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OBJECTIVE: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease-causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non-genetic causes. METHODS: We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed. RESULTS: We identified 9 patients diagnosed with late-onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. INTERPRETATION: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024.
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OBJECTIVES: To determine prevalence and clinical associations of anti-FHL1 autoantibodies in patients with idiopathic inflammatory myopathies (IIM), and to evaluate autoantibody levels over time. METHODS: Sera at the time of diagnosis from patients with IIM (n = 449), autoimmune disease controls (DC, n = 130), neuromuscular diseases (NMD, n = 16) and healthy controls (HC, n = 100) were analyzed for anti-FHL1 autoantibodies by Enzyme-Linked ImmunoSorbent Assay (ELISA). Patients with IIM FHL1+ and FHL1- were included in a longitudinal analysis. Serum levels were correlated to disease activity. RESULTS: Autoantibodies to FHL1 were more frequent in patients with IIM (122/449, 27%) compared with DC (Autoimmune DC and NMD, 13/146, 9%, p< 0.001) and HC (3/100,3%, p< 0.001). Anti-FHL1 levels were higher in IIM [median (IQR)=0.62 (0.15-1.04)] in comparison with DC [0.22 (0.08-0.58)], HC [0.35 (0.23-0.47)] and NMD [0.48 (0.36-0.80)] p< 0.001. Anti-FHL1+ patients with IIM were younger at time of diagnosis compared with the anti-FHL1- group (p= 0.05) and were seronegative for other autoantibodies in 25%.In the first follow-up anti-FHL1+ sample 20/33 (60%) positive at baseline had turned negative for anti-FHL1 autoantibodies. Anti-FHL1 autoantibodies rarely appeared after initiating treatment. Anti-FHL1 autoantibody levels correlated with CK (r = 0.62, p= 0.01), disease activity measure MYOACT (n = 14, p= 0.004) and inversely with manual muscle test-8 (r=-0.59, p= 0.02) at baseline. CONCLUSIONS: Anti-FHL1 autoantibodies were present in 27% of patients with IIM, of these 25% were negative for other autoantibodies. Other autoimmune diseases had lower frequencies and levels. Anti-FHL1 levels often decreased with immunosuppressive treatment, correlated with disease activity measures at diagnosis and rarely appeared after start of treatment.
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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
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Arritmias Cardíacas/genética , Cardiomiopatía Hipertrófica/mortalidad , Insuficiencia Cardíaca/genética , Proteínas Represoras/genética , Adulto , Animales , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/fisiopatología , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Muerte Súbita Cardíaca/patología , Desmina/genética , Modelos Animales de Enfermedad , Femenino , Ligamiento Genético/genética , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Homocigoto , Humanos , Masculino , Mutación , Linaje , Fenotipo , Pez Cebra/genéticaRESUMEN
PURPOSE OF REVIEW: The continued development in the field of immunohistochemistry (IHC) has improved the ability to diagnose muscle diseases. Many hereditary diseases are diagnosed by the absence or abnormal localization of proteins. Detection of secondary pathological protein expression is also used in diagnostics, and to study disease processes. We relate and discuss recent reports, where IHC has been an important tool in the investigation of muscle diseases. RECENT FINDINGS: In idiopathic inflammatory myopathies, IHC has extended its role to diagnose subgroups. This is most evident concerning immune-mediated necrotizing myopathy and antisynthetase syndrome. The availability of new antibodies has increased the sensitivity of a muscle biopsy to diagnose several hereditary myopathies. The introduction of protein restoration therapies in muscular dystrophies also comes with the need to detect and measure protein levels. For the study of disease processes at the protein level, in both acquired and hereditary myopathies IHC, often combined with gene studies, PCR-based methods, western blotting and electron microscopy, continues to bring forth interesting results. SUMMARY: IHC is an integrated tool in muscle pathology, where recent studies contribute to improved diagnostic skills and increased insights into disease processes.
