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Background: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. Methods and results: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. Conclusion: The addition of these substitutions--including the first report of a dinucleotide mutation (c.1814‗1815TT>GC)--to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations. [ABSTRACT FROM AUTHOR]

Background: Defects of the mitochondrial genome are recognised as common causes of genetic disease. Sequencing of large portions or even the entire mitochondrial genome is routine in many laboratories for the investigation of mitochondrial disease. However, establishing whether a detected sequence change is polymorphic or pathogenic is still a major difficulty because of its highly polymorphic nature. This has major implications for the patient and the family. Objective: To describe a scoring system for determining the likelihood that a given sequence variant in one of the seven mitochondrially encoded complex I (MTND) genes is truly pathogenic. Results: The scoring system was applied to 50 reported MTND mutations. Using this system, 21 of the mutations analysed fell into the group of neutral sequence variants, 10 were classified as possibly pathogenic, three as probably pathogenic, and 16 as almost certainly pathogenic. Conclusions: The proposed scoring system should advance the interpretation of sequence variants and ensure that candidate pathogenic mutations are rigorously investigated. [ABSTRACT FROM AUTHOR]

Aim: To study the normal distributions of mitochondria and voltage gated Na(+) channels in the human optic nerve head in order to gain insight into the potential mechanisms of optic nerve dysfunction seen in the inherited optic neuropathies. METHODS: Five fresh frozen human optic nerves were studied. Longitudinally orientated, serial cryosections of optic nerve head were cut for mitochondrial enzyme histochemistry and immunolabelling for cytochrome c oxidase (COX) subunits and voltage gated Na(+) channel subtypes (Na(v) 1.1, 1.2, 1.3, and 1.6). RESULTS: A high density of voltage gated Na(+) channels (subtypes Na(v) 1.1, 1.3, and 1.6) in the unmyelinated, prelaminar, and laminar optic nerve was found. This distribution co-localised both with areas of high COX activity and strong immunolabelling for COX subunits I and IV. CONCLUSIONS: Increased numbers of mitochondria in the prelaminar optic nerve have previously been interpreted as indicating a mechanical hold up of axoplasmic flow at the lamina cribrosa. These results suggest that this increased mitochondrial density serves the higher energy requirements for electrical conduction in unmyelinated axons in the prelaminar and laminar optic nerve and is not a reflection of any mechanical restriction. This could explain why optic neuropathies typically occur in primary inherited mitochondrial diseases such as Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibres (MERRF), and Leigh's syndrome. Secondary mitochondrial dysfunction has also been reported in dominant optic atrophy, Friedreich's ataxia, tobacco alcohol amblyopia, Cuban epidemic optic neuropathy, and chloramphenicol optic neuropathy. These diseases are rare but these findings challenge the traditional theories of optic nerve structure and function and may suggest an alternative approach to the study of commoner optic neuropathies such as glaucoma. [ABSTRACT FROM AUTHOR]

Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that preferentially causes blindness in young adult males, affecting about 1 in 25 000 of the British population. It is characterised by bilateral subacute loss of central vision owing to focal degeneration of the retinal ganglion cell layer and optic nerve. Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA (mtDNA) point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the respiratory chain. An intriguing feature of LHON is that only ∼50% of males and ∼10% of females who harbour a pathogenic mtDNA mutation actually develop the optic neuropathy. This marked incomplete penetrance and gender bias imply that additional mitochondrial and/or nuclear genetic factors must be modulating the phenotypic expression of LHON. It is also likely that environmental factors contribute to the onset of visual failure. However, these secondary precipitating factors remain poorly defined at present. In this review, we describe the natural history of this optic nerve disorder and highlight issues relating to clinical diagnosis, management, and genetic counselling. We also discuss the findings of recently published studies and the light they shed on the complex aetiology and pathophysiology of LHON. [ABSTRACT FROM AUTHOR]

Objectives: Carnitine palmitoyltransferase (CPT) deficiency is one of the most common defects of mitochondrial fatty acid oxidation. Two different enzymes (CPT-I and CPT-II) are involved. Due to problems in measuring enzyme activity, relatively little is known about the substrate specificity of each of the human enzymes. This is of considerable importance in the treatment of patients. The objectives were to establish a reliable method for the measurement of CPT activity in whole cells, to use this to characterise the substrate specificity of each enzyme, and finally, to determine if medium chain triglycerides would be of benefit in the treatment of deficient patients.Methods: A simple permeabilisation technique was used which allows the measurement of CPT activity in a small amount of cultured skin fibroblasts or peripheral blood cells. Using this technique three patients were identified with CPT deficiency. In two of these patients, one with CPT-I deficiency and one with CPT-II deficiency, a complete substrate specificity profile of the mitochondrial carnitine acyltransferases was established for all saturated even chain acyl-CoA esters.Results: For both enzymes the highest CPT activity was with C12-CoA. About 70% of total cellular carnitine octanoyltransferase activity was due to mitochondrial CPT. As CPT is involved in the transport of medium chain fatty acids the metabolic response of a patient with CPT-II deficiency to dietary medium chain triglycerides was assessed. Despite the normal production of ketone bodies there was a significant medium chain dicarboxylic aciduria in the patient, indicating a limited capacity of the CPT independent mitochondrial uptake of medium chain fatty acids.Conclusions: CPT deficiency can easily be diagnosed in permeabilised cultured skin fibroblasts. Both CPT-I and CPT-II are more active with medium chain length substrates than previously assumed. Care should therefore be taken in the treatment of these patients with medium chain triglycerides. [ABSTRACT FROM AUTHOR]

A previously asymptomatic 30 year old man presented with rhabdomyolysis, muscle weakness, and acute encephalopathy after strenuous exertion in the cold without adequate food intake. Serum and muscle carnitine concentrations were decreased. Urinary excretion of carnitine and glycine esters and biochemical examination of skeletal muscle and fibroblasts led to the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency. A point mutation at nucleotide position 985 of the coding region of the MCAD gene was found. The MCAD protein was synthesised in the patient's fibroblasts at a normal rate, but was unstable. In general, patients in whom the 985 point mutation has been established show much more severe clinical symptoms and other symptoms than those seen in this patient. The relation of the 985 point mutation and the residual MACD activity to the symptoms is not as straightforward as previously thought. [ABSTRACT FROM AUTHOR]

Valproate is an important anticonvulsant which is rarely associated with fatal hepatotoxicity. Previous experiments have shown that valproate inhibits several metabolic processes in isolated rat hepatocytes and when administered to starved rats causes a fall in the blood concentrations of glucose and ketone bodies. Since these changes may be related to the hepatotoxicity, the effect of valproate administration on intermediary metabolism in man was studied. One gram of valproate given orally to fasted normal humans caused a 78% fall in the concentration of 3-hydroxybutyrate and a 60% fall in total ketones. Also the concentrations of lactate, pyruvate, alanine and glycerol increased after valproate administration. Similar changes were observed after intravenous administration of 400 mg of valproate. Valproate clearly has a significant effect on intermediary metabolism in the liver and this is probably related to the mechanism of the hepatotoxicity. [ABSTRACT FROM AUTHOR]

Studies of the efficacy of anticonvulsant drugs are difficult to undertake and historically have been of poor quality. Randomised comparisons of drugs are few in number, and have failed to detect significant differences between drugs. This is surprising in view of the strong feelings that many clinicians have about the relative efficacy of the drugs they use. A review of the literature emphasises the need for further studies in this field. [ABSTRACT FROM AUTHOR]

Serum phenytoin concentrations were monitored prospectively in 26 patients with previously untreated partial epilepsy, during monotherapy with phenytoin. Only six remained entirely seizure-free, although only four experienced further tonic-clonic seizures. There was no correlation between serum phenytoin concentrations and freedom from partial seizures in those patients in whom such seizures recurred. There did appear to be a correlation between serum phenytoin concentration and freedom from tonic-clonic seizures. [ABSTRACT FROM AUTHOR]

Eighty-eight patients with the onset of epilepsy in adult life were randomly allocated to treatment with sodium valproate (600 mg/day), or phenytoin (300 mg/day), and followed up for at least 12 months. Both drugs were highly effective in the control of tonic-clonic seizures, irrespective of whether they were accompanied by focal features, but were markedly less effective in the control of partial seizures. Two patients exhibited acute allergic reactions to phenytoin. No significant differences have yet emerged in the efficacy of the two drugs, and valproate may be considered as a "fist-line" anticonvulsant in the treatment of adult onset epilepsy. [ABSTRACT FROM AUTHOR]

The mitochondrial myopathies are a heterogeneous group of disorders some of which may be caused by mutations in the mitochondrial genome. Mitochondrial DNA from 10 patients with mitochondrial myopathy and their mothers was analysed using five restriction enzymes and 11 mitochondrial probes in bacteriophage M13. No abnormalities were found in seven out of the 10 patients. Polymorphisms which have not previously been reported were detected in three patients and two of their mothers. These results exclude the presence of deletions or insertions of greater than 60 bp in the region of the mitochondrial genome examined. Any causative mitochondrial DNA mutations in these disorders are therefore likely to be point mutations or small structural rearrangements. [ABSTRACT FROM PUBLISHER]

