Chris Turner

Clinical correlates of mitochondrial function in Huntington's disease muscle.

Huntingtons disease (HD) is caused by an abnormally expanded CAG repeat in the IT‐15 gene, which encodes a widely expressed protein called huntingtin. Abnormalities of mitochondrial respiratory chain function, specifically complex II/III, have been identified in HD striatum and defects of energy metabolism have been demonstrated in vivo in skeletal muscle in both symptomatic and presymptomatic HD patients. We have investigated respiratory chain function using histochemical and biochemical methods in HD skeletal muscle from 12 patients and compared these with 12 age and sex‐matched controls. The data from the HD patients were related to clinical parameters of HD including the Unified Huntingtons Disease Rating Scale (UHDRS). There were positive correlations between CAG repeat years (a product of CAG repeat length and age) and both motor (P < 0.002) and cognitive (P < 0.01) scores of the UHDRS. There was no significant difference in the activities of complexes I to IV compared to age‐matched controls. However, there were significant correlations for individual HD complex II/III activities with disease duration (P = 0.017), repeat years (P = 0.032), and cognitive scores (P = 0.019). There was also evidence from ultrastructural studies that inclusion formation may occur in HD muscle. These results provide additional evidence that mutant huntingtin influences mitochondrial complex II/III function in non‐neuronal tissue (skeletal muscle) and suggest that muscle may be a potential marker of disease progression in HD.

Mitochondrial Dysfunction in Neurodegenerative Disorders and Ageing

In eukaryotic cells, mitochondria are the organelles that produce the majority of adenosine triphosphate (ATP) required for normal neuronal function and survival. ATP is generated by oxidative phosphorylation (OXPHOS) within mitochondria from intermediates, such as NADH and FADH2which are produced by s-oxidation and the Kreb’s cycle.

Myotonic dystrophy: diagnosis, management and new therapies.

PURPOSE OF REVIEW Myotonic dystrophies type 1 and type 2 are progressive multisystem genetic disorders with clinical and genetic features in common. Myotonic dystrophy type 1 is the most prevalent muscular dystrophy in adults and has a wide phenotypic spectrum. The average age of death in myotonic dystrophy type 1 is in the fifth decade. In comparison, myotonic dystrophy type 2 tends to cause a milder phenotype with later onset of symptoms and is less common than myotonic dystrophy type 1. Historically, patients with myotonic dystrophy type 1 have not received the medical and social input they need to maximize their quality and quantity of life. This review describes the improved understanding in the molecular and clinical features of myotonic dystrophy type 1 as well as the screening of clinical complications and their management. We will also discuss new potential genetic treatments. RECENT FINDINGS An active approach to screening and management of myotonic dystrophies type 1 and type 2 requires a multidisciplinary medical, rehabilitative and social team. This process will probably improve morbidity and mortality for patients. Genetic treatments have been successfully used in in-vitro and animal models to reverse the physiological, histopathological and transcriptomic features. SUMMARY Molecular therapeutics for myotonic dystrophy will probably bridge the translational gap between bench and bedside in the near future. There will still be a requirement for clinical screening of patients with myotonic dystrophy with proactive and systematic management of complications.

Mitochondrial matters of the brain: the role in Huntington's disease.

Even before the discovery of the mutant htt gene as the cause of Huntington’s Disease (HD), abnormal energy metabolism and mitochondrial dysfunction had been suggested as a possible pathogenic mechanism in HD. These initial investigations described defects in energy metabolism using Positron Emission Tomography (PET) and Nuclear Magnetic Resonance (NMR) Spectroscopy in symptomatic and pre-symptomatic HD patients. Concurrently, 3-nitroproprionic acid, a mitochondrial complex II inhibitor, was found to replicate many of the pathological and clinical features of HD when administered to animals. Subsequently, reductions in mitochondrial respiratory chain enzyme activities in HD brain and muscle, HD mice models and cellular HD models were discovered and confirmed impaired mitochondrial function as an important component of pathogenesis. A unifying hypothesis linking chronic ATP depletion, oxidative stress and mitochondrial dysfunction culminated in the “slow excitotoxic theory” of HD pathogenesis. More recently, the localization of mutant htt within mitochondria and the association between transcriptional dysregulation caused by impaired PGC-1α activity with abnormal mitochondrial biogenesis and function has provided further links with additional potential pathogenic mechanisms.

A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia

The authors performed a clinical and genetic study of a large consanguineous English family with uncomplicated autosomal recessive hereditary spastic paraplegia (ARHSP). Linkage to the previously described SPG5A locus was established with maximum multipoint lod score of 4.84. The locus was refined to a 23.6 cM interval between markers D8S1833 and D8S285. No evidence of oxidative phosphorylation defects was found in muscle biopsies from two affected individuals.

Understanding users: a prerequisite for developing new technologies

The LEADERS Project has sought to develop innovative methods of delivering archive material to users via the Internet. In practice, this has been achieved through the development of open‐source tools that can be used by Archivists to build on‐line applications where transcripts and images of archive documents are delivered alongside contextual information from finding aids and authority records. This article explains how and why archive users have been placed at the centre of the LEADERS Project. It focuses on our preliminary research into who is currently visiting archive repositories and introduces our segmentation model for profiling types of users, as well as the results of our user survey, which we based on this model. This research was a prerequisite for the project: it has given us a broad understanding of the market for our product and has provided us with the background data necessary to ensure that we can go on to engage a representative sample of users to give us feedback on our work.

A multicentre postal survey investigating the contribution of illness perceptions, coping and optimism to quality of life and mood in adults with muscle disease:

Objective: To replicate the finding that illness perceptions influence quality of life in adults with muscle disease and to explore the additional influence of coping and optimism on quality of life and mood. Design: A postal survey including questionnaires recording quality of life, mood, illness perceptions, optimism, coping and functional impairment. Setting: National Health Service muscle clinics in the United Kingdom. Participants: A convenience sample of adults with muscle disease. Interventions: Not applicable. Main outcome measures: Individualised Neuromuscular Quality of Life Questionnaire, Hospital Anxiety and Depression Scale. Results: A total of 226 completed questionnaires were returned. Although functional impairment explained most of the variance in three out of eight quality of life domains, psychological factors explained greater amounts of variance (between 19% and 52% of variance) in all other quality of life domains and in both mood domains (between 45% and 48% of variance). Overall, illness perceptions explained much of the variance in quality of life and mood score (between 5% and 37% of variance), while coping (up to 8% of variance) and optimism (up to 15% of variance) explained smaller amounts of variance. Conclusion: The results confirm that illness perceptions are associated with quality of life in muscle disease and suggest that they also influence mood. The addition of optimism and coping variables into the analysis yielded small increases in the proportions of variance in quality of life and mood which were explained. These results have implications for the composition of future psychological interventions.

Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1 - The patients' perspective

Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinils use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients.

PROPERTIES OF DEVELOPING LATERAL GENICULATE NEURONES IN THE MOUSE

This study describes the properties of neurones recorded in vitro from the dorsal lateral geniculate nucleus (dLGN) of the mouse between developmental stages El 6 and P36 and represents the first systematic study of the development of rodent thalamic neurones. The results demonstrate that thalamo‐cortical neurones in the mouse dLGN undergo a series of important changes as they mature. Prenatally recorded cells had low resting potentials and could not generate action potentials but as they mature, mouse dLGN neurones become more polarised and show an increase in membrane time constant and spike threshold, while action potentials increase in amplitude and decrease in width. The low‐threshold spike (LTS) complex appears at the time of birth, but does not show properties typical of adult cells until at least the third postnatal week. Immature action potentials are primarily sodium‐dependent but gain a significant calcium component in the second postnatal week, which is associated with a supra‐threshold oscillation of the membrane potential. The electrical activity during this critical period is strongly influenced by the interaction of powerful inward and outward rectification with calcium conductances which determines the appearance of voltage responses to intracellular current injection. The membrane potential in recordings from neurones during the first postnatal week was dominated by intense TTX‐sensitive depolarising synaptic‐like events which attained amplitudes of 60mV in several neurones at stages P5–P8. These changes are discussed in relationship to the formation of appropriate connections in the developing visual system.

User feedback: Testing the leaders demonstrator application

The LEADERS Project has developed a set of open-source tools that can be used by archivists to create online applications where digital representations of archive documents are presented alongside relevant contextual information. These tools use Extensible Markup Language (XML) technologies and are built around three well-known encoding standards: Encoded Archival Description (EAD), Encoded Archival Context (EAC) and the Text Encoding Initiative (TEI). A fundamental aspect of the LEADERS Project has been to gain user feedback as part of the research and development process. To this end, a demonstrator application has been constructed and has since been tested by a representative sample of archive users who took part in moderated discussions on its strengths and weaknesses. This article describes the results from the user testing of the demonstrator and discusses how different types of users reacted to the applications interface design, search functionality and detailed displays. It is hoped that this feedback from users will be useful to future implementers as a guide in the design of new online archive applications created using the LEADERS tools.