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Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder due to a (CCTG)n repeat expansion in intron 1 of the CNBP gene. In this article, we report the clinicopathologic findings in 50 patients seen at a single site over a 27 year period. DM2 was the fifth most common type of muscular dystrophy seen at our center with a 5-fold lower frequency as compared to DM1. Age of symptom onset ranged from 15 to 72 years, and the mean duration between symptom onset and diagnosis was 7.4 years. Weakness referable to the proximal lower extremities was the presenting symptom in 62% of patients. The degree of generalized weakness varied from severe in 30% to no weakness in 20% of patients. Clinical myotonia was noted in 18% and myotonic discharges on electromyography in 97% of patients. Pain symptoms were uncommon in our cohort. A significant correlation was noted between limb weakness and degree of muscle pathologic changes. There was no correlation between CCTG repeat size and other clinicopathologic findings. Six patients (12%) had cardiac abnormalities including one who developed progressive nonischemic dilated cardiomyopathy ultimately leading to cardiac transplantation. In 21 patients followed for 2 or more years, we noted a mean rate of decline in total Medical Research Council score of about 1% per year.

Laing distal myopathy (LDM) is an autosomal dominant disorder caused by mutations in the slow skeletal muscle fiber myosin heavy chain (MYH7) gene on chromosome 14q11.2. The classic LDM phenotype-including early-onset, initial involvement of foot dorsiflexors and great toe extensors, followed by weakness of neck flexors and finger extensors-is well documented. Since the original report by Laing et al in 1995, the spectrum of MYH7-related myopathies has expanded to include congenital myopathies, late-onset myopathies, myosin storage myopathy, and scapuloperoneal myopathies. Most patients with LDM harbor mutations in the midrod domain of the MYH7 gene, but rare cases document disease-associated mutations in the globular head region. In this report, we add to the medical literature by describing the clinicopathological findings in 8 affected family members from 4 new LDM families-including 2 with novel MYH7 mutations (Y162D and A1438P), one with dual mutations (V39M and K1617del), and one family (E1508del) with severe early-onset weakness associated with contractures, respiratory insufficiency, and dilated cardiomyopathy. Our families highlight the ever-expanding clinical spectrum and genetic variation of the skeletal myopathies related to MYH7 gene mutations.

Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

The distal myopathies are a rare and heterogeneous group of neuromuscular disorders. Patients present with weakness of the hands, distal lower extremities, or both. Age of onset varies from early childhood to late adulthood. Most of the disorders causing distal myopathic weakness are genetically based. The list of genetic disorders associated with distal-onset weakness is ever-expanding and complicated by pronounced genetic heterogeneity, phenotypic variability, and complex multisystem involvement. There are no known effective disease-modifying treatments for the distal myopathies. Evaluation, symptomatic management, and periodic monitoring of patients in a multidisciplinary neuromuscular center are the mainstays of care.

Sporadic inclusion body myositis (IBM) is the most common acquired myopathy affecting patients over age 50. The discovery of an autoantibody directed against a 43–44 kD protein (anti-cytosolic-5′-nucleotidase 1A or anti-cN1A) has provided support for the hypothesis of an immune-mediated pathogenesis. Previous studies have reported variable test sensitivity and specificity, and inconsistent results on the predictive value. In our cohort of 40 patients with clinico-pathologically or clinically defined IBM, we found the sensitivity of the anti-cN1A antibody test to be 50%. Comparing characteristics for test positive and test negative groups, we found that patients in our cohort testing positive for the anti-cN1A antibody were significantly more likely to be older than age 60 years at symptom onset. We found no positive association between anti-cN1A reactivity and other clinical, laboratory, and muscle histopathologic findings. Based on all clinical studies published to date including the present, the anti-cN1A antibody test shows high diagnostic specificity, moderate sensitivity, and a low predictive value in regards to age of onset, disease severity and other associated clinicopathological findings.

