Mitochondrial Sensorineural Hearing Loss: A Retrospective Study and a Description of Cochlear Implantation in a MELAS Patient

Hearing 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

The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: Report from the SSIEM Adult Metabolic Physicians Group

There are few centres which specialise in the care of adults with inborn errors of metabolism (IEM). To anticipate facilities and staffing needed at these centres, it is of interest to know the distribution of the different disorders

Non-neural phenotype of spinal and bulbar muscular atrophy: Results from a large cohort of Italian patients

Objective: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. \ua9 2016 Published by the BMJ Publishing Group Limited

Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial

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

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Position Paper on Diagnosis, Prognosis and Treatment by the MNGIE International Network

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 March 30th‐31st, 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: (1) diagnostic pathway; (2) prognosis and the main predictors of disease progression; (3) efficacy and safety of treatments; and (4) 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

FROM PATHOGENESIS TO TREATMENT OF MNGIE AND OTHER MITOCHONDRIAL DEPLETION SYNDROMES

L'Encefalomiopatia Neurogastrointestinale Mitocondriale (MNGIE) \ue8 una rara malattia dovuta a una mutazione del gene TYMP che determina perdita di funzione dell'enzima timidina fosforilasi (TP). Clinicamente \ue8 caratterizzata da dismotilit\ue0 gastrointestinale, cachessia, ptosi e oftalmoparesi, neuropatia periferica e leucoencefalopatia. L'et\ue0 media al decesso \ue8 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\u2019s. 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. \u2028Additionally, 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

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

Mitochondrial sensorineural hearing loss: a retrospective study and a description of cochlear implantation in a MELAS patient.

Hearing 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

Clinical Study Mitochondrial Sensorineural Hearing Loss: A Retrospective Study and a Description of Cochlear Implantation in a MELAS Patient

Hearing 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