Referencias científicas Nº 158

http://www.sciencedirect.com/science/article/pii/S1367593116301855

Blood–brain barrier peptide shuttles

• Macarena Sánchez-Navarro¹,
• Ernest Giralt^1,2,
• Meritxell Teixidó^1,

Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics. The most recent advances in the field are analysed here.

http://onlinelibrary.wiley.com/wol1/doi/10.1002/mds.27023/abstract

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study

1. Ian H. Harding PhD^1,*,
2. Louise A. Corben PhD^1,2,
3. Martin B. Delatycki PhD^1,2,3,
4. Monique R. Stagnitti BSc(Hons)¹,
5. Elsdon Storey PhD⁴,
6. Gary F. Egan PhD^1,5and
7. Nellie Georgiou-Karistianis PhD

¹ABSTRACT

Background: Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear.

Methods: In this cross-sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single-finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity.

Results: During simple finger tapping, cerebral hyperactivation in individuals with Friedreich ataxia at the lower end of clinical severity and cerebral hypoactivation in those more severely affected was observed in premotor/ventral attention brain regions, including the supplementary motor area and anterior insula. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within dorsolateral prefrontal regions of the executive control network and superior parietal regions of the dorsal attention system. Greater offline motor precision was associated with less activation in the dorsal attention network.

Discussion: Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia. © 2017 International Parkinson and Movement Disorder Society

http://www.mdpi.com/1420-3049/22/6/887/htm

In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles

Lucia Montenegro *, Maria N. Modica, Loredana Salerno, Anna Maria Panico, Lucia Crascì, Giovanni Puglisi and Giuseppe Romeo

Department of Drug Sciences, University of Catania, V. le A. Doria 6, 95125 Catania, Italy

Abstract:

Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity. IDE and its derivatives loaded SLN showed good physico-chemical and technological properties (spherical shape, mean particle sizes 23–25 nm, single peak in the size distribution, ζ potential values −1.76/−2.89 mV, and good stability at room temperature). In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.

http://onlinelibrary.wiley.com/wol1/doi/10.1002/hbm.23655/abstract 

Structural signature of classical versus late-onset friedreich’s ataxia by Multimodality brain MRI

1. Thiago Junqueira R. Rezende¹,
2. Alberto Rolim M. Martinez¹,
3. Ingrid Faber¹,
4. Karen Girotto¹,
5. José Luiz Pedroso²,
6. Orlando G. Barsottini²,
7. Iscia Lopes-Cendes³,
8. Fernando Cendes¹,
9. Andreia V. Faria⁴and
10. Marcondes C. França¹

Abstract

Introduction

Friedreich’s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA.

Methods

We enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging in a 3 T device; three-dimensional high-resolution T1-weighted images and diffusion tensor images were used to assess gray and white matter, respectively. We used T1 multiatlas approach to assess deep gray matter and cortical thickness measures to evaluate cerebral cortex and DTI multiatlas approach to assess white matter. All analyses were corrected for multiple comparisons.

Results

Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).

Conclusion

The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.

http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0178354&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plosone%2FPLoSONE+%28PLOS+ONE+-+New+Articles%29

Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy

• Amanda R. Stram,
• Gregory R. Wagner,
• Brian D. Fogler,
• Melanie Pride,
• Matthew D. Hirschey,
• Mark Payne

Abstract

Introduction

The childhood heart disease of Friedreich’s Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA.

Methods

A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression.

Results

Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.

Conclusion

These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early

http://www.resverlogix.com/media/news-releases.html?article=134233#.WSsQpmjyjct

RECENT PUBLICATION AND PATENT APPLICATION REFERENCING APABETALONE SUPPORT ITS CONTINUED DEVELOPMENT AND SUCCESS

May 23, 2017

Nature Reviews Nephrology and Pfizer Inc. discuss BET bromodomain inhibition and apabetalone as viable drug candidates

CALGARY, May 23, 2017 /CNW/ – Resverlogix Corp. («Resverlogix» or the «Company») (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).  The publication, titled «Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD,» is published in the prominent journal Nature Reviews Nephrology. This article describes the mechanisms that link Alkaline Phosphatase (ALP) to vascular calcification, inflammation, and cardiovascular disease. The Pfizer patent application was filed for the purpose of protecting their invention of using BET-family bromodomain inhibitors as a method of increasing frataxin in the treatment of patients with Friedreich’s ataxia. Resverlogix’ apabetalone, a BET bromodomain inhibitor, is specifically listed in Pfizer’s patent. The patent describes the ataxia as a rare regressive inherited disease characterized by progressive damage to the nervous system and movement problems.