Introduction: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. Methods: We describe a rapidly progressive myopathy in a previously healthy 33-year-old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. Results: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. Conclusions: This report illustrates a late-onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy. Muscle Nerve 52: 289–293, 2015

We report the case of a 58-year-old woman with a progressive and seemingly sporadic myopathy who, later through whole exome sequencing, was diagnosed as a manifesting carrier of a myotubularin 1 gene mutation (c.342_342 + 4delAGTAA). As the case was a diagnostic challenge for 7 years, we thought it would be helpful to report the patient and review the other 25 cases thus far described. The manifesting carrier state is a rare cause for myopathic weakness in a female but should be strongly considered in kindreds with known affected males with myotubularin 1 gene mutations, and families with history of gestational polyhydramnios or male infantile death. Although the clinical phenotype is quite variable, the findings of ptosis, ophthalmoparesis, facial weakness, and asymmetrical limb involvement should raise the suspicion of the manifesting carrier state. Necklace fibers appear to be a highly sensitive and specific pathologic finding in such cases.

Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD), and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L-CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 - 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype-phenotype correlations.

Importance New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene. Objective To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing. Design, Setting, and Participants Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions. Main Outcomes and Measures Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7). Results Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1 . The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals. Conclusions and Relevance This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.

The objectives of this study were to characterize the clinical features of facioscapulohumeral muscular dystrophy (FSHD) in patients with borderline (/=35 kb) EcoRI fragments and to compare patients with borderline EcoRI fragments with FSHD patients harboring fragments of35 kb.: Most patients with FSHD harbor 4q35 EcoRI fragments of less than 35 kb. The clinical findings in patients with borderline fragments are not well known.: The authors conducted a retrospective review of patients with FSHD followed at a regional neuromuscular center over a 12-year period.: Eleven patients with DNA-positive FSHD, found to harbor borderline (/=35 kb) EcoRI fragments (group 1), were compared with 30 patients with fragments of35 kb (group 2). Group 1 patients were less likely (18%) to present with the classic FSHD phenotype as compared with group 2 patients (63%). Statistically significant differences in clinical disease severity and manual muscle testing scores were noted between the 2 groups, with group 1 patients showing less severe weakness and disability at presentation.: Patients with borderline fragments are more likely to have a partial or less severe form of FSHD, probably resulting from a less disruptive DNA alteration at the 4q35 locus.

We report a family with markedly variable myopathic weakness due to facioscapulohumeral muscular dystrophy (FSHD). The proband developed mild late-onset proximal limb weakness. Her two daughters had severe infantile facial diplegia, initially diagnosed as Möbius syndrome, and mild childhood-onset limb weakness and scapular winging. Results of facial muscle electromyography and muscle histopathology supported a myopathic disorder. This case study further highlights the broad clinical spectrum and intrafamily variability in FSHD, and the occasional absence of a positive correlation between fragment size and disease onset. Moreover, this study underscores the importance of considering FSHD in cases of infantile facial diplegia, especially in patients not demonstrating the full clinical features of Möbius syndrome. In difficult cases, facial muscle electromyography may help to differentiate myopathic from neuropathic weakness, and help guide further diagnostic studies.

This is the report a case of diabetic muscle infarction (DMI) associated with multiple recurrences and a review of the literature on DMI from the first description in 1965 to the present. Specifically the review of the clinical, laboratory, and muscle histopathologic features of 86 reported cases of DMI.Patients with DMI usually present with acute or subacute focal lower extremity muscle pain or swelling. Elevations in the white blood cell count and erythrocyte sedimentation rate are common laboratory findings. Magnetic resonance imaging, a highly sensitive diagnostic test in DMI, shows increased T2-weighted signal and edema in affected muscles. Typical muscle histopathology includes muscle fiber necrosis and endomysial inflammation. Slow symptomatic improvement usually occurs over a period of 1 to 6 months. Conservative therapy and analgesics seem appropriate for most patients. Although self-limiting, DMI is often associated with recurrent muscle infarctions and multisystem diabetes-related complications. Diabetes-induced arteriosclerosis and microangiopathy are the suggested causes of DMI.It is concluded that DMI is an uncommon but probably underrecognized disorder causing focal muscle pain and swelling, usually of thigh or calf muscles, in patients with diabetes mellitus complicated by poorly controlled hyperglycemia and multiorgan complications.

