Current and emerging treatment options in the management of Friedreich ataxia

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia. Oxidative damage within the mitochondria seems to have a key role in the disease phenotype. Therefore, FRDA treatment options have been mostly directed at antioxidant protection against mitochondrial damage. Available evidence seems to suggest that patients with FRDA should be treated with idebenone, because it is well tolerated and may reduce cardiac hypertrophy and, at higher doses, also improve neurological function, but large controlled clinical trials are still needed. Alternatively, gene-based strategies for the treatment of FRDA may involve the development of small-molecules increasing frataxin gene transcription. Animal and human studies are strongly needed to assess whether any of the potential new treatment strategies, such as iron-chelating therapies or treatment with erythropoietin or histone deacetylase inhibitors and other gene-based strategies, may translate into an effective therapy for this devastating disorder. In this review, we try to provide an answer to some questions related to current and emerging treatment options in the management of FRDA

Mitochondrial Epilepsy, a Challenge for Neurologists

Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options

Giant Schwannoma with Endoabdominal Development: A Case of Radiculopathy

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Mitochondrial DNA (mtDNA) haplotypes and dysfunctions in presbyacusis.

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Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis.

Background The causes of Amyotrophic Lateral Sclerosis (ALS) are unknown. A bulk of evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. Methods We assessed, in cerebrospinal fluid (CSF) and in plasma of 49 ALS patients and 8 controls, the amount of oxidized proteins (AOPP, advanced oxidation protein products), the total antioxidant capacity (FRA, the ferric reducing ability), and, in CSF, two oxidation products, the 4-hydroxynonenal and the sum of nitrites plus nitrates. Results The FRA was decreased (p = 0.003) in CSF, and AOPP were increased in both CSF (p = 0.0039) and plasma (p = 0.001) of ALS patients. The content of AOPP was differently represented in CSF of ALS clinical subsets, resulting in increase in the common and pseudopolyneuropathic forms (p < 0.001) and nearly undetectable in the bulbar form, as in controls. The sum of nitrites plus nitrates and 4-hydroxynonenal were unchanged in ALS patients compared with controls. Conclusion Our results, while confirming the occurrence of oxidative stress in ALS, indicate how its effects can be stratified and therefore implicated differently in the pathogenesis of different clinical forms of ALS

Gly482Ser PGC-1α gene polymorphism and exercise-related oxidative stress in amyotrophic lateral sclerosis patients

The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS

A Multisystem Mitochondrial Disease Caused by a Novel MT-TL1 mtDNA Variant: A Case Report

Background: Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A&gt;G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis.Case study: Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274 3275delAC MT-TL1 gene mutation.Conclusions: Our case demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274 3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement

Lack of Association between Nuclear Factor ErythroidDerived 2-Like 2

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients ( = 145) and healthy controls ( = 168), three SNPs in Nrf2 gene promoter: −653 A/G, −651 G/A, and −617 C/A and evaluated, in a subset ( = 73) of patients, advanced oxidation protein products (AOPP), ironreducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP ( &lt; 0.05) and decreased levels of FRAP ( &lt; 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the −65

Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy

Objective: To determine whether a set of functional tests, clinical scales, patient-reported questionnaires, and specific biomarkers can be considered reliable outcome measures in patients with primary mitochondrial myopathy (PMM), we analyzed a cohort of Italian patients. Methods: Baseline data were collected from 118 patients with PMM, followed by centers of the Italian network for mitochondrial diseases. We used the 6-Minute Walk Test (6MWT), Timed Up-and-Go Test (x3) (3TUG), Five-Times Sit-To-Stand Test (5XSST), Timed Water Swallow Test (TWST), and Test of Masticating and Swallowing Solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional Pain Inventory as patient-reported outcome measures; and FGF21, GDF15, lactate, and creatine kinase (CK) as biomarkers. Results: A total of 118 PMM cases were included. Functional outcome measures (6MWT, 3TUG, 5XSST, TWST, and TOMASS) and biomarkers significantly differed from healthy reference values and controls. Moreover, functional measures correlated with patients' perceived fatigue and pain severity. Patients with either mitochondrial or nuclear DNA point mutations performed worse in functional measures than patients harboring single deletion, even if the latter had an earlier age at onset but similar disease duration. Both the biomarkers FGF21 and GDF15 were significantly higher in the patients compared with a matched control population; however, there was no relation with severity of disease. Conclusions: We characterized a large cohort of PMM by evaluating baseline mitochondrial biomarkers and functional scales that represent potential outcome measures to monitor the efficacy of treatment in clinical trials; these outcome measures will be further reinvestigated longitudinally to define the natural history of PMM

Delayed Development of Aneurysmal Dilatations in Patients with Extracranial Carotid Artery Dissections

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