Friedrich's Ataxia Research Articles

A rare cause of immune dysregulation, prolidase deficiency: a case report and review of the literature.

We report a pediatric patient with prolidase deficiency, caused by a mutation in the PEPD gene, which encodes the enzyme prolidase D, with a lupus-like clinic and marked dysmorphic features along with pulmonary, neurological, skeletal, and immune system involvement. In addition to being the first known case in the literature where Friedrich's ataxia and prolidase deficiency were observed together, we aimed to highlight that this diagnosis should be considered in patients with autoimmunity and additional systemic findings such as treatment-resistant skin lesions, intellectual disability, and pulmonary manifestations. Furthermore, we sought to compare this case with others documented in the literature.

Ayurveda Management of Sarvangavata with special reference to Friedrich Ataxia

The collective meaning of Vatavyadhi indicates the specific disorder occurring due to Vata Dosha. Wherever, Vata Dosha get vitiated it first enters in all Srotas of the body and then creates different types of Vata Vyadhi describe in Classical Ayurvedic text. Sarvangavata is one of the most common disorders among Vata Nanatmaja Vikara. The global prevalence of Friedrich’s Ataxia incidence seen in 1 among 50,000. Objective: The aim of this study was to access the efficacy of Panchakarma modalities in Friedrich Ataxia condition. Material and Method: A 20 year old male patient who is K/C/O- Diabetes Mellitus (Type 1) since 1 year (insulin dependent) stopped since 2 months and N/K/C of Hypertension and IHD came to hospital with complain of reduced strength in bilateral upper and lower limb since 3years and associated with difficulty in walking and slurred speech since 2 years which was diagnosed with Sarvangavata and was treated with Sarvanga Abhyanga with Mahanarayana Taila followed by Dashamoola Qwatha Seka for 5 days, Virechanakarma for 13 days, Sarvanga Abhyanga with Mahanarayana Taila followed by Nadi Sweda for 7 days, Mustadhi Yapana Basti for 10 days, physiotherapy and Shamana Yoga’s. Result: After completion of one and half month of total treatment, the patient as found markly improvement gait, muscle tone and gain in strength in bilateral upper and lower limb. Conclusion: Sarvangavata can occur due to Beejopgataja, Dhatuksaya and Abhigataja where Vataja Lakshana were predominantly seen in this type of case and can be manage with different types of Sweda like Dashamoola Kayaseka, Virechana, Mustadi Yapana Basti, physiotherapy. Different Panchakarma modalities helped the patient markly improvement for doing his routine activities.

PASTE, Don't Cut: Genome Editing Tool Looks Beyond CRISPR and Prime

PASTE, Don't Cut: Genome Editing Tool Looks Beyond CRISPR and Prime

Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects.

Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient’s cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.

Cur@SF NPs alleviate Friedreich\u2019s ataxia in a mouse model through synergistic iron chelation and antioxidation

Abnormal iron metabolism, mitochondrial dysfunction and the derived oxidative damage are the main pathogeneses of Friedrich's ataxia (FRDA), a single-gene inherited recessive neurodegenerative disease characterized by progressive cerebellar and sensory ataxia. This disease is caused by frataxin (FXN) mutation, which reduces FXN expression and impairs iron sulfur cluster biogenesis. To date, there is no effective therapy to treat this condition. Curcumin is proposed harboring excellent ability to resist oxidative stress through Nrf2 activation and its newly found ability to chelate iron. However, its limitation is its poor water solubility and permeability. Here, we synthesized slow-release nanoparticles (NPs) by loading curcumin (Cur) into silk fibroin (SF) to form NPs with an average size of 150 nm (Cur@SF NPs), which exhibited satisfactory therapeutic effects on the improvement of FRDA manifestation in lymphoblasts (1 μM) derived from FRDA patients and in YG8R mice (150 mg/kg/5 days). Cur@SF NPs not only removed iron from the heart and diminished oxidative stress in general but also potentiate iron-sulfur cluster biogenesis, which compensates FXN deficiency to improve the morphology and function of mitochondria. Cur@SF NPs showed a significant advantage in neuron and myocardial function, thereby improving FRDA mouse behavior scores. These data encourage us to propose that Cur@SF NPs are a promising therapeutic compound in the application of FRDA disease.Graphical

A Case Report on Late-onset Friedrich's Ataxia and Response on Parkinsonism Treatment

Friedrich's ataxia is a progressive neurodegenerative disease that affects the posterior cord of the spinal tract. We present a case of an 83-year-old male with resting tremor and rigidity that had gradually worsened over the past few years. The patient has been diagnosed with Friedrich's ataxia. Unlike typical Friedrich ataxia, this patient does not have a shortened life expectancy. There is a small percentage of atypical patients demonstrate late-onset of disease, isolated spastic paraparesis without ataxia, and retained or exacerbated deep tendon reflex. Although there is no association between Parkinson's disease and Friedrich's ataxia; in our case, treatment of tremor and rigidity improves the patient's quality of life.

