Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Use of Capillary Electrophoresis Immunoassay to Search for Potential Biomarkers of Amyotrophic Lateral Sclerosis in Human Platelets.

Capillary electrophoresis immunoassay (CEI), also known as capillary western technology, is becoming a method of choice for screening disease relevant proteins and drugs in clinical trials. Reproducibility, sensitivity, small sample volume requirement, multiplexing antibodies for multiple protein labeling in the same sample, automated high-throughput ability to analyze up to 24 individual samples, and short time requirement make CEI advantageous over the classical western blot immunoassay. There are some limitations of this method, such as the inability to utilize a gradient gel (4%-20%) matrix, high background with unrefined biological samples, and commercial unavailability of individual reagents. This paper describes an efficient method for running CEI in a multiple assay setting, optimizing protein concentration and primary antibody titration in one assay plate, and providing user-friendly templates for sample preparation. Also described are methods for measuring pan TDP-43 and phosphorylated TDP-43 derivative in platelet lysate cytosol as part of the initiative in blood-based biomarker development for neurodegenerative diseases.

Investigation of the psychometric properties of the inclusion body myositis functional rating scale with rasch analysis.

INTRODUCTION: The Inclusion Body Myositis Functional Rating Scale (IBMRFS) is a 10-item clinician-rated ordinal scale developed for people with inclusion body myositis. METHODS: Single observations of the IBMFRS were collected from 132 patients. After Rasch analysis, modifications were made to the scale to optimize fit to the Rasch model while maintaining clinical validity and utility. RESULTS: The original IBMFRS did not fit the assumptions of the Rasch model because of multidimensionality of the scale. Items assessed local dependence, disordered step thresholds, and differential item functioning. Deconstructing the scale into upper limb (IBMFRS-UL) and lower limb (IBMFRS-LL) scales improved fit to the Rasch model. A 9-item scale with the swallowing item removed (IBMFRS-9) remained multidimensional but demonstrated the ability to discriminate patients along the severity continuum. IBMFRS-UL, IBMFRS-LL, and IBMFRS-9 scores were transformed to a 0-100 scale for comparability. DISCUSSION: This analysis has led to the development of 3 optimized versions of the IBMFRS. Muscle Nerve 60: 161-168, 2019.

Satisfactory Response With Achieving Maintenance Low-Dose Prednisone in Generalized Myasthenia Gravis.

OBJECTIVES: To estimate the satisfactory response rate (SR%) with achieving maintenance, low-dose prednisone in acetylcholine receptor antibody-positive generalized myasthenia gravis. METHODS: In this retrospective study, we estimate the SR% as defined by (remission/minimal manifestations status for at least 6 months using 7.5 mg or less of prednisone daily, for maintenance treatment at 2, 4, and 6 years after symptoms onset) for patients who were not taking steroid-sparing immunosuppressant (SSI) as a primary outcome and for patients taking an SSI as a secondary outcome. RESULTS: Forty-five patients were not taking an SSI at 2 years, 34 patients at 4 years, and 17 patients at 6 years; SR% was 44.4%, 64.7%, and 58.8%, respectively. Thirty-six patients were taking an SSI at 2 years, 22 patients at 4 years, and 15 patients at 6 years; the SR% was 50.0%, 45.4%, and 66.7%, respectively. CONCLUSIONS: Nearly half of the generalized myasthenia gravis patients who were not taking an SSI achieved an SR.

Less is More in Diabetic Neuropathy Diagnosis: Comparison of Quantitative Sudomotor Axon Reflex and Skin Biopsy.

OBJECTIVES: To compare the frequency of abnormalities in epidermal nerve fiber density (ENFD) and quantitative sudomotor axon reflex (QSART) in patients with diabetic distal symmetric polyneuropathy (DSPN). METHODS: Nerve conduction studies, ENFD, and QSART data were obtained pre- and postexercise, in patients enrolled in a prospective diabetic neuropathy study. McNemar's test was applied to compare the yield of ENFD and QSART. RESULTS: Eighteen patients (58 ± 4 years) were enrolled, with 36 data collection points. In diabetic DSPN and diabetic large fiber DSPN (DSPN-L), abnormal ENFD (77% and 100% respectively) is more frequent than abnormal QSART (39% and 35%, respectively) (P value = 0.001 in diabetic DSPN and P value = 0.0002 in diabetic DSPN-L), whereas in diabetic small fiber DSPN (DSPN-S), both tests have similar yields (47%). CONCLUSIONS: ENFD has a high diagnostic yield in diabetic DSPN and DSPN-L. Including QSART data adds little to the sensitivity of EFND in DSPN-S.

Defining SOD1 ALS natural history to guide therapeutic clinical trial design.

IMPORTANCE: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. OBJECTIVE: To establish an updated natural history of ALSSOD1. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. MAIN OUTCOMES AND MEASURES: Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. RESULTS: Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). CONCLUSIONS AND RELEVANCE: SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

Targeting protein homeostasis in sporadic inclusion body myositis.

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

OBJECTIVES: The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. METHODS: Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. RESULTS: Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. CONCLUSIONS: Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS.

Symptom Management and End-of-Life Care in Amyotrophic Lateral Sclerosis.

The number of available symptomatic treatments has markedly enhanced the care of patients with amyotrophic lateral sclerosis (ALS). Once thought to be untreatable, patients with ALS today clearly benefit from multidisciplinary care. The impact of such care on the disease course, including rate of progression and mortality, has surpassed the treatment effects commonly sought in clinical drug trials. Unfortunately, there are few randomized controlled trials of medications or interventions addressing symptom management. In this review, the authors provide the level of evidence, when available, for each intervention that is currently considered standard of care by consensus opinion.

Disease course and therapeutic approach in dermatomyositis: A four-center retrospective study of 100 patients.

Dermatomyositis is a life-altering inflammatory disorder of skin and muscle. Details regarding the natural course of this disorder, the effects of specific therapies on its progression, and the optimal therapeutic dosage and duration of prednisone are limited. We performed a retrospective medical record review of dermatomyositis patients at four medical centers. All patients were over the age of 21 and had a clinical diagnosis of dermatomyositis with pathological confirmation. We reviewed average muscle strength, corticosteroid use, creatine kinase levels, and supplemental immunosuppressant use during the 36-month period following each patient's initial assessment. One hundred patients participated with an average age of 50.1 years. Average muscle strength improved and prednisone requirements lessened six months after initial assessment. There was no difference in the mean change in muscle strength or cumulative corticosteroid use over 36 months among those initially treated with methotrexate, mycophenolate mofetil, pulse IVIG, or azathioprine. There was a 5% mortality rate in dermatomyositis patients due to infections. Treated dermatomyositis patients demonstrate the most significant improvement in strength during the first six-to-twelve months following their initial clinical assessment. Additional prospective studies are needed to determine the relative benefit of select immunosuppressant agents in preserving strength and reducing corticosteroid use in dermatomyositis.

A genome-wide association study of myasthenia gravis.

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Pompe disease: literature review and case series.

Pompe disease is a rare multi-systemic metabolic myopathy caused by autosomal recessive mutations in the acidic alpha glucosidase (GAA) gene. Significant progress had been made in the diagnosis and management of patients with Pompe disease. Here, we describe our experience with 12 patients with various forms of Pompe disease including 4 potentially pathogenic, novel GAA variants. We also review the recent the recent advances in the pathogenesis, diagnosis, and treatment of individuals with Pompe disease.

Leg amyotrophic diplegia: prevalence and pattern of weakness at US neuromuscular centers.

