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To characterize the cardiorespiratory abnormalities in patients with necrotizing autoimmune myopathy (NAM).

Alzheimer's disease (AD) is the most common neurodegenerative disease as well as the leading cause of dementia (1,2). Identification of disease-causing mutations in the amyloid precursor protein, presenilin 1, and [...]

Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders characterized by muscle weakness, elevated creatine kinase levels, and myopathic electromyographic findings. Most IMMs feature the presence of inflammatory infiltrates in muscle. However, the inflammatory exudate may be absent. Indeed, necrotizing autoimmune myopathy (NAM), also called immune-mediated necrotizing myopathy, is characterized by a necrotizing pathologic process with no or minimal inflammation in muscle. The recent discovery of antibodies associated with specific subtypes of autoimmune myopathies has played a major role in characterizing these diseases. Although diagnostic criteria and classification of IMMs currently are under revision, on the basis of the clinical and muscle histopathologic findings, IMMs can be differentiated as NAM, inclusion body myositis (IBM), dermatomyositis, polymyositis, and nonspecific myositis. Because of recent developments in the field of NAM and IBM and the controversies around polymyositis, this review will focus on NAM, IBM, and dermatomyositis.

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IMPORTANCE: Necrotizing autoimmune myopathy (NAM) is characterized pathologically by necrotic muscle fibers with absent or minimal inflammation. It is often accompanied by statin therapy, connective tissue diseases, cancer, and autoantibodies specific for signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). Data are limited concerning differences among etiologic subgroups and treatment outcomes in NAM. OBJECTIVES: To describe the clinical, serologic, and electrophysiologic characteristics of NAM, compare patient subgroups, and determine clinical outcome predictors. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of medical records for 63 adult Mayo Clinic patients assigned the clinical and histopathologic diagnosis of NAM from January 1, 2004, through December 31, 2013. Patients were stratified by presumed cause and autoantibody status. MAIN OUTCOMES AND MEASURES: Clinical, electrophysiologic, and pathologic characteristics were collected and compared among patient subgroups. Predictors of response to treatment were identified by univariate logistic regression. RESULTS: Lower extremity weakness predominated (46 [73%]). Distal weakness (26 [41%]), dysphagia (22 [35%]), and dyspnea (23 [37%]) were common. Twenty-two patients (35%) were receiving a statin medication at onset, 6 had cancer, and 3 had a connective tissue disease. The median creatine kinase level was 5326 U/L. In 13 patients (24%), SRP-IgG was detected, and in 17 patients (34%), HMGCR-IgG was detected (one-third of whom had not received statin medication). One patient was dual seropositive. Facial weakness was more common in SRP-IgG–positive patients. Myotonic discharges were more common in statin-associated NAM. Prednisone monotherapy was insufficient to control disease in most patients; 30 (90%) of 32 patients required 2 or more immunotherapeutic agents. Relapse occurred in 16 (55%) of 29 patients during immunosuppressant taper or discontinuation. Predictors of favorable outcome were male sex and use of 2 or more immunotherapeutic agents within 3 months of onset. CONCLUSIONS AND RELEVANCE: Necrotizing autoimmune myopathy was idiopathic in half of this cohort with clinical and histopathologically defined disease. In the remainder, NAM was associated with statin medication, cancer, or connective tissue disease. One in 4 patients was SRP-IgG positive, and 1 in 3 was HMGCR-IgG positive. The disease was usually not controlled by corticosteroid monotherapy. Presentation, course, and outcomes did not differ significantly in seropositive, seronegative, and statin-associated cases. Early aggressive immunosuppressant therapy improved outcomes, and risk of relapse was high during medication dose reduction or withdrawal.

IMPORTANCE: Documentation of muscle pathology compatible with targeting of sarcolemmal aquaporin-4 (AQP4) by complement-activating IgG implies involvement of organs beyond the central nervous system in neuromyelitis optica spectrum disorders. OBSERVATIONS: We report on a 51-year-old woman who had relapsing optic neuritis, transverse myelitis, AQP4-IgG seropositivity, and recurrent myalgias with hyperCKemia. A muscle biopsy revealed scattered myofibers with internal nuclei, atrophy, and regeneration but no necrosis. Mild inflammatory exudates, in endomysial and perivascular spaces, consisted of lymphocytes, histiocytes, and scattered eosinophils. The sarcolemma exhibited loss of AQP4 and deposition of IgG and complement activation products, characteristics not seen in control biopsy samples of healthy muscle and immune-mediated myopathies. CONCLUSIONS AND RELEVANCE: Recurrent hyperCKemia accompanying AQP4-IgG seropositivity reflects targeting of skeletal muscle AQP4 by pathogenic IgG. The entity of autoimmune AQP4 myopathy extends the neuromyelitis optica spectrum beyond the central nervous system.

