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OBJECTIVE: In Friedreich's ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo. METHODS: Skeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects. RESULTS: FRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: (1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and (2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression. INTERPRETATION: Our findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA.
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Eritropoetina , Ataxia de Friedreich , Animais , Humanos , Transcriptoma/genética , Leptina/genética , Ataxia de Friedreich/patologia , Eritropoetina/genética , RNA , Músculo Esquelético/metabolismo , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismoRESUMO
BACKGROUND: Pain is a frequent yet poorly characterized symptom of multiple system atrophy (MSA). Understanding the factors influencing pain and its burden is crucial for improving the symptomatic treatment and quality of life of MSA individuals. OBJECTIVE: This study aimed at assessing the prevalence, characteristics, and current treatment strategies for pain in MSA. METHODS: A community-based, online survey was conducted from February to May 2023. Invitations were extended to MSA individuals and informal MSA caregivers through patient advocacies and social media. RESULTS: We included 190 persons with MSA and 114 caregivers. Eighty-seven percent of MSA individuals reported pain, which was more prevalent among women (odds ratio [OR]: 6.38 [95% confidence interval, CI: 1.27-32.08], P = 0.025) and low-income groups (OR: 5.02 [95% CI: 1.32-19.08], P = 0.018). Neck and shoulders (58%), back (45%), and legs (45%) were mostly affected. In the neck and shoulders, pain was associated with MSA core features, like orthostatic intolerance (OR: 4.80 [95% CI: 1.92-12.02], P = 0.001) and antecollis (OR: 3.24 [95% CI: 1.54-6.82], P = 0.002). Seventy-six percent of individuals experiencing pain received treatment, mostly nonsteroidal anti-inflammatory drugs (47%), acetaminophen (39%), and opioids (28%). Only 53% of respondents reported at least partial satisfaction with their current pain management. Pain mostly impacted work, household activities, and hobbies of MSA individuals, and caregivers' social activities. CONCLUSIONS: Pain is more prevalent than previously reported in MSA and particularly affects women and low-income groups. Despite its frequency, pain management remains suboptimal, highlighting an urgent therapeutic need, likely entailing an optimized management of MSA core motor and non-motor features. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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INTRODUCTION/AIMS: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS. METHODS: NfL was measured in serum in n = 37 patients with MMN and n = 37 age- and sex-matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling. RESULTS: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p < .01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963-1.000], sensitivity 94.6%, specificity 100%, cut-off 44.00 pg/mL). DISCUSSION: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process.
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Esclerose Lateral Amiotrófica , Polineuropatias , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores , Filamentos Intermediários , Prognóstico , Polineuropatias/diagnóstico , Proteínas de NeurofilamentosRESUMO
Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.
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Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Feminino , Masculino , Humanos , Mialgia/genética , Estudos Retrospectivos , Anoctaminas/genética , Mutação/genética , Doenças Musculares/epidemiologia , Doenças Musculares/genética , Doenças Musculares/patologia , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Atrofia/patologiaRESUMO
BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.
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Cardiopatias/metabolismo , Doenças Musculares/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Biomarcadores , Estudos de Casos e Controles , Feminino , Cardiopatias/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Estudos Prospectivos , RNA Mensageiro/análise , Reprodutibilidade dos Testes , Troponina I/genética , Troponina T/genéticaRESUMO
We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Doenças Musculares , Humanos , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/complicações , Doenças Musculares/complicações , Amiloide , Pré-AlbuminaRESUMO
BACKGROUND AND PURPOSE: Hereditary myopathies with limb-girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW. METHODS: This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses. RESULTS: Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next-generation sequencing (NGS) than by single-gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7-19.9) and 17.8 (7.9-27.8) years for single-gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants. CONCLUSIONS: Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.
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Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Anoctaminas/genética , Áustria/epidemiologia , Estudos de Coortes , Humanos , Debilidade Muscular/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Pentosiltransferases/genéticaRESUMO
BACKGROUND AND PURPOSE: Neurological sequelae from coronavirus disease 2019 (COVID-19) may persist after recovery from acute infection. Here, the aim was to describe the natural history of neurological manifestations over 1 year after COVID-19. METHODS: A prospective, multicentre, longitudinal cohort study in COVID-19 survivors was performed. At a 3-month and 1-year follow-up, patients were assessed for neurological impairments by a neurological examination and a standardized test battery including the assessment of hyposmia (16-item Sniffin' Sticks test), cognitive deficits (Montreal Cognitive Assessment < 26) and mental health (Hospital Anxiety and Depression Scale and Post-traumatic Stress Disorder Checklist 5). RESULTS: Eighty-one patients were evaluated 1 year after COVID-19, out of which 76 (94%) patients completed a 3-month and 1-year follow-up. Patients were 54 (47-64) years old and 59% were male. New and persistent neurological disorders were found in 15% (3 months) and 12% (10/81; 1 year). Symptoms at 1-year follow-up were reported by 48/81 (59%) patients, including fatigue (38%), concentration difficulties (25%), forgetfulness (25%), sleep disturbances (22%), myalgia (17%), limb weakness (17%), headache (16%), impaired sensation (16%) and hyposmia (15%). Neurological examination revealed findings in 52/81 (64%) patients without improvement over time (3 months, 61%, p = 0.230) including objective hyposmia (Sniffin' Sticks test <13; 51%). Cognitive deficits were apparent in 18%, whereas signs of depression, anxiety and post-traumatic stress disorders were found in 6%, 29% and 10% respectively 1 year after infection. These mental and cognitive disorders had not improved after the 3-month follow-up (all p > 0.05). CONCLUSION: Our data indicate that a significant patient number still suffer from neurological sequelae including neuropsychiatric symptoms 1 year after COVID-19 calling for interdisciplinary management of these patients.
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COVID-19 , Anosmia/diagnóstico , Anosmia/etiologia , COVID-19/complicações , COVID-19/diagnóstico , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2RESUMO
BACKGROUND AND PURPOSE: Elevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain-Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false-positive results, mainly as a result of lack of age-adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age-dependent URL. METHODS: Patients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age-dependent URL. RESULTS: Ninety-seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age-dependent URL. At 0-3, 4-7, 8-14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age-dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Qalb ). CONCLUSION: Fewer true-positives for CSF total protein and Qalb must be considered in suspected GBS, especially in the early disease course.
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Síndrome de Guillain-Barré , Adulto , Feminino , Síndrome de Guillain-Barré/epidemiologia , Humanos , MasculinoRESUMO
BACKGROUND AND PURPOSE: Since the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several reports indicated neurological involvement in COVID-19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia. METHODS: Creatine kinase, markers of inflammation, pre-existing diseases and statin use were extracted from records of Austrian hospitalised COVID-19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID-19 patients were additionally compared to an historical group of hospitalised influenza patients. RESULTS: Three hundred fifty-one patients with SARS-CoV-2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID-19 and in 28% of influenza patients. CK was higher in severe COVID-19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID-19 patients were older, more frequently male, had more comorbidities, and more frequently had a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID-19, and 35.7% of intensive care unit (ICU)-admitted patients had CK levels >1,000 U/L compared to only 4.7% of ICU-admitted COVID-19 patients. CONCLUSIONS: HyperCKemia occurs in a similar frequency in COVID-19 and influenza infection. CK levels were lower in COVID-19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date, it remains unclear whether hyperCKemia is due to a virus-triggered inflammatory response or direct muscle toxicity.
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COVID-19 , Influenza Humana , Humanos , Influenza Humana/complicações , Influenza Humana/epidemiologia , Masculino , Músculos , Pandemias , SARS-CoV-2RESUMO
Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat- and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal).
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Neuropatias Amiloides Familiares/genética , Pré-Albumina/genética , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/patologia , Humanos , Mutação , Pré-Albumina/metabolismoRESUMO
PURPOSE: To assess whether autonomic failure belongs to the clinical spectrum of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant genetic disorder showing progressive cerebellar and brainstem dysfunction. METHODS: We evaluated cardiovascular autonomic function in 8 patients with SCA2 and 16 age- and gender-matched healthy controls. Other autonomic domains were examined through standardized questionnaires and by testing the skin sympathetic reflex. RESULTS: Patients with SCA2 showed normal responses to cardiovascular autonomic function tests, with the exception of lower baroreflex sensitivity upon standing compared to controls. In questionnaires, 7 out of 8 patients reported bladder disturbances, while 3 out of 6 tested patients had no skin sympathetic reflex. CONCLUSIONS: We did not observe clinically overt cardiovascular autonomic failure in patients with SCA2. Other autonomic domains (i.e., bladder and sudomotor function) may be affected in the disease.
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Sistema Nervoso Autônomo/fisiopatologia , Ataxias Espinocerebelares/fisiopatologia , Adulto , Barorreflexo , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Reflexo , Pele/inervação , Ataxias Espinocerebelares/diagnóstico , Sistema Nervoso Simpático/fisiopatologia , Manobra de ValsalvaRESUMO
Nerve entrapment syndromes of the upper extremity are associated with structural abnormalities or by an intrinsic abnormality of the nerve. Nerve entrapment syndromes generally have a typical clinical presentation, and findings on physical examination and in conjunction with electrodiagnostic studies imaging is used to evaluate the cause, severity, and etiology of the entrapment. With the development of high-frequency linear array transducers (12-24 MHz), ultrasound (US) is incomparable in terms of spatial resolution to depict morphological aspects and changes in nerves. US can identify the abnormalities causing entrapment, such as fibrous bands, ganglia, anomalous muscles, and osseous deformities, with the advantage of dynamic assessment under active and passive examination. US is a unique diagnostic modality that allows superb visualization of both large and small peripheral terminal nerve branches of the upper extremity and enables the correct diagnosis of various nerve entrapment syndromes.
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Cotovelo/inervação , Síndromes de Compressão Nervosa/diagnóstico por imagem , Ultrassonografia/métodos , Punho/inervação , Humanos , Extremidade Superior/inervaçãoRESUMO
We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1.
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Doença de Charcot-Marie-Tooth/genética , Proteína P2 de Mielina/genética , Adolescente , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Condução Nervosa/genética , Linhagem , Adulto JovemRESUMO
The present guidelines on dermatomyositis (DM) represent an excerpt from the interdisciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30% of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic workup. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5-20% of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30% of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1-2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of intravenous immunoglobulins is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for one to three years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include antimalarial agents (also in combination), methotrexate, and corticosteroids. Intravenous immunoglobulins or rituximab may also be helpful. UV protection is an important prophylactic measure.
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Dermatologia/normas , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Técnicas de Diagnóstico Neurológico , Neurologia/normas , Guias de Prática Clínica como Assunto , Corticosteroides/uso terapêutico , Alemanha , Imunossupressores/uso terapêuticoRESUMO
Immune checkpoint inhibitors (ICIs) have significantly improved the clinical outcome in multiple types of advanced or metastatic malignancies and are prescribed increasingly. However, immune-related adverse events (irAEs) occur frequently. Here, we present a patient with multifocal motor neuropathy and melanoma, with worsening of muscle weakness upon ICI therapy and concomitant use of steroids for the treatment of hepatitis, which was considered an irAE. Upon treatment with highly dosed immunoglobulins and steroid tapering, the patients' muscular symptoms improved while hepatitis resolved. This case highlights the importance of careful evaluation of patients with multifocal motor neuropathy treated with ICIs, highlights the risks of treatment with steroids in multifocal motor neuropathy patients and suggests an alternative treatment of irAEs with intravenous immunoglobulins.
[Box: see text].
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Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/imunologia , Masculino , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/efeitos adversos , Pessoa de Meia-Idade , Polineuropatias/induzido quimicamente , FemininoRESUMO
Diagnostic approach and treatment of idiopathic inflammatory myopathies have changed considerably during the past decades. In this review, new insights in the pathogenesis, the role of muscle biopsy, and magnetic resonance imaging in the diagnostic process in children with suspected myositis are discussed. Current treatment strategies and complication management is described in detail.
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Miosite/diagnóstico , Miosite/terapia , Pediatria , Criança , HumanosRESUMO
Objective: The gene MT-TF encodes the mitochondrial tRNA of phenylalanine (tRNAphe). Its variations have been described as extremely rare etiologies of a variety of mitochondrial phenotypes. Methods: By means of whole-exome sequencing (WES), we detected a novel likely causative MT-TF variant (m.610T>C) in a family presenting with a combined movement disorder and epilepsy phenotype. The variant was present at 97% heteroplasmy in the peripheral blood and in a homoplasmic state in skin fibroblast-derived DNA. Results: The inaugural manifestation in the index patient was new-onset refractory myoclonic status epilepticus (NORSE) at the age of 29 years. Her son presented later with developmental regression and myoclonic epilepsy. On the beginning of valproate because of ongoing myoclonic seizures, the index patient developed a generalized brain edema requiring bilateral craniotomy. In the course of the disease, epileptic manifestations abated, and both patients developed a severe movement disorder phenotype with prominent spastic-dystonic features. Both patients did not display any further sign of mitochondrial disease. Discussion: Our report expands the clinicogenetic background of tRNAphe disease spectrum and highlights pitfalls in the diagnostics and management of mitochondrial epilepsy. The present findings advocate the introduction of rapid genetic testing in the diagnostic flow chart of NORSE in adults.
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(1) Background: This study aims to assess the diagnostic accuracy of parameters based on a combination of transcranial magnetic stimulation (TMS) and electrical stimulation (ES) in the differentiation between idiopathic and secondary facial palsy in a large cohort of patients. (2) Methods: Patients with unilateral facial palsy ≤7 days after symptom onset were included. Compound muscle action potential (CMAP) amplitudes were measured after stimulation of both facial nerves at (A) the internal acoustic meatus using TMS, CMAP-TMS, and (B) at the stylomastoid foramen using electrical stimulation, CMAP-ES. To express the degree of nerve dysfunction in the facial canal specifically, the amplitude reduction of the CMAP-TMS in relation to CMAP-ES was calculated and expressed as a percentage (amplitude reduction over the facial canal, ARFC). Receiver Operating Characteristic (ROC) curves were constructed to assess the diagnostic accuracy of ARFC as a marker to discriminate between patients with idiopathic and secondary facial palsy. (3) Results: Data from 498 patient records were analyzed. Idiopathic facial palsy was diagnosed in 424 patients, and secondary facial palsy in 74 patients. The area under the ROC curve for ARFC was 0.398. (4) Conclusions: The overall diagnostic accuracy of this method to differentiate secondary from idiopathic facial palsy is low.
RESUMO
Friedreich's ataxia (FRDA) is a severe multisystemic disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. Thus, we performed a quantitative mass spectrometry-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n = 5) and controls. Obtained data files were processed using Proteome Discoverer and searched by Sequest HT engine against a UniProt human reference proteome database. Comparing skeletal muscle proteomics profiles between FRDA and controls, we identified 228 significant differentially expressed (DE) proteins, of which 227 were downregulated in FRDA. Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control, and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift toward fast-twitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2. Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle-omics as disease state readout in FRDA.