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Enfermedades Musculares , Distrofias Musculares , Miositis , Humanos , Inmunohistoquímica , Músculo Esquelético , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Distrofias Musculares/diagnóstico , Distrofias Musculares/genéticaRESUMEN
BACKGROUND: One-third of patients with non-alcoholic fatty liver disease (NAFLD) develop dysmetabolic iron overload syndrome (DIOS), the pathogenesis of which is unknown. Altered production of the iron-regulatory peptide hepcidin has been reported in NAFLD, but it is unclear if this is related to iron accumulation, lipid status or steatohepatitis. METHODS: Eighty-four patients with liver disease, 54 of which had iron overload, underwent liver biopsy (n = 66) and/or magnetic resonance imaging (n = 35) for liver iron content determination. Thirty-eight of the patients had NAFLD, 29 had chronic liver disease other than NAFLD, and 17 had untreated genetic hemochromatosis. Serum hepcidin was measured with ELISA in all patients and in 34 controls. Hepcidin antimicrobial peptide (HAMP) mRNA in liver tissue was determined with real-time-quantitative PCR in 36 patients. RESULTS: Serum hepcidin was increased similarly in NAFLD with DIOS as in the other chronic liver diseases with iron overload, except for genetic hemochromatosis. HAMP mRNA in liver tissue, and serum hepcidin, both correlated to liver iron content in NAFLD patients (r2 = 0.45, p < 0.05 and r2 = 0.27, p < 0.05 respectively) but not to body mass index, NAFLD activity score or serum lipids. There was a good correlation between HAMP mRNA in liver tissue and serum hepcidin (r2 = 0.39, p < 0.01). CONCLUSIONS: In NAFLD with or without dysmetabolic iron overload, serum hepcidin and HAMP mRNA in liver correlate to body iron content but not to the degree of steatohepatitis or lipid status. Thus, the dysmetabolic iron overload syndrome seen in NAFLD is not caused by an altered hepcidin synthesis.
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Hepcidinas/sangre , Hierro/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Adulto , Anciano , Biopsia , Índice de Masa Corporal , Enfermedad Crónica , Femenino , Ferritinas/sangre , Expresión Génica , Hemocromatosis/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Sobrecarga de Hierro/metabolismo , Lípidos/sangre , Hígado/diagnóstico por imagen , Hígado/patología , Hepatopatías/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/genética , ARN Mensajero/metabolismo , Transferrina/metabolismoRESUMEN
Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.
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Colorantes Fluorescentes/química , Proteínas/química , Tiofenos/química , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras Transductoras de Señales/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Técnicas Biosensibles , Humanos , Cuerpos de Inclusión/química , Cuerpos de Inclusión/metabolismo , Ligandos , Microscopía Fluorescente , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Proteínas/análisis , Proteína Sequestosoma-1RESUMEN
Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
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Salud de la Familia , Proteínas Musculares/genética , Enfermedades Musculares/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Quinasas/genética , Insuficiencia Respiratoria/genética , Actinas/metabolismo , Adulto , Anciano , Conectina , Extremidades/patología , Femenino , Estudios de Asociación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Enfermedades Musculares/complicaciones , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Insuficiencia Respiratoria/complicaciones , SueciaRESUMEN
Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. There is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. A T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well.
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Debilidad Muscular/etiología , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión , Biopsia , Diagnóstico Diferencial , Femenino , Humanos , Inflamación/diagnóstico , Masculino , Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/epidemiología , Miositis por Cuerpos de Inclusión/etiología , Miositis por Cuerpos de Inclusión/fisiopatología , Miositis por Cuerpos de Inclusión/terapia , Pronóstico , Distribución por Sexo , Insuficiencia del TratamientoRESUMEN
BACKGROUND Solid pseudopapillary neoplasm (SPN) of the pancreas, which predominantly affects young women, is an uncommon condition with low malignant potential. It is often asymptomatic. This tumor has a low metastatic rate and a good prognosis in contrast to other pancreatic tumors. Approximately 14% of SPNs develop liver metastasis, but for SPNs with malignant features liver metastasis has been reported to occur in over 55% of cases. Complete surgical resection is the treatment of choice for increasing the survival rate in metastatic recurrent disease. When surgical resection is impossible, liver transplantation has shown promising results in a few cases. The purpose of this article is to present the first case of a male patient who underwent liver transplantation for this indication. CASE REPORT We present the case of a 60-year-old male patient who previously had pancreas surgery, numerous liver resections, and chemotherapy for SPN, but nevertheless developed recurrence of multiple liver metastases. His metastatic liver disease was regarded as unresectable. The lymphatic structure was also affected. The patient underwent orthotopic liver transplantation with a deceased donor graft after multidisciplinary evaluation. Resection of involved lymphatic structures was also performed. At 2-year follow-up, the patient was alive and recurrence free. CONCLUSIONS This is the first published report of a male patient who underwent liver transplantation due to SPN metastasis. Our case demonstrates that liver transplantation should be further investigated for selected cases of SPN of the pancreas with liver metastatic disease when surgical resection is deemed unattainable.
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Neoplasias Hepáticas , Trasplante de Hígado , Neoplasias Pancreáticas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Páncreas/cirugía , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , PancreatectomíaRESUMEN
INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition associated with fibroinflammatory lesions that can occur at almost any anatomical site. It often presents as a multiorgan disease that may mimic malignancy, infection, or other immune-mediated conditions. Autoimmune pancreatitis (AIP) type 1 is the most prominent manifestation of IgG4-RD in the digestive tract, with common extra-pancreatic inflammation. We present the first patient with AIP and involvement of the testicles and nasal cavity. PATIENT AND METHODS: A case of a patient with AIP type 1 and other organ involvement (bile ducts, testicles, nasal polyps, and lungs) is described. Additionally, a systematic review of AIP type 1 with testicular and nasal involvement was conducted. RESULTS: The systematic review found two cases of AIP type 1 with testicular involvement and 143 cases with AIP type 1 with nasal cavity involvement. None of them had both testicular and nasal involvement. CONCLUSIONS: This is the first case of AIP type 1 with other organ involvement, including testicular and nasal involvement, to be described. The number of patients with nasal and testicular involvement described in the literature is low. Creating awareness of this rare clinical condition is necessary, especially due to the very effective available treatment with corticosteroids and rituximab.
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The selenium salt selenite (SeO(3)(2-)) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x(c)(-) antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.
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Sistema de Transporte de Aminoácidos y+/metabolismo , Cistina/metabolismo , Espacio Extracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Selenio/metabolismo , Selenito de Sodio/toxicidad , Compuestos de Sulfhidrilo/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antiportadores/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cistina/análogos & derivados , Cistina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Espacio Extracelular/efectos de los fármacos , Glutatión/análogos & derivados , Glutatión/farmacología , Humanos , Modelos Biológicos , Compuestos de Organoselenio/farmacología , Oxidación-Reducción/efectos de los fármacosRESUMEN
Background: The objective of this study is to assess the frequency of autoantibodies against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in a single center myositis cohort and to analyze associations with statin exposure, clinical features, and outcome of disease course. Methods: A total of 312 patients with idiopathic inflammatory myopathies (IIMs) followed at the rheumatology clinic, Karolinska University Hospital, were identified in the Euromyositis registry between 1988 and 2014 and were classified according to the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) criteria. Available serum samples were analyzed for anti-HMGCR autoantibodies by ELISA. Positive sera were confirmed by immunoprecipitation. Clinical data were extracted from Euromyositis registry and medical records. Muscle samples were examined by two pathologists blinded to the subjects' autoantibody status. Results: Of 312 patients, 13 (4.3%) were positive for anti-HMGCR. Two of the 13 (15%) anti-HMGCR-positive patients had histories of statin use versus 12 (4.2%) in the anti-HMGCR-negative group. In the anti-HMGCR-positive group, five (38%) had a clinical phenotype compatible with dermatomyositis. Muscle biopsies of patients with HMGCR autoantibodies showed findings consistent with immune-mediated necrotizing myopathy in all cases except for one. Five (38%) patients required treatment with intravenous immunoglobulin compared to seven (2.3%) without this antibody. At the last visit, seven patients had chronic, active disease course, and five of 13 patients were in remission, including three without treatment. Conclusions: Patients with IIM related to anti-HMGCR autoantibodies may present with a wide range of symptoms, more than previously anticipated. When a broad approach to screening for these antibodies is applied, only a minority of patients was found to have previous statin exposure. The results of this study justify the addition of anti-HMGCR autoantibodies to routine diagnostic procedures in patients with myositis.
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Enfermedades Autoinmunes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Miositis , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Miositis/diagnóstico , Miositis/tratamiento farmacológicoRESUMEN
Adipocyte hypertrophy and expression of adipokines in subcutaneous adipose tissue (SAT) have been linked to steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis in morbidly obese (BMI ≥ 40 kg/m2) subjects. It is unknown if this is also true for subjects with NAFLD with lesser degrees of obesity (BMI < 35 kg/m2). Thirty-two subjects with biopsy-proven NAFLD and 15 non-diabetic controls matched for BMI underwent fine-needle biopsies of SAT. Adipocyte volume was calculated. RNA-sequencing of SAT was performed in a subset of 20 NAFLD patients. Adipocyte volume and gene expression levels were correlated to the presence of NASH or significant fibrosis. Subjects with NAFLD had larger adipocyte volume compared with controls, (1939 pL, 95% CI 1130-1662 vs. 854 pL, 95% CI 781-926, p < 0.001). There was no association between adipocyte volume and the presence of NASH. Gene expression of adipokines previously described to correlate with NASH in morbid obesity, was not associated with NASH or fibrosis. Our results suggest that persons with NAFLD have larger SAT adipocytes compared with controls and that adipocytes are involved in the pathophysiology of hepatic steatosis in NAFLD. However, adipocyte volume was not associated with NASH or fibrosis in NAFLD subjects with varying degrees of obesity.
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Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Obesidad Mórbida/complicaciones , Adipoquinas , Adipocitos , Biopsia con Aguja Fina , Fibrosis , HipertrofiaRESUMEN
Radical tumor resection (pR0) is prognostic for disease-free and overall survival after resection of perihilar cholangiocarcinoma (pCCA). However, no universal agreement exists on the definition of radical resection and histopathological reporting. The aim of this study was to provide a standardized protocol for histopathological assessment and reporting of the surgical specimen obtained after resection for pCCA. All consecutive patients operated for pCCA with curative intent at the Karolinska University Hospital, Stockholm, Sweden between 2012 and 2021 were included. A standardized protocol for histopathological assessment and reporting of the surgical specimen after liver resection for pCCA is presented. A detailed mapping of the transection margins and dissection planes was performed. The results of applying different existing pR0 definitions were compared. Sixty-eight patients with pCCA were included. Five transection margins and two dissection planes were defined. By defining pR0 as cancer-free margins and planes tolerating distances <1mm, the pR0 rate was 66%. However, when pR0 was set as >1mm from invasive cancer to all resection margins and dissection planes, the pR0 rate fell to 16%. This study supports the use of thorough and standardized pathological handling, assessment and reporting of resection margins and dissection planes of surgical specimens of pCCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/cirugía , Hepatectomía , Humanos , Tumor de Klatskin/patología , Tumor de Klatskin/cirugía , Márgenes de Escisión , Estudios RetrospectivosRESUMEN
Case histories of two unrelated patients suffering from sensory ataxic neuropathy, dysarthria/dysphagia and external ophthalmoplegia (SANDO) are reported. Both patients showed compound heterozygosity for POLG1 gene mutations, and presented with symptom of the clinical characteristics of SANDO. A patient with a p.A467T and p.W748S, well-known mutations showed a progressive course with early onset and multisystem involvement, including symptoms characteristics for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The second patient showed a less well-known p.T251I and p.G848S mutations with late onset and dysphagia/dysarthria dominated, moderate symptoms. This later is the second published case history, when these POLG1 gene mutations are the possible background of late onset SANDO, dominantly presenting with bulbar symptoms.
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Disartria/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Oftalmoplejía/diagnóstico , Anciano , ADN Polimerasa gamma , ADN Polimerasa Dirigida por ADN/genética , Disartria/complicaciones , Disartria/genética , Femenino , Neuropatía Hereditaria Motora y Sensorial/complicaciones , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Masculino , Persona de Mediana Edad , Oftalmoplejía/complicaciones , Oftalmoplejía/genéticaRESUMEN
Polymyositis and inclusion body myositis are idiopathic inflammatory myopathies, with a pathology characterized by partial invasion of non-necrotic muscle fibres by CD8+ cytotoxic T-cells, leading to fibre degeneration. Although the main effector pathway of CD8+ T-cells is to induce apoptosis of target cells, it has remained unclear if apoptosis occurs in these diseases, and if so, if it is mediated by CD8+ T-cells. In consecutive biopsy sections from 10 patients with partial invasion, muscle fibres and inflammatory cells were assessed by immunohistochemistry and apoptotic nuclei by the TUNEL assay. Analysis of muscle fibre morphology, staining pattern and quantification were performed on digital images, and they were compared with biopsies from 10 dermatomyositis patients and 10 controls without muscle disease. Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8+ T-cells, granzyme B+ cells and macrophages, but lacked FAS receptor expression. In contrast, apoptotic myonuclei were rare in dermatomyositis and absent in controls. The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8+ cytotoxic T- cells, acting in parallel to the process of partial invasion.
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Apoptosis/inmunología , Fibras Musculares Esqueléticas/patología , Miositis por Cuerpos de Inclusión/inmunología , Polimiositis/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Biopsia , Estudios de Cohortes , Femenino , Humanos , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Fibras Musculares Esqueléticas/inmunología , Miositis por Cuerpos de Inclusión/patología , Polimiositis/patologíaRESUMEN
Selenium compounds influence cell growth and are highly interesting candidate compounds for cancer chemotherapy. Over decades an extensive number of publications have reported highly efficient growth inhibitory effects with a number of suggested mechanisms f especially for redox-active selenium compounds. However, the studies are difficult to compare due to a high degree of variations in half-maximal inhibitor concentration (IC50) dependent on cultivation conditions and methods to assess cell viability. Among other factors, the variability in culture conditions may affect the experimental outcome. To address this, we have compared the maintenance effects of four commonly used cell culture media on two cell lines, A549 and HepG2, evaluated by the toxic response to selenite and seleno-methylselenocysteine, cell growth and redox homeostasis. We found that the composition of the cell culture media greatly affected cell growth and sensitivity to selenium cytotoxicity. We also provided evidence for change of phenotype in A549 cells when maintained under different culture conditions, demonstrated by changes in cytokeratin 18 (CK18) and vimentin expression. In conclusion, our results have shown the importance of defining the cell culture medium used when comparing results from different studies.
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OBJECTIVE: We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. METHODS: Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. RESULTS: We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. CONCLUSIONS: We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.
Asunto(s)
Proteínas de la Membrana/genética , Proteínas Musculares/genética , Atrofia Muscular Espinal/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación/genética , Curvaturas de la Columna Vertebral/patología , Anciano , Disferlina , Femenino , Humanos , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Distrofia Muscular de Cinturas/complicaciones , Curvaturas de la Columna Vertebral/complicaciones , Curvaturas de la Columna Vertebral/genéticaRESUMEN
OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of Östergötland, Sweden. MATERIAL AND METHODS: We reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented. RESULTS: Four of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of Östergötland was 7.3 per million/year. CONCLUSIONS: The results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM.