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Background Despite the inevitability of disease progression in amyotrophic lateral sclerosis, there is a high degree of prognostic heterogeneity in all subtypes. Some bulbar-onset (BO) patients may develop rapid anarthria yet remain ambulant for a prolonged period, whereas others progress rapidly, with early generalisation of motor weakness to the limbs and respiratory muscles. Diagnostic delay is a common occurrence in ALS, and many BO patients report having attended other specialist clinics prior to diagnosis. Methods A retrospective descriptive study of BO ALS patients seen in a tertiary clinic over a six year period. Results Forty-nine BO ALS patients were studied. Median survival from symptom onset was 27months (range 6–84). 63% of subjects were female and the mean age at symptom onset was 68years. Half had been referred to another speciality prior to diagnosis, either otolaryngology or stroke clinics, but this did not influence diagnostic latency or survival. Emotionality was reported in 45% of patients. Neurophysiological assessment was performed in 80%, brain imaging recorded in 69%, and antibody testing for myasthenia gravis in 22%. The median time to symptomatic progression beyond the bulbar region was approximately 1year, with equal proportions progressing to the upper or lower limbs. The median interval from onset to anarthria was 18months, and to loss of ambulation 22months. There was a close correlation between the two ( r 2 =0.6) and median survival from loss of ambulation was only 3months. Gastrostomy was carried out in 78% of patients with a median time of 13months from symptom onset, and 3months from diagnosis. Median survival from gastrostomy was 10months. Conclusions Survival in bulbar-onset ALS is highly variable. Half of the patients were referred to an inappropriate clinic prior to diagnosis. The time interval to the development of anarthria predicted the timing of subsequent loss of ambulation accurately from which survival may then be only a few months.

The increasing use of distributed functions in vehicles can introduce unexpected and undesirable emergent behavior. This can be as a result of transient events such as sudden drops in the supply voltage. In this situation system behavior is often not adequately specified or controlled. This paper presents a novel approach to automotive electronic systems testing addressing robustness against low voltage transient conditions. The paper will discuss the technical output as well as performance in real-world test usage. The proposed approach uses a combination of pseudo-random number generator algorithms to generate parameterized supply voltage waveforms simulating low voltage transient conditions, used to drive the system-under-test (SUT). Two measures are used to judge whether the SUT has passed or failed the test; the detection of unintended recorded Diagnostic Trouble Codes (DTCs) from the error memory of each Electronic Control Unit (ECU) and the detection of unexpected system functionality by a human observer or automated vision system.

The childhood motor neuron disease spinal muscular atrophy (SMA) results from reduced expression of the survival motor neuron (SMN) gene. Previous studies using in vitro model systems and lower organisms have suggested that low levels of Smn protein disrupt prenatal developmental processes in lower motor neurons, influencing neuronal outgrowth, axon branching and neuromuscular connectivity. The extent to which these developmental pathways contribute to selective vulnerability and pathology in the mammalian neuromuscular system in vivo remains unclear. Here, we have investigated the pre-symptomatic development of neuromuscular connectivity in differentially vulnerable motor neuron populations in Smn(-/-);SMN2 mice, a model of severe SMA. We show that reduced Smn levels have no detectable effect on morphological correlates of pre-symptomatic development in either vulnerable or stable motor units, indicating that abnormal pre-symptomatic developmental processes are unlikely to be a prerequisite for subsequent pathological changes to occur in vivo. Microarray analyses of spinal cord from two different severe SMA mouse models demonstrated that only minimal changes in gene expression were present in pre-symptomatic mice. In stark contrast, microarray analysis of late-symptomatic spinal cord revealed widespread changes in gene expression, implicating extracellular matrix integrity, growth factor signalling and myelination pathways in SMA pathogenesis. Taken together, these data suggest that reduced Smn levels induce SMA pathology by instigating rapidly progressive neurodegenerative pathways in lower motor neurons around the time of disease onset rather than by modulating pre-symptomatic neurodevelopmental pathways.