OBJECTIVE: To identify the frequency of leg amyotrophic diplegia (LAD) at a US academic center, describe the pattern of weakness, and provide comparative data from 8 additional major US academic institutions. BACKGROUND: LAD is a leg onset variant of progressive muscular atrophy (PMA). LAD weakness is confined to the legs for at least 2 years, and there are no upper motor neuron signs. DESIGN/METHODS: We present a retrospective chart review of 24 patients with the LAD presentation from the University of Kansas Medical Center ( n = 8 cases) and from 8 US academic institutions (n = 16 cases). RESULTS: Of the 318 subjects identified in the University of Kansas Medical Center Neuromuscular Research Database, 82% (260 subjects) had amyotrophic lateral sclerosis (ALS), 1.9% (6) had familial ALS, 6.6% (21) had primary lateral sclerosis, and 9.2% (29) had lower motor neuron (LMN) disease. Of these 29 cases, 16 had PMA, 5 had brachial amyotrophic diplegia, while 8 had LAD. The mean LAD age of onset was 58 years with a male/female ratio of 3/1. Onset was asymmetric in 7/8. We identified a pelviperoneal pattern of weakness (sparing of knee extension and/or ankle plantar flexion) in 4 cases and distal predominant weakness in 3 cases. All patients had electrodiagnostic findings consistent with motor neuron disease confined to the lower extremities. We present LAD disease duration and survival data from 8 major academic neuromuscular centers. At last follow-up, weakness progressed to involve the arms in 6/24 LAD cases and of these 6 cases, 2 patients died from progression to typical ALS. From onset of symptoms, mean survival in LAD is 87 months, with 92% of cases being alive. CONCLUSIONS/RELEVANCE: The natural history of LAD differs from typical forms of ALS and PMA. LAD is a slowly progressive disorder that accounts for a fourth of LMN disease cases. An asymmetric pelviperoneal pattern of weakness should heighten the suspicion for LAD.

Facial onset sensorimotor neuronopathy syndrome: a case series.

OBJECTIVE: Facial onset sensorimotor neuronopathy (FOSMN) is a recently described neurological syndrome characterized by slow onset of facial sensory abnormalities and subsequent development of motor deficits. Except for 1 patient, FOSMN has so far been identified only in men. METHODS: We describe a case series of 3 women with FOSMN. We report their clinical, laboratory, and neurophysiological findings. RESULTS: The age of onset ranged from 39 to 72 years (mean, 60 years) with presentation 4-7 years after symptom onset. The first symptom was slowly progressive facial numbness, which was followed years later by dysphagia and impaired corneal reflexes. Dysarthria occurred in 2 patients, and mild arm weakness was noted in 2. Muscle stretch reflexes were increased in 1 patient, and in another case, arm sensation was reduced. Laboratory studies were unremarkable, and magnetic resonance imaging of the brain in 3 patients and of the cervical spine in 2 patients was normal. Nerve conduction studies showed reduced leg compound muscle action potential amplitudes in 1 patient and asymmetrically reduced arm sensory nerve action potentials in another case. In 2 patients, electromyography showed widespread active denervation in arm muscles in conjunction with the involvement of leg muscles in 1 case and the tongue in the other patient. We identified chronic neurogenic motor unit action potentials in the genioglossus muscle of all 3 cases while facial EMG performed in case 3 showed similar findings. Blink reflexes were abnormal in all patients. We treated 1 patient with high-dose intravenous methylprednisolone followed by intravenous immunoglobulin without any improvement, and she required percutaneous endoscopic gastrostomy (PEG) tube placement. CONCLUSIONS: This is the first case series describing 3 women with the FOSMN syndrome. We expand phenotype of FOSMN to include upper motor neuron signs and normal arm sensory nerve action potentials.

Retrospective chart review of duloxetine and pregabalin in the treatment of painful neuropathy.

The primary aims of our study were to compare pregabalin and duloxetine in a neuromuscular clinic for diabetic neuropathic pain (DPN) and to study the effect of these medications in cryptogenic sensory polyneuropathy. We performed a retrospective chart review of 143 patients who were started on pregabalin or duloxetine during a 10-month period in a tertiary neuromuscular outpatient center for neuropathic pain. Duloxetine and pregabalin were started in 103 and 91 patients, respectively. Ninety-two patients tried only one of the two medications while both medications were used at different time periods in 51 patients. Follow-up was available for 87 patients on pregabalin and 89 patients on duloxetine. More patients with neuropathic pain reported an improvement with pregabalin (33%) than duloxetine (21%). Duloxetine (38%) had a higher frequency of side effects compared to pregabalin (30%). However, these differences between pregabalin and duloxetine were not statistically significant. Despite the study's limitations of retrospective design, these findings suggest that both pregabalin and duloxetine are probably effective for neuropathic pain, secondary to diabetes or cryptogenic sensory peripheral neuropathy in a tertiary care academic neuromuscular center. Prospective randomized controlled comparative effectiveness studies are required for both drugs in the treatment of neuropathic pain.

