A centronuclear myopathy-causing mutation in dynamin-2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease.

AIMS: Dynamin-2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin-2 CNM-causing mutation influences the CNS function. METHODS: Heterozygous mice harbouring the p.R465W mutation in the dynamin-2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. RESULTS: HTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin-2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. CONCLUSION: Our findings suggest that the dynamin-2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice.

Dysferlinopathy is an autosomal recessive muscular dystrophy resulting from mutations in the dysferlin gene. Absence of dysferlin in the sarcolemma and progressive muscle wasting are hallmarks of this disease. Signs of oxidative stress have been observed in skeletal muscles of dysferlinopathy patients, as well as in dysferlin-deficient mice. However, the contribution of the redox imbalance to this pathology and the efficacy of antioxidant therapy remain unclear. Here, we evaluated the effect of 10 weeks diet supplementation with the antioxidant agent N-acetylcysteine (NAC, 1%) on measurements of oxidative damage, antioxidant enzymes, grip strength and body mass in 6 months-old dysferlin-deficient Bla/J mice and wild-type (WT) C57 BL/6 mice. We found that quadriceps and gastrocnemius muscles of Bla/J mice exhibit high levels of lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activities, which were significantly reduced by NAC supplementation. By using the Kondziela's inverted screen test, we further demonstrated that NAC improved grip strength in dysferlin deficient animals, as compared with non-treated Bla/J mice, without affecting body mass. Together, these results indicate that this antioxidant agent improves skeletal muscle oxidative balance, as well as muscle strength and/or resistance to fatigue in dysferlin-deficient animals.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Disease duration and disability in dysfeRlinopathy can be described by muscle imaging using heatmaps and random forests.

INTRODUCTION: The manner in which imaging patterns change over the disease course and with increasing disability in dysferlinopathy is not fully understood. METHODS: Fibroadipose infiltration of 61 muscles was scored based on whole-body MRI of 33 patients with dysferlinopathy and represented in a heatmap. We trained random forests to predict disease duration, Motor Function Measure dimension 1 (MFM-D1), and modified Rankin scale (MRS) score based on muscle scoring and selected the most important muscle for predictions. RESULTS: The heatmap delineated positive and negative fingerprints in dysferlinopathy. Disease duration was related to infiltration of infraspinatus, teres major-minor, and supraspinatus muscles. MFM-D1 decreased with higher infiltration of teres major-minor, triceps, and sartorius. MRS related to infiltration of vastus medialis, gracilis, infraspinatus, and sartorius. DISCUSSION: Dysferlinopathy shows a recognizable muscle MRI pattern. Fibroadipose infiltration in specific muscles of the thigh and the upper limb appears to be an important marker for disease progression. Muscle Nerve 59:436-444, 2019.

The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes.

BACKGROUND: Mutations in the gene encoding for dysferlin cause recessive autosomal muscular dystrophies called dysferlinopathies. These mutations induce several alterations in skeletal muscles, including, inflammation, increased membrane permeability and cell death. Despite the fact that the etiology of dysferlinopathies is known, the mechanism that explains the aforementioned alterations is still elusive. Therefore, we have now evaluated the potential involvement of connexin based hemichannels in the pathophysiology of dysferlinopathies. RESULTS: Human deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). The presence of these connexins was also observed in human myotubes derived from immortalized myoblasts derived from other patients with mutated forms of dysferlin. In addition to the aforementioned connexins, these myotubes expressed functional connexin based hemichannels, evaluated by ethidium uptake assays, as opposed to myotubes obtained from a normal human muscle cell line, RCMH. This response was reproduced in a knock-down model of dysferlin, by treating RCMH cell line with small hairpin RNA specific for dysferlin (RCMH-sh Dysferlin). Also, the presence of P2X7 receptor and the transient receptor potential channel, TRPV2, another Ca(2+) permeable channels, was detected in the myotubes expressing mutated dysferlin, and an elevated resting intracellular Ca(2+) level was found in the latter myotubes, which was in turn reduced to control levels in the presence of the molecule D4, a selective Cx HCs inhibitor. CONCLUSIONS: The data suggests that dysferlin deficiency, caused by mutation or downregulation of dysferlin, promotes the expression of Cx HCs. Then, the de novo expression Cx HC causes a dysregulation of intracellular free Ca(2+) levels, which could underlie muscular damage associated to dysferlin mutations. This mechanism could constitute a potential therapeutical target in dysferlinopathies.

Broadening the imaging phenotype of dysferlinopathy at different disease stages.

