Congenital and Hereditary Diseases of the Spinal Cord, Seminars in Ultrasound, CT and MRI

Lily L. Wang, Karin S. Bierbrauer, Available online 14 July 2016, ISSN 0887-2171, doi:10.1053/j.sult.2016.07.002.

Friedreich’s ataxia is a hereditary autosomal recessive movement disorder usually beginning in childhood and progresses with age. The cerebellum and the spinal cord are involved. The autonomic system can be involved as the disease progresses. Cardiac disease, diabetes, scoliosis are common associations. Genetic testing offers a conclusive diagnosis in patients with a compatible history and clinical examination. Imaging in Friedreich’s ataxia has been mostly focused in the brain. Spinal findings are non-specific on conventional MRI with cervical cord atrophy.

A longitudinal study of the SF-36 version 2 in Friedreich ataxia

G. Tai, L. A. Corben, E. M. Yiu and M. B. Delatycki; Acta Neurologica Scandinavica, Version of Record online: 28 SEP 2016 DOI: 10.1111/ane.12693

This study aimed to examine the relationship between SF-36 version 2 (SF-36V2) summary scores and Friedreich ataxia (FRDA) clinical characteristics, and to investigate the responsiveness of the scale, in comparison with the Friedreich Ataxia Rating Scale (FARS), over 1, 2 and 3 years.

Our findings suggest that despite physical decline, individuals with FRDA have relatively stable mental well-being. This study demonstrates that the SF-36V2 is unlikely to be a useful tool for identifying clinical change in FRDA therapeutic trials.

Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Semiha Kurt, Betul Cevik, Durdane Aksoy, E. Irmak Sahbaz, Aslı Gundogdu Eken, and A. Nazli Basak. Case Reports in Neurological Medicine Volume 2016 (2016), Article ID 4515938, 7 pages doi:10.1155/2016/4515938

Open access article distributed under the Creative Commons Attribution License

Other movement disorders

Silverdale MA, Medicine (2016), doi:10.1016/j.mpmed.2016.06.010

Structural problems usually show on cranial magnetic resonance imaging. The age of onset often helps to reach a diagnosis in chronic cerebellar disorders. Many genetic conditions present at a younger age, whereas other conditions such as multiple system atrophy present at an older age. Cranial imaging can help in chronic cerebellar disorders: some conditions cause cerebellar atrophy (e.g. ataxia telangiectasia) whereas others usually do not (e.g. Friedreich’s ataxia).

Mitochondrial dysfunction and diabetic retinopathy

Toke Bek, Chair, Mitochondrion, Available online 22 July 2016, ISSN 1567-7249, doi:10.1016/j.mito.2016.07.011

Friedreich's spinal ataxia, Diabetes mellitus in this condition is due to a loss of pancreatic beta cell function secondary to the mitochondrial dysfunction (Kersten et al 2014). One patient followed in the author's clinic had no registered diabetic retinopathy after five years of diabetes duration but had no light perception because of the neurological deficits of the disease.

The physiological basis of therapies for cerebellar ataxias

Hiroshi Mitoma and Mario Manto; Therapeutic Advances in Neurological Disorders September 2016 9: 396-413, doi:10.1177/1756285616648940

In conclusion, the understanding of the physiological basis of the various therapies is a critical step for clinicians dealing with CAs. We suggest that some degree of reversibility can be achieved if the therapies of CAs are administered as early as possible and take into account the pathogenesis behind the disorder. Novel therapies should take into account the mechanisms of the cerebellar circuitry in order to be effective

Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells.

Coskun, V. and Lombardo, D. M. (2016), J. Neurosci. Res.. doi: 10.1002/jnr.23924

Analysis of the hearts of patients with FA shows detectable iron accumulation, supporting the idea of iron overload as the disease mechanism. The innervation pattern of the heart by parasympathetic, sympathetic, and sensory neurons, as well as their interaction with the cardiac conduction system, is critical for the homeostatic operation of the cardiovascular system. In situations such as exercise, traumatic injury, or blood loss, a compensatory increase in cardiac output is achieved by a corresponding increase in adrenergic activity.