Spinal muscular atrophy is a severe motor neuron disease caused by inactivating mutations in the SMN1 gene leading to reduced levels of full-length functional SMN protein. SMN is a critical mediator of spliceosomal protein assembly, and complete loss or drastic reduction in protein leads to loss of cell viability. However, the reason for selective motor neuron degeneration when SMN is reduced to levels which are tolerated by all other cell types is not currently understood. Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death. However, it remains unclear whether splicing abnormalities are present during early stages of the disease, which would be a requirement for a direct role in disease pathogenesis. We performed exon-array analysis of RNA from SMN deficient mouse spinal cord at 3 time points, pre-symptomatic (P1), early symptomatic (P7), and late-symptomatic (P13). Compared to littermate control mice, SMA mice showed a time-dependent increase in the number of exons showing differential expression, with minimal differences between genotypes at P1 and P7, but substantial variation in late-symptomatic (P13) mice. Gene ontology analysis revealed differences in pathways associated with neuronal development as well as cellular injury. Validation of selected targets by RT–PCR confirmed the array findings and was in keeping with a shift between physiologically occurring mRNA isoforms. We conclude that the majority of splicing changes occur late in SMA and may represent a secondary effect of cell injury, though we cannot rule out significant early changes in a small number of transcripts crucial to motor neuron survival., Author Summary The identification of mutations in the Survival Motor Neuron (SMN) gene as the cause of the severe motor neuron disorder spinal muscular atrophy is one of a number of discoveries implicating selective motor neuron vulnerability to defects in processing of RNA and its associated ribonucleoprotein complexes. An unresolved issue is whether loss of the general cellular function of SMN in spliceosomal assembly, which is predicted to result in widespread defects in mRNA splicing, is directly responsible for motor neuron death. We have used exon-specific microarrays to assess the degree of altered splicing in the spinal cord in a mouse model of SMA. Our finding that the vast majority of splicing changes are a late feature of the disease and may represent a shift to alternative isoform expression, rather than loss of splicing fidelity, provides evidence that widespread splicing disturbance is not a primary feature of the disease pathogenesis but a secondary effect of cell injury in a late phase of the disease. However, our study cannot rule out a role for subtle early changes in one or a few transcripts crucial to motor neuron survival expressed at low levels or in only in a sub-population of spinal cord cells.

An important feature of amyotrophic lateral sclerosis (ALS), which is common to other major neurodegenerative diseases such as Alzheimer disease and Parkinson disease, is that the minority (5%–10%) of patients with an inherited form of ALS cannot be distinguished clinically from the majority who have no family history. This has encouraged the view that understanding the genetic, molecular, and cellular basis of familial ALS (fALS) will provide major insights into pathogenesis, and ultimately lead to the generation of effective therapies, for the much commoner sporadic form of disease. For more than a decade, the only gene clearly associated with fALS was SOD1 , which accounts for 20% of familial cases.1 The most significant development in ALS research since that initial breakthrough was the discovery that TDP-43 protein is both a constituent of ubiquitinated inclusions in ALS spinal cord motor neurons2 and also mutated in approximately 5% of patients with fALS.3 A smaller number of patients with ALS carry mutations in the gene for angiogenin4 but more than three-quarters of familial ALS cases have remained unexplained. It has long been clear that there are more ALS genes to be discovered. …

A 68-year-old man developed “pins and needles” of his fingertips and toes in December 2005 along with cramp-like muscle pains in his forearms and calves. Over the next 6 months he noticed “coldness” of his hands and feet, his arms felt “sore” and his fingers were often “shaky” and felt “gritty”. His feet felt as though they were “covered in sand” and he became unsteady. By June 2006 he was frequently falling. He described “not knowing where” his feet were and his “knees giving way”. By November 2006 his mobility was restricted to using a wheelchair. He also had difficulty with manual dexterity, leading to problems with dressing and feeding. Over this period he had intermittent diarrhoea and constipation but his weight and appetite were stable. His past medical history is outlined in table 1 and included longstanding abdominal pain and alteration in bowel habit for which he had been extensively investigated. View this table: Table 1 Patient’s past medical history In November 2006 his medications included: fluoxetine 20 mg once daily for depression, omeprazole 20 mg once daily, folic acid 5 mg once daily, Adcal D3 three tablets once daily, ferrous sulphate 200 mg three times a day, alfacalcidol 1 μg once daily, hyoscine butlylbromide 10 mg three times a day, and intramuscular vitamin B12 injections 1 mg every 3 month which he had been receiving for the past 10 years. There was no family history of neurological illness. He was an ex-smoker who had given up 36 years previously, and he consumed alcohol occasionally. On examination in November 2006 he was thin, weighing only 50.2 kg (body mass index 17.5 kg/m2). There was finger clubbing but no generalised lymphadenopathy and the rest of the general examination was unremarkable. He had normal higher mental function, cranial nerves and speech, muscle bulk and tone, and full power in …

SUMMARY Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, GarsC201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The GarsC201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.

