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LPIN1 mutations are a known common cause of autosomal recessive, recurrent and life-threatening acute rhabdomyolysis of childhood-onset. The first episode of rhabdomyolysis usually happens in nearly all cases before the age of 5 and death is observed in 1/3 of patients. Here we present two cases of acute rhabdomyolysis with a milder phenotype caused by LPIN1 mutation presenting in adolescence (11 years old) and adulthood (40 years old) after Parvovirus infection and metabolic stress, respectively. In our opinion, the mutation types, epigenetic factors, the environment exposition to triggers or the existence of proteins with a similar structure of LPIN1, may have a role in modulating the onset of rhabdomyolysis. LPIN1 should be included on a panel of genes analysed in the investigation of adult individuals with rhabdomyolysis. Metabolic and viral stressors should be included in the list of possible rhabdomyolysis precipitant.

Background Headache and Neurological Deficits with cerebrospinal fluid (CSF) Lymphocytosis (HaNDL) is an increasingly recognised syndrome but the aetiology remains unclear. HaNDL has striking clinical features similar to Familial Hemiplegic Migraine (FHM), commonly related to gene mutations encoding the P/Q-type voltage-gated calcium channel (VGCC). Case report We report a case of HaNDL associated with high P/Q-type voltage-gated calcium channel antibodies. Extensive investigations excluded alternative diagnoses and CSF lymphocytosis resolved within 3 months. The case was complicated by raised intracranial pressure resulting in an enlarged blind spot, papilloedema and bilateral lateral rectus palsies. Conclusion This novel association of P/Q-type voltage-gated calcium channel antibodies with HaNDL has implications for the pathology of HaNDL and spectrum of voltage-gated calcium channel-antibody disorders. We compare the clinical features of FHM and HaNDL and the potential pathological role of these antibodies. This case also highlights that raised intracranial pressure is a common feature of HaNDL, rarely resulting in serious complications.

Background Large-scale electronic primary care datasets can provide up-to-date, accurate epidemiological information on rarer diseases. In the UK, approximately 70,000 people are estimated to be living with neuromuscular disease (NMD), but this approximation is over 10 years old and used historical estimates from different sources. While GPs are unlikely to make NMD diagnoses themselves, specialist diagnoses from hospital discharges and clinic letters are well recorded and electronically searchable within primary care records. The recent expansion of the Clinical Practice Research Datalink (CPRD) allows timely reporting on the recorded incidence and prevalence of NMD in the UK over the last 20 years. Methods A harmonised dataset of CPRD GOLD and Aurum was developed to provide annual denominators of actively registered patients between 2000 and 2019. A Read code hierarchy was developed for a wide range of NMDs; the database was then searched electronically to estimate incidence and (lifetime) prevalence rates in each year. To compare trends over time, rates were age standardised to the most recent CPRD population (2019). Results The combined CPRD database contained approximately 13 million patients actively registered in each year. By 2019, 28,230 active patients had ever received a Read code for one of the NMDs (223.6 per 100,000), which would scale up to approximately 149,000 people in the UK. Lifetime prevalence rates per 100,000 were higher among males (239.0) than females (208.3). The most common classifications were Guillain-Barre syndrome (40.1), myasthenia gravis (33.7), muscular dystrophy (29.5), Charcot-Marie-Tooth (29.5) and inflammatory myopathies (25.0). Since 2000, overall prevalence grew by 63% but incidence remained steady over time. All age groups showed an increase in prevalence, with the largest increases seen at older ages (≥65-years). Among individual conditions since about 2008, incidence of myasthenia gravis has been steadily rising while new cases of muscular dystrophy fell over the same period. Conclusions Lifetime recording of many NMDs on primary care records exceeds current estimates of people living with these conditions; these are important data for health service and care planning. Temporal trends suggest this number is steadily increasing and there may be twice as many people living with these conditions than currently thought. While this may be partially due to increases in recording, it cannot be simply explained by new cases as incidence is largely unchanged over time. The increase in prevalence among older ages suggest increases in life expectancy among those living with NMDs may have taken place.

