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This chapter extends the use of the technique described in the previous chapter to two-dimensional (2D) protein gels, as well as containing some alternatives and modifications to the method.

We used 31P magnetic resonance spectroscopy (31P-MRS) to assess in vivo skeletal muscle mitochondrial function in 10 Leber's hereditary optic neuropathy patients/carriers with a mitochondrial DNA (mtDNA) mutation at one of three nucleotide positions, 11,778, 14,484, and 3,460. We studied one affected patient for each mutation and two unaffected carriers with the 11,778 or 3,460 mutation and three carriers with 14,484. All subjects were homoplasmic except the two 3,460 carriers, who showed 80% and 15% of mutated mtDNA. 31P-MRS at rest disclosed some abnormalities in all subjects. In particular, the phosphorylation potential was below the normal range in all cases. During recovery from exercise, the maximum rate of mitochondrial ATP production (Vmax) was reduced to 27% of normal in the 11,778 mutation and to 53% in the 14,484 mutation patient/carrier groups. Mitochondrial Vmax was within the normal range in all subjects with the 3,460 mutation but correlated inversely with the percentage of mutated mtDNA. This in vivo study shows that the 11,778 mutation causes a mitochondrial impairment more severe than the 14,484 and that the 3,460 mutation results in only a mild depression of muscle mitochondrial function.

Mitochondrial disorders may be caused by mutations either in mitochondrial or in nuclear genes involved in the synthesis or regulation of respiratory chain subunits. The unique nature of the mitochondrial genome calls for a different approach to genetic counselling and risk analysis.

A significant proportion of patients with inborn errors of the mitochondrial respiratory chain exhibit movement disorders, particularly dystonia. Point mutations of mitochondrial DNA (mtDNA) are usually expressed systemically, and defects of platelet respiratory chain function have been described in patients with mtDNA mutations and Leber's hereditary optic neuropathy (LHON). Recent reports have documented families with dystonia in association with LHON and mtDNA complex I gene mutations. We have examined mitochondrial function in platelet mitochondria from patients with familial generalized dystonia (linked or not linked to 9q34) and sporadic focal dystonia. We confirm a previous report of a specific complex I defect in patients with sporadic focal dystonia but could not find any abnormality in patients with familial generalized dystonia, linked or not to 9q34. These results support the existence of a mitochondrial deficiency in sporadic focal dystonia and provide a biochemical dimension to the clinical and genetic distinction between focal and generalized familial dystonia.

The cause of neuronal cell death in Parkinson's disease is unknown but there is accumulating evidence suggesting that oxidative stress may be involved in this process. Current evidence shows that in the substantia nigra there is altered iron metabolism, decreased levels of reduced glutathione and an impairment of mitochondrial complex I activity. However, these changes seem to be unique to the substantia nigra and have not been found in other areas of the brain known to be altered in Parkinson's disease, such as substantia innominata. In addition they do not appear to be related to the presence of Lewy bodies, as other areas of the brain containing Lewy bodies do not show evidence of either oxidative stress or mitochondrial dysfunction. Oxidative stress has now been demonstrated in Alzheimer's disease and its presence appears to be correlated with regions of marked pathological changes.

Wellcome Trust/MRC Joint Call in Neurodegeneration award United Kingdom Medical Research Council Wellcome Trust Parkinson's Disease UK Kattan Trust Objectives: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. the right: left asymmetry index and striatal asymmetry index was calculated.Results: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). the asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions: the asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss. UCL, Dept Clin Neurosci, Inst Neurol, London, England Birmingham Womens Hosp, Reg Genet Unit, Dept Clin Genet, Birmingham, W Midlands, England Natl Taiwan Univ Hosp, Coll Med, Dept Neurol, Taipei, Taiwan Natl Taiwan Univ Hosp, Coll Med, Dept Nucl Med, Taipei, Taiwan Hosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, São Paulo, Brazil Hosp Univ Insular Gran Canaria, Dept Neurol, Parkinsons & Movement Disorders Unit, Las Palmas Gran Canaria, Spain Univ Salerno, Ctr Neurodegenerat Dis, Salerno, Fisciano Provin, Italy UCL, Inst Neurol, Sobell Dept Motor Sci, London, England Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands Aristotle Univ Thessaloniki, G Papanikolaou Hosp, Dept Neurol 3, GR-54006 Thessaloniki, Greece Gen Hosp S Michele AOB G Brotzu, Neurol Serv, Cagliari, Italy Gen Hosp S Michele AOB G Brotzu, Stroke Unit, Cagliari, Italy Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil UCL Inst Neurol, Dept Mol Neurosci, London, England Univ Navarra, Div Neurosci, Ctr Appl Med Res, Neurogenet Lab, E-31080 Pamplona, Spain CNR, Inst Biostruct & Bioimaging, I-80125 Naples, Italy Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil Wellcome Trust/MRC Joint Call in Neurodegeneration award: WT089698 United Kingdom Medical Research Council: G1001983 Web of Science

