POLG Research Articles

Successful treatment of POLG‐related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet

Epilepsy is a common manifestation of mitochondrial disease associated with mutations of the mitochondrial polymerase γ (POLG). Prognosis of mitochondrial epilepsy is often poor and there are few reports of successful treatment of POLG-related epilepsy. We describe a 26-year-old woman who experienced severe headache during a three-day period, followed by symptoms of visual flashing, speech difficulty, and generalised seizures. EEG recording showed non-convulsive status epilepticus (left occipital area) and brain MRI revealed parieto-occipital T2-hyperintensities. Visual aura and aphasia persisted despite antiepileptic medication with phenytoin, oxcarbazepine, and levetiracetam. Mitochondrial disorder was clinically suspected and a homozygous c.2243G>C mutation (p.Trp748Ser) was discovered in the POLG1 gene. The patient was then set on a low glycaemic index treatment (LGIT) variant of the ketogenic diet, after which the headaches, aphasia, and visual aura progressively improved and disappeared. She returned home two weeks after onset of symptoms and has not had further seizures. She continues to receive levetiracetam monotherapy and LGIT. We conclude that, at least for this patient, the combination of three antiepileptic drugs and LGIT is effective and well tolerated as treatment for severe episodes of POLG-related mitochondrial epilepsy.

Polg2 is essential for mammalian embryogenesis and is required for mtDNA maintenance

Mammalian mitochondrial DNA (mtDNA) is replicated by the heterotrimeric Pol γ comprised of a single catalytic subunit, encoded by Polg, and a homodimeric accessory subunit encoded by the Polg2 gene. While the catalytic subunit has been shown to be essential for embryo development, genetic data regarding the accessory subunit are lacking in mammalian systems. Here, we describe the generation of heterozygous (Polg2(+/-)) and homozygous (Polg2(-/-)) knockout (KO) mice. Polg2(+/-) mice are haplosufficient and develop normally with no discernable difference in mitochondrial function through 2 years of age. In contrast, the Polg2(-/-) is embryonic lethal at day 8.0-8.5 p.c. with concomitant loss of mtDNA and mtDNA gene products. Electron microscopy shows severe ultra-structural defects and loss of organized cristae in mitochondria of the Polg2(-/-) embryos as well as an increase in lipid accumulation compared with both wild-type (WT) and Polg2(+/-) embryos. Our data indicate that Polg2 function is critical to mammalian embryogenesis and mtDNA replication, and that a single copy of Polg2 is sufficient to sustain life.

A NEW PHENOTYPE OF PAPT: PROGRESSIVE ATAXIA, PALATAL TREMOR AND OPTIC ATROPHY

We present the case of a 40-year-old man who developed progressive ataxia and palatal tremor (PAPT), in association with bilateral optic atrophy and upper motor neuron signs. MRI showed evidence...

Early-onset Ataxia With Progressive External Ophthalmoplegia Associated With POLG Mutation

Autosomal recessive ataxias caused by mutations of the polymerase γ (POLG) gene make an important group of progressive ataxias accompanied by a diverse spectrum of neurological disorders. Because the clinical picture can be quite miscellaneous, it is challenging to assort patients to any of the currently described syndromes; therefore, to provide such a patient with a conclusive diagnosis can be challenging for the neurologist. A typical magnetic resonance imaging finding is probably the most useful landmark in the diagnostic process, which will steer the clinician toward POLG gene testing. To illustrate this, we present a case of progressive ataxia caused by A467T and W748S mutations of POLG gene, who presented with overlapping symptoms of autosomal recessive mitochondrial ataxic syndrome and SANDO, as well as choreoathetotic movements and dysphonia. After lengthy investigations, magnetic resonance imaging showed T2 and FLAIR hyperintensities in the thalamus, inferior olives, and cerebellum, which led us to the analysis of POLG mutations.