Aim: To investigate a possible association between mitochondrial haplogroups and primary open angle glaucoma (POAG). Methods: Genomic DNA was extracted from 140 POAG patients and 75 healthy individuals. Restriction enzyme digest analysis of polymerase chain reaction (PCR) amplified fragments was used to determine the mitochondrial haplogroup of each patient and control. Results: The median age was 73 years for the POAG patients (range 51-87, SD 8.01) and 78 years for the controls (range 68-90, SD 4.4). Mean lOP was 20.8 mm Hg for the patients (SD 2.6) and 16.2 mmHg for the controls (SD 3.4). Median cup/disc ratio was 0.8 and 0.3 for patients and controls respectively. No statistically significant difference was found in the haplogroup distribution between the POAG patients and the healthy individuals (Fisher's exact test). Conclusion: In this cohort, mitochondrial haplogroups do not appear to contribute to the pathogenesis of POAG. [ABSTRACT FROM AUTHOR]

In two prospective studies of anticonvulsant therapy there was a high incidence of drug-induced skin reactions to phenytoin (7%) and carbamazepine (16.6%). High initial serum concentrations of these drugs appeared to be a factor influencing the occurrence of such skin reactions. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article on 16189C polymorphic sequence variant and late onset dementia.

This article focuses on a study that finds no association of the mitochondrial DNA A 12308G polymorphism with increased risk of stroke in patients with the A3242G mutation. Only 50% of patients carrying the A3243G mutation have stroke-like episodes and the reason for this clinical variability remains poorly understood. It is responsible for 80% of cases of MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, and is also associated with several other phenotypes including maternally inherited diabetes and deafness and chronic progressive external ophthalmoplegia. Researchers carried out a large, multicentre study to investigate the A12308G polymorphism in a group of 107 unrelated family index cases harbouring the A3243G mutation.

An abstract of the article "Role of Mitochondria in a Mouse Model of Multiple Sclerosis," by V. Hogan, K. White, J. Edgar, I. Griffiths, D. Turnbull, and P. Nichols is presented.

Presents an abstract of the article "Sequence Variation in the Mitochondrial Genome: What is the Pathogenic Mutation?" by Robert W. Taylor, J.L. Elson, R. McFarland, A.L. Mitchell, N. Howell, and D.M. Turnbull.

Aims: To define the prevalence of non-sustained tachyarrhythmias and bradyarrhythmias in patients with the m.3243A>G mitochondrial genotype and a previously defined, profile, associated with 'high sudden-death risk'., Methods and Results: Patients at high risk of sudden death because of combinations of ventricular hypertrophy, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes family phenotype, epilepsy or high mutation load, due to the m.3243A>G mutation, were identified from a mitochondrial cohort of 209 patients. All recruited had serial ECG and echo assessments previously according to schedule, had an ECG-loop recorder implanted and were followed for as long as the device allowed. Devices were programmed to detect non-sustained brady- or tachy-arrhythmias. This provided comprehensive rhythm surveillance and automatic downloads of all detections to a monitoring station for cardiology interpretation. Those with sinus tachycardia were treated with beta-blockers and those with ventricular hypertrophy received a beta-blocker and ACE-inhibitor combination.Nine consecutive patients, approached (37.2±3.9 years, seven males) and consented, were recruited. None died and no arrhythmias longer than 30s duration occurred during 3-year follow-up. Three patients reported palpitations but ECGs correlated with sinus rhythm. One manifest physiological, sinus pauses >3.5 s during sleep and another had one asymptomatic episode of non-sustained ventricular tachycardia., Conclusions: Despite 'high-risk' features for sudden death, those studied had negligible prevalence of arrhythmias over prolonged follow-up. By implication, the myocardium in this genotype is not primarily arrhythmogenic. Arrhythmias may not explain sudden death in patients without Wolff-Parkinson-White or abnormal atrioventricular conduction or, it must require a confluence of other, dynamic, proarrhythmic factors to trigger them., Competing Interests: Competing interests: In addition to the institutional support from the organisations listed under acknowledgments above, all authors have completed the ICMJE uniform disclosure form with declarations as follows: JB: research grant from Duchenne UK; Trial Data Monitoring Committee member, Sarepta Therapeutics, Cambridge, MA, USA; Consulting fees from EspeRare Foundation, Geneva, Switzerland. YSN: declares no conflicts of interest. MT: declares no conflicts of interest. MGDB: declares no conflicts of interest. SM: declares no conflicts of interest. DT: declares receipt of grants from Wellcome Trust and MRC; consulting fees from IMEL Biotherapeutics, Tokyo, Japan, Nanna Therapeutics, Cambridge, UK and Casma Therapeutics, Cambridge, MA, USA; Trustee and Board Member UK Dementia Research Institute (unpaid). GSG: research awards NIHR BRC, Newcastle upon Tyne and Wellcome Trust., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)