Myotonia is a condition characterized by impaired relaxation of muscle following sudden forceful contraction. We systematically screened all 23 exons of the CLCN1 gene in 88 unrelated patients with myotonia and identified mutations in 14 patients. Six novel mutations were discovered: five were missense (S132C, L283F, T310M, F428S and T550M) found in heterozygous patients, and one was a nonsense mutation (E193X) in a homozygous patient. While five patients had a clinical diagnosis of myotonia congenita, the patient with the F428S mutation exhibited symptoms characteristic of paramyotonia congenita--a condition usually thought to be caused by mutations in the sodium channel gene SCN4A. Nevertheless, no mutations in SCN4A were identified in this patient. The functional consequences of the novel CLCN1 sequence variants were explored by recording chloride currents from human embryonic kidney cells transiently expressing homo- or heterodimeric mutant channels. The five tested mutations caused distinct functional alterations of the homodimeric human muscle chloride ion channel hClC-1. S132C and T550M conferred novel hyperpolarization-induced gating steps, L283F and T310M caused a shift of the activation curve to more positive potentials and F428S reduced the expression level of hClC-1 channels. All showed a dominant-negative effect. For S132C, L283F, T310M and T550M, heterodimeric channels consisting of one wild-type (WT) and one mutant subunit exhibited a shifted activation curve at low intracellular [Cl(-)]. WT-F428S channels displayed properties similar to WT hClC-1, but expressed at significantly lower levels. The novel mutations exhibit a broad variety of functional defects that, by distinct mechanisms, cause a significant reduction of the resting chloride conductance in muscle of heterozygous patients. Our results provide novel insights into functional alterations and clinical symptoms caused by mutations in CLCN1.

Multifocal motor neuropathy (MMN) is a chronic, immune-mediate, peripheral myelinopathy. Inherent in its name, MMN implies involvement of two or more motor nerves. We report three patients with weakness and partial motor conduction block restricted to a single nerve and localized to sites that are not at risk for entrapment or compression injury. None of the patients had sensory involvement and all showed a favorable response to intravenous immunoglobulin therapy. Based on these observations and reports of three additional patients, we believe that monofocal motor neuropathy is a partial form of MMN and should be treated as such.

The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells.We describe a rapidly progressive myopathy in a previously healthy 33-year-old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death.Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene.This report illustrates a late-onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy.

Facioscapulohumeral dystrophy (FSHD) is a dominantly inherited myopathy usually associated with a deletion at locus 4q35. Typically, FSHD patients present with a recognizable constellation of signs including weakness of facial, shoulder and pelvic girdle, humeral, and anterior foreleg muscles; preservation of some muscles including the deltoids; and other characteristic features including prominent scapular winging, anterior axillary folds, and horizontally positioned clavicles. We performed clinical and FSHD genetic studies on four patients with atypical clinical features who were cared for at a regional neuromuscular center. The four patients, each harboring 4q35 deletions, presented with atypical phenotypes including facial-sparing scapular myopathy, limb-girdle muscular dystrophy, distal myopathy, and asymmetric brachial weakness. This report demonstrates the expanding clinical heterogeneity in patients harboring the 4q35 deletion.

Background: Autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD-AD) is a disorder characterized clinically by humeropelvic weakness, contractures, and cardiomyopathy, and genetically by mutations in the lamin A/C gene on 1q21.2-q21.3. Of the 14 lamin A/C gene mutations reported thus far, the four involving the rod domain have been associated with isolated cardiomyopathy and conduction-system disease. This is the first report of rod domain mutations in patients with the full EDMD-AD phenotype.Methods: Clinical, pathologic, and genetic data are provided on two families with EDMD-AD.Results: In both families, the full clinical spectrum of EDMD-AD was demonstrated. For the proband in family 1, sequence analysis detected a mutation within exon 2 of the lamin A/C gene. The missense mutation was due to a A448C base substitution causing a Thr150Pro amino acid change. For the proband of family 2, sequence analysis detected an in-frame 3-bp deletion (AAG 778-780 or 781-783) removing one of two adjacent lysine residues (K 260 or 261) of exon 4. Both mutations were in the central rod domain of the lamin A/C gene.Conclusions: Mutations in the rod domain of the lamin A/C gene may cause the full clinical spectrum of EDMD-AD.

Vitamin D deficiency and osteomalacia are frequently associated with muscle weakness and atrophy. We present a 78-year-old man with complaints of progressive painless weakness who was referred to us with a diagnosis of suspected motor neuron disease. Results of the neurological examination were remarkable, showing diffuse limb weakness and atrophy, rare fasciculations, normal sensory examination, no bulbar weakness, and no upper motor neuron signs. Electromyography revealed mild chronic changes, denervation and re-innervation, without fibrillations or positive waves. Serum laboratory studies showed an elevated serum parathyroid hormone and markedly reduced vitamin D level. Although the etiology of the vitamin D deficiency was not determined, the patient made a substantial clinical improvement following vitamin D therapy. Vitamin D deficiency and secondary hyperparathyroidism need to be included in the differential diagnosis of patients presenting with a progressive lower motor neuron disease.