«We welcome the attention drawn to Resverlogix and apabetalone from significant industry groups such as Nature Reviews Nephrology and Pfizer. Due to the dramatic growth of BET Bromodomain publications over the past decade, it is not surprising that our advanced Phase 3 compound, apabetalone, is now drawing expanded attention from the global academic and pharmaceutical communities,» stated Donald McCaffrey, President and Chief Executive Officer.

Discussion on ALP and Cardiovascular Disease in Chronic Kidney Disease (CKD)

In the May, 2017 edition, Nature Reviews Nephrology published an article titled: «Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD,» (Haarhaus et al. Nature Reviews Nephrology). In addition to the discussion of the ALP mechanism and links to disease, the authors also discuss «new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.»  The article dedicates a paragraph to RVX-208 (apabetalone) and cites four different publications involving RVX-208 (apabetalone).

Findings on Frataxin Expression and Friedreich’s Ataxia  

Recently, Pfizer applied for a patent titled: «Regulators of Frataxin» (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich’ ataxia (FA).  RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich’s ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.

http://www.neurology.org/content/88/20/1942

Nrf2, cellular redox regulation, and neurologic implications

1. Eduardo E. Benarroch, MD

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently.^1–5 Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia.^6–10 Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection.^10–12 This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.

FOOTNOTES

• Go toorg for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the article.

http://journal.frontiersin.org/article/10.3389/fimmu.2017.00508/full

Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration

Heather M. Wilkins^1,2, Ian W. Weidling^2,3, Yan Ji^1,2 and Russell H. Swerdlow^1,2,3,4*

• ¹Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
• ²University of Kansas Alzheimer’s Disease Center, Kansas City, KS, USA
• ³Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
• ⁴Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA

Inflammation is increasingly implicated in neurodegenerative disease pathology. As no acquired pathogen appears to drive this inflammation, the question of what does remains. Recent advances indicate damage-associated molecular pattern (DAMP) molecules, which are released by injured and dying cells, can cause specific inflammatory cascades. Inflammation, therefore, can be endogenously induced. Mitochondrial components induce inflammatory responses in several pathological conditions. Due to evidence such as this, a number of mitochondrial components, including mitochondrial DNA, have been labeled as DAMP molecules. In this review, we consider the contributions of mitochondrial-derived DAMPs to inflammation observed in neurodegenerative diseases.

Introduction

Inflammatory pathways are activated through either pathogen-initiated or damage-initiated events. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate similar inflammatory cascades and are therefore difficult to distinguish. Inflammation stimulated by DAMPs is an area of study that has recently gained notice. In particular, DAMPs derived from mitochondrial components are interesting due to the prokaryotic origin of this organelle. Furthermore, mitochondrial-derived DAMP molecules may play a role in heart disease, arthritis, liver disease, trauma, and sepsis (1–5).

Neuroinflammation and mitochondrial dysfunction are observed across numerous neurodegenerative diseases (6–8). Mitochondrial dysfunction can induce inflammation and vice versa. Mitochondrial dysfunction may modulate the release of mitochondria-derived DAMP molecules (9, 10). Here, we discuss the relationship between neuroinflammation, mitochondrial dysfunction, and mitochondria-derived DAMP molecules in the context of neurodegenerative diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267338/

Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Kai Cai,^† Marco Tonelli,^‡ Ronnie O. Frederick,^‡ and John L. Markley*^†‡

Go to:

Abstract

Ferredoxins play an important role as an electron donor in iron–sulfur (Fe–S) cluster biosynthesis. Two ferredoxins, human mitochondrial ferredoxin 1 (FDX1) and human mitochondrial ferredoxin 2 (FDX2), are present in the matrix of human mitochondria. Conflicting results have been reported regarding their respective function in mitochondrial iron–sulfur cluster biogenesis. We report here biophysical studies of the interaction of these two ferredoxins with other proteins involved in mitochondrial iron–sulfur cluster assembly. Results from nuclear magnetic resonance spectroscopy show that both FDX1 and FDX2 (in both their reduced and oxidized states) interact with the protein complex responsible for cluster assembly, which contains cysteine desulfurase (NFS1), ISD11 (also known as LYRM4), and acyl carrier protein (Acp). In all cases, ferredoxin residues close to the Fe–S cluster are involved in the interaction with this complex. Isothermal titration calorimetry results showed that FDX2 binds more tightly to the cysteine desulfurase complex than FDX1 does. The reduced form of each ferredoxin became oxidized in the presence of the cysteine desulfurase complex when l-cysteine was added, leading to its conversion to l-alanine and the generation of sulfide. In an in vitro reaction, the reduced form of each ferredoxin was found to support Fe–S cluster assembly on ISCU; the rate of cluster assembly was faster with FDX2 than with FDX1. Taken together, these results show that both FDX1 and FDX2 can function in Fe–S cluster assembly in vitro.

