Russell Lane

Immune reactivity to glutamic acid decarboxylase 65 in stiff-man syndrome and type 1 diabetes mellitus

BACKGROUND The immune response to an isoform of glutamic acid decarboxylase (GAD), GAD65, is associated with two clinically distinct diseases, stiff-man syndrome (SMS) and type 1 (insulin-dependent) diabetes mellitus. We sought to identify differences in the cellular and humoral immune responses to GAD in these two diseases. METHODS We compared T-cell responses in 14 SMS patients with axial disease and 17 patients with type 1 diabetes. FINDINGS Peripheral blood T cells of eight SMS patients recognised different immunodominant epitopes of GAD65 compared with T cells from 17 patients with type 1 diabetes. GAD regions 81-171 and 313-403 induced a dominant T-cell response in six of eight patients with SMS but in only one of 17 patients with type 1 diabetes (p=0.001). No SMS patients responded dominantly to GAD fragments 161-243 and 473-555 compared with ten patients with type 1 diabetes (p=0.008). GAD antibodies were detected in 11 of 14 SMS patients (seven with diabetes) and 11 of 17 patients with type 1 diabetes; IgG1 was dominant in both groups. SMS patients, however, were more likely than patients with diabetes to have isotypes other than IgG1 (p=0.03), in particular, IgG4 or IgE isotypes, which were not detected in patients with type 1 diabetes (p=0.012). INTERPRETATION Our findings indicate differences between patients with SMS and type 1 diabetes in cellular (epitope recognition) and humoral (isotype pattern) responses to GAD65. Thus the same autoantigen can elicit distinct immune responses in patients with SMS, even when associated with diabetes, compared with patients with type 1 diabetes.

A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease

Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.

Rhabdomyolysis: Has many causes, including statins, and may be fatal

electronic records are rarely useable as the master clinical record. The NHS wants this to change. In theory, an appropriate and effective information infrastructure has much to offer, providing information to underpin commissioning, quality control, clinical governance, and performance management as well as being the prime clinical information source for individual patient care. But it needs to be provided in the context of local multidisciplinary teams involved in the care of patients in complex care pathways, tailored to local facilities and resources. With a workforce of over 1.3 million, the NHS is one of the world’s largest employers. Its national programme for information technology is the largest and most ambitious public sector information technology procurement project to date. The rest of the world watches our progress with interest, as this kind of record sharing technology, although familiar in web based commerce, is novel in a large scale health environment. So far the new team running the national health technology programme has proved pragmatic and effective, and the reality of NHS wide clinical record technology is closer than ever. But involving front line clinicians in the evolution of their workplace information systems is essential. If safeguards to confidentiality and accuracy of patient information prove insufficient, then both patients and the caring professions will not use the spine, and the money will have been wasted.

Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome

OBJECTIVES To examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with chronic fatigue syndrome in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity. METHODS Quadriceps needle muscle biopsies were obtained from 105 patients with chronic fatigue syndrome and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET). RESULTS Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Patients with increased lactate responses to exercise did have significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found. CONCLUSION Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.

Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

The skeletal muscle ryanodine receptor plays a crucial role in excitation-contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca(2+) release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

Enterovirus related metabolic myopathy: a postviral fatigue syndrome

Objective: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients. Methods: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points. Results: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET− patients. PCR products were most closely related to coxsackie B virus. Conclusions: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.

The relationship of spinal muscular atrophy to motor neuron disease: Investigation of SMN and NAIP gene deletions in sporadic and familial ALS

Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10% of cases. Of these familial cases around 20% are associated with mutations of SOD-1. The genetic basis of the disease in the remaining familial cases, and genetic risk factors in sporadic cases, are unknown. Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with both familial and sporadic motor neuron disease show only lower motor neuron signs, in common with SMA patients, and families containing individuals with phenotypes of both childhood SMA and adult motor neuron disease have been reported. We therefore examined the SMA locus as a candidate for ALS, in 54 patients with sporadic motor neuron disease, and 10 single-generation familial patients (with no evidence of SOD-1 mutations), and in a single patient with Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were detected. The difficulties of classification of lower motor neuron presentations of motor neuron diseases are discussed. The demonstration that mutations diagnostic of SMA are not found in ALS patients helps distinguish these conditions.

ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non‐Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%–25% in unselected undiagnosed cases.

Investigation of a null mutation of the CNTF gene in familial amyotrophic lateral sclerosis

Neurotrophic factors, such as ciliary neurotrophic factor (CNTF), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a human neurodegenerative disease primarily of upper and lower motor neurones. A null mutation of the CNTF gene has recently been described. The mutation is an intronic point mutation (G to A) which generates a new splice acceptor site and a 4 bp insertion within the CNTF coding region, and prevents the expression of the normal protein. We investigated this as a candidate gene in 49 families with ALS, where the genetic component may be expected to be strongest. 65% were normal homozygotes, and 35% were heterozygotes for the mutation. No mutant homozygotes were detected. The absence of CNTF protein expression associated with the homozygote mutation does not appear to be of major significance in the development of ALS.

Exercise responses and psychiatric disorder in chronic fatigue syndrome.

Fatigue, exercise intolerance, and myalgia are cardinal symptoms of the chronic fatigue syndrome, but whether they reflect neuromuscular dysfunction or are a manifestation of depression or other psychiatric or psychological disorders diagnosed in a high proportion of fatigued patients in the community is unclear.1 In previous studies patients with the chronic fatigue syndrome showed exercise intolerance in incremental exercise tests, which seemed to be related to an increased perception of effort; also, blood lactate concentrations in some patients tended to increase more rapidly than normal at low work rates, implying inefficient aerobic muscle metabolism.2 We examined venous blood lactate responses to exercise at a work rate below the anaerobic threshold in relation to psychiatric disorder. We studied 96 consecutive patients meeting the Oxford criteria for diagnosis of the chronic fatigue syndrome3 by using the subanaerobic threshold exercise …