Idiopathic Parkinson's disease (PD) involves a documentable decline in the activity of mitochondrial complex I in substantia nigra (1-3). We have EPR spectroscopy to investigate complex I in human substantia nigra and globus pallidus. EPR signals characteristic of the iron-sulfur centers of complexes I and II were observed with globus pallidus, with no significant difference between control and PD. These complex 1 signals could not be clearly observed in substantia nigra. Instead, nitric oxide (NO.) radicals in PD nigra were detected at g approximately 2.08, 1.98 due to [haem-NO] formation. Although an EPR signal indicative of haem-NO was observed with control nigra, it lacked the distinctive g approximately 1.98 trough observed with PD nigra. As PD is associated with a reactive gliosis, the difference in the haem-NO EPR signal, between control and PD nigra, may result from cytotoxic NO. generated by microglia in PD substantia nigra.

Rapid advances are being made in our understanding of the pathogenesis of neurodegenerative diseases, particularly those in which specific DNA mutations have been identified. beta-amyloid has been shown to induce free radical formation both directly and via an effect on endothelial function. There is presuasive evidence for cytochrome oxidase dysfunction with oxidative stress and damage in the brains of patients with Alzheimer's disease. The confirmation of the complex II inhibitor 3-nitropropionic acid as a toxin model for Huntington's disease, together with the demonstration of reduced mitochondrial function in Huntington's disease caudate, supports the proposition that mutant huntingtin may exert its effect through an abnormality of energy metabolism.

Although the Huntington's disease (HD) gene defect has been identified, the structure and function of the abnormal gene product and the pathogenetic mechanisms involved in producing death of selective neuronal populations are not understood. Indirect evidence from several sources indicates that a defect of energy metabolism and consequent excitotoxicity are involved in HD. Toxin models of HD may be induced by 3-nitropropionic acid or malonate, both inhibitors of succinate dehydrogenase, complex II of the mitochondrial respiratory chain. We analyzed mitochondrial respiratory chain function in the caudate nucleus (n = 10) and platelets (n = 11) from patients with HD. In the caudate nucleus, severe defects of complexes II and III (53-59%, p < 0.0005) and a 32-38% (p < 0.01) deficiency of complex IV activity were demonstrated. No deficiencies were found in platelet mitochondrial function. The mitochondrial defect identified in HD caudate parallels that induced by HD neurotoxin models and further supports the role of abnormal energy metabolism in HD. The relationship of the mitochondrial defect to the role of huntingtin is not known.

There is evidence for a 37% deficiency of complex I activity in Parkinson's disease (PD), which appears to be specific for PD amongst parkinsonian syndromes and selective for the substantia nigra within the central nervous system. Rat studies have shown that, in the context of a normal nigrostriatal dopaminergic cell population, L-dihydroxyphenylalanine (L-dopa) causes a reversible 25% defect of complex I activity in nigral and striatal tissue. Analysis of striatal tissue from PD patients after prolonged exposure to high-dose L-dopa does not show such a defect. Results of these and other studies suggest that L-dopa therapy does not cause complex I deficiency in PD striatum. However, it cannot be excluded that, in the particular environment of the PD substantia nigra, L-dopa may enhance a preexisting complex I defect.

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.

The polypeptide composition of dorsal root ganglia from 8 human controls, 6 Friedreich's ataxia (FA) patients and 1 patient with diabetic neuropathy was studied by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis (PAGE). Silver-stained gels demonstrated a decrease in a 40-kDa protein in FA patients. This protein appeared to be present in normal amounts in the diabetic ganglion, suggesting that this 40-kDa protein deficiency was not simply a reflection of reduced neuronal numbers but may be specific for FA.

Inactivation of the mitochondrial respiratory chain in response to iron-induced oxidative stress has been studied in cultured cells. Iron loading resulted in malondialdehyde production, decreased levels of glutathione and reduced specific activities of both complexes I and IV of the respiratory chain. These results are discussed with respect to idiopathic Parkinson's disease, which is associated with increased iron levels and a specific decrease in complex I activity in the substantia nigra.

