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Biomedical subjects

R W Taylor

Publications and source records attributed to R W Taylor.

At least 19 recordsLinked to original sources
PubMed2007

Mitochondrial disease--its impact, etiology, and pathology.

Mitochondria are ubiquitous organelles that are intimately involved in many cellular processes, but whose principal task is to provide the energy necessary for normal cell functioning and maintenance. Disruption of this energy supply can have devastating consequences for the cell, organ, and individual. Over the last two decades, mutations in both mitochondrial DNA (mtDNA) and nuclear DNA have been identified as causative in a number of well-characterized clinical syndromes, although for mtDNA mutations in particular, this relationship between genotype and phenotype is often not straightforward. Despite this, a number of epidemiological studies have been undertaken to assess the prevalence of mtDNA mutations and these have highlighted the impact that mtDNA disease has on both the community and individual families. Although there has been considerable improvement in the diagnosis of mitochondrial disorders, disappointingly this has not been matched by developments toward effective treatment. Nevertheless, our understanding of mitochondrial biology is gathering pace and progress in this area will be crucial to devising future treatment strategies. In addition to mitochondrial disease, evidence for a central role of mitochondria in other processes, such as aging and neurodegeneration, is slowly accumulating, although their role in cancer remains controversial. In this chapter, we discuss these issues and offer our own views based on our cumulative experience of investigating and managing these diseases over the last 20 years.

Aging↗
PubMed2006

Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.

Brain↗
PubMed2006

POLG1, C10ORF2, and ANT1 mutations are uncommon in sporadic progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.

The authors sequenced POLG1, C10ORF2, and ANT1 in 38 sporadic progressive external ophthalmoplegia patients with multiple mitochondrial DNA (mtDNA) deletions. Causative mutations were identified in approximately 10% of cases, with two unrelated individuals harboring a novel premature stop codon mutation (1356T>G). None had a mutation in C10ORF2 or ANT1. In the majority of patients, the primary nuclear genetic defect is likely to affect other unknown genes important for mtDNA maintenance.

Adenine Nucleotide Translocator 1↗
PubMed2006

Pure myopathy associated with a novel mitochondrial tRNA gene mutation.

The authors describe a 47-year-old man who presented with proximal muscle weakness, myalgia, elevated creatine kinase, and features of a pure myopathic syndrome in whom they have identified a novel mutation in the mitochondrial tRNA(Ala) gene. This 5591G>A transition is heteroplasmic, segregates with cytochrome c oxidase deficiency in single muscle fibers, and fulfills recognized criteria for pathogenicity. This case exemplifies the wide-ranging clinical spectrum of mitochondrial disease presentations.

Creatine Kinase↗
PubMed2006

Long-term effects of popular dietary approaches on weight loss and features of insulin resistance.

OBJECTIVE: High-carbohydrate (HC)-high-fibre diets are recommended for weight loss and for treating and preventing diseases such as diabetes and cardiovascular disease. We report a randomised trial comparing high-fat (HF) and high-protein (HP) diets with the conventional approach. RESEARCH DESIGN AND METHODS: A total of 93 overweight insulin-resistant women received advice following randomisation to HF, HP or HC dietary regimes, to achieve weight loss followed by weight maintenance over 12 months. Weight, body composition and measures of carbohydrate and lipid metabolism were investigated. RESULTS: Retention rates were 93% for HP and 75% for HC and HF. Features of the metabolic syndrome improved in all groups during the first 6 months, to a greater extent on HF and HP than an HC. During the second 6 months the HF group had increases in waist circumference (mean difference 4.4 cm (95% CI 3.0, 5.8)), fat mass (2.3 kg (1.5, 3.1)), triglycerides (0.28 mmol/l (0.09, 0.46)) and 2 h glucose (0.70 mmol/l (0.22, 1.18)). Overall there was substantial sustained improvement in waist circumference, triglycerides and insulin in the HP group and sustained but more modest changes on HC. Dietary compliance at 12 months was poor in all groups. CONCLUSIONS: HP and HC approaches appear to be appropriate options for insulin-resistant individuals. When recommending HP diets appropriate composition of dietary fat must be ensured. HC diet recommendations must include advice regarding appropriate high-fibre, low glycaemic index foods.

Adult↗
PubMed2006

Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement.

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.

Adult↗
PubMed2005

Cytochrome c oxidase deficient muscle fibres: substantial variation in their proportions within skeletal muscles from patients with mitochondrial myopathy.

Mitochondrial DNA (mtDNA) disease is a common cause of myopathy and the presence of histochemically demonstrated cytochrome c oxidase (COX) deficiency is an extremely useful diagnostic feature. However, there is currently no quantitative information regarding the variability of COX deficiency within or between muscles. This study addresses this issue by studying a number of skeletal muscle samples obtained at post-mortem from three patients with mitochondrial disease due to established mitochondrial DNA defects. COX deficient muscle fibres were enumerated in sections of these muscles and analysed according to patient, individual muscle, position within a particular muscle and sample size. Descriptive statistics were generated followed by an analysis of variance (ANOVA) to assess the effect of these parameters on the mean percentage of COX deficient fibres. We observed statistically significant variation in the percentage of COX deficient fibres within individual muscles from each patient for samples sizes of between 100 and 400 fibres. Our results have implications for the way in which biopsies of skeletal muscle are used for the assessment of disease severity, progression and response to treatment.

Adult↗
PubMed2005

Sequence variation in mitochondrial complex I genes: mutation or polymorphism?

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.

DNA, Mitochondrial↗
PubMed2005

Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.

OBJECTIVE: To investigate three families and one sporadic case with a recessively inherited ataxic syndrome. METHODS: Clinical and genetic studies were performed in six individuals. Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing. RESULTS: The patients have a distinctive, progressive disorder that starts with episodic symptoms such as migraine-like headache or epilepsy. Ataxia, which is a combination of central and peripheral disease, develops later as does ophthalmoplegia. The commonest form of epilepsy was focal and involved the occipital lobes. Myoclonus was common and patients have a high risk of status epilepticus. MRI typically shows signal changes in the central cerebellum, olivary nuclei, occipital cortex, and thalami. COX negative muscle fibers were found in four of six; in one patient these were rare and in another absent. Multiple mtDNA deletions were identified in all patients, although in two these were not apparent on Southern blotting and real time PCR was required to demonstrate the defect. Two families were homozygous for a previously described POLG mutation, G1399A (A467T). One family and the sporadic case had the same two new mutations, a G to C at position 1491 (Q497H) and a G to C at 2243 (W748S). CONCLUSIONS: Mutations in POLG cause a recessively inherited syndrome with episodic features and progressive ataxia. Characteristic changes on MRI are seen and although skeletal muscle may appear morphologically normal, multiple mtDNA deletions can be detected using real-time PCR.

Adolescent↗
PubMed2004

Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women.

AIMS/HYPOTHESIS: A diet low in saturated fatty acids and rich in wholegrains, vegetables and fruit is recommended in order to reduce the risk of obesity, cardiovascular disease and type 2 diabetes mellitus. However there is widespread interest in high-fat ("Atkins Diet") and high-protein ("Zone Diet") alternatives to the conventional high-carbohydrate, high-fibre approach. We report on a randomised trial that compared these two alternative approaches with a conventional diet in overweight insulin-resistant women. METHODS: Ninety-six normoglycaemic, insulin-resistant women (BMI >27 kg/m(2)) were randomised to one of three dietary interventions: a high-carbohydrate, high-fibre (HC) diet, the high-fat (HF) Atkins Diet, or the high-protein (HP) Zone Diet. The experimental approach was designed to mimic what might be achieved in clinical practice: the recommendations involved advice concerning food choices and were not prescriptive in terms of total energy. There were supervised weight loss and weight maintenance phases (8 weeks each), but there was no contact between the research team and the participants during the final 8 weeks of the study. Outcome was assessed in terms of body composition and indicators of cardiovascular and diabetes risk. RESULTS: Body weight, waist circumference, triglycerides and insulin levels decreased with all three diets but, apart from insulin, the reductions were significantly greater in the HF and HP groups than in the HC group. These observations suggest that the popular diets reduced insulin resistance to a greater extent than the standard dietary advice did. When compared with the HC diet, the HF and HP diets were shown to produce significantly (p<0.01) greater reductions in several parameters, including weight loss (HF -2.8 kg, HP -2.7 kg), waist circumference (HF -3.5 cm, HP -2.7 cm) and triglycerides (HF -0.30 mmol/l, HP [corrected] -0.22 mmol/l). LDL cholesterol decreased in individuals on the HC and HP diets, but tended to fluctuate in those on the HF diet to the extent that overall levels were significantly lower in the HP group than in the HF group (-0.28 mmol/l, 95% CI 0.04-0.52, p=0.02). Of those on the HF diet, 25% showed a >10% increase in LDL cholesterol, whereas this occurred in only 13% of subjects on the HC diet and 3% of those on the HP diet. CONCLUSIONS/INTERPRETATION: In routine practice a reduced-carbohydrate, higher protein diet may be the most appropriate overall approach to reducing the risk of cardiovascular disease and type 2 diabetes. To achieve similar benefits on a HC diet, it may be necessary to increase fibre-rich wholegrains, legumes, vegetables and fruits, and to reduce saturated fatty acids to a greater extent than appears to be achieved by implementing current guidelines. The HF approach appears successful for weight loss in the short term, but lipid levels should be monitored. The potential deleterious effects of the diet in the long term remain a concern.

Body Mass Index↗
PubMed2004

Two-year changes in bone and body composition in young children with a history of prolonged milk avoidance.

No previous longitudinal studies of calcium intake, anthropometry and bone health in young children with a history of avoiding cow's milk have been undertaken. We report the 2-year changes of a group of 46 Caucasian children (28 girls, l8 boys) aged 8.1+/-2.0 years (mean +/- SD) who had low calcium intakes at baseline and were short in stature, with elevated body mass index, poor skeletons and lower Z scores for both areal bone mineral density (BMD, in grams per square centimeter) and volumetric density (bone mineral apparent density, BMAD, in grams per cubic centimeter), compared with a reference population of milk drinkers. At follow-up, adverse symptoms to milk had diminished and modest increases in milk consumption and calcium intake had occurred. Total body bone mineral content (BMC) and bone area assessed by dual energy X-ray absorptiometry had increased (P<0.05), and calcium intake from all sources was associated with both these measures (P<0.05). However, although some catch-up in height had taken place, the group remained significantly shorter than the reference population (Z scores -0.39+/-1.14), with elevated body mass index (Z scores 0.46+/-1.0). The ultradistal radius BMC Z scores remained low (-0.31+/-0.98). The Z scores for BMD had improved to lie within the normal range at predominantly cortical sites (33% radius, neck of femur and hip trochanter) but had worsened at predominantly trabecular sites (ultradistal radius and lumbar spine), where values lay below those of the reference group (P<0.05). Similarly, although volumetric BMAD Z scores at the 33% radius had normalized, BMAD Z scores at the lumbar spine remained below the reference population at follow-up (-0.67+/-1.12, P<0.001). Our results demonstrate persisting height reduction, overweight and osteopenia at the ultradistal radius and lumbar spine in young milk avoiders over 2 years of follow-up.

Absorptiometry, Photon↗