To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations.

Although sleep disturbances are common in myotonic dystrophy type 1 (DM1), sleep disturbances in myotonic dystrophy type 2 (DM2) have not been well-characterized. We aimed to determine the frequency of sleep disturbances in DM2.

Purpose:The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA–related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome.Methods:The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR–based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR–based Sanger sequencing using multiple pairs of primers.Results:Our results demonstrated the uniform coverage of the entire mitochondrial genome. Massively parallel sequencing of the single amplicon revealed the presence of single-nucleotide polymorphisms and nuclear homologs of mtDNA sequences that cause the erroneous and inaccurate variant calls when PCR/Sanger sequencing approach was used. This single amplicon massively parallel sequencing strategy provides an accurate quantification of mutation heteroplasmy as well as the detection and mapping of mitochondrial DNA deletions.Conclusion:The ability to quantitatively and qualitatively evaluate every single base of the entire mitochondrial genome is indispensible to the accurate molecular diagnosis and genetic counseling of mitochondrial DNA–related disorders. This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome.Genet Med 2013:15(5):388–394

ADOA: autosomal dominant optic atrophy

OBJECTIVE To investigate the molecular etiology of 2 unrelated patients with a multisystem mitochondrial disorder accompanied by optic atrophy in one of them. DESIGN Clinical examination and neurophysiological, radiological, morphological, and molecular analyses. SETTING Tertiary care neuromuscular clinic and molecular genetics laboratory. PATIENTS A 65-year-old man (patient 1) with dyschromatopsia and vision loss since childhood developed progressive external ophthalmoplegia, ptosis, and myopathy in the seventh decade of life and was found to have optic atrophy. A 63-year-old man (patient 2) with a similar phenotype, without visual symptoms, experienced also hearing loss and parkinsonism. MAIN OUTCOME MEASURES Description of the clinical and molecular findings. RESULTS A muscle biopsy specimen showed ragged-red, ragged-blue, and cytochrome c oxidase–negative fibers in both patients. Because optic atrophy in patient 1 suggested an autosomal dominant OPA1-related disorder, the OPA1 gene was first sequenced, the results of which did not detect any mutations. Southern blot and polymerase chain reaction analyses of muscle mitochondrial DNA revealed multiple deletions. Sequencing of POLG detected a novel variant, c.3104 + 3A>T, in both patients. Patient 1 was compound heterozygous for a known p.F749S mutation; patient 2 had p.G848S as the second mutation. Analysis of POLG complementary DNA showed that c.3104 + 3A>T results in skipping of exon 18. CONCLUSION Early-onset dyschromatopsia and optic atrophy can occur not only in OPA1-related but also in POLG-related disorders with significant impact on genetic counseling.Arch Neurol. 2011;68(6):806-811--

The end‐plate species of acetylcholinesterase (AChE) is an asymmetric enzyme consisting of a collagenic tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of the T isoform of the catalytic subunit (AChET) via a proline‐rich attachment domain. The principal function of the tail subunit is to anchor asymmetric AChE in the synaptic basal lamina. Human end‐plate AChE deficiency was recently shown to be caused by mutations in COLQ. We here report nine novel COLQmutations in 7 patients with end‐plate AChE deficiency. We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQmutant with ACHETin COS cells. We classify the newly recognized and previously reported COLQmutations into four classes according to their position in ColQ and their effect on AChE expression. We find that missense mutations in the proline‐rich attachment domain abrogate attachment of catalytic subunits, that truncation mutations in the ColQ collagen domain prevent the assembly of asymmetric AChE, that hydrophobic missense residues in the C‐terminal domain prevent triple helical assembly of the ColQ collagen domain, and that other mutations in the C‐terminal region produce asymmetric species of AChE that are likely insertion incompetent. Ann Neurol 2000;47:162–170.

To demonstrate early aging in patients with LMNAmutations after hypothesizing that they have a biological age older than chronological age, as such finding impacts care.