Emerging therapies for mitochondrial disorder

Helen Nightingale, Gerald Pfeffer, David Bargiela, Rita Horvath, Patrick F. Chinnery. Brain, 1633-1648 First published online: 3 May 2016 DOI:10.1093/brain/aww081

Open Access, (Creative Commons Attribution License)

From a clinical perspective, nuclear-genetic enzyme defects show the greatest promise. Stem cell therapy is already being used in specific contexts, and its efficacy and safety being evaluated, and gene therapy trials in mouse models show clear benefits. Unfortunately, each one of these rare genetic diseases may require their own proprietary approach, and the impact needs to be evaluated long-term. Small molecules are attractive because they have the potential to provide a more generic solution applicable across the mitochondrial disease spectrum, and a greater understanding of cell signalling pathways opens up several unexpected disease targets. For some of these drugs, clinical evaluation is imminent, particularly for those being repurposed or repositioned drugs such as bezafibrate. It is critical at this stage that laboratory and clinical scientists work closely with patient organizations to ensure that the ultimate aims of therapy will actually tackle issues that are important to patients. Given limited resources, this will ensure that new treatments improve quality of life—a prerequisite if these treatments are going to be adopted by healthcare systems worldwide.

Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases

Mirjam Plantinga, Erwin Birnie, Kristin M Abbott, Richard J Sinke, Anneke M Lucassen, Juliette Schuurmans, Seyma Kaplan, Marian A Verkerk, Adelita V Ranchor and Irene M van Langen; European Journal of Human Genetics (2016) 24, 1417–1423; doi:10.1038/ejhg.2016.43

OPEN ACCESS

‘You should at least ask’. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research

Pauline McCormack, Anna Kole, Sabina Gainotti, Deborah Mascalzoni, Caron Molster, Hanns Lochmüller and Simon Woods; European Journal of Human Genetics (2016) 24, 1403–1408; doi:10.1038/ejhg.2016.30

One of the means of doing this is to ensure that patient organisations are represented in ongoing governance of a global platform such as RD-Connect as part of ensuring that participants feel they have an equivalent level of protection and control in these global interactions as they do in their local relationships with researchers.

Longitudinal study of gait lower limb coordination and rehabilitative indications in patients affected by Ataxia of Friedreich (FRDA)

M. Petrarca, G. Vasco, S. Gazzellini, S. Carniel, A. Pisano, E. Bertini, E. Castelli, Gait & Posture, Volume 49, Supplement 1, September 2016, Pages S2-S3, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.07.025.

The resulting walking pattern is the product of a complex interaction between cerebellar dysfunction and sensory loss,compromising both balance control and multi-joint coordination. It is possible to speculate on the reduction of sensibility and of selective muscular control which produces increased exploitation of the body biomechanical properties.

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Merav Darash-Yahanaa, Yair Pozniakb, Mingyang Luc, Yang-Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A. Jennings, Eli Pikarsky, Tamar Geiger, José N. Onuchic, Ron Mittler and Rachel Nechushtai, PNAS early/2016/09/07, DOI:10.1073/pnas.1612736113

Freely available online through the PNAS open access option.

Disrupted expression of frataxin, another protein involved in Fe-S biogenesis, in hepatocytes of transgenic mice similarly led to impaired mitochondrial function, oxidative stress, and the development of multiple hepatic tumors. Moreover, ISCU and frataxin are regulated at the transcriptional level by p53 controlling the levels of ROS in cells

Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia

LOS ALTOS, CA--(Marketwired - Sep 16, 2016) - Dr. Theresa Zesiewicz, principal investigator in Retrotope's first-in-human clinical trial of RT001 in Friedreich's ataxia (FA), today presented early results from Retrotope's Phase I/II trial conducted at the University of South Florida Ataxia Research Center and the Collaborative NeuroSciences Network in Long Beach, CA. The trial, a randomized, double-blind, comparator controlled, two-dose study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacokinetic (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important activity measures were tested, found to be highly correlated to well-studied disease severity scales and showed multiple, unexpected, robust signals of drug effect at one or more doses.

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Michela Guaraldo, Paolo Santambrogio, Elisabetta Rovelli, Augusta Di Savino, Giuseppe Saglio, Davide Cittaro, Antonella Roetto & Sonia Levi; Scientific Reports 6, Article number: 33432 (2016) doi:10.1038/srep33432

The reagents Aza and NaB make the DNA accessible to transcription factors and activate FTMT expression. Our findings sustain that the moderate induction of FTMT expression by epigenetic therapy could be useful in disease characterized by oxidative stress, as FRDA.

UF and the Advocacy Group GoFAR Announce Gene Therapy program for Friedreich’s Ataxia

Press release: Gainesville - FL, Torino - IT, Sept.13, 2016

USF Health and FARA to host patient-focused scientific symposium Sept. 15

USF Health and FARA to host patient-focused scientific symposium Sept. 15 [Video], Written by Anne DeLotto Baier · September 12, 2016

International experts from academia and industry will gather to discuss advances in Friedreich’s ataxia from the laboratory to the clinic.