Neurodegenerative Diseases and the Auditory-Vestibular System

Neurodegenerative Diseases and the Auditory-Vestibular System

Discrepancy of Nerve Cells to Form Ataxia, A Rare Neurological Disease, Intimated With Sub Population of Regenerative Cells to Amend Flaws

Discrepant results due to lack of phenotype-specific species to species relevance to pharmacological results from in vitro cell testing cause inappropriate approaches to treatments to rare conditions in the brain. One such condition is Friedrich Ataxia. The prime focus is on this extreme condition, a neurodegenerative condition that sets precedence for clinical trials. Compounds such as nicotinamide and resveratrol were selected and used in the treatment of Ataxia, the condition shows no improvement. These compounds contracted various responses in iPSC derived neuron generation and more discoverable approach to drug delivery system in vitro conditions. The cell types from iPSC were considered nonrelevant for the disease derived from fibroblasts and more relevant to disease derived from neurons differentiated iPSC cells. This above illustrates the value of utilizing human iPSC cells to improve drug discovery and cure. The over the reacting theory of human iPSC cells are advanced further to discover the potent application of stem cells and further discuss the feasibility of transplantation of Friedrich Ataxia(FA) patients bone marrow-derived mesenchymal stem cells to discover the GAA expansion and reduced FXN and mRNA expression. There is scope for discussion for the assessment of the proliferative ability of pluripotency of FR from bone marrow. The characteristics of bone marrow in vitro differentiation have two types of cells, peripheral neurons, and cardiomyocytes. Also, this chapter leads to series of discussions on the need for testing applications on bone marrow mesenchymal stem cells, mutated gene correction that will play a critical role in gene-based cell therapy, and human artificial chromosomes intact with FXN genes differentiated into neurons or cardiomyocytes.

Effect of (+)- Epicatechin treatment in Friedrich's ataxia on myocardial oxygenation and perfusion assessed by cardiac magnetic resonance imaging

Effect of (+)- Epicatechin treatment in Friedrich's ataxia on myocardial oxygenation and perfusion assessed by cardiac magnetic resonance imaging

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms.

Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.

A Primer of Deuterium in Drug Design

A Primer of Deuterium in Drug Design

Clinical features of 63 patients with ataxia

Ataxia can be classified as genetic, sporadic or acquired. To report the clinical features of a group of patients with ataxia. Review of medical records of patients consulting in a specialized center in movement disorders. Those records in which the diagnosis of "ataxia" or "ataxic syndrome" appeared, were selected for the review. Of 4,282 records surveyed, the diagnosis of ataxia appeared in 95. After eliminating repeated or incomplete records, 63 were reviewed. Ataxia was sporadic, genetic and acquired in 27, 22 and 14 patients, respectively. The mean age at presentation for genetic, acquired and sporadic ataxia was 24, 46 and 53 years respectively. All autosomal dominant ataxias were type 3 spinocerebellar ataxia (SCA). Friedrich's ataxia was the most common recessive form. Most sporadic forms of ataxia were multiple system atrophy with predominant cerebellar ataxia (MSA-C) subtype. Considering the heterogeneity of patients with ataxia, we propose a method to approach them.

Phenotypic and Genotypic Analysis of Hereditary Ataxia Patients in Sakarya City, Turkey.

Hereditary ataxias are a group of heterogeneous diseases in regard to their clinical and genetic characteristics. Ataxia that progresses slowly may be accompanied by pyramidal and extrapyramidal findings, articulation disorders, ophthalmic movement disorders, neuropathic complaints, cognitive and behavioral abnormalies, and epilepsy. Definitive diagnosis in hereditary ataxias is based on molecular assays. History, clinical examination, laboratory and neuroimaging assist diagnosis. In our study, thirty-seven patients of suspected hereditary ataxia were examined with their clinical and genetic aspects, and the results compared with literature. Our study included 37 patients in 22 families who presented to our center between 2010-2016, and whose familial history and phenotypic features indicated hereditary ataxia. The patients were studied for clinical findings, family tree, neuroimaging, and laboratory findings. Advanced genetic investigations were performed on peripheral venous blood samples for hereditary ataxia. Of the 37 patients included in our study, 21 were females and 16 were males. Genetic analyses resulted in spinocerebellar ataxia (SCA) in four families (10 patients), Friedrich ataxia (FA) in three families (eight patients), and recessive ataxia due to point mutation in one family (two patients). SCA subtyping revealed SCA 1, 2, 6 and 8 in our patients. The remaining 16 patients included in our study could not be solved so far and are under investigation. Hereditary ataxias are rare neurodegenerative disorders. Large genetic pool, ethnic and local differences complicate diagnosing even further. Our study contributes to the literature by reflecting phenotypic and genotypic characteristics of hereditary SCA patients in our region and reporting rare hereditary ataxia genotypes.

138. Potential Therapeutic Treatment of Friedrich's Ataxia Using Highly Specific Engineered Meganucleases

Friedreich's ataxia (FRDA) is a recessive genetic disorder that results in progressive neuromuscular deterioration. The most common causative genetic alteration of this disorder is an expansion of a trinucleotide (GAA/TTC) repeat within the first intron of the Frataxin (FXN) gene. This triplet expansion causes transcriptional defects, resulting in low FXN mRNA and protein levels. In patients, the correlation between number of repeats and severity of the disease, age of onset and cardiomyopathy indicates that the repeat expansion is the primary cause of FRDA, thus making it a potential therapeutic target. We are investigating the potential use of our engineered meganuclease technology to precisely remove these trinucleotide repeats as a therapeutic treatment for FRDA. We have designed a pair of meganucleases that introduce double-strand breaks on either side of the FXN trinucleotide repeat region, generating compatible 3’ overhangs that can be repaired by direct ligation, resulting in precise excision of the intervening region. Introduction of this pair of meganucleases into FRDA patient fibroblasts in cell culture results in the successful deletion of the causative repeat region in greater than 15% of the transfected cells. This removal of the FRDA repeat region has been confirmed using both digital PCR-based analytics and deep sequencing. Additional analysis of Frataxin mRNA production, Frataxin protein levels, and cellular metabolism will further demonstrate the utility of the repeat excision approach for FRDA gene therapy.

Foetal and neonatal intracranial haemorrhage in term newborn infants: Hacettepe University experience.

In this study, we aimed to evaluate the incidence, risk factors, causes and clinical management of intracranial haemorrhage (ICH) diagnosed during foetal life or in the first month of life in term neonates with a discussion of the role of haematological risk factors. This study included term neonates (gestational age 37-42 weeks) with ICH diagnosed, treated and followed up in the Neonatal Intensive Care Unit of Hacettepe University, Ankara, Turkey, between January 1994 and January 2014. Medical follow-up was obtained retrospectively from hospital files and prospectively from telephonic interviews and/or clinical visits. During the study period, 16 term neonates were identified as having ICH in our hospital. In six (37.5%) neonates, ICH was diagnosed during foetal life by obstetric ultrasonography, and in 10 (62.5%) neonates, it has been diagnosed after birth. Haemorrhage types included intraventricular haemorrhage (IVH) in eight (50.0%), intraparenchymal haemorrhage in six (37.5%), subarachnoid haemorrhage in one (6.2%) and subdural haemorrhage in one (6.2%) neonate. IVH was the most common (n = 5/6, 83.3%) haemorrhage type among neonates diagnosed during foetal life. Overall, haemorrhage severity was determined as mild in three (18.7%) neonates, moderate in three (18.75%) neonates and severe in 10 (62.5%) neonates. During follow-up, one infant was diagnosed as afibrinogenemia, one diagnosed as infantile spasm, one cystic fibrosis, one orofaciodigital syndrome and the other diagnosed as Friedrich ataxia. Detailed haematological investigation and search for other underlying diseases are very important to identify the reason of ICH in term neonates. Furthermore, early diagnosis, close monitoring and prompt surgical interventions are significant factors to reduce disabilities.

Myocardial hypertrophy in infants in pediatric practice

Aim. To identify the features of the diseases associated with myocardial hypertrophy, for an earlier differential diagnosis to determine the treatment tactics and to initiate the early treatment.
 Methods. Clinical examination, family history, cardiac ultrasound with Doppler, ECG, 24-hour ECG monitoring, and computed tomographic aortography and genetics counseling (if indicated) were preformed.
 Results. During 14 years of observations, 92 patients were included, among them: children with idiopathic hypertrophic cardiomyopathy - 49 (53%), followed by children with Noonan syndrome - 11 (11.9%), Pompe disease - 6 (6.5%), hypertension - 6 (6.5%), Leopard syndrome - 5 (5,4%), Friedrich ataxia - 4 (4.3%), Danon disease - 3 (3.2%), cardiofaciocutaneous syndrome, fatty acids beta-oxidation disorder and mucopolysaccharidosis type I (Hurler syndrome) - 2 (2.1%), carnitine deficiency and GM1-gangliosidosis - 1 (1.2%).
 Conclusion. Consudering the possibilities of modern medicine, diagnosis of left and/or right ventricular hypertrophy in pediatric general practice and pediatric cardiology is an important factor for the subsequent diagnostic search, earliest possible specific therapeutic interventions to prevent unfavorable outcomes of the diseases.

191. Frataxin: A Putative Biomarker for Minimal Effective Dosage of AAV Gene Therapy

Friedrich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet repeat expansion in the frataxin gene (FXN), which encodes the mitochondrial protein frataxin. Deficiency in frataxin expression results in severe mitochondrial dysfunction leading to progressive gait abnormality, impaired muscle coordination, muscle weakness, hyporeflexia, dysmetria, dysarthria, and hypertrophic cardiomyopathy. Currently, there are no approved treatments for FRDA, which is the most common occurring autosomal recessive ataxia, affecting 1 in 50,000 people worldwide. Precise quantification of frataxin levels is critical for establishing the effectiveness of potential therapies. Therefore, methods that improve detection of FXN expression will facilitate the implementation of novel therapies into a clinical setting. Our overall objective is to establish an approach for effective gene transfer and quantification of frataxin levels sufficient to restore mitochondrial function. Stable isotope labeling of amino acids in cell culture or in mammals (SILAC/M) is a novel and sensitive mass spectrometry based approach we propose for the quantification of frataxin levels; therefore enabling determination of required levels for correction of FXN deficiency.We have generated a rAAV2/9-FXN vector expressing codon optimized human FXN for use in models of FRDA. Renal epithelial cells (REC) were isolated from control and FRDA patients, and was SILAC used to quantify AAV-mediated FXN expression in-vitro. Induced pluripotent stem cells (IPSC) were generated from REC's, and subsequently differentiated to cardiomyocytes and neurons. AAV-mediated correction of FXN was verified by increased mitochondrial activity including reduced iron deposition and increased aconitase function in FRDA cells. Preliminary results show that SILAC/M are able to accurately measure endogenous and vector derived FXN expression in-vitro and in-vivo. Moreover, improvement in mitochondrial function was correlated with levels of FXN expression in vitro. Future studies will involve systemic dosing of rAAV9-FXN in a novel model of FRDA.

A novel approach of human embryonic stem cells therapy in treatment of Friedrich's Ataxia

Introduction: Friedreich’s ataxia (FrDA) is an autosomal recessive inherited disease that damages nervous system and impairs muscle coordination. FrDA usually begins in childhood and is caused by expanded GAA triplet repeat within the first intron of the frataxin (FXN) gene leading to reduced level of mitochondrial protein frataxin. there is no effective treatment for FrDA. If stem cells are transplanted near the affected cells under oxidative stress in FrDA patients, they can produce tropic factors, thereby increasing the survival of the cells. In FrDA, the mechanism to remove the reactive oxygen species (rOs) is impaired leading to oxidative stress and cell death. stem cells may have ability to protect cells susceptible to oxidative stress that occurs in FrDA. In our previous studies we have shown the improvement in the patients’ condition who were suffering from cerebral palsy and cortical visual impairment after human embryonic stem cells (hEscs) therapy. case series: Herein, I report three cases of Fr DA patients who were treated with hEscs therapy. All the patients were suffering from problems like difficulty in walking, standing or climbing stairs and muscle weakness. After undergoing hEscs therapy, improvement in condition of all the patients was observed.

Mitochondrial metals as a potential therapeutic target in neurodegeneration

Transition metals are critical for enzyme function and protein folding, but in excess can mediate neurotoxic oxidative processes. As mitochondria are particularly vulnerable to oxidative damage due to radicals generated during ATP production, mitochondrial biometal homeostasis must therefore be tightly controlled to safely harness the redox potential of metal enzyme cofactors. Dysregulation of metal functions is evident in numerous neurological disorders including Alzheimer's disease, stroke, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedrich's ataxia. This review describes the mitochondrial metal defects in these disorders and highlights novel metal-based therapeutic approaches that target mitochondrial metal homeostasis in neurological disorders.

The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders

A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer’s disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich’s ataxia and Parkinson’s disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron–sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson’s disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.