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Five-year glioblastoma (GBM) survivors (LTS) are the minority of the isocitrate dehydrogenase (IDH)-wild-type GBM patients, and their molecular fingerprint is still largely unexplored. This multicenter retrospective study analyzed a large LTS-GBM cohort from nine Italian institutions and molecularly characterized a subgroup of patients by mutation, DNA methylation (DNAm) and copy number variation (CNV) profiling, comparing it to standard survival GBM. Mutation scan allowed the identification of pathogenic variants in most cases, showing a similar mutational spectrum in both groups, and highlighted TP53 as the most commonly mutated gene in the LTS group. We confirmed DNAm as a valuable tool for GBM classification with a diagnostic refinement by using brain tumor classifier v12.5. LTS were more heterogeneous with more cases classified as diffuse pediatric high-grade glioma subtypes and having peculiar CNVs. We observed a global higher methylation in CpG islands and in gene promoters of LTS with methylation levels of distinct gene promoters correlating with prognosis.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Niño , Glioblastoma/patología , Estudios Retrospectivos , Isocitrato Deshidrogenasa/genética , Variaciones en el Número de Copia de ADN , Neoplasias Encefálicas/patología , Mutación , Pronóstico , Metilación de ADN , SobrevivientesRESUMEN
BACKGROUND: Surgery of the fourth ventricle is challenging due to the presence of several surrounding delicate structures. Traditional approaches do not offer an easy visualization of these areas, especially those on the roof. Thanks to the most recent developments in neurosurgical endoscopy, it is possible to access the fourth ventricle via physiological pathways, avoiding unnecessary stress or damage to the nervous and vascular structures. METHODS: We present the case of a patient with a lesion at the lingula-superior medullary velum, and an history of surgically resected lung and pancreatic adenocarcinomas. An endoscopic biopsy of the lesion through the foramen of Magendie was performed. The few reports on this endoscopic approach were also critically reviewed. RESULTS: The retrograde endoscopic exploration through a suboccipital, trans-Magendie foramen approach using a flexible endoscope allowed the clear visualization of the superior medullary velum and the possibility to obtain diagnostic biopsies of the lesion with a minimally invasive technique. CONCLUSIONS: The trans-Magendie navigation with a flexible endoscope is a safe and elegant technique to approach lesions located in any point of the fourth ventricle, particularly in its rostral portion.
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Endoscopía , Cuarto Ventrículo , Humanos , Cuarto Ventrículo/patología , Endoscopía/métodos , BiopsiaAsunto(s)
Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Anciano de 80 o más Años , Autoantígenos/inmunología , Resultado Fatal , Humanos , MasculinoRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.
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Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/terapia , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/terapia , Consenso , ADN Mitocondrial/genética , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/metabolismo , Humanos , Cooperación Internacional , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/metabolismo , Mutación , Timidina Fosforilasa/genética , Timidina Fosforilasa/metabolismoRESUMEN
We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.
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Trasplante de Hígado , Encefalomiopatías Mitocondriales , Oftalmoplejía , Adulto , Estudios de Seguimiento , Humanos , Encefalomiopatías Mitocondriales/terapia , Timidina FosforilasaRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.
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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.
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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause a loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues, and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Other two MNGIE-type phenotypes have been described so far, which are linked to mutations in POLG and RRM2B genes. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped thymidine phosphorylase therapy) and newer, promising therapies are expected in the near future. Since successful treatment is strictly related to early diagnosis, it is essential that clinicians be warned about the clinical features and diagnostic procedures useful to suspect diagnosis of MNGIE-MTDPS1. The aim of this review is to promote the knowledge of the disease as well as the involved mechanisms and the diagnostic processes in order to reach an early diagnosis.
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ADN Mitocondrial , Miopatías Mitocondriales , Humanos , Mutación , ARN de Transferencia , VirulenciaRESUMEN
We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults.
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ADN Mitocondrial , Miopatías Mitocondriales/genética , Mutación Puntual , ARN de Transferencia de Lisina/genética , ARN de Transferencia de Metionina/genética , Adulto , Femenino , Genes Mitocondriales , Humanos , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , FenotipoRESUMEN
Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders.
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Open-heart operations in patients with mucopolysaccharidoses are exceedingly rare and pose distinct clinical challenges. Few reports exist of valve replacement in type VI mucopolysaccharidosis, mostly entailing combined mitral and aortic valve replacement. Here reported is the case of a young woman with mitral and aortic valve disease, in whom the surgical procedure was confined to the aortic valve. The rationale behind this strategy, particularly in light of the benefits offered by specific enzyme replacement therapy of type VI mucopolysaccharidosis, is discussed.
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Válvula Aórtica/cirugía , Válvula Mitral/cirugía , Mucopolisacaridosis VI/complicaciones , Adulto , Estenosis de la Válvula Aórtica/cirugía , Terapia de Reemplazo Enzimático , Femenino , Humanos , Estenosis de la Válvula Mitral/cirugía , Mucopolisacaridosis VI/terapiaRESUMEN
Progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and "KSS spectrum" (a category of which classic KSS represents the most severe extreme). The criteria for "KSS spectrum" include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials.
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Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , ADN Mitocondrial/genética , Eliminación de Gen , Síndrome de Kearns-Sayre/genética , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/genética , Enfermedades Musculares/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Fenotipo , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Adulto , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
CONTEXT: Bone fragility and low bone mass have been reported in small case series of patients with Pompe disease with severely reduced muscle strength or immobilization. OBJECTIVE: Our objective was to determine the prevalence of morphometric vertebral fractures and to evaluate bone mass in adults with late-onset Pompe disease. DESIGN: We conducted a multicenter cross-sectional observational study from August 2012 to December 2013. STUDY SETTING: All subjects were outpatients referred to University Referral Centers. PATIENTS: PATIENTS included 22 late-onset Pompe disease patients with progressive proximal myopathy and minimal respiratory involvement without other diseases affecting bone mass. MAIN OUTCOME MEASURE: The prevalence of morphometric vertebral fractures was systematically assessed by semiquantitative analysis of lateral spine x-rays (T4-L5). RESULTS: A high prevalence of morphometric vertebral fractures was found. At least 1 vertebral fracture was present in 17 of 22 patients (77%). All vertebral fractures were asymptomatic. Bone mineral density was normal in 36.5% of the patients, whereas 36.5% were osteopenic and 27% were osteoporotic in at least 1 site. Fracture prevalence was independent of muscular and respiratory functional parameters and of genotype. CONCLUSIONS: Our data show for the first time that asymptomatic and atraumatic vertebral fractures occur frequently in late-onset Pompe disease patients without a significant impairment of bone mass. Screening for asymptomatic vertebral fractures should be routinely performed in Pompe disease irrespective of the disease severity. Fracture risk should be confirmed in longitudinal studies.
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Densidad Ósea/fisiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Osteoporosis/epidemiología , Fracturas de la Columna Vertebral/epidemiología , Adolescente , Adulto , Anciano , Comorbilidad , Estudios Transversales , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico por imagen , Prevalencia , Radiografía , Fracturas de la Columna Vertebral/diagnóstico por imagen , Adulto JovenRESUMEN
Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.
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ADN Mitocondrial/uso terapéutico , Mitocondrias/metabolismo , Enfermedades Mitocondriales/terapia , Calcio/metabolismo , ADN Mitocondrial/genética , Transporte de Electrón/genética , Homeostasis , Humanos , Enfermedades Mitocondriales/metabolismo , Recambio Mitocondrial , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading.
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Enfermedades Mitocondriales/complicaciones , Mioclonía/epidemiología , Mioclonía/etiología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
An adult with Sandhoff disease presented with pure lower motor neuron phenotype. Twenty years later, he showed signs of upper motor neuron involvement. 25 years from the onset, his muscle weakness slightly worsened but he was fully independent in activities of daily living. GM2-gangliosidosis can manifest as a motor neuron disease with a slowly progressive course. The correct knowledge of the natural history can be really important to achieve the diagnosis, design new therapies and evaluate clinical trials.