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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]

The article focuses on mutations in mitochondrial DNA (mtDNA) and its clinical manifestations like mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and a biochemical deficiency of respiratory chain complex 1. It presents a report on three unrelated patients with MELAS in whom 3243A↠G mutation could not be detected, but who expressed a specific deficiency of complex 1 activity in both skeletal muscle and cultured fibroblasts. The findings suggest the importance of mtDNA mutations in aetiology of childhood respiratiory chain complex1 deficiency and underlines the importance of a cohesive diagnostic strategy where molecular genetic investigations are shaped by the biochemical and histological findings.

The perinatal mortality rates of mothers who delivered at St. Thomas's Hospital from 1969 to 1976 have been examined. The rate in the West Indian population was significant higher than in the United Kingdom white population. The increased West Indian mortality was confined to infants with a birth weight of more than 2.0 kg and a gestational age of more than 37 weeks. The relative risk of perinatal death for West Indian mothers compared with UK white mothers was 1.4 at birth weights of 2.5 kg to 2.9 kg, rising to 4.3 at 4.0 + kg. West Indian perinatal mortality in term babies of normal birth weight was higher in all maternal age and parity groups except parity 3, but the difference was greatest in women aged 30 or over. The African perinatal mortality rate was not significantly greater than the UK white rate although it followed the West Indian trends. Pre-eclampsia and forceps delivery were associated with a greatly increased perinatal mortality in West Indian babies. The excess West Indian mortality could not be explained completely by differences in the proportions of stillbirths and early neonatal deaths nor by the distribution of births by parity, maternal age, or social class. Possible explanations for the differences in mortality are discussed. [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]

We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease. [ABSTRACT FROM AUTHOR]

We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase γ gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease. [ABSTRACT FROM AUTHOR]

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.