 Tampa, FL (Sept. 12, 2016) — The University of South Florida (USF) will bring together leading researchers and patients searching for a treatment for Friedreich’s ataxia (FA) and related disorders at the eighth annual scientific symposium “Understanding Energy for A Cure.” The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 15, at the USF Sam and Martha Gibbons Alumni Center, 11810 USF Alumni Drive, Tampa, FL 33620.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Maya Kuperberg, Dorit Lev, Lubov Blumkin, Ayelet Zerem, Mira Ginsberg, Ilan Linder, Nirit Carmi, Sarah Kivity, Tally Lerman-Sagie, Esther Leshinsky-Silver; August 29, 2016, doi: 10.1177/0883073816664836

When a patient arrives with a suspected monogenic disease the authors first take detailed history, perform a full clinical exam, and create a family tree. If a specific genetic disease is suspected based on this data, direct traditional tests are to be performed. Only if the patient remains undiagnosed should the authors turn to whole exome sequencing. The authors were able to diagnose patients exhibiting nonspecific, atypical, or overlapping symptoms.

Over 300 genetic conditions are known to cause ataxia, and without additional specific symptoms achieving a diagnosis is very difficult. Whole exome sequencing studies on cerebellar ataxia have achieved a success rate of 18%-64%. The authors report a high success rate of 57.1% for patients with ataxia.

The Application of Human Spinal Cord Magnetic Resonance Spectroscopy to Clinical Studies: A Review, Seminars in Ultrasound, CT and MRI

Patrik Oliver Wyss, Andreas Hock, Spyros Kollias, Available online 12 July 2016, ISSN 0887-2171, doi:10.1053/j.sult.2016.07.005.

Friedreich’s ataxia (FRDA) is an autosomal recessive degenerative disorder affecting the nervous system and the heart. Spectroscopic measurements in the brain showed decreased NAA in the vermis and the cerebellar hemispheres and increased myo-Inositol in the vermis. The total amount of Cr in the cerebellar hemispheres and Glu in the vermis was higher suggesting an alteration in the glutamatergic neurotransmission system. Findings in the spinal cord were in accordance with those of the brain showing a reduction of NAA by 40% and an increase of mI by 46% reflecting neuronal damage and gliosis.

Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease

Juan P. Bolaños, Enrique Cadenas, Michael R. Duchen, Mark B. Hampton, Giovanni E. Mann, Michael P. Murphy, Free Radical Biology and Medicine, Available online 5 August 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.08.004.

The genetic deficiency of the mitochondrial protein frataxin is the cause of Friedreich ataxia. Frataxin deficiency is not associated with cognitive impairment, but with increased oxidative stress with alterations in lipid metabolism, which are discussed as potential therapeutic approaches in Friedreich ataxia. The mitochondrial Lon protease is involved in several neurological disorders, such as hereditary Parkinson’s disease, Friedreich ataxia, familial amyotrophic lateral sclerosis, brain ischemia and stroke. In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA binding protein.

Functional and Gait Assessment in Children and Adolescents Affected by Friedreich’s Ataxia: A One-Year Longitudinal Study

Gessica Vasco , Simone Gazzellini, Maurizio Petrarca, Maria Luisa Lispi, Alessandra Pisano, Marco Zazza, Gessica Della Bella, Enrico Castelli, Enrico Bertini, PLoS ONE 11(9): e0162463. doi:10.1371/journal.pone.0162463

Open access

Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models

Luana Naia, Tatiana R. Rosenstock, Ana M. Oliveira, Sofia I. Oliveira-Sousa, Gladys L. Caldeira, Catarina Carmo, Mário N. Laço, Michael R. Hayden, Catarina R. Oliveira, A. Cristina Rego; Mol Neurobiol (2016). doi:10.1007/s12035-016-0048-3

In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.

Friedreich ataxia induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor

Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz and Massimo Pandolfo3; Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw308 First published online: September 4, 2016

Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.

R loops and links to human disease

Patricia Richard, James L. Manley, Journal of Molecular Biology, Available online 4 September 2016, ISSN 0022-2836, doi:10.1016/j.jmb.2016.08.031.

More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).

Biomarkers and progress of antioxidant therapy for rare mitochondrial disorders

Lucia Chico, Daniele Orsucci, Annalisa Lo Gerfo, Letizia Marconi, Michelangelo Mancuso & Gabriele Siciliano. Expert Opinion on Orphan Drugs Volume 4, Issue 6, 2016, DOI:10.1080/21678707.2016.1178570



Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.