Patient-derived fibroblasts indicate oxidative stress status and may justify antioxidant therapy in OXPHOS disorders

Oxidative phosphorylation disorders are often associated with increased oxidative stress and antioxidant therapy is frequently given as treatment. However, the role of oxidative stress in oxidative phosphorylation disorders or patients is far from clear and consequently the preventive or therapeutic effect of antioxidants is highly anecdotic. Therefore, we performed a systematic study of a panel of oxidative stress parameters (reactive oxygen species levels, damage and defense) in fibroblasts of twelve well-characterized oxidative phosphorylation patients with a defect in the POLG1 gene, in the mitochondrial DNA-encoded tRNA-Leu gene (m.3243A>G or m.3302A>G) and in one of the mitochondrial DNA-encoded NADH dehydrogenase complex I (CI) subunits. All except two cell lines (one POLG1 and one tRNA-Leu) showed increased reactive oxygen species levels compared with controls, but only four (two CI and two tRNA-Leu) cell lines provided evidence for increased oxidative protein damage. The absence of a correlation between reactive oxygen species levels and oxidative protein damage implies differences in damage prevention or correction. This was investigated by gene expression studies, which showed adaptive and compensating changes involving antioxidants and the unfolded protein response, especially in the POLG1 group. This study indicated that patients display individual responses and that detailed analysis of fibroblasts enables the identification of patients that potentially benefit from antioxidant therapy. Furthermore, the fibroblast model can also be used to search for and test novel, more specific antioxidants or explore ways to stimulate compensatory mechanisms.

Hypertrophic olivary degeneration on magnetic resonance imaging in mitochondrial syndromes associated with POLG and SURF1 mutations

Hypertrophic olivary degeneration (HOD) is associated with lesions within the dento-rubro-olivary pathway or Guillain-Mollaret triangle and may be associated clinically with palatal tremor. Here we report HOD on brain magnetic resonance (MR) imaging in three patients with progressive mitochondrial syndromes in the absence of palatal tremor. Two of the patients were found to have identical compound heterozygous mutations in the POLG gene, encoding the catalytic subunit of the mitochondrial DNA polymerase-γ, but presented with different clinical phenotypes. The first patient displayed the clinical syndrome of sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis (SANDO), while the second patient was affected by a neurological disorder consisting of an ophthalmoplegia, myopathy, and neuropathy. The third case was a child with Leigh syndrome due to SURF1 gene mutations, who presented with a generalized tremor. We discuss the brain MR imaging findings in these three cases along with a literature review on the MR features of previously reported cases of patients with POLG gene mutations and Leigh disease due to SURF1 gene mutations. Our findings suggest that the presence of HOD, in the appropriate clinical setting, should alert the clinician to the possibility of a mitochondrial disorder and the need to screen for mutations in POLG and SURF1 genes.

PEO1 Gene (Twinkle) Mutation and Multi-Organ Failure Following Propofol Infusion (IN7-1.005)

Objective: Present a case of mitochondrial myopathy and multi-organ failure following propofol infusion. Background Mitochondrial DNA deletions are associated with a variety of clinical syndromes including chronic progressive external ophthalmoplegia (CPEO) due to nuclear as opposed to mitochondrial mutations. The nuclear PEO1 gene encodes for Twinkle, a helicase required for mitochondrial DNA replication and stability. Clinically, autosomal dominant Twinkle mutations are associated with CPEO. POLG mutations result in defects in the DNA polymerase gamma and can be associated with either autosomal dominant or autosomal recessive CPEO. Mitochondrial myopathies are associated with a sensitivity to propofol, and patients are more susceptible to developing a propofol infusion syndrome with resultant multi-organ dysfunction. Design/Methods: Literature review and illustrative case. Results: A 62-year old woman with a history of congenital ptosis and ophthalmoplegia was admitted for elective right eye enucleation for a corneal ulcer following levator resection. During the procedure, she was given propofol for anesthesia and the surgery was uneventful. Postoperatively, she developed a series of medical complications including Takotsubo cardiomyopathy, congestive heart failure, acute renal failure, and encephalopathy. She also developed dysarthria, bifacial and proximal muscle weakness, and difficulty weaning from the ventilator. Muscle biopsy was done showing a mitochondrial myopathy with scattered ragged red fibers and cytochrome oxidase negative muscle fibers. Genetic analysis showed nuclear mutations in the PEO1 and POLG genes. Conclusions: This patient had a mitochondrial myopathy presenting with CPEO, and after elective surgery, developed muti-organ dysfunction. She had the PEO1 mutation in addition to a POLG mutation. The literature on propofol use in mitochondrial myopathies is limited, but it has been associated with propofol infusion syndrome, and may have led to her poor clinical course. Disclosure: Dr. Harrison has nothing to disclose. Dr. Valerio has nothing to disclose. Dr. Buffam has nothing to disclose. Dr. Mezei has received personal compensation for activities with Genzyme as a speaker.