We describe a case of functional vitamin B12 deficiency where the repeated measurement of a serum B12 level within the normal range led to delay in the diagnosis of subacute combined degeneration of the spinal cord, and possibly permanent neurological damage as a result. Failure of intracellular transport of B12 by transcobalamin-2 can lead to functional B12 deficiency but with apparently normal serum levels, and is suggested by raised levels of either serum methylmalonic acid or homocysteine, associated with low levels of transcobalamin-2. Such patients may respond to repeated high-dose injections of B12.

Background Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA). Results TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords. Conclusion These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.

Mutations in protein kinase Cgamma (PKCgamma) cause the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14). In this study, expression of an extensive panel of known SCA14-associated PKCgamma mutations as fusion proteins in cell culture led to the consistent formation of cytoplasmic aggregates in response to purinoceptor stimulation. Aggregates co-stained with antibodies to phosphorylated PKCgamma and the early endosome marker EEA1 but failed to redistribute to the cell membrane under conditions of oxidative stress. These studies suggest that Purkinje cell damage in SCA14 may result from a reduction of PKCgamma activity due its aberrant sequestration in the early endosome compartment.

Gain-of-function mutations in the Cu,Zn-superoxide dismutase (SOD1) gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis (ALS). At present, transgenic expression of 12 human SOD1 mutations driven by the endogenous promoter is disease-causative and uniformly lethal in mice and rats, despite tremendous biochemical and biophysical variation between the mutants tested. This contrasts with the subclinical motor neuron disease phenotypes of wild-type SOD1 transgenic and knockout mice. Molecular mechanisms such as glutamate-induced excitotoxicity, axonal transport blockade, mitochondrial dysfunction, neuroinflammation and apoptosis triggered by mutant SOD1 catalysed oxidative reactions and/or protein misfolding are proposed to drive ALS pathogenesis. Around 100 genetic cross-breeding experiments with transgenic mutant SOD1 mice have been performed to verify these mechanisms in vivo. Furthermore, mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS. Transgenic mutant SOD1 rodents have also provided the benchmark preclinical tool for evaluation of over 150 potential therapeutic anti-oxidant, anti-aggregation, anti-glutamatergic, anti-inflammatory, anti-apoptotic and neurotrophic pharmacological agents. Recent promising findings from gene and antisense therapies, cell replacement and combinatorial drug approaches in transgenic mutant SOD1 rodents are also emerging, but await successful translation in patients. This review summarises the wealth of known genetic and therapeutic modifiers in rodent models with SOD1 mutations and discusses these in the wider context of ALS pathoetiology and treatment.

Distal hereditary motor neuropathy, also known as distal spinal muscular atrophy, is characterised by slowly progressive weakness and wasting of the hands and feet and has a heterogeneous genetic basis. One form of distal hereditary motor neuropathy is associated with mutations in the gene for the small heat shock protein HSPB1 (hsp27). Families have been described in which slowly progressive, symmetrical, lower limb predominant motor weakness is usually evident by middle age. Here we report a novel mutation, G84R, in an elderly patient presenting with strikingly asymmetrical weakness. Expression of this and other known mutations in cell culture demonstrated enhanced aggregation of mutant HSPB1 protein compared with wild-type.

