility she bears a child with mtDNA mutation. However, prenatal diagnosis of mitochondrial disease is necessary. Key words: Mitochondrial diseases; Pedigree; Genes, Mitochondrial; Mutation; Prenatal diagnosis

P.68 - Correlation of serum biomarkers and magnetic resonance spectroscopy (MRS) in monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) due to mtDNA A3243G mutation

P.68 - Correlation of serum biomarkers and magnetic resonance spectroscopy (MRS) in monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) due to mtDNA A3243G mutation

Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation

The cell penetrating peptide, Pep-1, has been shown to facilitate cellular uptake of foreign mitochondria but further research is required to evaluate the use of Pep-1-mediated mitochondrial delivery (PMD) in treating mitochondrial defects. Presently, we sought to determine whether mitochondrial transplantation rescue mitochondrial function in a cybrid cell model of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) disease. Following PMD, recipient cells had internalized donor mitochondria after 1 h, and expressed higher levels of normal mitochondrial DNA, particularly at the end of the treatment and 11 days later. After 4 days, mitochondrial respiratory function had recovered and biogenesis was evident in the Pep-1 and PMD groups, compared to the untreated MELAS group. However, only PMD was able to reverse the fusion-to-fission ratio of mitochondrial morphology, and mitochondria shaping proteins resembled the normal pattern seen in the control group. Cell survival following hydrogen peroxide-induced oxidative stress was also improved in the PMD group. Finally, we observed that PMD partially normalized cytokine expression, including that of interleukin (IL)-7, granulocyte macrophage–colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF), in the MELAS cells. Presently, our data further confirm the protective effects of PMD as well in MELAS disease.

Correction for Li and Guan, "Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and Diabetes".

Correction for Li and Guan, "Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and Diabetes".

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMP-activated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

P 166 - Ultrastructural Assessment of Mitochondrial Network in the Cultured Skin Fibroblasts from Patients Harboring tRNA Mutations

Single-point mutation of mitochondrial DNA (mtDNA) has been confirmed to be involved in some inheritance of mitochondrial myopathy such as Mitochondrial Encephalopathy, Lactic acidosis, And Stroke-like syndrome (MELAS) and Myoclonic Epilepsy and Ragged-Red Fibers (MERRF). The A-to-G mutation at nucleotide 8344 accounts for 80 to 90% of MERRF syndrome. More than 80% of MELAS patients carry the A3243G mutation. The location of these two point mutations were identified in the transfer RNA (tRNA). It remains unknown why these particular tRNA point mutations caused the abnormal phenotypes. Some studies have demonstrated that Reactive Oxygen Species (ROS) production, alteration in antioxidant defenses and detoxification enzymes is involved in the pathogenesis of MERRF and MELAS syndrome. More and more reports revealed a potential role of oxidative stress within dysregulated mitochondrial network in lesion tissue. However, structural integrity and appropriate distribution and dynamics of mitochondria have to be maintained to execute normal physiological functions. Therefore, we integrated light and electron microscopy to illuminate mosaic mechanisms of the altered mitochondrial distribution and dynamics in cultured skin fibroblasts from patients with mitochondrial tRNA mutations.

Giant Ring Mitochondria in a Patient With Heart Failure and Cerebral White Matter Disease Resulting From an MT-TL1 Mitochondrial Gene Mutation

BackgroundThe presence of giant ring mitochondria on endomyocardial biopsy is rarely reported and does not have a well-defined differential diagnosis. MethodsWe report the case of a 54-year-old man with heart failure and preserved ejection fraction and left ventricular hypertrophy, initially thought to have an infiltrative cardiomyopathy. ResultsThe patient was found to have extensive vacuolization caused by giant ring mitochondria on endomyocardial biopsy. Mitochondrial genetic testing revealed an A3243G mutation in the MT-TL1 gene, which is a mitochondrial encoded transfer RNA-leucine molecule. ConclusionsMitochondrial disease should be considered in patients presenting with unexplained cardiomyopathy and skeletal muscle, cerebral, or metabolic abnormalities. In this case, the presence of unexpected extensive cardiomyocyte vacuolization and giant, ring-shaped mitochondria on endomyocardial biopsy prompted mitochondrial genetic testing, which ultimately resulted in the correct diagnosis and treatment.

MELAS presenting as occipital lobe epilepsy: Not all occipital epilepsies are benign

We report an 11-year-old boy with normal development who initially presented with visual disturbances (perceiving flashes of light), photosensitivity and eye flickering. An electroencephalogram (EEG) showed occipital spike wave discharges and was treated with levetiracetam. He further developed myoclonic twitches and was investigated. Metabolic screen was negative including a normal brain MRI and normal serum lactate. The patient gained good seizure control with levetiracetam. He later presented with a gradual-onset occipital headache and further visual disturbances. He was found to have a right quadrantinopia and magnetic resonance imaging (MRI) of the brain showed a subacute ischaemia in the left occipital region. Childhood stroke screen was done and no particular cause was found. Serum lactate was again within the normal limits. At 15 years, he presented with an increasing seizure frequency. He developed a visual loss, with headaches, unsteadiness of his gait, slurred speech and fluctuating confusion. Computed tomography of the head showed a combination of anterior and posterior circulation stroke, with involvement of both the right and left posterior cerebral artery. MRI and magnetic resonance angiography showed similar findings. A lumbar puncture revealed high lactate levels in the cerebrospinal fluid. Mutation studies confirmed a diagnosis of MELAS with the A3243G mutation. Many consider occipital epilepsy in the paediatric patient as benign. Upon review of the literature, patients with MELAS have presented with adult-onset occipital seizures. We have identified only two patients, in America and Japan respectively, with MELAS presenting in childhood with occipital lobe epilepsy. However, these patients both presented with status epilepticus, with secondary generalisation. This is the first case to our knowledge of MELAS presenting with recurrent occipital seizures in a paediatric patient without the progression to status epilepticus. This highlights the need to consider MELAS early in childhood occipital epilepsy.

Study of common mitochondrial mutations in patients with nonsyndromic hearing loss

INTRODUCTION: Hearing loss is the most common sensorineural disorder involving one out of 1000 people. Around 50 of hearing losses occur due to genetic causes. Three mitochondrial mutations, A1555G in MTRNR1, A3243G in MTTL1, and A7445G in MTTS1, are the most important non-syndromic sensorineural causes of hearing loss in some populations. The aim of this review was to study common mitochondrial mutations in people with hearing loss in Iran. EVIDENCE ACQUISITION: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science were searched. EVIDENCE SYNTHESIS: Studies have indicated that the mitochondrial mutations A3243G, A1555G, and A7445G play no significant part in the development of hearing loss in Iran. Different variants of A7445C and G3316A have been identified in Iran. CONCLUSIONS: Further studies on other ethnicities and with a larger sample size are necessary to elucidate the role of these genes in hearing loss development in Iran. © 2017 EDIZIONI MINERVA MEDICA.