The clinical and neurophysiologic findings of two children presenting with focal weakness and atrophy in unusual nerve distributions and no apparent antecedent injuries are reported. Patient 1 presented with a droopy left shoulder that was initially attributed to scoliosis. Patient 2 presented with right biceps brachii atrophy that was first brought to his parent's attention during a routine physical examination. In addition to documenting focal spinal accessory and musculocutaneous mononeuropathies as the cause of weakness in Patients 1 and 2, respectively, nerve conduction studies also revealed evidence of superimposed diffuse demyelinating polyneuropathy in both children. The latter findings suggested the diagnosis of hereditary neuropathy with liability to pressure palsies and led to definitive DNA diagnoses.

We performed C8 nerve root stimulation in addition to other electromyographic (EMG) studies in a surgically proven case of classic thoracic outlet syndrome (TOS). The patient was a 19-year-old woman with a 2-year history of right hand cramps and progressive weakness and atrophy of hand muscles, especially the thenar eminence. Routine EMG studies showed evidence for an axon-loss lower trunk brachial plexopathy. Stimulation studies of the C8 nerve roots demonstrated proximal conduction block on the affected side only. The diagnosis was further supported by cervical spine radiographs, which demonstrated a cervical rib, and surgical exploration of the brachial plexus, which demonstrated upward compression and stretching of the lower trunk by a fascial band extending from the anomalous cervical rib to the first thoracic rib. The patient noted a modest improvement in hand function postoperatively. Root stimulation studies can help in the diagnosis of classic TOS by providing more precise localization and information regarding the degree, if any, of proximal motor conduction block.

Summary Congenital end-plate acetylcholinesterase (AChE) deficiency (CEAD), the cause of a disabling myasthenic syndrome, arises from defects in the COLQ gene, which encodes the AChE triple-helical collagenlike-tail subunit that anchors catalytic subunits of AChE to the synaptic basal lamina. Here we describe a patient with CEAD with a nonsense mutation (R315X) and a splice-donor–site mutation at position +3 of intron 16 (IVS16+3A→G) of COLQ . Because both A and G are consensus nucleotides at the +3 position of splice-donor sites, we constructed a minigene that spans exons 15–17 and harbors IVS16+3A→G for expression in COS cells. We found that the mutation causes skipping of exon 16. The mutant splice-donor site of intron 16 harbors five discordant nucleotides (at −3, −2, +3, +4, and +6) that do not base-pair with U1 small-nuclear RNA (snRNA), the molecule responsible for splice-donor–site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restore normal splicing. Analysis of 1,801 native splice-donor sites reveals that presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A→G mutations indicates that, on average, two of three nucleotides at positions +4 to +6 fail to base-pair, and that the nucleotide at +4 never base-pairs, with U1 snRNA. We conclude that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis -acting elements may also be important in assuring the fidelity of splicing.

The motor unit number estimate (MUNE), motor unit size, and conduction velocity (CV) of thenar surface-recorded motor unit action potentials (S-MUAPs) as collected by the automated F-wave technique were analyzed in 13 patients with amyotrophic lateral sclerosis (ALS) (aged 29-78 years, mean: 61) and 10 age-matched normal subjects (aged 49-81 years, mean: 64). Totals of 96 and 100 thenar S-MUAPs were collected from ALS patients and normal subjects, respectively. There were significant differences (P < 0.001) in the mean estimated numbers and sizes of motor units between the ALS patients (MUNE: 41.9, S-MUAP size: 699.6 microV/ms) and normal subjects (MUNE: 151.2, S-MUAP size: 244.1 microV/ms). The mean S-MUAP CV was 46.3 m/s (range: 32-59) for ALS patients and 56.5 m/s (range: 43-69) for normal subjects (P < 0.001). Mean median motor nerve CVs, measured in the forearm segment, were not significantly different (P = 0.79) between ALS patients (53.4 m/s) and normal subjects (52.9 m/s), however. Thenar motor unit CVs are significantly reduced in ALS patients as compared to normal controls, and this may be due to proximal motor nerve slowing.