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity. We measured mitochondrial respiratory chain enzyme activities in platelets from 18 normal healthy non-smoking controls and compared them with those from 23 similarly healthy cigarette smoking individuals. A 24% decrease (p < 0.02) was observed in the mean NADH CoQ1 reductase (complex I) activity of the smoking group compared with that of the non-smoking group. There was no significant change in the activity of any of the other respiratory chain enzymes. This is the first demonstration in vivo of mitochondrial inhibition by a common environmental agent. The results offer a novel mechanism of action for the cellular toxicity, or even mutagenicity, associated with cigarette smoking. In addition, these data have important implications for the interpretation of platelet mitochondrial complex I activities in disease states. They are particularly relevant to our interpretation and understanding of the complex I deficiency in Parkinson's disease platelets.

Two articles in this issue of Neurology describe the use of coenzyme Q10 in the treatment of neurologic disorders.1,2⇓ Coenzyme Q10 (ubiquinone) is the carrier of electrons from complexes I and II to complex III of the mitochondrial electron transport chain. It can act as either an antioxidant or prooxidant depending on the cell’s redox potential and the relative proportion of the oxidized and reduced forms of coenzyme Q10. Primary coenzyme Q10 deficiency has been associated with at least three rare neurologic syndromes that can involve both muscle and CNS.1 Of potentially greater importance is that mitochondrial dysfunction has been demonstrated to be present in Parkinson’s disease,3,4⇓ Huntington’s disease,5,6⇓ and Friedreich’s ataxia,7 and coenzyme Q10 has been suggested to be a potential treatment in these disorders.8-10⇓⇓ Di Giovanni et al.1 report two brothers who presented in adolescence with myopathy and one with seizures. Muscle biopsies demonstrated ragged red fibers and signs of …

Background: Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy.Methodology/Principal Findings: In this study, we investigated the impact of Parkin mutations on mitochondrial function and morphology in a human cellular model. Fibroblasts were obtained from three members of an Italian PD family with two mutations in Parkin (homozygous c.1072delT, homozygous delEx7, compound-heterozygous c.1072delT/delEx7), as well as from two relatives without mutations. Furthermore, three unrelated compound-heterozygous patients (delEx3-4/duplEx7-12, delEx4/c.924C>T and delEx1/c.924C>T) and three unrelated age-matched controls were included. Fibroblasts were cultured under basal or paraquat-induced oxidative stress conditions. ATP synthesis rates and cellular levels were detected luminometrically. Activities of complexes I-IV and citrate synthase were measured spectrophotometrically in mitochondrial preparations or cell lysates. The mitochondrial membrane potential was measured with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide. Oxidative stress levels were investigated with the OxyBlot technique. The mitochondrial network was investigated immunocytochemically and the degree of branching was determined with image processing methods. We observed a decrease in the production and overall concentration of ATP coinciding with increased mitochondrial mass in Parkin-mutant fibroblasts. After an oxidative insult, the membrane potential decreased in patient cells but not in controls. We further determined higher levels of oxidized proteins in the mutants both under basal and stress conditions. The degree of mitochondrial network branching was comparable in mutants and controls under basal conditions and decreased to a similar extent under paraquat-induced stress.Conclusions: Our results indicate that Parkin mutations cause abnormal mitochondrial function and morphology in non-neuronal human cells.

The mitochondrial respiratory chain and oxidative phosphorylation system are responsible for the production of ATP by aerobic metabolism. Defects of the respiratory chain are increasingly recognised as important causes of human disease, and neurodegenerative disorders in particular. This article will seek to review the clinical and biochemical effects of respiratory chain defects, and summarise what is known about the molecular mechanisms that underlie them. Increasing age is also associated with a decline in mitochondrial function. The biochemical correlates of this dysfunction and the possible molecular defects that may cause it will also be reviewed.

The pathogenesis of Parkinson's disease may be influenced by genetic and environmental factors. Cytochrome P450 mono-oxygenases help to protect against toxic environmental compounds and individual variations in cytochrome P450 expression might, therefore, influence susceptibility to environmentally linked diseases. The frequency of mutant CYP2D6 alleles was studied in 229 patients with Parkinson's disease and 720 controls. Individuals with a metabolic defect in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene with the poor metaboliser phenotype had a 2.54-fold (95% Cl 1.51-4.28) increased risk of Parkinson's disease. Determination of CYP2D6 phenotype and genotype may help to identify those at greatest risk of Parkinson's disease and may also help to identify the environmental or metabolic agents involved in the pathogenesis of this disease.

