Case Of Leigh Syndrome Research Articles

Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes-MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing.

Клінічний випадок синдрому Лея у дитини раннього віку

У статті наведена інформація щодо причин, поширеності, клінічних проявів, методів діагностики та лікування мітохондріальних захворювань. Описано власне клінічне спостереження дитини з синдромом Лея.

Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review.

Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.

T9ESTIMATING THE EFFECT OF CIGARETTE SMOKING ON MULTIPLE PSYCHIATRIC OUTCOMES USING MENDELIAN RANDOMISATION

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

A novel compound heterozygous variant of ECHS1 identified in a Japanese patient with Leigh syndrome

Leigh syndrome (LS) is a heterogeneous neurodegenerative disorder caused by mitochondrial dysfunction. Certain LS cases have mutations in ECHS1, which encodes a short-chain enoyl-CoA hydratase involved in the metabolism of fatty acids and branched-chain amino acids in mitochondria. Using exome sequencing, we diagnosed a Japanese patient with LS and identified the patient as a compound heterozygote for a novel variant of ECHS1, consisting of NM_004092.4:c.23T>C (p.Leu8Pro) and NM_004092.4:c.176A>G (p.Asn59Ser).

A Novel Animal Model Prepared by Blocking (FOXRED1 gene) for neuro-toxicological studies of Leigh Syndrome

Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantianigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for neuro-toxicological studies of Leigh syndrome due to defective mitochondrial complex I (CI), which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.

FOXRED1 silencing in mice: a possible animal model for Leigh syndrome.

Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantia nigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for Leigh syndrome due to defective CI, which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.

Leigh Syndrome: Report of a Rare Case with Late Onset Presentation

Leigh's syndrome, or sub acute necrotizing encephalomyelopathy, is a rare inherited neurometabolic disease of infancy and early childhood with variable course and prognosis. Rarely, it occurs in juveniles and adults. The diagnosis is difficult and still remains to challenge the clinicians on the basis of history; hence the role of imaging is very essential. It is the neuroimaging, chiefly the Magnetic Resonance Imaging showing characteristic symmetrical necrotic lesions in the basal ganglia and/or brain stem that leads to the diagnosis. Late-onset varieties are rare and only few cases were reported all over the world. Here, I report a case of late onset (juvenile) Leigh syndrome presenting with an acute polyneuropathy. Neuroimaging confirmed it to be a case of Leigh syndrome.

A case report on a novel MT-ATP6 gene variation in atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients.

Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families. Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect. We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.

Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation

We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation.

Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia.

Mitochondrial disease can present with a wide range of clinical phenotypes, and knowledge of the clinical spectrum of mitochondrial DNA mutation is constantly expanding. Leigh syndrome (LS) has been reported to be caused by the m.13513G>A mutation in the ND5 subunit of complex I (MT-ND5 m.13513G>A). We present a case of a 12-month-old infant initially diagnosed with tachyarrhythmia requiring defibrillation, subsequent presentation with hypertension and hyponatraemia secondary to renal salt loss and presumed inappropriate ADH secretion. Complex I activity in the muscle tissue was 54%, and mutation load in the muscle and lymphocytes was 50%. This case of Leigh syndrome caused by the m.13513G>A mutation in the ND5 gene illustrates that hyponatraemia due to renal sodium loss and inappropriate ADH secretion and hypertension can be features of this entity in addition to the previously reported cardiomyopathy and WPW-like conduction pattern and that they present additional challenges in diagnosis and management.

Leigh syndrome with Fukuyama congenital muscular dystrophy: A case report

We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I+II deficiency has rarely been reported, suggesting a nuclear gene mutation.

Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2

Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. Mutations in genes encoding for subunits of the respiratory chain or assembly factors of respiratory chain complexes are often documented in LS cases. Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) enzyme deficiencies account for a significant proportion of mitochondrial disorders, including LS. In an attempt to expand the repertoire of known mutations accounting for LS, we describe the clinical, radiological, biochemical and molecular data of six patients with LS found to have novel mutations in two complex I subunits (NDUFV1 and NDUFS2). Two siblings were homozygous for the previously undescribed R386C mutation in NDUFV1, one patient was a compound heterozygote for the R386C mutation in NDUFV1 and a frameshift mutation in the same gene, one patient was a compound heterozygote for the R88G and R199P mutations in NDUFV1, and two siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2. After the novel mutations were identified, we employed prediction models using protein conservation analysis (SIFT, PolyPhen and UCSC genome browser) to determine pathogenicity. The R386C, R88G, R199P, and E104A mutations were found to be likely pathogenic, and thus presumably account for the LS phenotype. This case series broadens our understanding of the etiology of LS by identifying new molecular defects that can result in complex I deficiency and may assist in targeted diagnostics and/or prenatal diagnosis of LS in the future.

SURF1 missense mutations promote a mild Leigh phenotype

SURF1 gene mutations are the most common cause of Leigh syndrome (LS), a rare progressive neurodegenerative disorder of infancy, characterized by symmetric necrotizing lesions and hypervascularity in the brainstem and basal ganglia, leading to death before the age of 4 years. Most of the reported mutations create premature termination codons, whereas missense mutations are rare. The aim of the study was to characterize the natural history of LS patients carrying at least one missense mutation in the SURF1 gene. Nineteen such patients (8 own cases and 11 reported in the literature) were compared with a reference group of 20 own c.845_846delCT homozygous patients, and with other LS(SURF-) cases described in the literature. Disease onset in the studied group was delayed. Acute failure to thrive and hyperventilation episodes were rare, respiratory failure did not appear before the age of 4 years. Dystonia, motor regression and eye movement dissociation developed slowly. The number of patients who survived 7 years of life totaled 9 out of 15 (60%) in the 'missense group' and 1 out of 26 (4%) patients with mutations leading to truncated proteins. (i) The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients, (ii) normal magnetic resonance imaging (MRI) findings, normal blood lactate value, and only mild decrease of cytochrome c oxidase (COX) activity are not sufficient reasons to forego SURF1 mutation analysis in differential diagnosis.

Leigh Syndrome: An MR Study of Three Cases

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is the most common childhood mitochondrial encephalopathy, accounting for more than 50% of cases in this age group. Its estimated incidence is 1:40,000 - 1:77,000 liveborn infants a year. LS is a rare progressive multisystem fatal disorder inherited by autosomal recessive, X-linked and maternal transmission. Clinical onset is predominantly in the first two years of life (average: six months); 50% of patients die within a year, even though there are later- and even adult-onset forms with a more protracted evolution. LS is due to a deficit of various respiratory chain and Krebs cycle enzymes resulting in insufficient production of adenosine triphosphate (ATP), in particular cytochrome-c-oxidase (COX), pyruvate carboxylase, pyruvate dehydrogenase complex and complex I of the respiratory chain, which share an autosomal recessive and X-linked mode of transmission. Cases with maternal inheritance (MILS) are due to a mitochondrial DNA (mtDNA) point mutation. LS is clinically heterogeneous in relation to the severity of the metabolic dysfunction and is characterized by muscle involvement and especially CNS disorders, particularly psychomotor retardation, ocular symptoms, hypotonia and pyramidal signs. Death is most commonly due to respiratory failure, status epilepticus and sudden coma. The major neuropathological findings, first described by Leigh in 1951, are symmetrical foci of spongy necrosis associated with vessel proliferation and reactive gliosis in basal nuclei, brainstem and thalamus grey matter. The neuronal metabolic alteration can also affect the white matter, resulting in delayed myelination or hypomyelination. The diagnosis rests on clinical signs, elevated CSF lactate, pyruvate and alanine, and biochemical and neuroradiological data. We describe two patients with LS studied with morphological MR associated with diffusion and spectroscopy techniques to assess the diagnostic potential of standard MR imaging and establish whether the association of functional MR methods can improve its diagnostic accuracy. A case of LS with a post-mortem MR study is also described. Three patients with a diagnosis of LS based on clinical, CSF and laboratory data were studied on a GE SIGNA EXCITE 1.5 T unit using an eight-channel phased-array head coil to acquire standard sequences (SE T1; TSE DP T2; FLAIR) and echo-planar diffusion-weighted sequences (DWI; b= 1000 s/mm2) with calculation of ADC maps. The spectroscopic study used single-voxel (TE/TR ms = 144/1500) and multi-voxel techniques (TE/TR ms = 144/1000) at the level of the basal nuclei. Bilateral and symmetrical involvement of basal nuclei grey matter with T2 hyperintensity was a consistent finding in the morphological MR study. In one patient, associated white matter involvement with T2 hyperintensity in periventricular and retrotrigonal areas reflected delayed myelination or hypomyelination. The deep grey matter changes, sometimes associated with white matter lesions, suggested a diagnosis of subacute necrotizing encephalomyelopathy, in line with the literature. Acute-phase ADC values in affected areas were lower than those of normal grey and white matter and displayed signal hyperintensity on DWI. Reduced ADC values are associated with restricted water diffusivity typical of cytotoxic edema. Spectroscopy showed a high lactate peak, reflecting altered anaerobic glycolysis, and a reduced NAA peak in affected areas, which are however non-specific findings. The most informative study in these patients is standard MR associated with functional techniques, which can confirm the diagnosis obtained with morphological imaging.

Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonenia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I + III and II + III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiancy, possibly caused by CoQ responsive oxphos deficiency.

Mitochondrial DNA depletion in Leigh syndrome

Leigh syndrome is a heterogenous neurologic disease characterized by seizures, developmental delay, muscle weakness, respiratory abnormalities, optic abnormalities, including atrophy and ophthalmoplegia, and progressive cranial nerve degeneration with early onset in infants and children. Diagnosis can be confirmed by characteristic pathologic findings of necrosis in the basal ganglia, thalamus, and brainstem. Severe dysfunction of mitochondrial energy metabolism is generally present and involved in the etiology of this degenerative central nervous system disease. At the molecular level, a number of point mutations have been located in mitochondrial DNA genes, including ATPase6 and tRNA Lys genes, and in nuclear genes encoding subunits of oxidative enzymes, such as pyruvate dehydrogenase. Biochemically these mutations are responsible for enzymatic defects in either respiratory complexes (I, IV, or V) or pyruvate dehydrogenase. We describe here the first case of Leigh syndrome with marked depletion of mitochondrial DNA levels in skeletal muscle and abnormal activities in skeletal muscle of mitochondrial respiratory complexes I, III, IV, and V.

Compulsory hyperventilation and hypocapnia of patients with Leigh syndrome associated with SURF1 gene mutations as a cause of low serum bicarbonates.

Experimental data show that elevation of intracellular pH leads to severe lesions of brain cells. Acidification of intracellular fluid by accumulation of lactate may compensate the effect of respiratory alkalosis. Increased serum pH, and low PCO2, associated with hyperlactataemia (sometimes incorrectly called 'acidosis') have been reported in children with Leigh syndrome (LS). The aim of the study was to determine whether respiratory alkalosis is characteristic of patients with LS due to SURF1 mutations. All venous blood gas data (88 samples) of 18 spontaneously breathing LS patients with recently established SURF1 mutations, hospitalized during 1986-2000, were retrospectively reviewed. The data of an affected boy who survived on a respirator for more than 3 months (79 daily samples) were analysed separately. In spontaneously breathing patients, the data indicated that the patients had compensated or partially compensated respiratory alkalosis (pH 7.388+/-0.060, Pco2 29.2+/-5.7 mmHg, HCO3- 17.4+/-3.0 mmol/L, BE -6.7+/-3.2 mmol/L). Bicarbonate excretion was detected in urine of two examined LS cases in spite of decreased serum HCO3-. In the affected child maintained on a respirator, simple manipulation of the inspired CO2 tension to establish a normal pressure of 35-45 mmHg automatically caused an increase of serum HCO3- concentration to a normal value of 26.3+/-2.9 mmol/L (and BE to +2.2+/-3.1 mmol/L), in spite of cytochrome oxidase (COX) deficiency due to a confirmed SURF1 mutation. We suggest that respiratory alkalosis (hypocapnia) of Leigh syndrome patients with SURF1 mutations results from compulsory hyperventilation and speculate that hypocapnia may contribute to Leigh-like brain damage in the SURF1-deficient patients as well as in other patients presenting with Leigh-like syndrome. The supposition that accumulation of lactate may protect the brain of LS patients from alkalosis-related damage requires further study. Avoidance of any factors stimulating hyperventilation of LS patients and caution when attempting to correct low plasma bicarbonate are suggested.

Leigh syndrome: historical perspective and clinical variations.

Leigh syndrome (LS) has emerged as the quintessential neuropathological signature of a mitochondrial encephalopathy. Did D. Leigh ever imagine this possibility in 1951 when he described the neuropathology of a young infant who died after 6 weeks of devastating neurological symptoms [9]? It is unlikely. But to his credit he recognized the histopathological overlap between his case and Wernicke encephalopathy; and he speculated about the role of an altered thiamine-dependent process as the basis for the similarity. Not far off the mark as we would learn over the next several decades. Leigh’s case showed sparing of the mamillary bodies and the putamen. The former observation has remained true but the latter appears now to be an exception. The difficulty in defining LS as a clinical entity followed subsequent observations by noted neuropathologists who reported the histopathology of LS in all age groups with a diversity of clinical prodromes and phenotypes. This debate was perhaps best epitomized by Crosby and Chou [2] when they described ragged-red fibers (RRF) in LS. At the time, this report engendered a vigorous debate as to whether the patient had LS or Kearns–Sayre syndrome (KSS). The current view of this historic controversy is the fact that both LS and KSS are mitochondrial diseases. RRF are rarely seen in LS, and are the rule in KSS. Montpetit et al. [11] described the clinical findings in a series of LS cases and concluded that the condition was mainly a subcortical brainstem syndrome. For the reasons stated earlier, the disease phenotype was not clearly defined. Insights into the biochemical basis for LS emerged in the 1960s. Worsley et al. [13] described two siblings with lactic acidosis. At autopsy, LS was confirmed. This report also represented the first description of familial lactic acidosis. In 1968, Hommes et al. described pyruvate carboxylase (PC) deficiency associated with LS. This association later was disputed by several authors. On the other hand, LS has been described with biotinidase deficiency, a form of multiple carboxylase deficiency. Willems et al. [12] described a young child with cytochrome c oxidase (COX) deficiency and LS, viewed by many at that time as an implausible correlate. In 1979, De Vivo et al. described an infant with LS and defective activation of the pyruvate dehydrogenase complex [3]. It was presumed that the basic defect involved the pyruvate dehydrogenase-specific phosphatase. Two other siblings, a male and female, also had LS suggesting autosomal recessive inheritance. The importance of COX deficiency in LS was emphasized by DiMauro et al. in 1987 when five patients were described with generalized partial COX deficiency and LS [4]. Numerous reports have since appeared linking COX deficiency and LS (Table 1). In 1990, Fujii et al. [7] described two children with complex I deficiency and LS, and Morris et al. [10] emphasized the deficiency of complex I as a common correlate to LS. In 1990, Holt et al. described a new mitochondrial disease associated with heteroplasmy and maternal inheritance [8]. This condition later was referred to as the NARP syndrome (neuropathy, ataxia and