Supporting Treatment Adherence in Rare Disease

PM360, Health Psychology by John Weinman, PhD and Kate Perry on May 25th, 2016

Living with a rare disease presents multiple challenges to patients and their families, including those associated with adherence to long-term treatments. As with other chronic conditions, the discipline of health psychology enables us to identify the barriers and motivators specific to individuals with rare disease—and helps us create successful interventions for improved self-management.

Four Key Considerations for Rare Disease Treatment Adherence:
1. Family involvement
2. Lack of local knowledge
3. Perceived stigma
4. Feelings of isolation

The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion

Stevanoni M, Palumbo E, Russo A (2016). PLoS Genet 12(7): e1006201. doi:10.1371/journal.pgen.1006201

Open access (Creative Commons Attribution License)



In this study we defined the replication program of the FXN gene in human cells, providing for the first time a wide view of origin firing and fork progression within an endogenous genomic context harboring an expanded GAA-repeat. In comparison to the normal FXN sequence, we found an altered replication timing of the mutated alleles. According to our results, the replication of expanded FXN alleles is slowed or delayed during the first half of the S-phase as compared with the wildtype sequence, while a normalization of this effect can be inferred in the second part of the S-phase.

Progression of Friedreich ataxia: quantitative characterization over 5 years

Patel, M., Isaacs, C. J., Seyer, L., Brigatti, K., Gelbard, S., Strawser, C., Foerster, D., Shinnick, J., Schadt, K., Yiu, E. M., Delatycki, M. B., Perlman, S., Wilmot, G. R., Zesiewicz, T., Mathews, K., Gomez, C. M., Yoon, G., Subramony, S. H., Brocht, A., Farmer, J. and Lynch, D. R. (2016), Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.332

Open access article (Creative Commons Attribution-NonCommercial-NoDerivs License)

Objective: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.

Non-coding RNAs as drug targets

Masayuki Matsui & David R. Corey, Nature Reviews Drug Discovery (2016), doi:10.1038/nrd.2016.117

The ability of ncRNAs to control gene expression makes them potential targets for drug development. However, the drug discovery process is never easy. Uncertainty about how ncRNAs function (and even whether they have a function) makes lead identification and development even more challenging.

Expanded repeats within introns, 3ʹ untranslated regions (UTRs) or 5ʹ UTRs can produce toxic mutant RNAs (for example, as seen in myotonic dystrophy) or affect the production of proteins (for example, as seen in Friedreich ataxia and Fragile X syndrome).

Case study: Friedreich ataxia.Our laboratory has targeted steric-block locked nucleic acid (LNA) ASOs and duplex RNAs to the expanded GAA repeat in cells derived from patients with Friedreich ataxia. These compounds reduce R‑loop formation and increase frataxin mRNA and protein levels to those found in wild-type cells.

A Study to Characterize the Cardiac Phenotype of Individuals With Friedreich's Ataxia (CARFA Study)

ClinicalTrials.gov Identifier: NCT02840669, First received: July 19, 2016

Locations: Hôpital Pitié-Salpêtrière, Paris, France, Sponsors and Collaborators: Annapurna Therapeutics, Adverum Biotechnologies & Weill Medical College of Cornell University

This study is designed to characterize the cardiac manifestations of FA using cardiac magnetic resonance (CMR), echocardiography, serum cardiac biomarkers and evaluation of fatigue severity, in the context of the neurological disease.

Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Diagnostic

Labile Low-Molecular-Mass Metal Complexes in Mitochondria: Trials and Tribulations of a Burgeoning Field

Paul A. Lindahl and Michael J. Moore, Biochemistry, Article ASAP, DOI: 10.1021/acs.biochem.6b00216, Publication Date (Web): July 19, 2016

Iron, copper, zinc, manganese, cobalt, and molybdenum play important roles in mitochondrial biochemistry, serving to help catalyze reactions in numerous metalloenzymes.
The iron transported through the high-affinity importers mitoferrin 1 and 2 (or Mrs3/4) is ultimately utilized in the biosynthesis of ISC and heme cofactors. Indeed, the majority of Fe that accumulates in mitochondria of frataxin-deficient cells passes through these carrier proteins.
FeIII nanoparticles accumulate in the mitochondria of yeast cells lacking the frataxin homologue (Yfh1), which also contain deficient amounts of ISCs and hemes. What is less commonly realized is that Zn-protoporphyrin IX accumulates in mitochondria from this same strain. Curiously, excess ZnSO4 in the medium prevents the accumulation of Fe in mitochondria of Δyfh1 cells, increases the growth rate of this strain, and mitigates ROS damage. Surprisingly, these responses are not caused by an increase in ISC or heme synthesis, which makes them difficult to explain.

Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Juan Botas, María Dolores Moltó. PLoS ONE 11(7): e0159209. doi:10.1371/journal.pone.0159209

Open Access (Creative Commons Attribution License)

We report several novel genetic modifiers of eye morphology and motor dysfunction in the FRDA fly model. These data provide further support for the notion that disruptions in metal homeostasis may be a primary contributor to FRDA disease pathogenesis.

Crystal Structure of Bacillus subtilis Cysteine Desulfurase SufS and Its Dynamic Interaction with Frataxin and Scaffold Protein SufU

Blauenburg B, Mielcarek A, Altegoer F, Fage CD, Linne U, Bange G, Mohamed A. Marahiel. PLoS ONE 11(7): e0158749. doi:10.1371/journal.pone.0158749

Open access (article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited).

Frenkel: one of the forerunners of neurorehabilitation? / Frenkel: ¿un precursor de la neurorrehabilitación?

Cano-de-la-Cuerda R, Rev Neurol. 2016 Jul 16;63(2):79-84.

[Article in Spanish]

Neurorehabilitation is understood as the process intended to reduce the deficiency, limitation of activity and restriction of participation experienced by people as a result of a neurological diseases, and where the professionals involved in this field will aim to reduce the functional involvement degree of the patient.

Cerebellar Dysfunction and Ataxia in Patients with Epilepsy: Coincidence, Consequence, or Cause?

Filip P, Bareš M, Brázdil M.; Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8KH0NBT

Open-access  (article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License.)

Other spinocerebellar ataxias might also be accompanied by epilepsy, although this is probably a coincidence. There was a case report of mesiotemporal epilepsy in an SCA13 patient and one of nocturnal frontal lobe epilepsy in an SCA17 patient. There was also a description of epilepsy in patients with Friedreich ataxia. A list of all possible conditions exceeds the scope of this article.