INTRODUCTION: MRI characterization of dysferlinopathy has been mostly limited to the lower limbs. We aimed to broaden the MRI description of dysferlinopathy and to correlate it with objective measures of motor dysfunction. METHODS: Sequential whole-body axial MRI was performed in 27 patients with genetically confirmed dysferlinopathy classified according to disease duration. Spearman correlations of fatty infiltration scores versus Motor Function Measure (MFM) were calculated. RESULTS: Significant fatty infiltration was symmetrically present in early stages mainly in the posterior compartments of legs and thighs, thigh adductors, pelvic girdle, and some paravertebral muscles and the subscapularis. Later, fatty infiltration involved leg and thigh anterior compartments, arms and forearms, paravertebral, and trunk muscles. MRI infiltration score correlated positively with disease duration and negatively with MFM scale. CONCLUSIONS: We expand MRI characterization of dysferlinopathy and provide evidence for use of MRI scoring combined with motor functional scales to assess the natural course of disease. Muscle Nerve, 2016 Muscle Nerve 54: 203-210, 2016.

Toward an objective measure of functional disability in dysferlinopathy.

INTRODUCTION: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales. METHODS: Thirty-one patients with genetically confirmed dysferlinopathy were assessed using the motor function measure (MFM), Modified Rankin Scale (MRS), Muscle Research Council (MRC) scale, serum creatine kinase (CK) assessment, baseline spirometry data, and echocardiographic and electrophysiologic studies. RESULTS: MFM and MRC scores showed a significant negative correlation with disease duration and inverse correlation with MRS, but not with onset age, clinical phenotype, or CK levels. Percent forced vital capacity (%FVC) correlated negatively with disease duration and onset age. Eight known pathogenic mutations were identified recurrently, 4 of which accounted for 79% of the total. CONCLUSIONS: The results suggest that MFM is a reliable outcome measure that may be useful for longitudinal follow-up in dysferlinopathy. Recurrent mutations suggest a founder effect in the Chilean population.

Dynamin-2 in nervous system disorders.

Dynamin-2 is a pleiotropic GTPase whose best-known function is related to membrane scission during vesicle budding from the plasma or Golgi membranes. In the nervous system, dynamin-2 participates in synaptic vesicle recycling, post-synaptic receptor internalization, neurosecretion, and neuronal process extension. Some of these functions are shared with the other two dynamin isoforms. However, the involvement of dynamin-2 in neurological illnesses points to a critical function of this isoform in the nervous system. In this regard, mutations in the dynamin-2 gene results in two congenital neuromuscular disorders. One of them, Charcot-Marie-Tooth disease, affects myelination and peripheral nerve conduction, whereas the other, Centronuclear Myopathy, is characterized by a progressive and generalized atrophy of skeletal muscles, yet it is also associated with abnormalities in the nervous system. Furthermore, single nucleotide polymorphisms located in the dynamin-2 gene have been associated with sporadic Alzheimer's disease. In the present review, we discuss the pathogenic mechanisms implicated in these neurological disorders.

Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity.

Congenital unilateral overgrowth of the upper extremity affecting only the muscle tissue is rare. We describe on the clinical, histopathological, and neuroimaging findings in a 6-year-old girl with a congenital, non-progressive muscle enlargement of the entire left upper limb with an ipsilateral hand deformity. No cutaneous stigmata or additional features were detected. Sanger sequencing for the AKT1, PIK3CA, and PTEN genes identified an activating c.3140A>G, p.H1047R mutation in the PIK3CA gene from the affected muscle DNA. We demonstrate that isolated congenital muscular upper limb overgrowth with aberrant hand muscles is another condition related genetically to the PIK3CA-related overgrowth spectrum.

Muscle magnetic resonance imaging and histopathology in ACTA1-related congenital nemaline myopathy.

INTRODUCTION: Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. METHODS: We assessed the clinical, histopathological, MRI, and molecular findings in a 19-year-old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. RESULTS: Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. CONCLUSIONS: We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1-related NM.

Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.

Background and Objectives: Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. Methods: A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. Results: All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. Discussion: This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.

Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis.

BACKGROUND: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far. METHODS: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs. RESULTS: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy. CONCLUSIONS: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.

Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.

Tropomyosin 3 (TPM3) gene mutations associate with autosomal dominant and recessive nemaline myopathy 1 (NEM1), congenital fiber type disproportion myopathy (CFTD) and cap myopathy (CAPM1), and a combination of caps and nemaline bodies. We report on a 47-year-old man with polyglobulia, restricted vital capacity and mild apnea hypopnea syndrome, requiring noninvasive ventilation. Physical assessment revealed bilateral ptosis and facial paresis, with high arched palate and retrognathia; global hypotonia and diffuse axial weakness, including neck and upper and lower limb girdle and foot dorsiflexion weakness. Whole body MRI showed a diffuse fatty replacement with an unspecific pattern. A 122 gene NGS neuromuscular disorders panel revealed the heterozygous VUS c.709G>A (p.Glu237Lys) on exon 8 of TMP3. A deltoid muscle biopsy showed a novel histological pattern combining fiber type disproportion and caps. Our findings support the pathogenicity of the novel TPM3 variant and widen the phenotypic gamut of TMP3-related congenital myopathy.

