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FROM PATHOGENESIS TO TREATMENT OF MNGIE AND OTHER MITOCHONDRIAL DEPLETION SYNDROMES
No full textL'Encefalomiopatia Neurogastrointestinale Mitocondriale (MNGIE) è una rara malattia dovuta a una mutazione del gene TYMP che determina perdita di funzione dell'enzima timidina fosforilasi (TP). Clinicamente è caratterizzata da dismotilità gastrointestinale, cachessia, ptosi e oftalmoparesi, neuropatia periferica e leucoencefalopatia. L'età media al decesso è 35 ani. Attualmente esistono 2 possibili cure: trapianto di cellule staminali ematopoietiche e terapia enzimatica sostitutiva con eritrociti incapsulati.
Noi descriviamo in questa tesi le due metodiche terapeutiche e i risultati ottenuti nei nostri pazienti.
Parallelamente abbiamo sviluppato un nuovo approccio terapeutico, basato sull'utilizzo di nucleosidi e inibitori farmacologici del loro catabolismo, utile sia per la MNGIE che per altre malattie mitocondriali caratterizzate da deplezione e delezioni multiple del DNA. Vengono descritti i risultati pre-clinici.Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the gene TYMP encoding thymidine phosphorylase (TP). Onset of symptoms occurs during the second or third decade of life and the clinical picture is characterized by external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy and leukoencephalopathy. The natural course of the disease is progressive and devasting, and patients die at a mean age of 35 years; however, age at onset and clinical presentation may vary even among patients with identical TYMP mutations, and the rate of disease progression is not uniform.
The pathogenesis of the disease is due to the nucleotide pool imbalance into the mitochondria, that determines development of point mutations, multiple deletions and depletion of mitochondrial DNA (mtDNA).
Enzyme replacement therapy, based on carrier erythrocyte entrapped thymidine phosphorylase (EE-TP), and hematopoietic allogeneic stem cell transplantation (AHSCT) are currently available in clinical practice.
MNGIE is a first of an expanding group of disorders characterized by depletion of mtDNA, in which common pathogenic mechanisms are the nucleotide pool imbalance and/or the defect in the intergenomic cross-talk (i.e. communication between nuclear and mitochondrial DNA into the cells). Deoxyribonucleoside triphosphates (dNTPs) are the building blocks of DNA, and a constant supply is essential for the synthesis and maintenance of both the nuclear and mitochondrial genomes. Inborn errors of nucleotide metabolism frequently cause dNTP pool imbalances, leading to depletion of mtDNA in non- replicating tissues. mtDNA depletion, in turn, causes failure of the mitochondrial respiratory chain, resulting in cellular energy depletion and cell death.
We treated MNGIE patients with different approaches in order to assess the safety and efficacy of each treatment. We did an extensive clinical, biochemical and instrumental follow-up and we merge our results into a worldwide consortium that will establish benefits and risks of the different therapies.
The mitochondrial salvage pathway enzymes are responsible for the intra-mitochondrial, stepwise phosphorylation of recycled deoxyribonucleosides to their respective dNTP’s. The first, rate limiting phosphorylation step is catalyzed by two constitutive mitochondrial deoxyribonucleoside kinases; thymidine kinase 2 (TK2) which catalyze the phosphorylation of deoxypyrimidines and deoxyguanosine kinase (dGK) which phosphorylates the deoxypurines. Mutations in both enzymes were identified in patients with MDS. A myopatic form of MDS was associated with altered TK2 and a hepatocerebral form, affecting both liver and brain was associated with defective dGK.
We performed a series of experiments in order to verify if the nucleoside supplementation and/or the inhibition of nucleoside catabolism should restore, at least partially, the mtDNA level in some MDS. We tested different combinations of nucleosides and nucleotides monophosphates in vitro, and we treated a MNGIE mouse model with different pharmacologic compounds.
AHSCT represents a promising effective treatment option in an otherwise unrelentingly progressive fatal disease, but the overall transplant related mortality still remains a major issue.
Although EE-TP strongly reduced plasma nucleosides without eliminating them to undetectable levels, significant clinical improvements were noted in our treated patient, as observed in patients who underwent AHSCT, suggesting a greater muscle mitochondrial oxidative function. EE-TP should be considered as a rescue or maintenance therapy prior to the availability of a suitable AHSCT donor or as an alternative therapy for patients who have irreversible end-stage disease and are without an optimally matched donor.
We showed that treatment with tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase (CDA), increases deoxycytidine (dCtd) concentration and partially prevents the thymidine-induced mtDNA depletion in cultured quiescent fibroblasts (cellular model of MNGIE). When THU and dCtd are co-administered, a positive correlation between circulating dCtd and mitochondrial dCTP is evidenced in targeted tissues such as brain and liver, indicating that mitochondrial dCTP pool size can be manipulated in vivo.
Additionally, we provide evidence that deoxyguanosine (dGuo), but not deoxyadenosine, supplementation is sufficient to completely prevent spontaneous mtDNA depletion in quiescent human dGK-deficient fibroblasts. Remarkably, we observe that the specific inhibition of purine nucleoside phosphorylase in fibroblasts by immucillin H prevents dGuo degradation and allows for mtDNA copy number stabilization at lower doses of the administered nucleoside.
In light of the present results, we propose the use of deoxyribonucleosides and/or the specific inhibitors of their catabolism, as a potential pharmacological approach for treating MDDSs due to defects in dNTP homeostasis
Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up
No full textAn 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
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Mitochondrial sensorineural hearing loss: a retrospective study and a description of cochlear implantation in a MELAS patient.
No full textHearing impairment is common in patients with mitochondrial disorders, affecting over half of all cases at some time in the course of the disease. In some patients, deafness is only part of a multisystem disorder. By contrast, there are also a number of "pure" mitochondrial deafness disorders, the most common probably being maternally inherited. We retrospectively analyzed the last 60 genetically confirmed mitochondrial disorders diagnosed in our Department: 28 had bilateral sensorineural hearing loss, whereas 32 didn't present ear's abnormalities, without difference about sex and age of onset between each single group of diseases. We reported also a case of MELAS patient with sensorineural hearing loss, in which cochlear implantation greatly contributed to the patient's quality of life. Our study suggests that sensorineural hearing loss is an important feature in mitochondrial disorders and indicated that cochlear implantation can be recommended for patients with MELAS syndrome and others mitochondrial disorders
Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA
No full textMutations in an increasing number of nuclear genes involved in deoxyribonucleotide homeostasis cause disorders associated with somatic mitochondrial DNA (mtDNA) abnormalities. Dysfunction of the products of these genes leads to limited availability of substrates for mtDNA replication and results in mtDNA depletion, multiple deletions or point mutations; mtDNA depletion is the molecular feature linked to greatest clinical severity. In this review, we discuss recent results demonstrating that enhancement of the salvage pathways by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Hence, we propose administration of selected deoxyribonucleosides and/or inhibitors of their catabolism as a pharmacological strategy to treat these diseases.
Copyright © 2013. Published by Elsevier Ltd
Strategies for treating mitochondrial disorders: an update.
No full textMitochondrial 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
Un caso di insufficienza renale acuta secondaria a malattia di MC-Ardle ad esordio tardivo. [A case of acute renal failure secondary to late-onset McArdle's disease].
No full textINTRODUZIONE: La malattia di McArdle, o glicogenosi tipo V, è una malattia autosomica recessiva dovuta alla carenza della fosforilasi muscolare, un enzima che gioca un ruolo chiave nella demolizione del glicogeno durante un esercizio fisico, ed è caratterizzata da affaticamento, mialgia, crampi e debolezza muscolare con un importante aumento nei livelli ematici di creatinchinasi e rabdomiolisi con mioglobinuria, che può portare ad insufficienza renale acuta. La malattia di McArdle generalmente si manifesta tra i 15 ed i 30 anni; una comparsa tardiva è davvero inusuale.
CASO CLINICO: riportiamo il caso di un paziente, maschio, di 68 anni, giunto in pronto soccorso per astenia, vertigini, diarrea ed oligoanuria. Il paziente è stato sottoposto a cinque sedute emodialitiche consecutive, con successiva ripresa della diuresi e ripristino della funzione renale. Il nostro paziente soffriva di astenia e dolore muscolare sin dalla giovane età: questi dati anamnestici, insieme ai persistenti livelli elevati di CPK ed in assenza di cause tossiche od infettive, ci hanno portato al sospetto di un disordine metabolico non comune, poi confermato dalla biopsia muscolare.
CONCLUSIONI: sino ad oggi non esistono specifiche terapie per la glicogenosi tipo V. Una dieta ricca in proteine e saccarosio, la supplementazione di vitamina B6 e di creatina non hanno portato risultati brillanti. La terapia piu’ adatta sembra essere una moderazione dell’esercizio fisico, che migliora la tolleranza all’attività muscolare e l’afflusso di sangue ai muscoli, provvedendo all’aumento di glucosio ed acidi grassi alle fibre muscolari.
INTRODUCTION:
Mc Ardles disease, also known as Type V glycogen storage disease, is a rare deficiency of the enzyme glycogen phosphorylase in muscle cells, inherited as an autosomal recessive trait. In the absence of this enzyme, muscles cannot break down glycogen during exercise, so in patients affected by McArdles disease even moderate physical activity produces cramps, pain and fatigue. Anaerobic activity leads to severe fixed contractures and rhabdomyolisis with myoglobinuria and raised serum creatine-kinase, which, in turn, can lead to acute renal failure. Disease onset is usually in early childhood, although diagnosis is often not made until the second or third decade.
CASE REPORT:
We present the case of a 68-year-old man who presented to the Emergency Room with fatigue, vertigo, diarrhea and oliguria. The patient underwent five daily hemodialysis sessions, diuresis reappeared and there was progressive recovery of renal function. The patient described episodes of fatigue and muscular pain occurring since childhood: the positive personal history, together with persistently raised CPK levels in the absence of any infective or toxic cause of myositis, led us to suspect the presence of this rare metabolic disease, which was subsequently confirmed by muscle biopsy.
CONCLUSION:
To date, there is no specific treatment for type V glycogenosis, although a diet rich in protein and saccarose, vitamin B6 supplementation and creatine administration are generally recommended. Moderate physical activity can help manage symptoms by improving exercise tolerance and blood supply to the muscles, ensuring provision of glucose and free fatty acids for the muscle fibers
Aortic and Mitral Valve Involvement in Maroteaux-Lamy Syndrome VI: Surgical Implications in the Enzyme Replacement Therapy Era
No full textOpen-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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