A 5 kilobase deletion in mitochondrial DNA (mtDNA) has been reported to be responsible for the specific complex I deficiency in the substantia nigra (SN) of the Parkinson's disease (PD) brain. We have studied mitochondrial respiratory chain function in the SN from control and PD subjects, and analysed mtDNA, extracted from the same tissues, by Southern biot and the polymerase chain reaction (PCR). Quantitation of the levels of the deletion indicate that it does not contribute to the pathogenesis of PD nor to a complex I deficiency but seems likely to be an age-related observation.

Incubation of 10 mM 1-methyl-4-phenylpyridinium (MPP+) with sonicated beef heart mitochondria caused an irreversible time-dependent decrease in NADH-ubiquinone-1 (CoQ1) reductase activity (52% inhibition after 1 h). Inclusion of glutathione, ascorbate, or catalase in the incubation mixture protected the NADH-CoQ1 reductase activity. These results suggest that the interaction of MPP+ with complex I induces free radical generation, which in turn leads to the irreversible inhibition of complex I activity. The generation of free radicals by neurotoxin-induced inhibition of complex I has important implications for our interpretation of the increased oxidative stress observed in Parkinson's disease substantia nigra and for our understanding of the cause(s) of dopaminergic cell death in this disorder.

Increased sedation, somnolence, and sleep episodes seem to occur with several, if not all, dopamine agonists and dopaminergic treatment. Patients at risk of sleep episodes can be identified by well-chosen questions, and could be managed by appropriate measures including dose reduction.

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Impairment of the mitochondrial electron transport chain (ETC) and an increased frequency in deletions of mitochondrial DNA (mtDNA), which encodes some of the subunits of the ETC, have been reported in the substantia nigra of PD brains. The identification of mutations in the PINK1 gene, which cause an autosomal recessive form of PD, has supported mitochondrial involvement in PD. The PINK1 protein is a serine/threonine kinase localized in mitochondria and the cytosol. Its precise function is unknown, but it is involved in neuroprotection against a variety of stress signalling pathways.Methodology/Principal Findings: In this report we have investigated the effect of silencing PINK1 expression in human dopaminergic SH-SY5Y cells by siRNA on mtDNA synthesis and ETC function. Loss of PINK1 expression resulted in a decrease in mtDNA levels and mtDNA synthesis. We also report a concomitant loss of mitochondrial membrane potential and decreased mitochondrial ATP synthesis, with the activity of complex IV of the ETC most affected. This mitochondrial dysfunction resulted in increased markers of oxidative stress under basal conditions and increased cell death following treatment with the free radical generator paraquat.Conclusions: This report highlights a novel function of PINK1 in mitochondrial biogenesis and a role in maintaining mitochondrial ETC activity. Dysfunction of both has been implicated in sporadic forms of PD suggesting that these may be key pathways in the development of the disease.

It is estimated that the dopaminergic neuronal loss that causes the characteristic motor features of Parkinson’s disease (PD) has reached 50–70% by diagnosis and it is progressive. Clinical, imaging and pathological studies suggest that the cell loss begins 7–10 years before the onset of clinical features sufficient to allow the diagnosis of PD. During this period of pre-diagnostic neurodegeneration, compensatory mechanisms are developed to maintain normal basal ganglia function.1 Eventually, these fail and symptoms emerge, enabling a diagnosis which is usually based on the combination of bradykinesia, rigidity and tremor. The delay from symptom onset to diagnosis is variable and …

Dopamine replacement therapy with levodopa has been the mainstay of symptomatic treatment of Parkinson disease (PD) for almost 40 years. While this drug remains the "gold standard," several additional dopaminergic drugs have been introduced to provide alternatives for patients with PD. Practical challenges in the management of PD include determining the point at which drug therapy should begin and with what, the sequence and combination of drugs required as the disease progresses, and the place for parenteral therapy and surgery in advanced disease. Although levodopa offers effective symptom relief at all stages, its risk of inducing motor complications has led many to advocate alternative drugs for initiation in suitable patients. Dopamine agonists and monoamine oxidase (MAO) B inhibitors offer effective relief of the motor features of PD in early and more advanced disease and are associated with a low risk for motor complications. However, they are not as potent as levodopa. Parenteral dopamine agonist or levodopa delivery offers a useful intermediate or alternative to surgery.

