Friday, August 31, 2018

Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia

Karen A.G. Takazaki, Thiago Junqueira R. Rezende, Alberto R.M. Martinez, Carelis González, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. França, Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia, Clinical Neurophysiology, 2018, doi:10.1016/j.clinph.2018.08.017.

We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease.

Friedreich’s Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases

Vamshi K. Rao, Christine J. DiDonato and Paul D. Larsen; Case Reports in Neurological Medicine Volume 2018, Article ID 8587203, 5 pages doi:10.1155/2018/8587203

In conclusion, if the index of suspicion is high for Friedrich’s ataxia then frataxin sequencing should be performed if there is a repeat expansion detected only on one allele. Secondly, for the most part, compound heterozygous patients have an earlier age of onset that directly correlates with the trinucleotide expansion size. Finally, whether there is a unique phenotype to the nonsense mutations requires further study before counseling families regarding natural history of disease.

Magnetic susceptibility of the dentate in a longitudinal study of Friedreich ataxia

Phillip G D Ward, Ian H Harding, Parnesh Raniga, Tom G Close, Louise A Corben, Martin B Delatycki, Monique R Stagnitti, Elsdon Storey, Nellie Georgiou-Karistianis, and Gary F Egan; International Society for Magnetic Resonance in Medicine, (Abstract #3731) 16-21 June 2018 Paris (France)

We performed in-vivo measurements of the magnetic susceptibility in the dentate nucleus in individuals with Friedreich ataxia and healthy controls over a two-year longitudinal study using quantitative susceptibility mapping. The results show a significant susceptibility difference between individuals with Friedreich ataxia and control subjects, and a strong correlation with disease severity in the Friedreich ataxia cohort. These findings may lead to the development of a sensitive biomarker of disease severity and progression in Friedreich ataxia.

Regional cortical folding morphometry in Friedreich ataxia using Laplace Beltrami based gyrification index

Rosita Shishegar, Imis Dogan, Martin B. Delatycki, Gary F. Egan, Elsdon Storey, Louise A. Corben, and Nellie Georgiou-Karistianis; International Society for Magnetic Resonance in Medicine, (Abstract #3616) 16-21 June 2018 Paris (France)

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder mainly affecting the spinal cord and dentate nuclei of the cerebellum. Although there is growing evidence of cerebral atrophy and cortical thinning in FRDA, no research has investigated the pattern of cortical folding (gyrification) in the disorder. We have proposed a new MRI analysis technique, Laplace Beltrami based gyrification index (LB-GI), and validated its use in individuals with FRDA. Preliminary results reveal significantly increased regional gyrification in the motor cortex in individuals with FRDA, compared to healthy controls. Overall, our results demonstrate that LB-GI is a sensitive technique which requires further investigation as a potential neuroimaging marker of disease progression in FRDA.


Sirio Cocozza, Teresa Costabile, Enrico Tedeschi, Filomena Abate, Camilla Russo, Agnese Liguori, Walter Del Vecchio, Francesca Paciello, Mario Quarantelli, Alessandro Filla, Francesco Saccà, and Arturo Brunetti; International Society for Magnetic Resonance in Medicine, (Abstract #4670) 16-21 June 2018 Paris (France)

We performed a seed-based Resting-State fMRI analysis in Friedreich’s Ataxia (FRDA) patients to assess possible brain functional connectivity (FC) changes in these patients, which are know to be charactherized by an impairment of neuropsychological functions. We found an increased FC in FRDA patients compared to controls in different brain regions, including the medial frontal gryrus, the angular gyri and cingulate gyrus, with a decreased cerebellar FC. Our findings of diffuse alterations of FC in FRDA patients compared to controls may shed new light on the pattern of supratentorial and infratentorial involvement and on dynamics of brain plasticity in this condition.

Thursday, August 30, 2018

Child Neurology: Friedreich ataxia with upper motor neuron findings

Elizabeth A. Harvey, Kimberly S. Jones; Neurology Aug 2018, 91 (9) 426-428; DOI: 10.1212/WNL.0000000000006086

A 16-year-old boy with hypertrophic cardiomyopathy, gait abnormalities, and balance problems was found to have Friedreich ataxia. Though Friedreich ataxia typically renders patients areflexic, this child had upper motor neuron findings of spasticity in both lower extremities, with crossed adductors, and 4+ deep tendon reflexes at the patella and Achilles bilaterally. This unusual presentation of an uncommon genetic disorder led to uncertainty of the patient's true diagnosis until genetic testing confirmed that he had 2 alleles with the Friedreich ataxia mutation.