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.

Risdiplam is a pre-mRNA splicing modifier designed to treat 5q-SMA. We describe our experience prescrib- ing Risdiplam to adults with type-2 SMA with a wider range of ages and comorbidities than in clinical trials.Risdiplam was prescribed for nine people aged 20 to 56-years; six males. Eight patients had homozygous exon-7 and 8 deletions; one had isolated homozygous exon-7 deletions. Seven patients had three copies of the SMN-2-gene, two had four copies. Seven patients had spinal surgery and two had severe scoliosis. They had between 0-5 comorbidities and 1-12 other drugs already prescribed and were all assessed for known interactions. They had blood tests (month 1, 3, and 6), ECG, and visual function assessment. Females of childbearing age were offered long-acting contraception and males were offered sperm banking.Seven patients required non-invasive ventilation while two had dysphagia (one with gastrostomy). Baseline forced-Vital-Capacity (19%-74%), RUL (score 0-19), CHOP-ATTEND (score 19-46), and 9-hole-peg-test and dynamometer were measured as appropriate.One experienced abdominal pain and increased weakness (Risdiplam was stopped). One patient had transaminitis and treatment was withheld and restarted later at a lower dose and is being gradually increased.We found Risdiplam is generally well tolerated, especially for those with greater disability and spinal surgery.

The need to improve care of patients with headache prompted development of a new model in South West London. The Headache Hub, piloted at St George’s University Hospitals NHS Foundation Trust, consisted of a multidisciplinary team; Consultant Neurologists, GP with Extended Role and Allied Health Professionals. The Hub triages new GP referrals and offers an online migraine group clinic (engaging patients through shared medical appointments in a group setting).Between April-December 2021, 171 GP referred patients were seen, of which 96 (48%) had Chronic Migraine (CM), 36 (18%) High Frequency Episodic Migraine and 23 (12%) Low Frequency Episodic Migraine patients. CM patients reported 31 ED attendances in the prior year and 53% had the highest unmet needs, HURT 8 (Headache Under Response to Treatment) score 17-24. Real-time data on waiting times enabled clini- cians to make informed follow up choices.Triage to “consultant only” occurred in 56% of referrals, enabling a subsequent reduction in consultant caseload to address tertiary headache waiting lists. Patient satisfaction was high (80%) and group clinic feedback highlighted beneficial shared experiences; “super productive and made me feel not so alone in a challenging time”.This model is being considered at other secondary care hospitals in the region.

We describe nusinersen, the only licensed treatment for adults with SMA in the UK, administra- tion with Single-Plane-Fluoroscopic-Guided(SPFG), Bi-Plane-Fluoroscopic-Guided(BPFG), or Computerised-Tomography-guided(CTG).We treated three patients with type-2-SMA (two with Severe-Scoliosis[SS], one with Posterior-Spinal- Fusion[PSF]) and four with type-3-SMA (two ambulant, one with Normal-Spine[NS] and one Mild-Lumbar- Spinal-Deformities[MLSD] and two non-ambulant; one each with PSF and MLSD) aged 17 to 57-years. All had homozygous exon-7 and 8 deletions. One had two copies, four had three copies, and the remainder had four copies of SMN-2-gene.At baseline, forced-vital-capacity was between 38% to 153%. Ambulant patients were assessed with HFMSE(score 37-60), RHS(scores 31-67) and, 6MTM(range 43-492m), and non-ambulant patients were assessed with CHOP-ATTEND(score 17-38), RUL(2-33), 9-hole-peg-test and dynamometer as appropriate.In type-2, patients with SS had a total of 6(20.7%) BPFG-injections. Only one had severe hypokalemia requiring ITU and treatment cessation. In one with PSF, BPFG-injection was unsuccessful.In type-3, SPFG-injections were successful in all 19 attempts with MLSD or NS. One each was complicated by transient low-pressure symptoms and radicular pain. Three CTG-injections on a patient with PSF were uncomplicated. All with successful LPs(96.5%) did not drop out.We found that nusinersen could be administered regardless of the spinal anatomy with interventional radiology.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65–1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016–19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: −0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

