ABSTRACT
BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.
Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II , Glycogen Storage Disease Type II/drug therapy , Humans , Enzyme Replacement Therapy/methods , EuropeABSTRACT
BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.
Subject(s)
Magnetic Resonance Imaging , Muscular Diseases , Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging/standards , Humans , Muscular Diseases/diagnostic imaging , Germany , Practice Guidelines as Topic , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathologyABSTRACT
BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
Subject(s)
Anticonvulsants , Mitochondrial Diseases , Seizures , Humans , Mitochondrial Diseases/complications , Mitochondrial Diseases/therapy , Seizures/therapy , Seizures/drug therapy , Anticonvulsants/therapeutic use , Consensus , Epilepsy/therapy , Epilepsy/drug therapy , Delphi TechniqueABSTRACT
BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.
Subject(s)
Magnetic Resonance Imaging , Muscle, Skeletal , Magnetic Resonance Imaging/standards , Magnetic Resonance Imaging/methods , Humans , Germany , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Diseases/diagnostic imaging , Practice Guidelines as Topic , Radiology/standards , Neurology/standardsABSTRACT
BACKGROUND: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. RESULTS: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. CONCLUSIONS: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases.
Subject(s)
Neuromuscular Diseases , Humans , Registries , Neuromuscular Diseases/genetics , Rare DiseasesABSTRACT
BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.
Subject(s)
Delivery of Health Care , Mitochondrial Diseases , Humans , Europe , Surveys and Questionnaires , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapyABSTRACT
OBJECTIVE: The molecular characteristics of sporadic inclusion body myositis (sIBM) have been intensively studied, and specific patterns on the cellular, protein and RNA level have emerged. However, these characteristics have not been studied in the context of HIV-associated IBM (HIV-IBM). In this study, we compared clinical, histopathological, and transcriptomic patterns of sIBM and HIV-IBM. METHODS: In this cross-sectional study, we compared patients with HIV-IBM and sIBM based on clinical and morphological features as well as gene expression levels of specific T-cell markers in skeletal muscle biopsy samples. Non-disease individuals served as controls (NDC). Cell counts for immunohistochemistry and gene expression profiles for quantitative PCR were used as primary outcomes. RESULTS: 14 muscle biopsy samples (7 HIV-IBM, 7 sIBM) of patients and 6 biopsy samples from NDC were included. Clinically, HIV-IBM patients showed a significantly lower age of onset and a shorter period between symptom onset and muscle biopsy. Histomorphologically, HIV-IBM patients showed no KLRG1+ or CD57+ cells, while the number of PD1+ cells did not differ significantly between the two groups. All markers were shown to be significantly upregulated at gene expression level with no significant difference between the IBM subgroups. CONCLUSION: Despite HIV-IBM and sIBM sharing important clinical, histopathological, and transcriptomic signatures, the presence of KLRG1+ cells discriminated sIBM from HIV-IBM. This may be explained by longer disease duration and subsequent T-cell stimulation in sIBM. Thus, the presence of TEMRA cells is characteristic for sIBM, but not a prerequisite for the development of IBM in HIV+ patients.
Subject(s)
HIV Infections , Myositis, Inclusion Body , Humans , Myositis, Inclusion Body/genetics , Cross-Sectional Studies , Proteins , T-Lymphocytes/pathology , HIV Infections/complications , HIV Infections/pathology , Muscle, Skeletal/pathologyABSTRACT
BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
Subject(s)
Mitochondrial Myopathies , Quality of Life , Humans , Female , Middle Aged , Male , Merozoite Surface Protein 1/therapeutic use , Mitochondrial Myopathies/drug therapy , Fatigue , Double-Blind Method , Treatment OutcomeABSTRACT
In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.
Subject(s)
Arthrogryposis , Myasthenia Gravis , Neuromuscular Diseases , Pregnancy , Female , Adult , Humans , Immunoglobulins, Intravenous , Receptors, Cholinergic , Myasthenia Gravis/therapy , Myasthenia Gravis/complications , Autoantibodies , Arthrogryposis/complicationsABSTRACT
Recessive mutations in the DNAJB2 gene, encoding the J-domain co-chaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.832 T > G p.(*278Glyext*83) mutation abolishes the stop codon of the DNAJB2a isoform resulting in a C-terminal extension of the protein, with no direct effect predicted on the DNAJB2b isoform of the protein. Analysis of the muscle biopsy showed reduction of both protein isoforms. In functional studies, the mutant protein mislocalized to the endoplasmic reticulum due to a transmembrane helix in the C-terminal extension. The mutant protein underwent rapid proteasomal degradation and also increased the turnover of co-expressed wild-type DNAJB2a, potentially explaining the reduced protein amount in the patient muscle tissue. In line with this dominant negative effect, both wild-type and mutant DNAJB2a were shown to form polydisperse oligomers.
Subject(s)
Neuromuscular Diseases , Peripheral Nervous System Diseases , Humans , Molecular Chaperones/genetics , Mutation , Protein Isoforms/genetics , Mutant Proteins/genetics , HSP40 Heat-Shock Proteins/geneticsABSTRACT
BACKGROUND: Outcome assessment in stroke patients is essential for evidence-based stroke care planning. Computed tomography (CT) is the mainstay of diagnosis in acute stroke. This study aimed to investigate whether CT-derived cervical fat-free muscle fraction (FFMF) as a biomarker of muscle quality is associated with outcome parameters after acute ischemic stroke. METHODS: In this retrospective study, 66 patients (mean age: 76 ± 13 years, 30 female) with acute ischemic stroke in the anterior circulation who underwent CT, including CT-angiography, and endovascular mechanical thrombectomy of the middle cerebral artery between August 2016 and January 2020 were identified. Based on densitometric thresholds, cervical paraspinal muscles covered on CT-angiography were separated into areas of fatty and lean muscle and FFMF was calculated. The study cohort was binarized based on median FFMF (cutoff value: < 71.6%) to compare clinical variables and outcome data between two groups. Unpaired t test and Mann-Whitney U test were used for statistical analysis. RESULTS: National Institute of Health Stroke Scale (NIHSS) (12.2 ± 4.4 vs. 13.6 ± 4.5, P = 0.297) and modified Rankin scale (mRS) (4.3 ± 0.9 vs. 4.4 ± 0.9, P = 0.475) at admission, and pre-stroke mRS (1 ± 1.3 vs. 0.9 ± 1.4, P = 0.489) were similar between groups with high and low FFMF. NIHSS and mRS at discharge were significantly better in patients with high FFMF compared to patients with low FFMF (NIHSS: 4.5 ± 4.4 vs. 9.5 ± 6.7; P = 0.004 and mRS: 2.9 ± 2.1 vs.3.9 ± 1.8; P = 0.049). 90-day mRS was significantly better in patients with high FFMF compared to patients with low FFMF (3.3 ± 2.2 vs. 4.3 ± 1.9, P = 0.045). CONCLUSION: Cervical FFMF obtained from routine clinical CT might be a new imaging-based muscle quality biomarker for outcome prediction in stroke patients.
Subject(s)
Ischemic Stroke , Stroke , Humans , Female , Middle Aged , Aged , Aged, 80 and over , Pilot Projects , Retrospective Studies , Tomography, X-Ray Computed , Muscles , Stroke/diagnostic imagingABSTRACT
Mitochondrial diseases are a heterogeneous group of multisystem disorders caused by impaired mitochondrial function. These disorders occur at any age and involve any tissue, typically affecting organs highly dependent on aerobic metabolism. Diagnosis and management are extremely difficult due to various underlying genetic defects and a wide range of clinical symptoms. Preventive care and active surveillance are strategies to try to reduce morbidity and mortality by timely treatment of organ-specific complications. More specific interventional therapies are in early phases of development and no effective treatment or cure currently exists. A variety of dietary supplements have been utilized based on biological logic. For several reasons, few randomized controlled trials have been completed to assess the efficacy of these supplements. The majority of the literature on supplement efficacy represents case reports, retrospective analyses and open-label studies. We briefly review selected supplements that have some degree of clinical research support. In mitochondrial diseases, potential triggers of metabolic decompensation or medications that are potentially toxic to mitochondrial function should be avoided. We shortly summarize current recommendations on safe medication in mitochondrial diseases. Finally, we focus on the frequent and debilitating symptoms of exercise intolerance and fatigue and their management including physical training strategies.
Subject(s)
Mitochondrial Diseases , Humans , Retrospective Studies , Mitochondria , Fatigue , ExerciseABSTRACT
Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) in late-onset Pompe disease (LOPD) shows beneficial effects in the first years often followed by a decline. We aimed to examine long-term ERT effects in an elderly LOPD cohort. Patients with age at diagnosis/start of ERT >50 years and ERT duration > seven years were included. Outcome parameters were MRC sum-score, 6 Minute Walk Test 6MWT, Quick Motor Function Test QMFT, forced vital capacity FVC sitting/supine, CK levels and rhGAA IgG antibody titers. We retrospectively analysed six patients with a median age at diagnosis/start of ERT of 63 years (range 52-69), and a median ERT duration of eight years (range 7-12). 6MWT improved in 4/6, and 2/6 each showed an improvement or stabilization in muscle strength and FVC supine. In contrast, FVC showed a decline in all patients in a sitting position, and QMFT worsened in 5/6. CK levels decreased in all patients. Antibody titers were not associated with treatment effects. Highest titers were present in best responders who were female, still ambulatory and without ventilatory support at follow-up. ERT effects were very heterogeneous and showed best results in 6MWT, followed by muscle strength in manual testing and FVC supine.
Subject(s)
Glycogen Storage Disease Type II , Aged , Cohort Studies , Enzyme Replacement Therapy/adverse effects , Female , Glycogen Storage Disease Type II/drug therapy , Humans , Male , Middle Aged , Muscle Strength , Retrospective Studies , Treatment Outcome , alpha-Glucosidases/therapeutic useABSTRACT
PURPOSE: To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations. METHODS: Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy. MAIN OUTCOME MEASURES: Phenotypic characteristics of mitochondrial retinopathy. RESULTS: Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination. CONCLUSIONS: Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.
Subject(s)
Fluorescein Angiography/methods , Mitochondrial Diseases/diagnosis , Retinal Degeneration/diagnosis , Retinal Pigment Epithelium/pathology , Visual Acuity , Adolescent , Adult , Aged , Electroretinography , Female , Fundus Oculi , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
To review our diagnostic and treatment approaches concerning sporadic inclusion body myositis (sIBM) and polymyositis with mitochondrial pathology (PM-Mito), we conducted a retrospective analysis of clinical and histological data of 32 patients diagnosed as sIBM and 7 patients diagnosed as PM-Mito by muscle biopsy. Of 32 patients identified histologically as sIBM, 19 fulfilled the 2011 European Neuromuscular Center (ENMC) diagnostic criteria for "clinico-pathologically defined sIBM" at the time of biopsy. Among these, 2 patients developed sIBM after years of immunosuppressive treatment for organ transplantation. Of 11 patients fulfilling the histological but not the clinical criteria, including 3 cases with duration <12 months, 8 later fulfilled the criteria for clinico-pathologically defined sIBM. Of 7 PM-Mito patients, 4 received immunosuppression with clinical improvement in 3. One of these later developed clinico-pathologically defined sIBM; 1 untreated patient progressed to clinically defined sIBM. Thus, muscle histology remains important for this differential diagnosis to identify sIBM patients not matching the ENMC criteria and the PM-Mito group. In the latter, we report at least 50% positive, if occasionally transient, response to immunosuppressive treatments and progression to sIBM in a minority. The mitochondrial abnormalities defining PM-Mito do not seem to define the threshold to immunosuppression unresponsiveness.
Subject(s)
Mitochondria/pathology , Myositis, Inclusion Body/diagnosis , Myositis, Inclusion Body/pathology , Polymyositis/pathology , Aged , Biopsy , Diagnosis, Differential , Disease Progression , Female , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Muscle, Skeletal/pathology , Myositis, Inclusion Body/drug therapy , Organ Transplantation , Polymyositis/drug therapy , Retrospective StudiesABSTRACT
BACKGROUND: The C22 mouse is a Charcot-Marie-Tooth 1A transgenic model with minimal axonal loss. OBJECTIVE: To analyse early skeletal muscle changes resulting from this dysmyelinating neuropathy. METHODS: Histology of tibialis anterior muscles of C22 mice and wild type litter mate controls for morphometric analysis and (immuno-)histochemistry for known denervation markers and candidate proteins identified by representational difference analysis (RDA) based on mRNA from the same muscles; quantitative PCR and Western blotting for confirmation of RDA findings. RESULTS: At age 10 days, morphometry was not different between groups, while at 21 days, C22 showed significantly more small diameter fibres, indicating the onset of atrophy at an age when weakness becomes detectable. Neither (immuno-)histochemistry nor RDA detected extrajunctional expression of acetylcholine receptors by age 10 and 21 days, respectively. RDA identified some mRNA up-regulated in C22 muscles, among them at 10 days, prior to detectable weakness or atrophy, integral membrane protein 2a (Itm2a), eukaryotic initiation factor 2, subunit 2 (Eif2s2) and cytoplasmic phosphatidylinositol transfer protein 1 (Pitpnc1). However, qPCR failed to measure significant differences. In contrast, Itm2a and Eif2s2 mRNA were significantly down-regulated comparing 21 versus 10 days of age in both groups, C22 and controls. Western blotting confirmed significant down-regulation of ITM2A protein in C22 only. CONCLUSION: Denervation-like changes in this model develop slowly with onset of atrophy and weakness at about three weeks of age, before detection of extrajunctional acetylcholine receptors. Altered Itm2a expression seems to begin early as an increase, but becomes distinct as a decrease later.
Subject(s)
Charcot-Marie-Tooth Disease/pathology , Muscle, Skeletal/pathology , Animals , Disease Models, Animal , Female , Humans , Membrane Transport Proteins , Mice , PhenotypeABSTRACT
BACKGROUND: Mitochondrial disorders are among the most common heritable diseases, with an overall lifetime risk of approximately one in 1500. Nonetheless, their diagnosis is often missed because of their extreme phenotypic and genotypic heterogeneity. METHODS: This review is based on publications retrieved by a selective literature search on the clinical features, genetics, pathogenesis, diagnosis, and treatment of mitochondrial diseases. RESULTS: Pathogenic defects of energy metabolism have been described to date in over 400 genes. Only a small number of these genes lie in the mitochondrial DNA; the corresponding diseases are either maternally inherited or of sporadic distribution. The remaining disease-associated genes are coded in nuclear DNA and cause diseases that are inherited according to Mendelian rules, mostly autosomal recessive. The most severely involved organs are generally those with the highest energy requirements, including the brain, the sensory epithelia, and the extraocular, cardiac, and skeletal musculature. Typical manifestations include epileptic seizures, stroke-like episodes, hearing loss, retinopathy, external ophthalmoparesis, exercise intolerance, and diabetes mellitus. More than two manifestations of these types should arouse suspicion of a disease of energy metabolism. The severity of mitochondrial disorders ranges from very severe disease, already evident in childhood, to relatively mild disease arising in late adulthood. The diagnosis is usually confirmed with molecular-genetic methods. Symptomatic treatment can improve patients' quality of life. The only disease-modifying treatment that has been approved to date is idebenone for the treatment of Leber hereditary optic neuropathy. Intravitreal gene therapy has also been developed for the treatment of this disease; its approval by the European Medicines Agency is pending. CONCLUSION: Patients with mitochondrial diseases have highly varied manifestations and can thus present to physicians in practically any branch of medicine. A correct diagnosis is the prerequisite for genetic counseling and for the initiation of personalized treatment.
Subject(s)
Mitochondrial Diseases , Optic Atrophy, Hereditary, Leber , Adult , DNA, Mitochondrial/genetics , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Quality of LifeABSTRACT
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
Subject(s)
Mitochondrial Diseases/genetics , Mitochondrial Diseases/physiopathology , Mitochondrial Diseases/therapy , DNA, Mitochondrial/genetics , Genetic Therapy/methods , Genetic Therapy/trends , High-Throughput Nucleotide Sequencing/methods , Humans , Mutation/geneticsABSTRACT
Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.