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy-derived cells.

Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) drive calcium signals involved in skeletal muscle excitation-transcription coupling and plasticity; IP(3)R subtype distribution and downstream events evoked by their activation have not been studied in human muscle nor has their possible alteration in Duchenne muscular dystrophy (DMD). We studied the expression and localization of IP(3)R subtypes in normal and DMD human muscle and in normal (RCMH) and dystrophic (RCDMD) human muscle cell lines. In normal muscle, both type 1 IP(3)Rs (IP(3)R1) and type 2 IP(3)Rs (IP(3)R2) show a higher expression in type II fibers, whereas type 3 IP(3)Rs (IP(3)R3) show uniform distribution. In DMD biopsies, all fibers display a homogeneous IP(3)R2 label, whereas 24 +/- 7% of type II fibers have lost the IP(3)R1 label. RCDMD cells show 5-fold overexpression of IP(3)R2 and down-regulation of IP(3)R3 compared with RCMH cells. A tetanic stimulus induces IP(3)-dependent slow Ca(2+) transients significantly larger and faster in RCDMD cells than in RCMH cells as well as significant ERK1/2 phosphorylation in normal but not in dystrophic cells. Excitation-driven gene expression was different among cell lines; 44 common genes were repressed in RCMH cells and expressed in RCDMD cells or vice versa. IP(3)-dependent Ca(2+) release may play a significant role in DMD pathophysiology.

Myofibers deficient in connexins 43 and 45 expression protect mice from skeletal muscle and systemic dysfunction promoted by a dysferlin mutation.

Dysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies.

Idiopathic inflammatory myopathy human derived cells retain their ability to increase mitochondrial function.

Idiopathic Inflammatory Myopathies (IIMs) have been studied within the framework of autoimmune diseases where skeletal muscle appears to have a passive role in the illness. However, persiting weakness even after resolving inflammation raises questions about the role that skeletal muscle plays by itself in these diseases. "Non-immune mediated" hypotheses have arisen to consider inner skeletal muscle cell processes as trigger factors in the clinical manifestations of IIMs. Alterations in oxidative phosphorylation, ATP production, calcium handling, autophagy, endoplasmic reticulum stress, among others, have been proposed as alternative cellular pathophysiological mechanisms. In this study, we used skeletal muscle-derived cells, from healthy controls and IIM patients to determine mitochondrial function and mitochondrial ability to adapt to a metabolic stress when deprived of glucose. We hypothesized that mitochondria would be dysfunctional in IIM samples, which was partially true in normal glucose rich growing medium as determined by oxygen consumption rate. However, in the glucose-free and galactose supplemented condition, a medium that forced mitochondria to function, IIM cells increased their respiration, reaching values matching normal derived cells. Unexpectedly, cell death significantly increased in IIM cells under this condition. Our findings show that mitochondria in IIM is functional and the decrease respiration observed is part of an adaptative response to improve survival. The increased metabolic function obtained after forcing IIM cells to rely on mitochondrial synthesized ATP is detrimental to the cell's viability. Thus, therapeutic interventions that activate mitochondria, could be detrimental in IIM cell physiology, and must be avoided in patients with IIM.

Spontaneous symptomatic improvement in a pediatric patient with anti-3-hydroxy-3-methylglutraryl-coenzyme A reductase myopathy.

Immune-mediated necrotizing myopathy with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase is a subgroup of idiopathic inflammatory myopathies mainly described in adults and requiring long term immunomodulatory therapy for remission. Pediatric patients have been reported as small series or sporadic cases. We report an eight-year-old girl with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, presenting with subacute proximal limb weakness, high creatine kinase and a muscle biopsy displaying necrotizing pattern, initially diagnosed as limb-girdle muscular dystrophy, but subsequently negative genetic testing. A noteworthy spontaneous improvement in her weakness suggested the possibility of an acquired autoimmune myopathy, confirmed by positive testing of anti-HMGCR antibodies titers. After four years of follow-up, she maintains normal strength with high levels of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody. This patient shows that spontaneous fluctuations and spontaneous long-lasting symptomatic remission can occur in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy. Some patients could present a wane and wax clinical course, an important aspect when assessing response to therapy.