Introduction:LMNAencodes the nuclear envelope proteins lamin A/C that are involved in ageing processes. Mutations in LMNAcause a spectrum of phenotypes which include muscular dystrophy, arrhythmogenic dilated cardiomyopathy, peripheral neuropathy, progeroid syndrome and overlap syndrome. Early diagnosis is crucial to prevent sudden cardiac death. We hypothesized that LMNAmutations result in an ECG biological age older than chronological age.Methods:In this study, we used AI-enabled ECG network to investigate standard digital 12-lead ECGs in genetically characterized LMNApatients.Results:We identified 33 LMNApatients with 331, 12-lead ECG available for analysis. Median age at symptoms onset was 23.5 (range: <1 to 61 years;15 females). Mean follow up time was 86 months (range: <1 to 367 months). Symptoms at onset included muscle weakness (n=10) or cardiac symptoms (n=18) and asymptomatic (n=5). We included a total of 1532 age sex matched controls. We found significant differences in positive age-gap (biologically older than chronological age) comparing LMNApatients (median of 17.5) versus controls (4.9 years; p<0.001, Figure 1). AI-ECG age with 10 years or higher age-gap was observed in 73% of LMNApatients compared to 27% in the controls (p<0.001). Consecutive serial analysis for all ECG’s in the study versus predicted age showed faster aging when comparing the rates of age-gap overtime in the LMNAgroup compared to controls (p<0.0001, Figure 2). Moreover, the subset analysis of 23 ECG in the 5 asymptomatic patients versus controls also showed significantly higher AI-ECG age-gap (p=0.004)Conclusions:An AI-ECG algorithm to detect biological age effectively demonstrates accelerated aging in patients with LMNA mutations related to physiological aging. Our findings further validate the role of AI-ECG to detect accelerated aging, expanding previous studies demonstrating higher mortality among individuals with in increased positive age-gap.

The congenital myasthenic syndromes include end-plate (EP) acetylcholinesterase deficiency, presynaptic abnormalities affecting the evoked release or size of transmitter quanta, and acetylcholine (ACh) receptor (AChR) channelopathies stemming from a kinetic abnormality and/or deficiency of AChR. A kinetic abnor mality predicts, and AChR deficiency may predict, one or more mutations in an AChR subunit gene. These clues have led to the identification of 53 mutations in different subunits of AChR in 55 kinships of the congenital myasthenic syndromes. The mutations either increase or decrease the response to ACh, produce AChR deficiency, or both. In the slow-channel syndromes, prolonged opening episodes of AChR cause cationic overloading of the EP and an EP myopathy; the mutations occur in different subunits and different domains of the subunits and have dominant positive effects. The M1 and M2 mutations slow channel closure, increase apparent affinity for ACh, and variably enhance desensitization, and the extracellular aG153S enhances affinity for ACh, promoting reopening of the diliganded receptor. In the low-affinity fast-channel syndrome, eP121L reduces affinity for ACh and reopening of the diliganded receptor, resulting in a de creased response to ACh and shorter burst durations. Severe EP AChR deficiency results from heterozy gous or homozygous mutations that terminate translation prematurely; these are concentrated in the e subunit, probably because substitution of the fetal ? for the adult e subunit can rescue the phenotype from fatal null mutations in e. Variable AChR deficiency and variable functional abnormalities stem from hetero allelic nonsense and missense mutations in AChR subunit genes. NEUROSCIENTIST 4:185-194, 1998

Sixteen patients treated with cisplatin (CDDP) 40 mg/m2 on days 1–5 every 4 weeks for three courses (cumulative dose 600 mg/m2) were clinically and neurophysiologically tested before, during and 1, 3, 6, 9 and 12 months after CDDP administration. The first symptoms of polyneuropathy occurred in 4 of 9 patients after the second course (cumulative dose 400 mg/m2). One month after treatment 1 of 9 patients was asymptomatic, 5 complained of symptoms and 3 showed clinical and neurophysiological signs of polyneuropathy. Three months after CDDP all patients were affected. Clinical and neurophysiological signs of severity progression were noted up to 6 months after treatment with CDDP.