Studies of twins are useful in investigating the role of genetics in disease. We describe a population based method of twin ascertainment in Parkinson's disease using doctors' records. All doctors in four East Anglian counties were asked to search their database for patients receiving drugs for Parkinson's disease. They were asked to confirm the diagnosis of Parkinson's disease so that we could exclude patients taking these drugs for other conditions. We contacted each patient by letter through their doctor to confirm the diagnosis and to inquire whether they were one of twins—zygosity was based initially on patients' self reports. Overall, 149 general practice surgeries took part (44% of those contacted; estimated study population 1.53 million). Seventy per cent (1527) of patients replied to the first letter, increasing to 87% (1898) after one reminder—2182 patients in total. …

Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and features develop such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used. We review clinical trials aimed at detecting neuroprotection in Parkinson disease and address the controversies surrounding the interpretation of these studies.

It is estimated that at least one in 500 people will be affected by specific genetic or other lifelong neuromuscular disorders. Inevitably this figure is likely to be a significant underestimate because of inadequate case ascertainment, as well as our limited ability to identify what is likely to be another large number of as yet unrecognised muscle disorders. Into the latter group may fall patients who complain of muscle weakness, fatigue, or aching in whom no specific abnormality can yet be identified. Thus, muscle diseases constitute an important area of clinical activity and such patients are seen by neurologists, rheumatologists, general physicians, and a variety of other specialists. Thus, an up to date, comprehensive, and accessible textbook is extremely valuable for the generalist, as well as for those with a specific interest in muscle disorders. This book has become a standard text for myologists and neurologists alike ever since its first publication in 1964. It has been through several editions and this most recent one has been supervised by three leading myologists. It is divided into four sections covering the scientific basis of muscle disease, methods of investigation, clinical features of muscle disorders, and, finally, the …

A 41-year-old right-handed engineer was admitted in 1998 with a 10-year history of absence seizures. The seizures were characterised by symptoms of olfactory deja vu. During the seizures witnesses reported that the patient was able to walk and undertake complex tasks. The seizures, of which the patient had no recollection, lasted for a few minutes and were followed by several hours of lethargy. They would occasionally occur following binge drinking. He had a past history of migraine with visual aura. One of the patient’s four siblings one was said to have “multiple sclerosis” but the exact nature of the diagnosis was not clear. His mother had thyroid disease and migraine and his father had diabetes but there was no other family history of note. On examination the patient had vitiligo. His BP was 120/80 mm Hg. He seemed to have brisker tendon reflexes on the left side and foot tapping was marginally diminished on the left. His abstract reasoning was mildly impaired. The remainder of the examination was normal. The following investigations were normal, negative or non-diagnostic: full blood count, liver function, thyroid function, ESR (8 mm/h), syphilis serology, blood lactate, amino acid profile, vitamin B12, folate, lupus anticoagulant, proteins C & S, activated protein C resistance, antibody to thrombin III, autoantibody screen, angiotensin converting enzyme concentrations in serum and cerebrospinal fluid (CSF), visual, brainstem and somatosensory evoked potentials, magnetic resonance imaging (MRI) of the neck vessels, and cardiac echocardiography. An electroencephalogram showed only mild non-specific left temporal disturbances of cerebral activity. CSF examination showed an opening pressure of 16·5 cm of water, glucose 4 mmol/L (peripheral 7 mmol/L), protein 0·96 g/L, lymphocytes 2 10/L, red cells 1 10/L, normal CSF lactate, and no oligoclonal bands. MRI of his head (figure) showed multiple areas of high signal in the white matter bilaterally and one in the pons posteriorly. These areas were confluent periventricularly. 4 months later the patient was readmitted following a sudden onset of unsteadiness of gait, diplopia, nausea, and vertigo. Over the next 48 h he developed slurred speech. On examination he had ataxia with multi-directional and rotatory nystagmus. There was marked cerebellar incoordination in the left arm. A repeat Fits and strokes

Sporadic inclusion body myositis (sIBM) is the most common muscle disorder affecting patients 50 years and older.1 It is histologically characterized by rimmed vacuoles and by non-necrotic muscle fibers invaded by mononuclear lymphocytes. The pathogenesis remains largely unknown. Prion protein (PrP) is one of a number of proteins described in vacuolated muscle fibers in sIBM, and there is evidence for its upregulation from both immunohistochemistry and mRNA studies.2 Various mutations in the PrP gene have been associated with hereditary prion disorders; in iatrogenic and sporadic cases of Creutzfeldt–Jakob …