Very-late-onset Friedreich’s ataxia: diagnosis in a kindred with late-onset cerebellar ataxia

Conor Fearon, Roisin Lonergan, Damien Ferguson, Susan Byrne, David Bradley, Yvonne Langan, Janice Redmond; Practical Neurology Published Online First: 29 August 2019. doi: 10.1136/practneurol-2019-002368

Friedreich’s ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25–39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich’s ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich’s ataxia and discuss the pitfalls and risk of misdiagnosis.

Iron Pathophysiology in Friedreich’s Ataxia

Li K. (2019) Iron Pathophysiology in Friedreich’s Ataxia. In: Chang YZ. (eds) Brain Iron Metabolism and CNS Diseases. Advances in Experimental Medicine and Biology, vol 1173. Springer, Singapore. DOI:10.1007/978-981-13-9589-5_7. Online ISBN: 978-981-13-9589-5

FXN is essential for mitochondrial function by the involvement of iron–sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. Though iron toxicity is commonly thought to be mediated via Fenton reaction, oxidative stress seems not to be the main problem to result in detrimental effects on cell survival, particularly neuron survival. Therefore, the basic research on FXN function is urgently demanded to understand the disease. This chapter focuses on the outcome of FXN expression, regulation, and function in cellular or animal models of FRDA and on iron pathophysiology in the affected tissues. Finally, therapeutic strategies based on the control of iron toxicity and iron cellular redistribution are considered. The combination of multiple therapeutic targets including iron, oxidative stress, mitochondrial function, and FXN regulation is also proposed.

Oral mobility reflects rate of progression in advanced Friedreich’s ataxia

Borel, S. , Gatignol, P. , Smail, M. , Monin, M. , Ewenczyk, C. , Bouccara, D. and Durr, A. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50879

Our objective was to identify a sensitive marker of disease progression in Friedreich’s ataxia. We prospectively evaluated speech, voice, and oromotor function in 40 patients at two timepoints. The mean disease duration was 20.8 ± 9.8 years and mean SARA score 23.7 ± 8.6 at baseline. Oral motor mobility, assessed by a combination of movements of the face, eyes, cheeks, lips, and tongue, decreased significantly after 1 year (P < 0.0001). The standardized response mean over 12 months was considered as large for oral mobility (1.26) but small for SARA (0.12). Oral mobility could therefore be a sensitive marker in therapeutic trials.

Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures

Christian Hohenfeld, Imis Dogan, Robin Schubert, Claire Didszun, Ludger Schöls, Matthis Synofzik, Ilaria A. Giordano, Thomas Klockgether, Jörg B. Schulz, Ralf Reilmann, Kathrin Reetz. Cerebellum (2019). doi:10.1007/s12311-019-01073-x

Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients.

Measuring peripheral nerve involvement in Friedreich’s ataxia

Creigh, P. D., Mountain, J. , Sowden, J. E., Eichinger, K. , Ravina, B. , Larkindale, J. and Herrmann, D. N. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50865

MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

Exicure, Inc.Announced important preclinical data supporting development of SNA technology in the central nervous system (CNS)

Exicure, Inc. (Nasdaq: XCUR), 8 Aug 2019, pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA™) constructs, today reported financial results for the second quarter ended June 30, 2019 and provided an update on corporate progress.

The first half of 2019 continued to bring advancements across our pipeline,”said Dr. David Giljohann, Exicure’s chief executive officer. “We are extremely pleased with the strong progress in both our neurology and oncology franchises, while we simultaneously strengthened our board leadership and balance sheet. Our non-human primate data confirmed our enthusiasm for neurological applications of our SNA platform. Our recent $63.3 million public offering, which closed on August 2, 2019 provides the financial resources to advance these opportunities,” he added.
Presented results from a biodistribution study of SNAs in the CNS of non-human primates.
SNAs were observed in all 46 regions of the brain examined.
Preclinical research underway in indications including Huntington’s disease, spinocerebellar ataxia type 3 (SCA3), SCA2, SCA1, Friedreich's ataxia and Batten disease.
Expect to nominate first candidate for neurological conditions late in 2019.

Mitochondrial disorders and drugs: what every physician should know

Orsucci D, Caldarazzo Ienco E, Siciliano G, Mancuso M.; Drugs in Context 2019; 8: 212588. DOI: 10.7573/dic.212588

In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.

Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Natalia Robledinos-Antón, Raquel Fernández-Ginés, Gina Manda, and Antonio Cuadrado, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9372182, 20 pages, 2019. doi:10.1155/2019/9372182.


Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.

Compassionate use of human recombinant insulin-like growth factor-1 therapy in Friedreich's ataxia

García Ron A, Rodriguez Mesa M. , Compassionate use of human recombinant insulin-like growth factor-1 therapy in Friedreich's ataxia del tratamiento como uso compasivo de mecasermina (factor de crecimiento insulínico recombinante humano tipo 1) en ataxia de Friedreich. Neurología. 2019. doi:10.1016/j.nrl.2017.11.004

As no curative treatment is currently available for FA, we believe that any drug potentially capable of halting or delaying disease progression without causing severe adverse effects merits further research. Further randomised controlled trials are needed to confirm the benefits obtained in our case, to try to determine the action mechanism of rhIGF-1, and to establish what can be expected during the long-term treatment of this and other neurodegenerative diseases.

Exploring the Potential of Small Molecule-Based Therapeutic Approaches for Targeting Trinucleotide Repeat Disorders

Arun Kumar Verma & Eshan Khan & Sonali R. Bhagwat & Amit Kumar; Mol Neurobiol (2019). doi:10.1007/s12035-019-01724-4

In recent years, neurological disorders have globally become a leading cause of disability and death. Neurological disorders are very common in both high- and low-income countries, and the number of patients is predicted to increase in the coming decades. Disorders caused by the expanded trinucleotide repeats (CAG, CGG, CCG, CTG, CUG, GAA, and GCN) in the genome, also described as trinucleotide repeat expansion disorders (TREDs), comprise of the major class of neurological diseases. Various TREDs have different modes of pathogenesis, but the severity and time of onset of disease depends on the trinucleotide repeat numbers. Numerous therapeutic strategies, including symptomatic treatment, blockage of mutant protein synthesis, targeting the toxic protein aggregates and degradation of RNA transcripts have been developed for the treatment of these diseases. However, various limitations to these therapeutic strategies have been reported, and therefore, researchers are exploring different avenues of therapeutics development. One of the recent developments include targeting the expanded repeats with small molecules. Small molecule binds with the secondary/tertiary structure of RNA (like bulges, loops, and hairpins) irrespective of its sequences. Altogether, small molecule-based therapeutics may have the advantage over others to be able to overcome the hurdles of the blood–brain barrier, poor absorption, and allergic reactions. In this review, we have summarized various TREDs and envisage the potential of small molecule-based therapeutics for targeting these hitherto incurable neurological disorders.