Recent observations suggest that some patients with congenital myasthenic syndromes respond favorably to ephedrine, pseudoephedrine, or albuterol. Conventional microelectrode studies, however, provide no clear explanation for a beneficial effect of ephedrine in endplate diseases. To gain further insight into how these drugs affect neuromuscular transmission, we investigated their effects on the kinetic properties of the acetylcholine (ACh) receptor. Single channel currents were recorded from rat lumbrical muscles endplates using low concentrations of ACh and 2.5–100 μM of drugs. Between 10–100 μM, each drug progressively increased the rate of channel closure in a concentration dependent manner, consistent with an open-channel block. Albuterol acted as a sequential fast-acting channel blocker, increasing the mean burst duration in a concentration dependent manner without altering the total open time per burst or the duration of intraburst blockages. Increasing concentrations of ephedrine and pseudoephedrine also increased the number of intraburst closures but decreased the total open time per burst. None of the drugs altered single channel conductance. The channel blocking effects of ephedrine and pseudoephedrine might reduce the synaptic overactivity that occurs in the slow-channel myasthenic syndromes or in endplate ACh esterase deficiency, but these effects occur at concentrations not attainable in clinical practice.

IMPORTANCE Orthostatic tremor (OT) is a high-frequency (13-18 Hz) leg tremor occurring in standing position. Orthostatic tremor has an unknown pathophysiologic mechanism. It is thought to be sporadic but siblings with OT from 3 unrelated families were reported. No mutations have been reported in OT. We describe a patient with OT carrying a C10orf2 TWINKLE mutation to highlight the possible association of OT with mitochondrial dysfunction and mutations in the mitochondrial replicative helicase Twinkle. OBSERVATIONS A man in his late 60s had ptosis and tremor on standing for 30 years, followed by development of progressive external ophthalmoplegia. Polygraphic recordings revealed an orthostatic synchronic tremor with 17.5-Hz frequency. Electromyography/nerve conduction studies showed evidence for a mild myopathy and associated mild axonal sensorimotor peripheral neuropathy. Muscle biopsy revealed ragged red fibers; mild cerebral atrophy was evident by magnetic resonance imaging. Molecular analysis revealed a novel heterozygous missense mutation at an evolutionarily conserved residue of the C10orf2 TWINKLE gene. CONCLUSIONS AND RELEVANCE Although the incidental association of OT and C10orf2 TWINKLE mutation is possible, the simultaneous onset of OT and eyelid ptosis at a much younger age than usually observed for OT raises the possibility of mitochondrial dysfunction and loss of mitochondrial DNA integrity in the pathogenesis of OT.

The authors present a case and image of a patient with refractory tongue weakness and characteristic triple furrowed pattern of atrophy due to autoimmune myasthenia gravis.

Introduction:Statins remain the first-line medications for risk reduction in the prevention of atherosclerotic cardiovascular disease. Statin-associated muscle symptoms (SAMS) are frequently reported with the use of statins. Among these, statin-associated immune-mediated necrotizing myopathy (SAIMNM) is an under-recognized, but serious disorder associated with statin use and the development of autoantibodies against HMG-CoA reductase (HMGCR).Methods:A retrospective review was conducted of 399 consecutive patients with suspected myopathy who were tested for anti-HMGCR antibodies at Mayo Clinic from 2010-2018. Of those, 35 patients tested positive, and 30 patients were ultimately diagnosed with SAIMNM. Data was collected and analyzed using JMP?Software.Results:Amongst the patients diagnosed with SAIMNM, the average age at the time of antibody testing was 58.1 years (range 15-82), and 15 patients (50.0%) were female. A statin exposure was identified in 22 (73.3%) patients, with atorvastatin being the most frequently reported in 13 cases. The median duration of time on a statin prior to symptoms was 2-3 years. The mean CK level was 8545 (SD = 4833) U/L at the time of presentation with 29 (96.7%) patients presenting with weakness and 16 (53.3 %) with muscle pain. The mean time from symptom presentation to diagnosis was 19.6 (SD = 25.3) months. The mean age at the time of antibody testing was significantly different between patients with a statin exposure history (65.0 years) and those without (39.1 years) (p=0.0005). A diagnosis of cancer was seen in 6 (20.0%) patients, and 11 (36.7%) patients had diabetes. A total of 28 (93.3%) of patients were treated with immunotherapy, and 25 (89.3%) of those patients had symptomatic improvement.Conclusions:The diagnosis of SAIMNM requires a high index of suspicion, as its presentation is similar to other more common SAMS, often leading to delays in diagnosis. SAIMNM should be considered in patients whose muscle symptoms persist despite discontinuation of statins, since unlike other SAMS, this condition is treated with immunotherapy with a high response rate.

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.