Search

Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment.OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic.METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases).RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform.CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology., info:eu-repo/semantics/published

Item does not contain fulltext Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Summary Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

Summary Background The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. Methods We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. Findings We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2 , and ALDH5A1 were most notable. Interpretation The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

Objective: To map the disease-causing locus in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura and to describe the clinical, electrophysiologic, and imaging characteristics. Methods: DNA samples from 21 family members were obtained and an 8 cM density genome-wide scan was performed. The authors interviewed 21 individuals and performed interictal EEG in 14 and brain MRI in 13 individuals. Results: Nine at risk family members and one deceased individual had epilepsy with occipital and temporal lobe symptomatology, variable age at onset, usually good prognosis, no epileptic EEG features, and normal brain MRI. Five of the 10 patients had a history of migraine with aura (p = 0.0026). Seizures and migraine attacks occurred as separate episodes in all but one patient. Three patients described light flashes both as epileptic and migraine aura. Epilepsy and migraine started at the same age in three patients and remitted simultaneously in two. The epileptic phenotype had a dominant mode of inheritance with a reduced penetrance of 75%. A conclusive two-point lod score of 3.3 was obtained for marker D9S257 at recombination fraction zero. Haplotype analysis defined a candidate region of 9.95 cM (5.96 Mb) between markers GATA152H04 and D9S253 located at chromosome 9q21-q22 based upon recombinations in affected individuals. Conclusions: The clinical association in this family of occipitotemporal lobe epilepsy and migraine with visual aura and the conclusive linkage of the occipitotemporal lobe epilepsy/migraine with aura trait to a single locus suggests a common monogenic gene defect.

The hereditary motor neuronopathies (HMN [MIM 158590]) are a heterogeneous group of disorders characterized by an exclusive involvement of the motor part of the peripheral nervous system. They are usually subdivided in proximal HMN, i.e., the classical spinal muscular atrophy syndromes and distal hereditary motor neuronopathies (distal HMN) that clinically resemble Charcot-Marie-Tooth syndromes. In this review, we concentrate on distal HMN. The distal HMN are clinically and genetically heterogeneous and were initially subdivided in seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been delineated. Since the introduction of positional cloning, 13 chromosomal loci and seven disease-associated genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive distal HMN. Most of the genes involved encode protein with housekeeping functions, such as RNA processing, translation synthesis, stress response, apoptosis, and others code for proteins involved in retrograde survival. Motor neurons of the anterior horn of the spinal cord seems to be vulnerable to defects in these housekeeping proteins, likely because their large axons have higher metabolic requirements for maintenance, transport over long distances and precise connectivity. Understanding the molecular pathomechanisms for mutations in these genes that are ubiquitous expressed will help unravel the neuronal mechanisms that underlie motor neuropathies leading to denervation of distal limb muscles, and might generate new insights for future therapeutic strategies.

Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of peripheral neuropathies. Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC. We refined the locus associated with DI-CMTB on chromosome 19p12-13.2 to 4.2 Mb in three unrelated families with CMT originating from Australia, Belgium and North America. After screening candidate genes, we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus. In transiently transfected cell lines, mutations of DNM2 substantially diminish binding of DNM2 to membranes by altering the conformation of the beta3/beta4 loop of the pleckstrin homology domain. Additionally, in the Australian and Belgian pedigrees, which carry two different mutations affecting the same amino acid, Lys558, CMT cosegregated with neutropenia, which has not previously been associated with CMT neuropathies.

Patients, in particular recipients of orthotopic liver transplants, receiving the immunosuppressant tacrolimus (FK-506), are at risk for developing central neurotoxic adverse events. We report the occurrence of a tacrolimus-induced peripheral neurotoxic event, i.e. pure motor axonal polyneuropathy of the lower limbs in a 44-year-old woman, 9 days after combined orthotopic liver and pancreas transplantation. She was treated for 5 days with intravenous immunoglobulins. Partial recovery followed over months to years. An overview of all 11 reported FK506-associated polyneuropathies is given.

The purpose of the study was to prospectively assess magnetic resonance (MR) imaging findings of lower limb musculature in an axonal Charcot-Marie-Tooth disease (CMT2) pedigree due to mutation in the dynamin 2 gene (DNM2). The series comprises a proband patient aged 55 years and her two affected daughters aged 32 and 23. MR imaging study included T1- and fat suppressed T2-weighted spin-echo sequences. MR imaging study showed extensive fatty infiltration of all calf muscle compartments with relative preservation of the deep posterior one. Fatty muscle infiltration increased distally in 19 out of 66 (23 %) visualized calf muscles in the three patients, but this percentage increased to 64 % in the youngest and least severe patient. Muscle edema without contrast enhancement was present in 23 % of calf muscles. There was massive fatty atrophy of foot musculature. We conclude that MR imaging study accurately depicts lower limb muscle involvement in CMT2 caused by DNM2 mutation.

SummaryWe report the clinical, neuroradiological, and molecular genetic findings in a patient with lipoid proteinosis or Urbach–Wiethe disease. Interestingly, in this patient epilepsy and migraine were the symptoms leading to the diagnosis of the disease, contrary to most patients in whom skin abnormalities are the first recognized symptoms.

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel α-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI. Hum Mutat 27(9), 914–920, 2006. © 2006 Wiley-Liss, Inc.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot–Marie–Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population. ispartof: Brain vol:129 issue:8 pages:2093-2102 ispartof: location:England status: published

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2 gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype–phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs.

Objective Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. Methods Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. Results In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. Interpretation MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies. Ann Neurol 2006;59:276–281

Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.

Generalised epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous epilepsy syndrome. Using positional cloning strategies, mutations in SCN1B, SCN1A, and GABRG2 have been identified as genetic causes of GEFS+. In the present study, we describe a large four generation family with GEFS+ in which we performed a 10 cM density genome-wide scan. We obtained conclusive evidence for a novel GEFS+ locus on chromosome 2p24 with a maximum two point logarithm of the odds (LOD) score of 4.22 for marker D2S305 at zero recombination. Fine mapping and haplotype segregation analysis in this family delineated a candidate region of 3.24 cM, corresponding to a physical distance of 4.2 Mb. Linkage to 2p24 was confirmed (p = 0.007) in a collection of 50 nuclear and multiplex families with febrile seizures and epilepsy. Transmission disequilibrium testing and association studies provided further evidence (p

We investigated the contribution of the human cerebellum to cerebral function during visual discrimination using PET and fMRI. The cognitive task was a successive discrimination of shades of brown with a parametric variation of the stimulus presentation rate and a constant task difficulty. The successive color discrimination task was contrasted to a dimming detection control task, with identical retinal input but with double the number of motor responses. Three sets of activated cerebellar and cerebral regions were observed: rate-dependent and rate-independent color discrimination networks and a motor-and-detection network. The rate-dependent color discrimination network included both an anterior and a posterior activation site in lobule-VI of the two lateral cerebellar hemispheres, whereas the rate-independent network involved a bilateral activation site in lateral Crus-I. Cerebellar sites of the motor-and-detection network were located in medial lobule-V bilaterally, in the vermis, and in posterior left Crus-I and right Crus-II. An additional fMRI study was performed to control for differences in motor output and response timing between the tasks. In this control study, the cerebellar activation sites of the rate-dependent and rate-independent color discrimination networks remained unaltered. The motor-and-detection network included cerebellar activations in posterior left Crus-I and right Crus-II, but none in lobule-V or the vermis. Thus, cerebellar activation sites of the motor-and-detection network could be subdivided into those related to a motor network and those belonging to a dimming detection network. We conclude that successive color discrimination activates multiple, functionally distinct cerebellar regions.

The present study tested the hypothesis that, unlike prosaccades, antisaccades require controlled processing, due to the prepotent response that needs to be inhibited. The effect of the Random time Interval Generation (RIG) task (Vandierendonck, A., De Vooght, G., & Van der Goten, K. (1998). European Journal of Cognitive Psychology, 10, 413-444) on these saccade latencies and errors was studied. This task has the advantage that it loads executive processes, with only minimal interference with verbal or visuo-spatial components. A first experiment compared saccade performance within the prosaccade and the antisaccade task, executed alone and in combination with the RIG task and fixed tapping (added to exclude possible motor component interference explanations). A second experiment investigated the influence of task characteristics on the effects found. Although it was shown that antisaccades are more prone to interference of an executive interference task, it seems that prosaccades are also vulnerable. Interference on prosaccades could originate from a controlled execution of these saccades. A third experiment confirmed that endogenously generated prosaccades are susceptible to dual-task interference and showed that controlled saccade execution, without the need to inhibit a prepotent response, is sufficient to produce interference.

LGMD2L is caused by mutations in the anoctamin-5-gene (ANO5). Limb-girdle muscle weakness can also be caused by an immune-mediated necrotizing myopathy (IMNM) with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase (HMGCR), which catalyzes a rate-limiting step in cholesterol biosynthesis and is inhibited by statins. We report on a 44-year-old patient with LGMD2L and HMGCR-associated-IMNM without previous statin exposure. He presented with myalgia, dysphagia and slowly progressive proximal weakness in the legs for four years. CK-levels were permanently increased (5000–7500 U/l). HMGCR-antibodies were detected in serum (D-Tek, Mons, Belgium). Electromyography and cardiac exams were normal. Vital capacity was mildly reduced (70%). Muscle biopsy revealed necrotic fibers and basophilic regenerating muscle fibers, without inflammation. Several fibers showed an abnormal MHC-I staining at their membranes. The MAC stain was normal. A whole-body muscle-MRI revealed symmetrical fatty degeneration in hamstrings and medial gastrocnemius muscles, without inflammatory changes. Based on this characteristic MRI pattern, which is unusual for IMNM and has been reported in LGMD2L, direct sequencing of ANO5 was performed and two known pathogenic compound heterozygous mutations were identified. Because of the presence of HMGCR-autoantibodies, oral steroids were started. Six weeks later, the patient suffered no longer from myalgia, the Mingazzini maneuver ameliorated, a swallowing test improved, CK-levels significantly decreased (from 5098 to 1900 U/l) and HMGCR-antibodies were no longer detectable. We conclude that it might be useful to screen for additional hereditary causes of necrotizing myopathies in statin-unexposed HMGCR-IMNM patients. Besides the diagnostic challenge, our case indicates the therapeutic dilemma of immunosuppressive treatment regimen in “double trouble necrotizing myopathies” which might be more frequent than previously suspected.