ABSTRACT
Movement disorders, especially dystonia, are a frequent manifestation of neurometabolic diseases. Proper characterization and classification of movement disorders is crucial but may be challenging in this setting. The diagnostic work-up should be focused first on treatable disease. Mixed movement disorders, marked orofacial involvement and associated neurological and extra-neurological features should prompt the clinician to consider the possibility of an underlying neurometabolic disorder. The diagnostic approach is based on the abrupt, paroxysmal or insidious nature of onset of the movement disorders, the clinical picture including neurological and systemic signs and symptoms, and the presence or absence of abnormalities on the brain MRI. In addition to specific treatment for the metabolic disease, when available, symptomatic treatment of the movement disorders can be proposed, remembering that these patients are particularly vulnerability to iatrogenesis.
Subject(s)
Metabolic Diseases/complications , Movement Disorders/etiology , Nervous System Diseases/complications , Amino Acid Metabolism, Inborn Errors/complications , Biogenic Monoamines/metabolism , Carbohydrate Metabolism, Inborn Errors/complications , Deep Brain Stimulation , Energy Metabolism/physiology , Humans , Lesch-Nyhan Syndrome/complications , Lysosomal Storage Diseases/complications , Magnetic Resonance Imaging , Metabolic Diseases/diagnosis , Metal Metabolism, Inborn Errors/complications , Movement Disorders/diagnosis , Nervous System Diseases/diagnosisABSTRACT
Skin fibroblasts are essential tools for biochemical, genetic and physiopathological investigations of mitochondrial diseases. Their immortalization has been previously performed to overcome the limited number of divisions of these primary cells but it has never been systematically evaluated with respect to efficacy and impact on the oxidative phosphorylation (OXPHOS) characteristics of the cells. We successfully immortalized with the human telomerase gene 15 human fibroblasts populations, 4 derived from controls and 11 from patients with diverse respiratory chain defects. Immortalization induced significant but mild modification of the OXPHOS characteristics of the cells with lower rates of oxygen consumption and ATP synthesis associated with their loose coupling. However, it never significantly altered the type and severity of any genetic OXPHOS defect present prior to immortalization. Furthermore, it did not significantly modify the cells' dependence on glucose and sensitivity to galactose thus showing that immortalized cells could be screened by their nutritional requirement. Immortalized skin fibroblasts with significant OXPHOS defect provide reliable tools for the diagnosis and research of the genetic cause of mitochondrial defects. They also represent precious material to investigate the cellular responses to these defects, even though these should afterwards be verified in unmodified primary cells.
Subject(s)
Fibroblasts/physiology , Oxidative Phosphorylation , Telomerase/metabolism , Adenosine Triphosphate/metabolism , Adult , Cell Survival , Cells, Cultured , Child , Child, Preschool , Fibroblasts/drug effects , Glucose/pharmacology , Humans , Middle Aged , Mitochondrial Myopathies/pathology , Skin/pathology , Telomerase/genetics , Time Factors , Transduction, Genetic/methodsABSTRACT
Mitochondrial respiratory chain abnormalities are a cause of neuromuscular diseases. They present with very diverse clinical presentations,involving either the central nervous system, the peripheral nervous system, or skeletal muscle, and may be due to mutations either in mitochondrial or nuclear genome. The aim of this review is to familiarise the clinician with these diseases, to evoke main syndromes, and to give guidelines for their diagnostic investigation.
Subject(s)
Mitochondrial Diseases/diagnosis , Nervous System Diseases/etiology , Algorithms , Biopsy , DNA, Mitochondrial/genetics , Disease Management , Electron Transport , Female , Genes, Mitochondrial , Humans , Magnetic Resonance Imaging , Male , Mitochondrial Diseases/classification , Mitochondrial Diseases/complications , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/pathology , Mitochondrial Encephalomyopathies/therapy , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/genetics , Muscle, Skeletal/pathology , Nervous System Diseases/therapy , Oxidative Phosphorylation , Sequence Deletion , SyndromeABSTRACT
INTRODUCTION: Although a rare entity, multiple gliomas must be recognized and distinguished from other causes of multiple brain lesions. METHODS: Clinical and radiological features of 33 multiple gliomas were reviewed, including 20 synchronous cases and 13 metachronous cases. RESULTS: In 17 patients, radiological features were highly suggestive of spread from a primary site (multifocal gliomas). No apparent dissemination route was identified in the other cases which were presumed to be multicentric gliomas. For nine patients (27 percent), a second neoplasia or cancer was found in first degree relatives suggesting a genetic predisposition. Overall median survival was 79 weeks (64 weeks for glioblastomas). The age at onset was the main prognostic factor. CONCLUSION: Multiple gliomas represent a heterogeneous entity, probably corresponding to different mechanisms. In our group, survival was comparable to unique glioma.
Subject(s)
Glioma/diagnostic imaging , Glioma/pathology , Adult , Age of Onset , Aged , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Brain Neoplasms/physiopathology , Female , Glioma/genetics , Glioma/physiopathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , RadiographyABSTRACT
We report the clinical features of two unrelated patients, a 51-year-old woman and a 54-year-old man, presenting proximal myopathy with lipomatosis. In both patients, muscle biopsies showed numerous ragged-red fibers. Molecular analysis were performed with denaturating gradient gel electrophoresis (DGGE) on muscle, blood, hair, buccal and urinary cells. The A8344G mutation of the tRNA-lysine gene of the mitochondrial DNA was detected in all tissues at high levels (more than 80 p cent). None of the patients had a contributive family history, and signs of central nervous system involvement were absent. These observations confirm that lipomatosis may be encountered in mitochondrial disorders and is tightly associated with the A8344G mutation.
Subject(s)
Adenine , DNA, Mitochondrial/genetics , Guanine , Lipomatosis/genetics , Muscular Diseases/genetics , Female , Humans , Lysine/genetics , Male , Middle Aged , Mutation , RNA, Transfer/geneticsSubject(s)
Antineoplastic Agents/adverse effects , Benzimidazoles/adverse effects , MAP Kinase Kinase Kinases/antagonists & inhibitors , Melanoma/drug therapy , Neck Muscles/drug effects , Neuromuscular Diseases/chemically induced , Protein Kinase Inhibitors/adverse effects , Skin Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Benzimidazoles/administration & dosage , Chemotherapy, Adjuvant , GTP Phosphohydrolases/genetics , Humans , MAP Kinase Kinase Kinases/metabolism , Male , Melanoma/enzymology , Melanoma/genetics , Melanoma/secondary , Membrane Proteins/genetics , Middle Aged , Mutation , Neck Muscles/diagnostic imaging , Neck Muscles/physiopathology , Neuromuscular Diseases/diagnosis , Neuromuscular Diseases/physiopathology , Protein Kinase Inhibitors/administration & dosage , Skin Neoplasms/enzymology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Syndrome , Treatment OutcomeABSTRACT
The authors report 7 years of follow-up evaluation of a patient with coenzyme Q10 (CoQ10) deficiency. Initial symptoms of exercise intolerance and hyperlactatemia improved markedly with substitutive treatment. However, CoQ(10) supplementation did not prevent the onset of a cerebellar syndrome. A switch to idebenone treatment resulted in clinical and metabolic worsening, which disappeared with subsequent CoQ10 treatment. CoQ10 defects may cause progressive neurologic disease despite supplementation.