F.L. Mastaglia

Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

Age at onset in two common neurodegenerative diseases is genetically controlled.

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria

Epidemiologic studies have helped to define the prevalence and incidence of PM, DM, and IBM and have highlighted differences in risk between men and women and in the age at onset for the different forms of myositis. Additionally, these studies have shown that there is a substantially higher risk of PM and DM in certain racial groups which is likely to be genetically determined. These differences are all likely to be fundamental in terms of the pathogenesis of these diseases but, as yet, their full significance remains uncertain. They do, however, suggest that the interplay between genetic and environmental initiating factors is different in the three disorders. Additional population-based studies in homogeneous racial groups, in parallel with studies of susceptibility genes for autoimmune disease, such as those encoding the MHC and inflammatory cytokines, are needed to throw further light on the role of genetic factors in the pathogenesis of the IIMs [47]. Because of the paucity of epidemiologic data on IBM, further studies are required to determine the degree of variation in prevalence in different populations and racial groups, as well as the consistency of the male association and age spectrum of manifestations of the disease. The particularly strong association with DR3 in this form of IIM [48] clearly points to the importance of genetic factors in pathogenesis, but further studies of DR3-associated genes in the MHC and of other candidate genes are needed to define more precisely the genes that convey susceptibility to the disease in different racial groups. Epidemiologic studies also have the potential to identify environmental factors that may play a part in disease initiation in genetically susceptible individuals. Seasonal patterns of disease onset have been reported, particularly in patients with DM [49-51] as well as seasonal variation in the frequency of relapses [52], pointing to the probable involvement of intercurrent infections, ultraviolet light exposure, or other environmental factors in disease initiation and reactivation. Further prospective studies are required to determine the contribution of environmental exposures and how they interact with genetic susceptibility factors to lead to myositis. One of the major limitations of a number of the previous epidemiologic studies is the lack of precision in the diagnostic criteria used and the classification of cases of IIM. The Bohan and Peter criteria [1] which were used in most studies after 1975, were introduced before IBM was recognized as an entity distinct from PM; most of the published incidence and prevalence figures for PM are therefore likely to be inaccurate. Multicentered, interdisciplinary, prospective studies, incorporating comprehensive clinical, laboratory, and pathologic information, are needed to develop and validate better diagnostic and classification criteria and to determine the true prevalence and incidence of the many forms of IIM.

The muscle silent period following transcranial magnetic cortical stimulation

Transcranial magnetic stimulation (TMS) of the motor cortex during tonic muscle contraction produces a motor evoked potential followed by a silent period in the electromyogram. We sought to characterize the TMS induced silent period and to compare it to the silent period induced by supramaximal peripheral nerve stimulation. TMS was delivered to the motor cortex using a 9 cm diameter circular coil and the surface electromyogram was recorded from the contralateral abductor pollicis brevis muscle in six normal subjects. Increasing TMS stimulus intensity from 10 to 50% above threshold resulted in an increase in the duration of the silent period from a mean of 50 ms to 185 ms. Increasing the level of tonic muscle contraction from 5% of maximum to maximum resulted in a decrease in silent period duration from a mean of 155 ms to 133 ms. In contrast, the duration of the silent period following supramaximal median nerve stimulation showed greater shortening under similar conditions, from a mean of 160 ms at 5% of maximum contraction to 99 ms at 75% of maximum contraction. The TMS induced silent period was present during a TMS induced increase in the reaction time for a ballistic movement, the onset of movement being delayed until the end of the silent period. Peripheral nerve stimulation did not produce a delay in movement onset. The present findings favour a cortical origin for the TMS induced silent period, probably on the basis of intracortical inhibition, rather than peripheral inhibition of spinal motoneurones which is considered to be the basis for the silent period following peripheral nerve stimulation.

Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches

Inclusion body myositis is the most common acquired muscle disease in older individuals, and its prevalence varies among countries and ethnic groups. The aetiology and pathogenesis of sporadic inclusion body myositis are still poorly understood; however genetic factors, ageing, and environmental triggers might all have a role. Unlike other inflammatory myopathies, sporadic inclusion body myositis causes slowly progressing muscular weakness and atrophy, it has a distinctive pattern of muscle involvement, and is unresponsive to conventional forms of immunotherapy. This review covers the clinical presentation, diagnosis, treatment, and the latest information on genetic susceptibility and pathogenesis of sporadic inclusion body myositis.

Transcranial magnetic stimulation mapping of the motor cortex in normal subjects: The representation of two intrinsic hand muscles

The TMS-mapped representations of two intrinsic hand muscles, abductor pollicis brevis (APB) and abductor digiti minimi (ADM), were quantified using a transcranial magnetic stimulation (TMS) mapping technique in 10 right handed and 6 left handed subjects. A 50 mm diameter figure eight coil was used. Stimulus sites were located using a latitude/longitude based coordinate system, stimulus intensity was threshold-adjusted and stimuli were applied during controlled low-level (10%) voluntary contraction of the target muscles. Maps of the corticomotor representation were generated by fitting a continuously defined three dimensional function to the data obtained from stimulation at specific scalp sites, and projecting this function onto a two dimensional surface using a radial projection. It was found that the mapped representations of APB and ADM were large and overlapping but that there was a statistically significant separation of the two areas, the APB area being more laterally placed than the ADM area. The TMS-mapped representations of the two muscles showed no significant interhemispheric differences and were similar in left and right handed subjects. Rotation of the magnetic coil through 90 degrees resulted in medial shift and elongation of the TMS-mapped representations but there was no change in the relative positions of the two areas. The TMS-mapped representations were found to be very reproducible when mapping was repeated after intervals of up to 181 days. The present technique of TMS mapping allows the representation of individual hand muscles in the primary motor cortex to be reliably and reproducibly mapped and should prove useful for further studies of the physiology and pathophysiology of the motor cortex in man.

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease

Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinsons disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. Ann Neurol 2003

Inflammatory myopathies : clinical, diagnostic and therapeutic aspects

The three major forms of immune‐mediated inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and inclusion‐body myositis (IBM). They each have distinctive clinical and histopathologic features that allow the clinician to reach a specific diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis‐specific antibodies are not helpful diagnostically but may be of prognostic value; most antibodies have low sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an inflammatory myopathy and to allow unusual varieties such as eosinophilic, granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized. The treatment of the inflammatory myopathies remains largely empirical and relies upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all of which have nonselective effects on the immune system. Further controlled clinical trials are required to evaluate the relative efficacy of the available therapeutic modalities particularly in combinations, and of newer immunosuppressive agents (mycophenolate mofetil and tacrolimus) and cytokine‐based therapies for the treatment of resistant cases of DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle injury in the inflammatory myopathies should lead to the development of more specific forms of immunotherapy for these conditions. Muscle Nerve 27:407–425, 2003

Progressive myopathy with up-regulation of MHC-I associated with statin therapy

Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug. What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug. We investigated the muscle pathology in 8 such cases. All had myofibre necrosis but only 3 had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of MHC-I expression even in non-necrotic fibres. Progressive improvement occurred in 7 cases after commencement of prednisolone and methotrexate, and in one case spontaneously. These observations suggest that statins may initiate an immune-mediated myopathy that persists after withdrawal of the drug and responds to immunosuppressive therapy. The mechanism of this myopathy is uncertain but may involve the induction by statins of an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibres.

Disorders of neuromuscular transmission caused by drugs

MORE than 30 drugs in current clinical use, other than those used in anesthesia, may interfere with neuromuscular transmission. This complication of drug therapy is unusual but has been well docume...