BackgroundReports of Guillain-Barré Syndrome (GBS) have emerged during the Coronavirus Disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS.MethodsThe epidemiology of GBS cases reported via the UK National Immunoglobulin Database were studied from 2016-2019 and compared to cases reported during the COVID-19 pandemic. For the cohort study, members of the British Peripheral Nerve Society reported all cases of GBS during the pandemic. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases were compared.ResultsThe UK GBS incidence from 2016-2019 was 1.65-1.88 per 100,000 people per year. GBS and COVID-19 incidence varied between regions and did not correlate (r = 0.06, 95% CI −0.56 to 0.63, p=0.86). GBS incidence fell between March and May 2020 compared to the same months of 2016-2019. Forty-seven GBS cases were included in the cohort study (13 definite, 12 probable COVID-19 and 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome. Intubation was more frequent in the COVID-19+ve cohort (7/13, 54% vs 5/22, 23% in COVID negative) thought to be related directly to COVID-19 pulmonary involvement.ConclusionsThis study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP, dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients, these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

We describe a case of a 70-year old man with sensorimotor chronic inflammatory demyelinating polyneuropathy (CIDP) with small-fibre involvement resulting in severe diffuse neuropathic pain which was refractory to immunotherapy and anti-neuropathic medication. His pain was successfully treated with implantation of a spinal cord stimulation (SCS) system comprising bilateral cervical and lumbar epidural leads. Following SCS programming, he experienced a 50% reduction in average pain severity with substantial improvement in quality of life, persisting at 18 months after surgery. SCS has been employed to treat a variety of neuropathic pain syndromes. However, this is the first report to our knowledge of SCS utilised effectively for pain in CIDP. This therapy should be considered in painful CIDP for neuropathic pain refractory to medical management, though further studies are required to evaluate its efficacy.

St George's Hospital hyperacute neurology service (HANS) is a comprehensive, consultant-delivered service set in a teaching hospital regional neuroscience centre. The service addresses deficiencies in acute neurological care previously highlighted by the Royal College of Physicians and the Association of British Neurologists. HANS adopts a disease-agnostic approach to acute neurology, prioritising the emergency department (ED) management of both stroke and stroke mimics alike alongside proactive daily support to the acute medical unit and acute medical take. Rapid access clinics provide a means to assess ambulatory patients, providing an outlet to reduce the burden of referral from primary care to acute medicine. This paper reports the results from the first year of the service. Admission was avoided in 25% of the cases reviewed in the ED. Compared to historic data, there was a significant improvement in the length of stay for non-stroke disorders while the occupancy of stroke beds by non-stroke cases reduced by 50%. The configuration of this service is replicable in other neuroscience centres and provides a framework to reduce the barriers facing patients who present with acute neurological symptoms.

WOS: 000483737700026, PubMed ID: 31344955, Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments., Medical Research CouncilMedical Research Council UK (MRC) [K025406]; Orphan Technologies, This study is funded by the Medical Research Council (K025406) and Orphan Technologies.

Headache is common. Up to 5% of attendances to emergency departments and acute medical units are due to headache. Headache is classified as either primary (eg migraine, cluster headache) or secondary to another cause (eg meningitis, subarachnoid haemorrhage). Even in the acute setting the majority of cases are due to primary causes. The role of the attending physician is to take a comprehensive history to diagnose and treat benign headache syndromes while ruling out sinister aetiologies. This brief article summarises the approach to assessment of headache presenting in acute and emergency care.

Interpersonal relationships are viewed as important contexts within which psychopathology emerges and persists or desists. Attachment theory describes the dynamics of long-term relationships between humans especially in families and lifelong friendships. The present study was aimed at investigating attachment styles in adult patients with epilepsy as compared to subjects with migraine and their potential correlates with a history of mood disorders.A consecutive sample of 219 adult outpatients with epilepsy (117) or migraine (102) was assessed with the Attachment Style Questionnaire (ASQ).Patients with epilepsy and a lifetime history of mood disorders presented elevated scores for Need for approval (p0.001) and Preoccupation with relationships (p0.001). Age correlated with the Relationships as secondary (r=0.322; p0.001) and Need for approval (r=0.217; p=0.019) subscales while age at onset correlated only with Relationships as secondary (r=0.225; p=0.015). Seizure-free patients presented lower scores for Need for approval (p=0.003). Patients with migraine and a lifetime history of mood disorders presented lower scores in Confidence (p=0.002) and higher scores in Discomfort with closeness (p=0.026).An anxious-preoccupied attachment correlated with mood disorders in epilepsy while it was an avoidant pattern in migraine. Our results bring further data on the role of psychological variables in mood disorders in epilepsy. Further studies will allow early identification of patients at risk and the development of preventive strategies.

Vijyarangam Senthilkumar Shanmugam (“Kumar”) was an incredible, brave, and sincere doctor. He completed his medical training in 2000, graduating from Madurai Medical College in India. On the eve of his final practical MBBS examination, he was riding his “bullet” motorbike to pay a visit to the temple in Madurai. On the way, he was forced to swerve to avoid some boys playing a ball game, one of whom ran out into the road. He crashed, breaking his forearm. He abandoned the motorbike and returned to his digs, where he attempted to reset his arm by himself. Eventually, his friends persuaded him …

Anti-aquaporin 4 (AQP4) antibody is a marker of neuromyelitis optica (NMO) spectrum diseases, characteristically presenting with myelitis longitudinally extensive transverse myelitis or optic neuritis (ON). While cerebral lesions are recognized, extensive brain involvement and cognitive impairment is rare. We report a case of subacute encephalopathy associated with fulminant subcortical brain lesions. A 19-year-old Jamaican woman reported decreased sensation and power in the left leg, recovering over 2 weeks without medical investigation. Eight months later, she developed painless bilateral visual loss (no perception of light on right, counting fingers on left), treated with intravenous methylprednisolone and plasma exchange. Vision improved gradually to 1/60 (right) and 6/6 (left). Recurrent ON 10 months later reduced acuity to counting fingers bilaterally. With further methylprednisolone, and azathioprine commencement (100 mg/day, low dose because of lymphopenia), acuities improved over 2 months. However, another relapse reduced vision to hand movements bilaterally, necessitating further plasma exchange. Two months thereafter, she developed gait failure, worsening vision, confusion and aggression, severe executive dysfunction, impaired attention, memory and verbal fluency, and suffered a generalized tonic–clonic seizure. There was no perception of light bilaterally, spastic paraparesis and hemisensory loss. With no response to further methylprednisolone and plasma exchange, she was given rituximab (375 mg/kg weekly for 4 weeks). Despite this, 2 weeks later she developed flaccid paraplegia with an extensive cord lesion from cervical to L1 vertebral segments. She remains profoundly disabled; blind, paraplegic, and with impaired comprehension. AQP4-IgG antibody titers were extremely high (maximal level 1:45,000 dilution). Double-stranded DNA antibodies (244 IU/l) and pANCA staining (myeloperoxidase antibody negative) were found. Cerebrospinal fluid (CSF) showed \3 white cells/ll, with normal protein (0.17 g/l). Oligoclonal bands were present in CSF, but not in blood. Antibodies to human T cell lymphotrophic virus (HTLV-1) were present in blood. Viral load was three HTLV-1 DNA copies per 100 peripheral blood mononuclear cells (3 % PBMCs) in blood and 14 % in CSF. MRI revealed T2-hyperintense changes in optic pathways, and numerous periventricular, callosal and juxtacortical white-matter lesions. Over 10 months, scans deteriorated (Fig. 1a, b). A brain biopsy, to exclude other treatable diagnoses, showed features consistent with necrotizing active demyelination (Fig. 1c, e, f; Fig. S1), and absence of AQP4 (Fig. 1d; Figs. S2, S3). Our patient presented with recurrent bilateral ON leading to blindness, and an evolving encephalopathy with necrotizing cerebral white matter destruction. Several features may explain this severity. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6651-y) contains supplementary material, which is available to authorized users.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence indicates non-neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1(G93A) expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co-culture model. SOD1(G93A) expression in astrocytes induced changes in mitochondrial function of both SOD1(G93A) and wild-type motoneurons. In the presence of SOD1(G93A) astrocytes, mitochondrial redox state of both wild-type and SOD1(G93A) motoneurons was more reduced and mitochondrial membrane potential decreased. While intra-mitochondrial calcium levels [Ca(2+)](m) were elevated in SOD1(G93A) motoneurons, changes in mitochondrial function did not correlate with [Ca(2+)](m). Thus, expression of SOD1(G93A) in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis.

In recruiting monozygotic (MZ) twins for our ongoing research into de novo mutations in phenotypically discordant MZ twins, we have come across an increasing number of participants who have been told they are dizygotic (DZ) but have almost identical traits and physical features, or MZ but present more like fraternal siblings. Current practice guidelines for classifying twins as either MZ or DZ, which are still largely based on chorionicity (the notion of whether or not the twins …

Purpose of review The idiopathic inflammatory myopathies are an important and treatable group of disorders. However, the potential toxicity associated with the immune therapeutic regimens used to treat these disorders may be significant; therefore, accurate diagnosis before such treatment is essential. The differential diagnosis is potentially large. Accurate diagnosis usually depends on a combination of careful clinical assessment in conjunction with detailed laboratory investigations. Muscle biopsy remains essential in achieving an accurate diagnosis that will then guide treatment. This review describes the diagnostic approach used.Recent findings There has been debate over the requirements for an accurate diagnosis of inflammatory myopathy (i.e., polymyositis and dermatomyositis). It is increasingly recognized that there can be clinical and muscle histopathologic overlap between the features of inflammatory myopathies and those of other muscle disorders, in particular, the genetic muscular dystrophies. Pathologic findings of inflammation and major histocompatibility complex upregulation, although typical of inflammatory myopathies, have been shown to occur in some muscular dystrophies, complicating the diagnostic process. Inclusion body myositis is much less responsive to immunotherapy and is now recognized as the most common acquired muscle disease in those older than 50 years of age. It is likely that genetic muscular dystrophies and inclusion body myositis account for some cases of apparently "treatment-resistant" myositis.Summary A thorough clinical assessment, including a detailed family history, complemented by electromyography and creatine kinase measurements, should be undertaken in any patient with presumed idiopathic inflammatory myopathy. In addition, a muscle biopsy remains essential in all cases. A precise tissue diagnosis confirming features of an active inflammatory process should be achieved before immunosuppressive treatment is commenced. An increasing array of immunocytochemical and histioenzymatic stains now allows a full analysis and will help to confirm or exclude virtually all the differential diagnostic possibilities considered in this review. Electron microscopy may also be valuable in selected cases. Close collaboration between clinicians and muscle pathologists is essential in allowing the most accurate interpretation of myopathologic findings in the clinical context.

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a late-onset motor neuron disease (MND) caused by an abnormal expansion of the CAG repeat in the androgen receptor (AR) gene on the X-chromosome, encoding a polyglutamine (poly-Q) sequence in the protein product. Mutant poly-Q-expanded AR protein is widely expressed but leads to selective lower motoneuron death. Although the mechanisms that underlie SBMA remain unclear, defective axonal transport has been implicated in MND and other forms of poly-Q disease. Transcriptional dysregulation may also be involved in poly-Q repeat pathology. We therefore examined axonal transport in a mouse model of SBMA recapitulating many aspects of the human disease. We found no difference in the expression levels of motor and the microtubule-associated protein tau, in the spinal cord and sciatic nerve of wild-type (WT) and SBMA mice at various stages of disease progression. Furthermore, we found no alteration in binding properties of motor proteins and tau to microtubules. Moreover, analysis of axonal transport rates both in cultured primary motoneurons in vitro and in vivo in the sciatic nerve of adult WT and mutant SBMA mice demonstrated no overt axonal transport deficits in these systems. Our results therefore indicate that unlike other motoneuron and poly-Q diseases, axonal transport deficits do not play a significant role in the pathogenesis of SBMA.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence indicates non-neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1(G93A) expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co-culture model. SOD1(G93A) expression in astrocytes induced changes in mitochondrial function of both SOD1(G93A) and wild-type motoneurons. In the presence of SOD1(G93A) astrocytes, mitochondrial redox state of both wild-type and SOD1(G93A) motoneurons was more reduced and mitochondrial membrane potential decreased. While intra-mitochondrial calcium levels [Ca(2+)](m) were elevated in SOD1(G93A) motoneurons, changes in mitochondrial function did not correlate with [Ca(2+)](m). Thus, expression of SOD1(G93A) in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis.

Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A--G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (Deltapsim) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A--G mutation; Complex I-linked respiration and Deltapsim were both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F1F0-ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain Deltapsim. This was confirmed by inhibition of glycolysis with 2-deoxy-D-glucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain Deltapsim, representing a potential pathophysiological mechanism in human mitochondrial disease.

Amyotrophic lateral sclerosis is a rare but fatal motoneuron disorder. Despite intensive research riluzole remains the only available therapy, with only marginal effects on survival. Here we review some of the recent advances in the search for a disease-modifying therapy for amyotrophic lateral sclerosis.Recent findings A number of established agents have recently been reinvestigated for their potential as neuroprotective agents, including beta-lactam antibiotics and minocycline. Progress has also been made in exploiting growth factors for the treatment of amyotrophic lateral sclerosis, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, heat-shock protein co-inducers, which upregulate cell stress responses thereby mediating neuroprotection. Nondrug-based therapies are also under development, with progress in gene-silencing and stem cell therapies.Summary In the past few years, significant advances have been made in both our understanding of amyotrophic lateral sclerosis pathogenesis and the development of new therapeutic approaches. However, caution must be exercised in view of the long-standing failure to successfully transfer therapeutic compounds to the clinic. A deeper awareness in the research community of the need for clinically relevant preclinical studies, coupled with a better understanding of the issues surrounding clinical trial design for amyotrophic lateral sclerosis, offers hope that the growing list of validated preclinical therapeutics can finally yield an effective disease-modifying treatment.

Granulysin expression or glucocorticoid receptor polymorphisms may be factors underlying the variable steroid response in patients with myopathies Idiopathic inflammatory myopathies and genetic muscular dystrophies are distinct and well-recognised clinical entities. However, it is increasingly evident that there is overlap in both the clinical presentation1 and the pathophysiology2 of the two groups. The preferred management of polymyositis and dermatomyositis has traditionally been with corticosteroids and, although controlled clinical trial data to support this are lacking, the efficacy of these drugs has long been established in clinical practice. However, not all patients respond to steroids. Non-response rates of up to 40% have been reported, but it has become increasingly clear in recent years that polymyositis in particular has been overdiagnosed, and many of these patients actually had inclusion-body myositis (IBM), for which there is no strong evidence of a response to steroids, or a form of muscular dystrophy. The classical Bohan and Peter criteria for the diagnosis of polymyositis have been modified to include other criteria, such as the presence of CD8+ T cell infiltration along with expression of major histocompatibility class I molecules …