Molecular Diagnostic Approaches to Metabolic Myopathies by Target Gene Capture and Next Generation Sequencing (P07.215)

Objective: To develop an effective molecular approach by target gene capture and next generation sequencing for the diagnosis of metabolic myopathies. Background Metabolic myopathy is a group of clinically and genetically heterogeneous diseases due to defects in cellular energy metabolism, which includes three major categories: glycogen storage diseases, fatty acid oxidation, and mitochondrial respiratory chain disorders. Clinical presentation, abnormal metabolites, and biochemical enzymatic analyses may help with the diagnosis of the disease, however, the ultimate definitive diagnosis is the identification of causative molecular defects in the genes responsible for the disease. Design/Methods: A group of 24 nuclear genes commonly found to be associated with metabolic myopathies were enriched by hybridization of genome DNA with target gene specific probes (NimbleGen) followed by next generation sequencing (NGS). In addition, one single pair of primer was used to amplify the whole 16.6 kb mitochondrial genome (mtDNA) for massively parallel sequencing by NGS. Results: The sequencing was performed using Illumina9s HiSeq 2000. Twelve individually barcoded samples were pooled and analyzed. QC samples are indexed accordingly and spiked in with each sample. The coverage depth for the nuclear genes was 500X and for the mitochondrial genome was 20,000X. This deep coverage allows accurate base calls and quantitative analysis of mtDNA mutation heteroplasmy. Our results demonstrated that mutations in POLG, OPA1, LCHAD, CPTII, PHKs , and PYGM genes were all correctly identified. In addition, heteroplasmy of mtDNA point mutations and large deletion with breakpoints were also accurately determined. Conclusions: Capture of target genes in combination with long range PCR of mtDNA followed by next generation massively parallel sequencing allows cost effective analyses of a group of genes commonly involved in metabolic myopathies. This approach also provides quantitative information of mtDNA point mutations and large deletions. Disclosure: Dr. Zhang has nothing to disclose. Dr. Cui has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Wong has nothing to disclose.

Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study

Background: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecu- lar etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. Methods: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. Results: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. Conclusions: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.

A case of myelopathy, myopathy, peripheral neuropathy and subcortical grey matter degeneration associated with recessive compound heterozygous POLG1 mutations

This 54year old woman presented with symptoms of sensory ataxic neuropathy, with cerebellar features. She developed further weakness, visual disturbances with diplopia, dysarthria and dysphasia. After her death at 66years, she was found to have compound heterozygous mutations of POLG1 gene in muscle, and Southern blot showed low levels of multiple deletions of mitochondrial DNA. Neuropathological examination showed profound dorsal column and dorsal spinocerebellar tract degeneration, degeneration of dorsal root ganglia and Clarke’s nucleus in spinal cord and severe predominantly sensory peripheral neuropathy. The brain showed severe neuronal loss and gliosis in substantia nigra, medial posterior thalamus and head of caudate. Excess numbers of COX-negative fibres and “ragged-red” fibres were found in five skeletal muscles sampled.

Polymerase gamma deficiency (POLG): Clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh’s encephalopathy

AimsDescription of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction. ResultsAt 31/2 months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh’s encephalopathy. ConclusionThe present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions.

CAG Repeat Variants in the POLG1 Gene Encoding mtDNA Polymerase-Gamma and Risk of Breast Cancer in African-American Women

The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mitochondrial DNA replication in humans, contains a polyglutamine tract encoded by CAG repeats of varying length. The length of the CAG repeat has been associated with the risk of testicular cancer, and other genomic variants that impact mitochondrial function have been linked to breast cancer risk in African-American (AA) women. We evaluated the potential role of germline POLG-CAG repeat variants in breast cancer risk in a sample of AA women (100 cases and 100 age-matched controls) who participated in the Women's Circle of Health Study, an ongoing multi-institutional, case-control study of breast cancer. Genotyping was done by fragment analysis in a blinded manner. Results from this small study suggest the possibility of an increased risk of breast cancer in women with minor CAG repeat variants of POLG, but no statistically significant differences in CAG repeat length were observed between cases and controls (multivariate-adjusted odds ratio 1.74; 95% CI, 0.49–6.21). Our study suggests that POLG-CAG repeat length is a potential risk factor for breast cancer that needs to be explored in larger population-based studies.

POLG gene and its importance in mitochondrial diseases

Mitochondria are peculiar organelles with their own genome that is composed of a 16.5 kb circular double-stranded DNA molecule (mtDNA). It encodes two rRNAs, 22 tRNAs and 13 structural proteins [1]. Interestingly, a great majority of the proteins in mitochondria -approximately 1500 in number- are encoded by nuclear DNA, which makes these delicate and vulnerable organelles inevitably and highly dependent to the eukaryotic cells’ internal environment. Nuclear DNA-encoded proteins are transcribed in the nucleus, synthesized in the...

A novel POLG gene mutation in a patient with SANDO.

The human mitochondrial genome is replicated by DNA polymerase γ, which is encoded by polymerase γ gene (POLG1) on chromosome 15q25. Patients with POLG1 mutations usually present as Alpers' syndrome or progressive external ophthalmoplegia. Our patient was a 48-year old woman with sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. Sequence analysis revealed that she has two heterozygous missense mutations in the POLG1, a c.1774C>T substitution in exon 10, which results in a p.L591F amino acid change; and a c.3286C>T substitution in exon 21, which results in a p.R1096C amino acid change. The 1774C>T substitution is a novel mutation. Previously described adult patients with one mutation in exon 10 and the other in exon 21 of POLG1 had presented with progressive external ophthalmoplegia. We now describe a patient with mutations in the same exons but suffering from the more complex clinical syndrome of sensory ataxic neuropathy, dysarthria, ophthalmoplegia.

P-712 - Polg mutation in a patient with recurrent major depression, cardiomyopathy and ataxia

Introduction Spinocerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Over the last decade, novel mitochondrial genetic diseases have been identified in which mutations in DNA polymerase γ (POLG) gene are involved. POLG1 is essential for mitochondrial (mt) DNA replication and repair. At present, more than 100 disease mutations in POLG have been indentified that are causally related to an array of multi-system neuropsychiatric diseases. Objectives The significance of POLG in the pathophysiology of complex neuropsychiatric disorders. Aims Studying the involvement of POLG mutation in major depression. Methods Detailed diagnostic evaluation, including genetic analysis, of a middle aged female patient with recurrent psychotic depression, slowly progressive gait instability and dilated cardiomyopathy. Results As to psychiatry, major depression with psychotic features was present. The diagnosis of dilatated cardiomyopathy was confirmed. MRI scanning of the brain demonstrated marked cerebellar atrophy. Neuropsychological functioning was characterized by a sub-average disability, lowered speed of information processing and a relatively intact working memory. Extensive genetic and metabolic investigation demonstrated a nucleotide substitution c.2207 A→G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. Conclusions This novel POLG mutation is considered to be the etiological explanation for the combination of major depression, cardiomyopathy, and ataxia. In patients with complex neuropsychiatric disorders, extensive diagnostic analyses is warranted, including the search for mitochondriopathies.