Wednesday, August 29, 2018

DNA repair in trinucleotide repeat ataxias

Yau, W. Y., O'Connor, E. , Sullivan, R. , Akijian, L. and Wood, N. W. (2018), FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14644

In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

Friday, August 24, 2018

Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System.

Nina Xie, Yafang Zhou, Qiying Sun, and Beisha Tang, Stem Cells International, vol. 2018, Article ID 7834175, 12 pages, 2018. doi:10.1155/2018/7834175.

Other representative candidates may include the Rett syndrome, Huntington’s disease, and Friedreich ataxia, where dCas9-epieffector complex may be harnessed to restore or repress the responsible gene to cure the disease.

In conclusion, all of the studies described above indicated that CRISPR/Cas9-mediated epigenome editing holds a great promise for epigenetic studies and therapeutics. However, there are still some limitations to be scrutinized. First of all, in terms of basic science studies, although most studies claimed high specificity in their experiments, however, the high specificity usually is the result of repeated optimization. A precise model that could predict deleterious off-target effects during the experiment design stage is still lacking. In addition, although transactivation or repression effects on multiple genes were well documented in publications, mechanisms underlying the phenomenon were not clear. Epigenetic mark profiling on epigenome scale was not sufficient. Local CHIP-seq data usually only focused on the characterization of one or few histone marks. Theoretically, we hope that epigenome editing could achieve targeted gene regulation by changing epigenetic marks specifically and freely according to our wills. To achieve this goal, high specificity and clarified mechanisms are the prerequisite. Therefore, more thorough off-target event assessments and more studies focusing on mechanisms underlying epigenome editing are needed.

Moreover, in terms of clinical applications, several issues need to be addressed prior to successful clinical translation. Firstly, the endurance of gene activation or a repression effect mediated by CRISPR/Cas9 remains to be undetermined. It has been thought that epigenome-editing-induced gene activation or repression is short-term. On the contrary, there was also evidence showing that a gene silencing effect mediated by the hit-and-run epigenome editing strategy could also be long-term and inheritable. A short-term effect is more suitable for antagonizing acute pathogenic factor exposure and the transdifferentiation process. However, for treating chronic diseases, a long-term effect is expected. Additionally, a safer and efficient delivery method should be developed [92]. Adeno-associated virus (AAV) vectors have been the prevailing delivery method for some time. By tagging a synthetic surface peptide, splitting the Cas9 protein or using its smaller orthologues, and choosing a suitable administration route, researchers significantly improved the packaging capacity and delivery efficiency of AAV vectors. However, for clinical applications, more optimization is required. The immunogenicity of AAV vectors, dCas9 proteins, and guide RNAs should be determined precisely. The off-target effects of AAV vectors or dCas9-epieffector complex should be minimized as much as possible to ensure clinical safety.

Company hopes to speed up payments for clinical trial patients

(Action News) KING OF PRUSSIA, Pa. Wednesday, August 22, 2018
Clinical trials help drive medical advances. However, some patients hedge at taking part because reimbursement for their expenses take time.

Two years ago, Kyle took part in a test of ClinCard, a reloadable debit card. Once a patient's ClinCard is established, money is loaded after each research visit... no check, no cash. It's instant money for the patient, and instant documentation for the trial site.

Thursday, August 23, 2018

PTC Therapeutics Successfully Completes Acquisition of Agilis Biotherapeutics

SOUTH PLAINFIELD, N.J., Aug. 23, 2018 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced that it has successfully completed the acquisition of Agilis Biotherapeutics, Inc., a private biotechnology company focused on the advancement of innovative gene therapy programs for rare genetic disorders that affect the central nervous system (CNS).
The acquisition also includes gene therapy programs in development, GT-FA, GT-AS, and GT-RLN, for Friedreich Ataxia, Angelman Syndrome and Cognitive Disorders associated with several neurodevelopmental and neurodegenerative disorders, respectively.