Objective: We aimed to investigate differences in fractional anisotropy (FA) between primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) and the relationship between FA and disease progression using tract-based spatial statistics (TBSS). Methods: Two scanners at two different sites were used. Differences in FA between ALS patients and controls scanned in London were investigated. From the results of this analysis, brain regions were selected to test for (i) differences in FA between controls, patients with ALS and patients with PLS scanned in Oxford and (ii) the relationship between FA and disease progression rate in the Oxford patient groups. Results: London ALS patients showed a lower FA than controls in several brain regions. Oxford patients with PLS showed a lower FA than ALS patients and than controls in the body of the corpus callosum and in the white matter adjacent to the right primary motor cortex (PMC), while ALS patients showed reduced FA compared with PLS patients in the white matter adjacent to the Superior frontal gyrus. Significant correlations were found between disease progression rate and (i) FA in the white matter adjacent to the PMC in PLS, and (ii) FA along the cortico-spinal tract and in the body of the corpus callosum in ALS. Conclusions:: We described significant FA changes between PLS and ALS, suggesting that these two presentations of motor neuron disease show different features. The significant correlation between FA and disease progression rate in PLS suggests the tissue damage reflected in FA changes contributes to the disease progression rate. Hum Brain Mapp 30:615-624, 2009. (C) 2008 Wiley-Liss, Inc.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive childhood form of motor neuron disease. Previous studies have highlighted nerve- and muscle-specific events in SMA, including atrophy of muscle fibres and post-synaptic motor endplates, loss of lower motor neuron cell bodies and denervation of neuromuscular junctions caused by loss of pre-synaptic inputs. Here we have undertaken a detailed morphological investigation of neuromuscular synaptic pathology in the Smn-/-;SMN2 and Smn-/-;SMN2;Delta7 mouse models of SMA. We show that neuromuscular junctions in the transversus abdominis (TVA), levator auris longus (LAL) and lumbrical muscles were disrupted in both mouse models. Pre-synaptic inputs were lost and abnormal accumulations of neurofilament were present, even in early/mid-symptomatic animals in the most severely affected muscle groups. Neuromuscular pathology was more extensive in the postural TVA muscle compared with the fast-twitch LAL and lumbrical muscles. Pre-synaptic pathology in Smn-/-;SMN2;Delta7 mice was reduced compared with Smn-/-;SMN2 mice at late-symptomatic time-points, although post-synaptic pathology was equally severe. We demonstrate that shrinkage of motor endplates does not correlate with loss of motor nerve terminals, signifying that one can occur in the absence of the other. We also demonstrate selective vulnerability of a subpopulation of motor neurons in the caudal muscle band of the LAL. Paralysis with botulinum toxin resulted in less terminal sprouting and ectopic synapse formation in the caudal band compared with the rostral band, suggesting that motor units conforming to a Fast Synapsing (FaSyn) phenotype are likely to be more vulnerable than those with a Delayed Synapsing (DeSyn) phenotype.

The said truth is that it is the greatest happiness of the greatest number that is the measure of right and wrong. Jeremy Bentham (1748–1832) The “greatest happiness principle” propounded by 19th century Utilitarian philosophers such as Jeremy Bentham and John Stuart-Mill directs that “right” actions are those which do the greatest good for the greatest number. Even if this philosophical principle has fallen into disrepute, having found its purest expression in the totalitarian excesses of fascism and communism, utilitarianism seems like a promising moral foundation, at least for public health medicine. However, medical research tends to be driven by the intellectual interests of individual researchers and rare diseases appear more often on grant applications than can be justified simply by the number of people affected. A commonly stated defence is that by understanding the pathophysiology of rare diseases we will learn something of importance about more common conditions. Are there good examples from neurology to support this approach? Most genetic diseases are rare whereas most common diseases are considered to be “complex”, by …

Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L-mutant human GlyRS. The S581L mutation is approximately 50A from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant-negative effect is more likely in this autosomal dominant disorder.

Magnetic resonance spectroscopic imaging—of prognostic value in amyotrophic lateral sclerosis?

Publisher Summary This chapter describes the various forms of inherited lower motor neuron degeneration and discusses the current knowledge regarding the molecular basis of these disorders and the pathways underlying the specific susceptibility of motor neurons to degeneration. By convention, the use of the term “spinal muscular atrophy” (SMA) is reserved for disorders characterized by progressive muscle wasting due to the loss of motor neurons in the ventral horns of the spinal cord. The three forms of childhood onset proximal SMA—previously known as Werdnig–Hoffmann disease (type I SMA), intermediate SMA (type II), and Kugelberg–Welander syndrome (type III)—are caused by mutations in the same gene, survival of motor neurons 1 (SMN1). Supportive treatment for types I and II SMA includes respiratory assessment and nutritional support as appropriate and for type II patients corrective spinal surgery for scoliosis. Distal SMAs or hereditary motor neuronopathies (HMN) are a range of conditions characterized by slowly progressive distal wasting and weakness in the absence of clinical or electrophysiological evidence of sensory involvement. Several families have been described in which distal motor neuropathy is associated with vocal cord paralysis leading to hoarseness and stridor.