We wish to report a case of CIDP in association with seminoma. A 43-year-old man without significant past medical history developed bilateral lower extremity more than upper extremity weakness about 6 months before presentation. Examination was significant for severe weakness (Medical Research Council, MRC, grade 0–1) of the foot and toe extensors and flexors, moderate weakness of the intrinsic hand muscles (MRC grade 3), mild weakness of proximal lower extremity muscles (MRC grade 4–5) and a steppage gait. Reflexes were hypoactive to absent, and perception of vibration and position sensations were reduced in the distal lower extremities. Laboratory testing included negative tests for HIV-1 and Borrelia burgdorferi infections, absence of monoclonal gammopathy on immunoelectrophoresis, negative antimyelin-associated glycoprotein antibody, and a cerebrospinal fluid (CSF) protein of 267 mg/dl (normal range 15– 45) with no cells and negative VDRL. Nerve conduction studies are shown in figure 1a. The electromyographic (EMG) needle examination showed scant fibrillations and positive sharp waves and diffusely reduced motor unit action potential recruitment in all muscles exam

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.

The following data were obtained on 21 amyotrophic lateral sclerosis (ALS) patients, aged 36-76 years (mean: 58 years), at baseline and months 4, 8, and 12: thenar motor unit number estimate (MUNE) using multiple point stimulation, mean thenar surface-recorded motor unit action potential negative-peak area, thenar compound muscle action potential amplitude, isometric hand grip strength, total Medical Research Council (MRC) manual muscle testing score, Appel ALS rating scale, and forced vital capacity (FVC). The absolute mean rate of change per month was significantly greater (P < 0.01) for MUNE values than for MRC and FVC values in the 21 ALS patients. In a subset of patients (n = 6) with slowly progressive disease, the absolute mean rate of change per month was significantly greater (P < 0.01) for MUNE values than for all other test values. In addition, MUNE values were the most sensitive index for documenting changes in disease progression over time.

Alpha-glucosidase deficiency is a rare cause of muscle disease in adults. The diagnosis relies on recognition of the salient clinical features and determination of significantly reduced alpha-glucosidase (GAA) activity. Lymphocytes are the usual tissue for diagnostic enzymology; discrepant results from analyses of different tissues are unusual. We report a patient with clinical, electromyographic, and biopsy findings indicative of alpha-glucosidase deficiency whose muscle and lymphocyte enzyme results were markedly discrepant on multiple analyses. As a result, we conclude that all patients with suspected alpha-glucosidase deficiency and a normal lymphocyte GAA assay should also have a determination of GAA activity in muscle or skin fibroblasts.

Acid maltase deficiency (AMD) is a rare cause of muscle disease in adult patients. The present report of 2 sibs and review of 36 previously reported cases illustrates the vast clinical variability in adult-onset AMD. This is 1 of only 3 reports to document tongue weakness and enlargement in an adult with AMD. The presenting signs and symptoms usually include progressive limb weakness, restrictive lung disease, or both. Consistent supportive abnormalities include a modest elevation in serum CK, a reduction in the forced vital capacity, and abnormal spontaneous activity (that is, myotonic discharges or fibrillations) in resting muscles during needle electromyography. The clinical spectrum is also extended to include distal limb weakness, scapular winging, asymmetric muscle weakness, and tongue involvement.

Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The presence of antibody-secreting plasma cells in IBM muscle implicates the humoral immune response in this disease. However, whether the humoral immune response actively contributes to IBM pathology has not been established. We sought to investigate whether the humoral immune response in IBM both in the periphery and at the site of tissue damage was directed towards self-antigens. Peripheral autoantibodies present in IBM serum but not control serum recognized self-antigens in both muscle tissue and human-derived cell lines. To study the humoral immune response at the site of tissue damage in IBM patients, we isolated single plasma cells directly from IBM-derived muscle tissue sections and from these cells, reconstructed a series of recombinant immunoglobulins (rIgG). These rIgG, each representing a single muscle-associated plasma cell, were examined for reactivity to self-antigens. Both, flow cytometry and immunoblotting revealed that these rIgG recognized antigens expressed by cell lines and in muscle tissue homogenates. Using a mass spectrometry-based approach, Desmin, a major intermediate filament protein, expressed abundantly in muscle tissue, was identified as the target of one IBM muscle-derived rIgG. Collectively, these data support the view that IBM includes a humoral immune response in both the periphery and at the site of tissue damage that is directed towards self-antigens.