Sensory neuronopathy in patients harbouring recessive polymerase γ mutations

Defects in the mitochondrial DNA replication enzyme, polymerase γ, are an important cause of mitochondrial disease with ∼25% of all adult diagnoses attributed to mutations in the POLG gene. Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment strategies are limited. In the present study, we use a combined approach comprising clinical, electrophysiological, neuropathological and molecular genetic investigations to unravel the mechanisms underpinning peripheral neuronopathy in autosomal recessive polymerase γ-related disease. Electrophysiological assessments documented a dorsal root ganglionopathy in all 11 cases. Of the 11 cases, eight also showed changes consistent with motor fibre loss. Detailed neuropathological investigation of two patients confirmed the electrophysiological findings, revealing atrophy of posterior columns and striking neuronal cell loss from the dorsal root ganglia, which was accompanied by severe mitochondrial biochemical abnormalities involving respiratory chain complexes I and IV due to clonally-expanded mitochondrial DNA deletions and a significant reduction in mitochondrial DNA copy number in affected neurons. We propose that the respiratory chain defects, secondary to mitochondrial DNA deletion and depletion, are likely to be responsible for pathology observed in the dorsal root ganglion and the sensory ganglionopathy documented electrophysiologically.

A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits

Human mitochondrial DNA (mtDNA) polymerase γ (pol γ) is the sole enzyme required to replicate and maintain the integrity of the mitochondrial genome. It comprises two subunits, a catalytic p140 subunit and a smaller p55 accessory subunit encoded by the POLG2 gene. We describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with adPEO and multiple mtDNA deletions. Biochemical studies of the recombinant mutant p55 protein showed a reduced affinity to the pol γ p140 subunit, leading to impaired processivity of the holoenzyme complex but did not show sensitivity to N-ethylmalaimide (NEM) inhibition, inferring a novel disease mechanism.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.

The phosphorescence oxygen analyzer as a screening tool for disorders with impaired lymphocyte bioenergetics

This study aimed to show the feasibility of using the phosphorescence oxygen analyzer to screen for clinical disorders with impaired cellular bioenergetics. [O2] was determined as function of time from the phosphorescence decay of Pd (II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. In sealed vials, O2 consumption by peripheral blood mononuclear cells was linear with time, confirming its zero-order kinetics. Cyanide inhibited O2 consumption, confirming the oxidation occurred in the mitochondrial respiratory chain. The rate of respiration (mean±SD, in μM O2 per min per 107 cells, set as the negative of the slope of [O2] vs. t) for adults was 2.1±0.8 (n=18), for children 2.0±0.9 (n=20), and for newborns (umbilical cord samples) 0.8±0.4 (n=18), p<0.0001. For an 8-year-old patient with reduced NADH dehydrogenase and pyruvate dehydrogenase activities in the muscle, the rate was 0.7±0.2 (n=3) μM O2 per min per 107 cells. For a 3-month-old patient with hepatocerebral mitochondrial DNA depletion syndrome (MDS) with confirmed mutations in the MPV17 gene, the rate was 0.6μM O2 per min per 107 cells. For an18 month-old patient with MDS and confirmed mutations in the POLG gene, the rate was 0.5μM O2 per min per 107 cells. For a 6-year-old patient with MDS and confirmed mutations in the POLG gene, the rate was 0.6μM O2 per min per 107 cells. For 1-week-old patient with congenital lactic acidemia and hypotonia (confirmed mutations in DLD gene), the rate was 1.5μM O2 per min per 107 cells. For three siblings (9-year-old male, 8-year-old male and 2-month-old female) with congenital progressive myopathy, the rates were 0.9, 0.6 and 1.2μM O2 per min per 107 cells, respectively. Four patients with congenital lactic acidemia (with inadequate work-up) were also studied; their rates were 0.2, 1.5, 0.3 and 1.7μM O2 per min per 107 cells. This novel approach permits non-invasive, preliminary assessment of cellular bioenergetics. Potential applications and limitations of this technique are discussed.

Mitochondrial DNA polymerase γ mutations: an ever expanding molecular and clinical spectrum

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic...