RESUMO
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.
Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Proteínas do Citoesqueleto/genética , DNA Mitocondrial , Doenças Mitocondriais/genética , Distrofias Musculares/genética , Mutação , Adolescente , Adulto , Atrofia , Células Cultivadas , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/patologia , Doenças Cerebelares/fisiopatologia , Criança , Variações do Número de Cópias de DNA , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Músculos/patologia , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Fenótipo , Adulto JovemRESUMO
A method is presented for calculating a background image to be subtracted from TI-201 myocardial perfusion images. The method was derived from experimental measurements of background components in which hearts of animals injected with TI-201 were replaced with hearts from nonradioactive animals. The algorithm generates a background image that accounts for TI-201 activity in surrounding tissues and within the cardiac chamber. Comparison of the computer-generated background images with background images of the experimental models showed a mean difference of about 3% (range 1-6%). Clinical images using this method of background generation and subtraction are presented.
Assuntos
Computadores , Coração/diagnóstico por imagem , Radioisótopos , Tálio , Animais , Volume Cardíaco , Cães , Aumento da Imagem , Perfusão , Cintilografia , Técnica de Subtração , Tálio/sangueRESUMO
A simplified solid-state enzymatic iodination procedure for routine labeling of unstable pure protein or complex amino acid-containing molecules is presented. The procedure was designed using agarose-bound lactoperoxidase to iodinate human IgG with iodine-125. This method consistently resulted in a labeling efficiency greater than 90% with high stability and undetectable gross structural alterations of the substrate as evaluated by immunodiffusion and electrophoresis. The technique presented is simple, efficient, and may be employed to yield a sterile, pyrogen-free labeled species.
Assuntos
Radioisótopos do Iodo , Marcação por Isótopo/métodos , Aminoácidos , Cromatografia em Camada Fina , Eletroforese , Humanos , Imunodifusão , Imunoglobulina G , LactoperoxidaseRESUMO
The authors analyze the postoperative course of 30 patients with anaplastic supratentorial gliomas to evaluate the usefulness of sequential brain scanning as an adjunct to clinical neurological examinations in the early detection of tumor recurrence. The correlation between sequential scanning and clinical evaluation was excellent; no examples of divergent resu;ts were seen. With the exception of scans made very early in the postoperative period or when postoperative scalp flap infections were present, initial postoperative scans were easily interpreted in terms of both the superficial (postcraniotomy) and parenchymal changes. The specific type of postoperative therapy (radiation therapy, chemotherapy, or both) could not be correlated with whether scan or examination ultimately changed first. However, analysis of original tumor location revealed that while sequential postoperative scanning offered no advantage over repetitive neurological examinations in the detection of recurrent tumor in the neurologically dominant left hemisphere, scan changes preceded examination changes in eight of 17 cases involving tumors of the neurologically nondominant right hemisphere.
Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Encefálicas/cirurgia , Feminino , Seguimentos , Glioma/cirurgia , Humanos , Masculino , Cuidados Pós-Operatórios , CintilografiaRESUMO
The authors compared radionuclide cerebral dynamic studies, brain scans, and clinical evaluation as indicators of recurrence of intracranial anaplastic gliomas and found cerebral dynamic studies more sensitive to tumor growth than static brain scans. The former may show changes prior to clinical evidence of tumor progression.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Circulação Cerebrovascular , Glioblastoma/diagnóstico , Recidiva Local de Neoplasia/diagnóstico por imagem , Barreira Hematoencefálica , Encéfalo/irrigação sanguínea , Mapeamento Encefálico , Angiografia Cerebral , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Infusões Parenterais , Expectativa de Vida , Exame Neurológico , Prognóstico , Cintilografia , Contagem de Cintilação/instrumentação , Tecnécio/administração & dosagemRESUMO
Relative spleen/liver activity ratio was determined from posterior projection images using a photodensitometric method. Ratios from scans of 22 patients with proven pancreatic carcinoma (12 from rectilinear scans and 10 from scintillation camera images) were determined and compared to studies from patients documented as normal and to randomly selected liver/spleen imaging studies which had been previously interpreted as normal. The mean ratio from the pancreatic carcinoma group was significantly lower than the means of the respective normal groups (p[t] less than .0001 for rectilinear scans and p[t] less than .001 for scintigrams). There was no significant difference between the means of the proven normal and randomly selected normal groups or between the two pancreatic carcinoma groups. Splenic vascular alteration is discussed as a possible reason for decreased splenic distribution of Tc-99m-sulfur colloid in this patient group.
Assuntos
Neoplasias Pancreáticas/diagnóstico por imagem , Baço/diagnóstico por imagem , Enxofre , Tecnécio , Adolescente , Adulto , Idoso , Criança , Humanos , Fígado/diagnóstico por imagem , Pessoa de Meia-Idade , Cintilografia , Coloide de Enxofre Marcado com Tecnécio Tc 99mAssuntos
Malformações Arteriovenosas/diagnóstico , Transtornos Cerebrovasculares/diagnóstico , Cintilografia , Adolescente , Adulto , Idoso , Malformações Arteriovenosas/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico , Angiografia Cerebral , Transtornos Cerebrovasculares/congênito , Transtornos Cerebrovasculares/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , TecnécioAssuntos
Cardiopatias Congênitas/diagnóstico , Testes de Função Cardíaca , Cintilografia , Tecnécio , Estenose da Valva Aórtica/diagnóstico , Criança , Anomalia de Ebstein/diagnóstico , Feminino , Humanos , Masculino , Métodos , Oscilometria , Fotografação , Estenose da Valva Pulmonar/diagnóstico , Tetralogia de Fallot/diagnóstico , Veia Cava Superior/anormalidadesAssuntos
Testes de Função Cardíaca , Defeitos dos Septos Cardíacos/fisiopatologia , Doenças das Valvas Cardíacas/fisiopatologia , Circulação Pulmonar , Tecnécio , Insuficiência da Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo , Cateterismo Cardíaco , Débito Cardíaco , Computadores , Átrios do Coração/fisiopatologia , Comunicação Interatrial/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Estenose da Valva Mitral/fisiopatologiaAssuntos
Pneumopatias/diagnóstico , Cintilografia , Adulto , Angiografia , Animais , Criança , Pré-Escolar , Cães , Feminino , Humanos , Pneumopatias/diagnóstico por imagem , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Circulação PulmonarAssuntos
Velocidade do Fluxo Sanguíneo , Pulmão , Perfusão , Circulação Pulmonar , Animais , Cães , Pulmão/fisiologia , Métodos , Cintilografia , Fluxo Sanguíneo Regional , Soroalbumina Radioiodada , XenônioAssuntos
Pneumopatias/fisiopatologia , Pulmão/fisiopatologia , Xenônio , Asma/fisiopatologia , Computadores , Fibrose Cística/fisiopatologia , Humanos , Injeções Intravenosas , Abscesso Pulmonar/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Métodos , Pneumonia/fisiopatologia , Artéria Pulmonar/anormalidades , Circulação Pulmonar , Embolia Pulmonar/fisiopatologia , Radiometria/instrumentação , Cintilografia , Respiração , Relação Ventilação-Perfusão , Xenônio/administração & dosagemAssuntos
Doença de Alzheimer/diagnóstico , Demência/diagnóstico , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia/diagnóstico , Soroalbumina Radioiodada/metabolismo , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico por imagem , Proteínas do Líquido Cefalorraquidiano/análise , Diagnóstico Diferencial , Humanos , Hidrocefalia de Pressão Normal/sangue , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Injeções Espinhais , Pneumoencefalografia , Cintilografia , Soroalbumina Radioiodada/administração & dosagem , Espaço Subaracnóideo/diagnóstico por imagemRESUMO
The results of seven laboratory tests of liver function, including spleen/liver activity ratios obtained by densitometric analysis of scans, are analyzed in 50 patients with proven Laennec's cirrhosis. In this series, the liver scan not only disclosed the liver gross anatomy and structural abnormality and established the best possible site for biopsy examination, but also, the increased splenic activity served as a useful diagnostic indication of Laennec's cirrhosis. Of 50 proven cases of Laennec's cirrhosis, 41 (82%) had abnormal spleen/liver ratios. An abnormal spleen/liver ratio in combination with abnormal results from any one or two other tests was relatively effective in the detection of cirrhosis. The accuracy is improved if the other laboratory tests are chosen from among tests for serum albumin, serum bilirubin, and SGOT. (Liver abnormalities other than cirrhosis can also present an abnormal spleen/liver ratio.) This simple determination extends the value of the liver scan commonly requested in search of metastases, primary lesions, or inflammatory processes, or in preparation for needle biopsy examination.