Ocular myasthenia gravis in an academic neuro-ophthalmology clinic: clinical features and therapeutic response.

OBJECTIVE: The frequency of ocular myasthenia gravis (OMG) in patients referred to an academic neuro-ophthalmology clinic for suspected myasthenia gravis is not known. Our objective was to determine the frequency of ocular OMG in patients referred to an academic neuro-ophthalmologist and determine alternate diagnoses and response to therapy. METHODS: We performed a retrospective chart review of patients presenting to the University of Kansas Neuro-Ophthalmology Clinic with suspected OMG over 9 years. We defined OMG as isolated ptosis/diplopia at initial presentation supported by at least one of the following abnormal tests: edrophonium test, ice test, Cogan lid twitch, fatigability on sustained upgaze, acetylcholine receptor binding antibody, greater than 10% decrement on repetitive stimulation, or abnormal single-fiber jitter. We also determined the cause of ptosis/diplopia if it was not the result of OMG. Patients who progressed from OMG to generalized disease were termed transformed myasthenia gravis (TMG). RESULTS: One hundred thirty-eight patients were referred with mean age at presentation 58 ± 19 years. Myasthenia gravis was diagnosed in 101 patients; 95 had OMG; six had generalized MG. Diagnosis in the other 37 was cranial nerve palsies (nine), levator dehiscence (five), multiple sclerosis (two), blepharospasm (two), decompensated phorias (three), accommodation spasm (four), exophoria (three), skew deviation (two), Graves disease (one), hypertropia (one), myopathy (one), neurosarcoidosis (one), progressive supranuclear palsy (one), Miller Fisher variant of Guillain-Barre syndrome (one), and obstructive sleep apnea (one). Mean follow-up was 3.0 ± 2.8 years. Test sensitivity/specificity in OMG was fatigability on sustained upgaze 0.80/0.63; ice pack 0.80/0.25; Cogan lid twitch 0.59/1.00; edrophonium 0.88/0.50; acetylcholine receptor binding antibody 0.38/1.00; repetitive nerve stimulation 0.24/1.00; and single-fiber electromyography 0.90/1.00. Pyridostigmine was used without prednisone in 59 of 97 patients with OMG and 12 of 59 developed TMG. Prednisone was used in 38 patients; 21 of 38 (55%) met Myasthenia Gravis Foundation of America improvement status and none had TMG. CONCLUSION: The diagnosis of myasthenia gravis was confirmed in the majority of patients referred to our academic neuro-ophthalmology clinic, but 27% did not have myasthenia gravis. It is possible that prednisone treatment of OMG may prevent progression to TMG, but further study is required.

Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience.

We performed a retrospective chart review on 53 muscle-specific kinase antibody (MuSK-Ab)-positive myasthenia gravis (MG) patients at nine university-based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9-79 years. Twenty-seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long-term (> or =3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG-related death. This survey reinforces several cardinal features of MuSK-Ab-positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long-term outcome is favorable in about 60% of cases.

Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients.

Twenty ALS patients with sialorrhea refractory to medical therapy were enrolled in this double-blind, randomized study to receive either 2,500 U of botulinum toxin type B (BTxb) or placebo into the bilateral parotid and submandibular glands using electromyographic guidance. Patients who received BTxb reported a global impression of improvement of 82% at 2 weeks compared to 38% of those who received placebo (P < 0.05). This significant effect was sustained at 4 weeks. At 12 weeks, 50% of patients who received BTxb continued to report improvement compared to 14% of those who received placebo. There were no significant adverse events, including dysphagia, in the BTxb group, and there was no significant increase in the rate of decline of vital capacity.

Whole-genome analysis of sporadic amyotrophic lateral sclerosis.

BACKGROUND: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. METHODS: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. RESULTS: We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS. CONCLUSIONS: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.