Autosomal recessive hereditary inclusion body myopathy (HIBM or IBM2) is a progressive adult onset muscle wasting disorder characterized by sparing of the quadriceps. IBM2 is also known as distal myopathy with rimmed vacuoles or nonaka myopathy. IBM2 is associated with mutations in the UDP-GlcNAc 2-Epimerase/ManNAc Kinase gene (GNE). GNE is the rate-limiting enzyme of N-Acetylneuraminate (Neu5Ac, Sialic acid) biosynthesis. The GNE coding region of 64 symptomatic patients were sequenced. Twenty-eight patients were found to bear GNE mutations. Ten novel mutations were identified among nine patients, including four nonsense (p.R8X, p.W204X, p.Q436X, and p.S615X) and five missense (p.R71W, p.I142T, p.I298T, p.L556S, and p.E2G) variations spanning both the epimerase and kinase domains of GNE. Additionally, a synonymous variation (p.Y591Y, codon tactat) was seen in a patient bearing compound heterozygous nonsynonymous mutations (p.S615X and p.Y675H). Six of the nine are Caucasian, one patient is Taiwanese, one patient is Asian Indian, and one patient is of European descent. These findings further expand the clinical and genetic spectrum of IBM2.

A 12-year-old male developed progressive proximal upper extremity weakness over a 3- to 4-year period. The clinical findings of proximal upper extremity weakness and atrophy, prominent scapular winging, and no sensory deficits or upper motor neuron signs suggested a neuromuscular disorder. Electromyography was consistent with a chronic denervating disorder involving the upper cervical anterior horn cells or their axons. A cervical magnetic resonance image revealed a large intramedullary mass extending from the inferior aspect of the fourth ventricle down to the level of T2. A biopsy of the lesion was consistent with a low-grade astrocytoma.

In order to further characterize and provide a possible mechanism for the asymmetrical involvement of forearm muscles in inclusion body myositis (IBM), we measured isometric hand and pinch grip strength, and forearm muscle girth on 15 IBM patients. Forearm muscle strength and girth were significantly greater on the dominant versus nondominant side: mean grip strength, 173.9 vs. 98.8 N; mean pinch strength, 47.6 vs. 29.7 N; and mean forearm girth, 22.5 vs. 19.9 cm. This observation may suggest a role for exercise in delaying the disease progression in IBM.

The centronuclear myopathies are a clinically and genetically heterogeneous group of disorders which share similar histological features on muscle biopsy. The familial cases have been classified genetically as X-linked or autosomal in inheritance. The autosomal forms usually have a later onset and milder course as compared to the X-linked form. Thirteen families with autosomal dominant centronuclear myopathy have been previously described. We describe an additional family with unique clinical features which initially suggested a facioscapulohumeral syndrome.

We report two children with transient myasthenia gravis preceded by viral illnesses. The first is a 5-year-old boy who developed oculobulbar weakness 2 weeks following a varicella-zoster infection. The second is a 4-year-old boy who developed facial diplegia and dysarthria several weeks following a viral pharyngitis. Myasthenia gravis was diagnosed based on the substantial decremental changes on 3 Hz repetitive motor nerve stimulation studies for the first child and on the positive edrophonium test and complete improvement in symptoms during pyridostigmine therapy for both children. In both cases, the symptoms gradually resolved and have not recurred following discontinuation of pyridostigmine. Molecular mimicry between the acetylcholine receptor and viral proteins might provide the nidus for the immune response in this variant of myasthenia gravis. ( J Child Neurol 2005;20:441—444.)

Two double-blind, placebo-controlled therapeutic trials using recombinant human insulin-like growth factor-I (rhIGF-I) were conducted in patients with mild-to-moderate ALS. This presentation will focus on the results of the first trial conducted at eight centers in North America. IGF-I is a naturally occurring single-chain polypeptide consisting of 70 amino acids. It is expressed by a number of tissues including muscle and CNS structures. Receptors for IGF-I are found throughout the body, including spinal motor neurons, muscle, and brain. Administration of rhIGF-I induces sprouting of peripheral nerves, enhances neuronal regeneration in animal models of axotomy or nerve injury, and enhances survival of spinal cord motor neurons in a variety of experimental systems of motor neuron death. These properties of rhIGF-I provided the rationale for the clinical trials in ALS. This study was designed to assess the effects of rhIGF-I in patients with mild-to-moderate ALS under the hypothesis that rhIGF-I would slow the rate of disease progression and disability compared with patients treated with placebo. The Appel ALS (AALS) rating scale [1] was selected as the primary outcome measure because it is an accurate index of disease severity, is reproducible, easy to administer, and uses traditional methods of assessment that have gained clinical acceptance (e.g., forced vital capacity [FVC], Medical Research Council [MRC] graded manual muscle testing, and timed activities such as walking specific distances). The AALS score is needed because none of the traditional methods accurately reflects the total activity of the disease because of the variable degree of affection of bulbar function, breathing, and limb strength or function. The AALS score is the sum of five component scores as follows: bulbar function, respiratory function, muscle strength, and muscle function of arm and leg. The five component scores are summed to obtain an AALS score. An AALS score for a patient without …

A Martin-Gruber anastomosis (MGA) commonly results in an abnormal decline in amplitude across the forearm segment when ulnar motor nerve conduction studies are performed. A recent report described a proximal MGA resembling partial conduction block in a patient with ulnar neuropathy at the elbow (UNE). As a result, we screened patients with similar findings. We detected a proximal MGA in three patients over a period of 2 years, which suggests that this may be an under-recognized anomaly. We conclude that a proximal MGA must be excluded in all cases of UNE showing apparent partial conduction block across the elbow segment.

Hereditary Inclusion Body Myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult onset and a typical muscle pathology. We have recently identified the gene encoding for a bifunctional enzyme, UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE), as the mutated gene in the prototype form of the disease presenting quadriceps sparing, particularly common in Middle Eastern Jews. Interestingly, we have identified the homozygous M712T Middle Eastern Jewish mutation also in two unrelated Middle Eastern Moslem families. We have also evaluated the involvement of GNE in several families from worldwide non-Jewish ethnic origins presenting symptoms similar to the Middle Eastern HIBM prototype. A total of 14 GNE mutations were identified (one nonsense and 13 missense), of which six are novel: an homozygous missense mutation in a consanguineous family from Italy and in a non consanguineous family from USA, and distinct compound heterozygotes in families from Germany, Italy, Ireland, Bahamas, USA and East India. This study brings to 17 the number of reported GNE mutations in quadriceps sparing myopathy, occurring either in the epimerase or the kinase domain of the enzyme. The mechanism leading to this unique phenotype still remains to be elucidated.

Acute conduction block injuries often result from nerve compression or trauma. The temporal pattern of clinical, electrophysiologic, and histopathologic changes following these injuries has been extensively studied in experimental animal models but not in humans. Our recent evaluation of a young man with an injury to the deep motor branch of the ulnar nerve following nerve compression from weightlifting exercises provided the opportunity to follow the course and recovery of a severe conduction block injury with sequential nerve conduction studies. The conduction block slowly and completely resolved, as did the clinical deficit, over a 14-week period. The reduction in conduction block occurred at a linear rate of -6.1% per week.

Background: Inclusion body myositis (IBM) remains without effective therapy. As anabolic steroids have myotrophic properties, the authors studied whether a synthetic androgen, oxandrolone, would have efficacy in IBM. Methods: A double-blind, placebo-controlled, crossover design was used. Patients received oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout period, followed by 12 weeks of the alternative treatment. Maximal voluntary isometric contraction testing (MVICT), manual muscle testing (MMT), and functional performance testing were obtained before and after each treatment period, with the whole-body MVICT score as the primary outcome measure. Results: Of 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had complete data for at least the first treatment period, with 13 completing the entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and 4.1 kg with placebo ( p = 0.06), whereas MMT demonstrated a median increase of 2.0 Medical Research Council points with drug and 0.9 point with placebo ( p = 0.33). Upper-extremity MVICT demonstrated a significant treatment effect, with strength increasing a median 6.3 kg with drug vs 2.5 kg with placebo ( p = 0.006). Stair climbing also increased a median of 1 step on average with drug versus no change with placebo ( p Conclusions: Oxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

Article abstract A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.