The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.

Mitochondrial ribosomes and translation factors co-purify with mitochondrial nucleoids of human cells, based on affinity protein purification of tagged mitochondrial DNA binding proteins. Among the most frequently identified proteins were ATAD3 and prohibitin, which have been identified previously as nucleoid components, using a variety of methods. Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. Altered ATAD3 expression also perturbs mtDNA maintenance and replication. These findings suggest an intimate association between nucleoids and the machinery of protein synthesis in mitochondria. ATAD3 and prohibitin are tightly associated with the mitochondrial membranes and so we propose that they support nucleic acid complexes at the inner membrane of the mitochondrion.

Mitochondrial DNA mutations and depletion in pediatric medicine.

Mitochondrial disorders are a group of diseases traditionally ascribed to defects of the respiratory chain, which is the only metabolic pathway in the cell that is under the control of the two separate genetic systems, the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). Therefore the genetic classification of the primary mitochondrial diseases distinguishes disorders due to mutations in mtDNA, which are sporadic or maternal inherited, from disorders due to mutations in nDNA, which are governed by the stricter rules of mendelian genetics. Pathological alterations of mtDNA fall into two main categories: primary mutations of mitochondrial DNA (point mutations and rearrangements) and mtDNA perturbation, due to mutations in nuclear genes whose products are involved in mtDNA maintenance or replication. This article will focus on the primary mitochondrial DNA mutations and mtDNA depletion syndromes related to neonatal-infant human pathology.

EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. CONCLUSION: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.

EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. CONCLUSION: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

EFNS guidelines on the molecular diagnosis of mitochondrial disorders.

OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1).

These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database (http://tools.niehs.nih.gov/polg/). We have also excluded mutations in C10orf2 associated with dominant adult onset disorders.

EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Disorders from perturbations of nuclear-mitochondrial intergenomic cross-talk.

In the course of evolution, mitochondria lost their independence, and mitochondrial DNA (mtDNA) became the 'slave' of nuclear DNA, depending on numerous nucleus-encoded factors for its integrity, replication and expression. Mutations in any of these factors may alter the cross-talk between the two genomes and cause Mendelian disorders characterized by qualitative (multiple deletions) or quantitative (depletion) alterations of mtDNA, or by defective translation of mtDNA-encoded respiratory chain components.

Clinical and molecular features of mitochondrial DNA depletion syndromes.

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-gammaA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype-phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

Ultrasound guided treatment of pseudoaneurysm caused by puncture of the common femoral artery.

Catheter-induced iatrogenic pseudoaneurysm is a complication on the rise as compared to the past. This is due to the increasingly frequent use of percutaneous endovascular intervention in the diagnosis and treatment of several diseases. We present a case which underlines the diagnostic and therapeutic role of color Doppler ultrasound (US) in this pathology.

Diagnosis and treatment of abdominal aortic endoleaks using color Doppler US: Two clinical cases.

Endovascular treatment of abdominal aortic aneurysm (AAA) involves placement of an endoluminal graft inside the aneurysmal sac in order to exclude it from blood circulation and thereby prevent the risk of aneurysmal sac rupture. A possible complication is endoleak, i.e. persistent blood flow outside the lumen of the endograft into the aneurysmal sac. The protocol for treatment monitoring includes abdominal computed tomography (CT) and color Doppler ultrasound (US). The aim of this case report is to present our experience in two cases of endoleak in which diagnosis and treatment were carried out using color Doppler US.

Thymidine phosphorylase deficiency causes MNGIE: an autosomal recessive mitochondrial disorder.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases.

[Scombroid syndrome with severe and prolonged cardiovascular involvement]. / Sindrome sgombroide con grave e prolungata compromissione cardiovascolare.

Scombroid poisoning is a form of ichthyosarcotoxism caused by eating spoiled fish, mainly of the scombroid family. Inappropriate storage of these fish can lead to the decarboxylation of histidine in the flesh to histamine by enterobacteria. The symptoms of histamine poisoning mimic those of an IgE-mediated food allergy, as well as flushing, headache, diarrhea and palpitations. However, in some cases, the scombroid poisoning can be characterized by very serious symptoms, as well as cardiovascular compromission. We describe two cases of scombroid poisoning with severe hypotension requiring continuous intravenous dopamine with resolution of symptoms only several hours later.

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency.

Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.

MNGIE: from nuclear DNA to mitochondrial DNA.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a unique autosomal recessive disorder with mitochondrial DNA alterations. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Muscle biopsies typically reveal mitochondrial abnormalities including ragged-red fibers and focal cytochrome c oxidase deficiency. Analysis of mitochondrial DNA in skeletal muscle shows partial depletion, multiple deletions, or both. To identify the cause of MNGIE, we mapped the disease locus to chromosome 22q13.32-qter. Within this region, we identified the gene encoding thymidine phosphorylase as the MNGIE gene. We have identified homozygous or compound-heterozygous thymidine phosphorylase gene mutations in 35 MNGIE patients (21 families) from diverse ethnic groups, including: Ashkenazi Jewish, Western European, Jamaican, Hispanic, and Japanese. We confirmed pathogenicity of the mutations by a spectrophotometric assay of thymidine phosphorylase activity with peripheral leukocytes of 15 MNGIE patients. Thymidine phosphorylase enzymatic activity was severely reduced, thus enabling us to conclude that the loss-of-function mutations in thymidine phosphorylase gene cause MNGIE. Thymidine phosphorylase catabolizes thymidine to thymine. In agreement with this notion, we noted that plasma thymidine level is increased more than 20-fold in MNGIE patients compared to controls. Therefore, we have hypothesized that increased thymidine causes mitochondrial nucleotide pool imbalance which, in turn, leads to motochondrial DNA alterations, via a mitochondria-specific thymidine salvage pathway. The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism.

[Pancytopenia caused by ticlopidine treated with filgrastim. Description of a case]. / Pancitopenia da ticlopidina trattata con filgrastim. Descrizione di un caso.

Ticlopidine is an antiplatelet agent that is used to reduce the occurrence of atherothrombotic arterial events, but it can sometime cause severe haematological side-effects. We describe the case of a 79-year old woman suffering from ischaemic cardiopathy and chronic cerebral vasculopathy treated with ticlopidine, who developed a rare pancytopenia on the 26th day of ticlopidine treatment. The patient was successful treated with intravenous antibiotics and with filgrastim, with complete reversion of the pancytopenia.