Distal hereditary motor neuronopathies (dHMNs) are a clinically and genetically heterogeneous group of disorders in which motor neurons selectively undergo age-dependant degeneration. Mutations in the small heat-shock protein HSPB1 (HSP27) are responsible for one form of dHMN. In this study, we have analysed the effect of expressing a form of mutant HSPB1 in primary neuronal cells in culture. Mutant (P182L) but not wild-type HSPB1 led to the formation of insoluble intracellular aggregates and to the sequestration in the cytoplasm of selective cellular components, including neurofilament middle chain subunit (NF-M) and p150 dynactin. These findings suggest a possible pathogenic mechanism for HSPB1 whereby the mutation may lead to preferential motor neuron loss by disrupting selective components essential for axonal structure and transport.

The onset of motor symptoms in amyotrophic lateral sclerosis (ALS) is strikingly focal. In three-quarters of cases, weakness emerges unilaterally in one limb, typically spreading contiguously over months to become bilateral.(1) An extremely rare clinical syndrome of upper motor neuron-predominant, progressive hemiparesis was first described by American neurologist Charles Karsner Mills (1845-1930).(2) More typical ALS shares a common histopathologic signature with frontotemporal dementia (FTD), consisting of ubiquitinated neuronal and glial inclusions containing the DNA and RNA binding protein, TDP-43. Cognitive impairment may be detected in at least one-third of ALS cases and involves mainly deficits in language, executive function, and fluency, with variable levels of behavioral impairments that all have overlap with the purer FTD syndromes. Frank FTD is seen in up to 15% of patients with ALS, in whom it typically occurs before or soon after the development of motor symptoms, and is associated with a more rapid disease progression.(3.)

Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.

PURPOSE OF REVIEW: Many forms of spinal muscular atrophy, a pure lower motor neuron disease, have been characterized clinically but the molecular basis of most of these is unknown. In this article we review recent developments in our understanding of the spinal muscular atrophies and how this knowledge has revealed important new insights into the causes of motor neuron vulnerability which may ultimately lead to novel therapies for this untreatable group of disorders. RECENT FINDINGS: The identification of the genetic basis of two forms of autosomal recessive spinal muscular atrophy has revealed that lower motor neurons appear to have a specific vulnerability to defects in RNA metabolism. Most notably, the survival motor neuron protein, deficient in the most common form of spinal muscular atrophy, plays a multifunctional role in ribonucleoprotein metabolism and pre-messenger RNA splicing. The role of this protein in motor neurons is currently under intense study. The identification of two other spinal muscular atrophy-causing genes has provided support for the central role of components of the RNA metabolic pathway in determining motor neuron survival. SUMMARY: Understanding the molecular basis of lower motor neuron vulnerability in disorders such as spinal muscular atrophy will ultimately allow these disabling disorders to be treated. In addition we can expect to learn much about basic neuronal biology and about the pathways that are relevant to more common neurodegenerative disorders such as amyotrophic lateral sclerosis.

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.

Sirs: Cerebral venous sinus thrombosis (CVT) is a life threatening condition with a broad range of clinical neurological presentations and a large differential diagnosis [1]. Early diagnosis may be crucial to the neurological outcome, which can often be favourable. Treatment with heparin may improve survival and disability [2] and patients who continue to deteriorate may be suitable for local thrombolysis [3]. CVT must be considered in any patient with sub-acute headache, seizures, disorders of consciousness or papilloedema. The condition can mimic stroke, abscess, tumour, encephalitis or idiopathic intracranial hypertension. Similarly, there is a wide range of underlying aetiologies including inherited thrombophilias, oral contraception, pregnancy, local intracranial sepsis and systemic inflammatory diseases such as Behcet’s disease. Therefore, the diagnosis cannot be reliably made on clinical grounds alone and is often delayed, particularly when out of hours neuroimaging is unavailable. MRI and MR angiography are the accepted methods of choice, though the sensitivity and specificity of this technique have never been compared with catheter angiography [4]. In other venocclusive conditions such as deep vein thrombosis (DVT) and pulmonary embolism (PE) diagnostic accuracy has been improved by estimation of d-dimer levels in plasma [5]. Because d-dimers may rise as part of the acute phase response, raised levels do not constitute diagnostic proof of thrombosis. However, a normal d-dimer level is used as a test of exclusion. We have performed a pilot study to investigate if, by analogy with deep venous thrombosis (DVT) and pulmonary embolism (PE), estimation of plasma d-dimers could aid the diagnosis of patients with possible CVT. We used the MDA D-dimer (Organon Teknika Corporation, Durham, USA) a quantitative immunoassay using latex microparticles coated with mouse monoclonal antibody to D-dimer (8–8G). These latex particles thus agglutinate in the presence of D-dimer and this process can be monitored using the photo-optical detection system of the MDA 180 automated coagulometer. The rate of agglutination is proportional to the Ddimer concentration and can be interpolated from a reference curve. Assays were complete within 15 minutes. The primary aim of this study was to establish if a normal level of d-dimers could reliably exclude the diagnosis of CVT. Successive patients with radiologically proven (MRI) venous sinus thrombosis presenting to a regional neurology unit underwent plasma d-dimer estimation before anticoagulant therapy was started. The following brief clinical descriptions serve to illustrate that these patients were representative of patients with sinus thrombosis as a whole: • Patient 1 was a 17-year-old female who presented with a six-day history of occipital headache associated with nausea and vomiting progressing to collapse with motor and sensory loss of the left side of her body. She was taking the oral contraceptive pill. MRI/MRV showed a right-sided lateral and sigmoid sinus thrombosis. D-dimer levels were 430 μg/l (normal value less than 500μg/l). She was subsequently found to have a strongly positive lupus anticoagulant test (DRVVT). She was anticoagulated and made a full recovery. • Patient 2, a 55-year-old female with a history of chronic schizophrenia, was admitted having collapsed. There was a background of one week of increasing lethargy and slurring of speech and loss of hearing in the left ear. MRI/MRV revealed left lateral and sigmoid sinus thrombosis and left mastoiditis, which was surgically drained. The d-dimer level was 392μg/l. She made a full neurological recovery. • Patient 3, a 31-year-old male from Saudi Arabia, had a background history of pulmonary embolus and hepatic vein thrombosis and had unilaterally stopped taking warfarin six months prior to this episode. There was a history of venous thrombosis in his mother and sister. He presented with two generalised seizures on the background of a one week history of occipital headache and MRI revealed extensive thrombosis of the sagittal sinus. D-dimer levels were 1392μg/l. He made a full recovery. • Patient 4 was of Afro-Caribbean origin and had a long standing history of intravenous heroin use. He presented with an acute confusional state and was found to be in hyperosmotic non-ketotic diabetic coma. With treatment of this his conscious level improved and he began to complain of headache. Contrast enhanced CT of the brain showed sagittal sinus thrombosis. Ddimer levels were 919μg/l and he was found to have Sickle cell trait. He made a full neurological recovery. LETTER TO THE EDITORS

Population registries, uncontaminated by the referral bias seen in clinic based case series, show that approximately 5% of amyotrophic lateral sclerosis (ALS) cases are familial.1 At most, only 30% of these cases are explained by mutations in the small number of currently identified ALS related genes, including SOD1, TDP-43 and FUS.2–4 The era of Mendelian genetics for the common neurodegenerative diseases is fast drawing to a close. There are very few large families left to collect and the sun is setting on linkage studies. It is unlikely that there is another gene which explains as many familial cases as SOD1 (approximately 20%). The potentially numerous and diverse gene defects responsible for the remaining 70% of familial ALS cases will likely be identified in the future by large scale ‘deep sequencing’ projects, either through targeting genes in specific pathways or by whole genome sequencing. There is a widespread and entirely reasonable assumption that the remaining 95% of ALS cases, which are classified as ‘sporadic’, are caused by a mixture of genetic and environmental effects, and that ALS is therefore a ‘complex’ disease like diabetes and stroke. However, in the case of ALS this is still a hypothesis and the most interesting area of uncertainty is not whether the totality of ALS has a genetic component, which it clearly does because we can identify genetic mutations in patients with familial disease and in a few cases with sporadic disease, but whether there is a subpopulation of sporadic ALS cases in which the genetic contribution is minimal or even …

Background Focality of onset and spread of pathology in MND are poorly understood. Biomarkers are needed to improve diagnosis and therapeutic monitoring, but must accurately reflect the inherent clinical and prognostic heterogeneity. Diffusion tensor imaging (DTI) is a sensitive MRI application for the noninvasive detection of white matter pathology. Methods High-field cerebral DTI was applied in an unbiased whole-brain analysis across a group of 24 unselected heterogeneous MND patients, and well-matched healthy controls. Patients were scored for clinical upper motor neurone (UMN) involvement, and disability (using the revised ALS Functional Rating Scale, ALSFRS-R). Results A consistent reduction in fractional anisotropy (FA) was demonstrated in the central corpus callosum (CC) of the MND patients, and correlated with disability. A separate whole-brain analysis in relation to UMN involvement highlighted the corticospinal tract (CST). Conclusions Corpus callosum FA is a promising biomarker for the heterogeneous syndrome of MND, and may provide a clue to the topographical spread of disease. FA reduction was related to disability, and did not simply reflect UMN involvement, which supports the inclusion of those subjects with apparently LMN/UMN-only phenotypes within one syndrome. The exquisite delineation of the CST in whole-brain analysis of FA in relation to clinical UMN involvement provided validation of both DTI and a “bedside score” as markers of UMN neuronal damage in MND.

Spinal muscular atrophy is a common cause of disability in childhood and is characterized by weakness and wasting of voluntary muscle. It is frequently fatal. The gene for this disorder has been identified as the SMN gene and is part of a highly complex duplicated region of chromosome 5 that is subject to a high rate of gene deletion and gene conversion. The severity of muscle weakness correlates with the amount of full-length SMN protein produced. Molecular genetic studies support a model in which patients are compound heterozygotes of deleted and converted alleles that predicts a progressively decreasing amount of protein product with severity of muscle weakness. The function of SMN is beginning to be understood and it appears to be involved in ribonucleoprotein biogenesis and thus indirectly in post-transcriptional processing of mRNA. There are theoretical grounds for motor neurons having a cell-specific vulnerability to disturbances of mRNA processing and transport and these are briefly reviewed.

The Survival Motor Neuron (SMN) gene shows deletions in the majority of patients with Spinal Muscular Atrophy (SMA), a disease of motor neuron degeneration. To date only two missense mutations have been reported in SMN in patients with SMA. The fact that no SMN-homologues have been forthcoming from database searching has resulted in a lack of hypotheses concerning the structural and functional consequences of these mutations. Recently SMN has been shown to interact with heterogeneous nuclear ribonu-cleoproteins (hnRNPs) suggesting a role in mRNA metabolism. We describe a novel missense mutation and the subsequent identification of a triplicated tyrosine-glycine (Y-G) peptide sequence at the C-terminal of SMN which encompasses each of the three predicted amino acid sequence substitutions. We have identified apparent orthologues of SMN in Caenorhabditis elegans and Schizosaccharomyces pombe. These sequences retain the highly conserved Y-G motif and provide additional support for a role of SMN in mRNA metabolism.

Objective: To explore the value of diffusion tensor imaging applied to those specific cerebral white matter tracts consistently involved pathologically in amyotrophic lateral sclerosis as a source of prognostic biomarkers. Design: Baseline clinical assessment and 3-T diffusion tensor imaging, repeated after approximately 6 months. Tract-based spatial statistics were used to assess voxelwise correlations of just the baseline diffusion tensor imaging indices with the progression rate (change in disability score/time interval) within the corticospinal tract and corpus callosum. Patients: The study involved 21 patients with amyotrophic lateral sclerosis and 3 patients with primary lateral sclerosis. Results: Correlation was observed between fractional anisotropy and progression rate for a region of the corticospinal tract spanning the posterior limb of the internal capsule, with a left hemisphere emphasis. Posterior limb of the internal capsule fractional anisotropy showed potential to distinguish those patients with rapid progression. Axial diffusivity significantly increased in this region in a paired t test analysis of baseline and follow-up diffusion tensor imaging, in keeping with axonal damage. No correlations were noted for the corpus callosum. Conclusions: Posterior limb of the internal capsule fractional anisotropy is a candidate prognostic marker in amyotrophic lateral sclerosis, with potential to identify incident cases with more rapid progression. ©2012 American Medical Association. All rights reserved.