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Neuromuscular disorders: therapeutic advancesCollation of diseases under the umbrella suffi x “-opathies” has become fashionable, even if the association between a particular protein and the underlying pathogenic process is not clear. Ubiquitinopathies are a case in point. Ubiquitin functions to bind and sequestrate misfolded protein, preventing damage to the cell. Intraneuronal cytoplasmic ubiquitinated inclusions have long been regarded as the pathological hallmark of amyotrophic lateral sclerosis (ALS) and, more recently, a subtype of frontotemporal dementia with ubiquitin pathology (FTD-U). The mystery of what is being ubiquitinated became clear in 2006. An international team of researchers led by Virginia Lee in Philadelphia isolated aggregated protein from the homogenised cerebral cortex of patients with FTD-U. Monoclonal antibodies generated against this protein were used to analyse brain tissue by gel electrophoresis; mass spectrometry was used to identify the major constituent of the ubiquinated inclusions as TAR-DNA

binding protein, TDP-43.1 Antibodies against TDP-43 show that it is a highly specifi c marker for ALS and FTD-U, not being found in the brains of patients with Alzheimer’s, Parkinson’s or other neurodegenerative diseases. TDP-43, as the major protein component of ubiquinated inclusions in both FTD-U and ALS, provides further evidence in favour of the notion that these diseases are related at the pathophysiological level. TDP-43 is normally found in the nucleus where it works as a cofactor in splicing, but in cells with ubiquitinated inclusions it is depleted from the nucleus, which might have adverse eff ects on motorneuron survival. The next few years will reveal whether TDP-43 has a central role in the pathogenesis of ALS or is simply a better marker than ubiquitin for some as yet undiscovered underlying process.

Our knowledge of the molecular basis of inherited neuromuscular junction disorders has expanded greatly in recent years with the identifi cation of

contaminated food products and germinate in the intestine, releasing the toxin. In the USA, 80–100 cases of infant botulism presenting with fl accid paralysis are identifi ed annually. The equine toxin used in adults is not suitable for infants, for whom the only treatment has been supportive therapy. An intravenous human botulism immunoglobulin (BIG-IV), derived from the plasma of botulinum toxoid immunised donors, has been developed. Arnon and colleagues8 reported an initial randomised, double-blind, placebo-controlled trial of BIG-IV in 122 infants diagnosed with infant botulism in the previous 3 days. BIG-IV recipients showed signifi cant reductions in mean durations of hospital stay (2·6 weeks vs 5·7 weeks), intensive care stay, mechanical ventilation, nutritional support, and amount of hospital charges compared with placebo recipients. BIG-IV was not associated with any severe adverse eff ects. Following this study, BIG-IV was given in an open-label study to 382 infants who had been diagnosed with infant botulism in the previous 3 weeks. The mean length of hospital stay was signifi cantly shorter in infants treated within 3 days of hospital admission (2·0 weeks vs 2·9 weeks). Again, BIG-IV was not associated with any signifi cant adverse events. These studies confi rm the safety and effi cacy of

BIG-IV, now available commercially as BabyBIG, which should be used early in the course of the illness if it is to provide benefi t.

M E TörökOxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, District 5, Ho Chi Minh City, Vietnametorok@oucru.org

MET is funded by Wellcome Training Fellowship in Clinical Tropical Medicine.

I thank Jeremy Farrar for stimulating discussions and for critical review of the manuscript.

1 Thompson MJ, Ninis N, Perera R, et al. Clinical recognition of meningococcal disease in children and adolescents. Lancet 2006; 367: 397–403.

2 Harnden A, Ninis N, Thompson M, et al. Parenteral penicillin for children with meningococcal disease before hospital admission: case-control study. BMJ 2006; 332: 1295–98.

3 Giuliani MM, Adu-Bobie J, Comanducci M, et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci USA 2006; 103: 10834–39.

4 Yu H, Jing H, Chen Z, et al. Human Streptococcus suis outbreak, Sichuan, China. Emerg Infect Dis 2006; 12: 914–20.

5 Carson PJ, Konweko P, Wold KS, et al. Long-term clinical and neuropsychological outcomes of West Nile virus infection. Clin Infect Dis 2006; 43: 723–30.

6 Dunfee RL, Thomas ER, Gorry PR, et al. The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia. Proc Natl Acad Sci USA 2006; 103: 15160–65.

7 Collinge J, Whitfi eld J, McKintosh E, et al. Kuru in the 21st century: an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74.

8 Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med 2006; 354: 462–71.

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mutations in nine genes encoding key components of the neuromuscular junction, including those in the acetylcholine receptor and the sodium channels (both causing channelopathies). An addition to the list comes with the identifi cation of mutations in Dok-7 as a cause of limb-girdle congenital myasthenia (LGM) without tubular aggregates, which mainly presents in children younger than 5 years as facial, proximal limb, and trunk weakness, and with variation in function over weeks to months rather than the short-term fatigue characteristic of classic autoimmune myasthenia gravis. Anticholinesterase medication can lead to worsening of symptoms. Neurophysiological, pathological, and pharmacological analyses indicate that these patients have abnormally small neuromuscular junctions but no evident defects in the key components of transmission. Dok-7 was identifi ed earlier this year as an interaction partner of muscle-specifi c kinase (MuSK), which plays a key part in the aggregation of acetylcholine receptor clustering at the neuromuscular junction during development (and is a target for autoantibodies in one form of myasthenia gravis). Beeson and colleagues2 did a targeted genetic screen and identifi ed recessive mutations in Dok-7 in 21 unrelated patients with LGM. Functional analysis suggests that Dok-7 mutations act to impair the maturation and maintenance of the neuromuscular junction, leading the authors to designate this disorder as a synaptopathy rather than a channelopathy. Parallels in the clinical features and anticholinesterase-inhibitor responses between patients with Dok-7 mutations and MuSK-antibody-associated myasthenia gravis suggest that reduced function in the muscle-specifi c kinase/Dok-7 pathway is common to both diseases.

The pressure for early translation of experimental treatments into therapeutic trials in patients with Xp21 dystrophies is intense. A major challenge is the safe and effi cient delivery of gene-based treatments to many muscles simultaneously. Many of the mutations leading to dystrophin loss in Duchenne muscular dystrophy are deletions in the central rod domain of the protein leading to premature truncation. This occurrence is potentially correctable by delivery of genetic constructs that induce skipping of the exon containing the mutation to restore functional, albeit shorter, protein. Two studies3,4 this year show that such constructs can be delivered intravenously with

evidence of functional recovery of dystrophic muscle. Both studies used antisense oligonucleotides injected into the tail vein of mdx mice (a model for muscular dystrophy). Improvements in muscle function were mirrored by restoration of dystrophin concentrations shown with immunochemistry and by a reduction in CPK concentrations. Although expression was variable, and perhaps of concern was lower in cardiac than in skeletal muscle, these studies bring us closer to systemic delivery of gene therapy in human clinical trials.

The treatment of ALS and related motorneuron disorders continues to be dominated by the promise of drugs in animal models that fail to show benefi t in clinical trials. An evidence-based approach to non-drug treatments was especially welcome this year with the fi rst controlled trial of non-invasive ventilation in ALS.5 In patients without severe bulbar function who tolerate nasal-positive pressure ventilation, signifi cant eff ects were seen on both quality of life and survival. As the authors point out this eff ect is much greater than that seen with any neuroprotective drug up to now. A number of questions about patient selection remain, but funders of healthcare will now have to acknowledge that access to non-invasive ventilation should be part of the standard management for patients with ALS. While waiting for a better understanding of the underlying causes and mechanisms of sporadic ALS to inform specifi c disease-modifying treatments, there is still much that can be done to improve patient care.

Kevin TalbotDepartment of Clinical Neurology, University of Oxford, Radcliff e Infi rmary, Oxford, OX2 6HE, UKkevin.talbot@clneuro.ox.ac.uk

I receive funding from the Motor Neuron Disease Association, Muscular Dystrophy Campaign, The Jennifer Trust for Spinal Muscular Atrophy, and The SMA Trust.

I am grateful to Angela Vincent for her comments and suggestions.

1 Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130–33.

2 Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 2006; 313: 1975–78.

3 Alter J, Lou F, Rabinowitz A, et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 2006; 12: 175–77.

4 Denti MA, Rosa A, D’Antona G, et al. Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model. Proc Natl Acad Sci USA 2006; 103: 3758–63.

5 Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Eff ects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006; 5: 140–47.