Ferredoxins play an important role as an electron donor in iron–sulfur (Fe–S) cluster biosynthesis. Two ferredoxins, human mitochondrial ferredoxin 1 (FDX1) and human mitochondrial ferredoxin 2 (FDX2), are present in the matrix of human mitochondria. Conflicting results have been reported regarding their respective function in mitochondrial iron–sulfur cluster biogenesis. We report here biophysical studies of the interaction of these two ferredoxins with other proteins involved in mitochondrial iron–sulfur cluster assembly. Results from nuclear magnetic resonance spectroscopy show that both FDX1 and FDX2 (in both their reduced and oxidized states) interact with the protein complex responsible for cluster assembly, which contains cysteine desulfurase (NFS1), ISD11 (also known as LYRM4), and acyl carrier protein (Acp). In all cases, ferredoxin residues close to the Fe–S cluster are involved in the interaction with this complex. Isothermal titration calorimetry results showed that FDX2 binds more tightly to the cysteine desulfurase complex than FDX1 does. The reduced form of each ferredoxin became oxidized in the presence of the cysteine desulfurase complex when l-cysteine was added, leading to its conversion to l-alanine and the generation of sulfide. In an in vitro reaction, the reduced form of each ferredoxin was found to support Fe–S cluster assembly on ISCU; the rate of cluster assembly was faster with FDX2 than with FDX1. Taken together, these results show that both FDX1 and FDX2 can function in Fe–S cluster assembly in vitro. 

https://www.intechopen.com/books/neurological-physical-therapy/physical-therapy-for-cerebellar-ataxia

Physical Therapy for Cerebellar Ataxia

RESEARCH-ARTICLE

Akiyoshi Matsugi^∗

Abstract

Ataxia, the incoordination and balance dysfunction in movements without muscle weakness, causes gait and postural disturbance in patients with stroke, multiple sclerosis, and degeneration in the cerebellum. The aim of this article was to provide a narrative review of the previous reports on physical therapy for mainly cerebellar ataxia offering various opinions. Some systematic reviews and randomized control trial studies, which were searched in the electronic databases using terms “ataxia” and “physical therapy,” enable a strategy for physical therapy for cerebellar ataxia. Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.

http://biorxiv.org/content/early/2017/05/12/137265 

Inducible And Reversible Phenotypes In A Novel Mouse Model Of Friedreich’s Ataxia

 Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C. Jordan, Daniel H. Geschwind

Abstract

Friedreich’s ataxia (FRDA), the most common inherited ataxia in humans, is caused by recessive mutations that lead to a substantial reduction in the levels of frataxin (FXN), a mitochondrial iron binding protein. FRDA is a multi-system disease, involving multiple neurological, cardiac, and metabolic manifestations whose study would be substantially advanced by animal models that faithfully recapitulate human disease features. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed. This inducible model of FRDA is likely to be of broad utility in therapeutic development and in understanding the relative contribution of reversible cellular dysfunction to the devastating phenotypes observed in this condition.

http://www.sciencedirect.com/science/article/pii/S0028390817302174

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

• James L. Miller^a,, ,
• Myriam Rai^b,
• Normand L. Frigon^a,
• Massimo Pandolfo^b,
• Juha Punnonen^a,1,
• Jeffrey R. Spencer^a,

Abstract

Friedreich’s ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human cortical cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FA patient-derived PBMC by 20%–40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. In vivo, STS-E412 increased Fxn mRNA and protein in wild-type C57BL6/j mice. RhEPO, STS-E412, and STS-E424 increase FXN expression in the heart of FXN-deficient KIKO mice. In contrast, FXN expression in the brains of KIKO mice increased following treatment with STS-E412 and STS-E424, but not following treatment with rhEPO. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo.

http://pubs.rsc.org/en/content/articlelanding/2017/mt/c7mt00031f#!divAbstract

Mechanisms of iron- and copper-frataxin interactions

Thi Hong Lien Han,  Jean-Michel Camadro,  Renata Santos,  Emmanuel Lesuisse,  Jean Michel El Hage Chahine  and  Nguyêt Thanh Ha-Duong

Abstract

Frataxin is a mitochondrial protein whose deficiency is the cause of Friedreich’s ataxia, a hereditary neurodegenerative disease. This protein plays a role in iron-sulfur cluster biosynthesis, protection against oxidative stress and iron metabolism. In an attempt to provide a better understanding of the role played by metals in its metabolic functions, the mechanisms of mitochondrial metal binding to frataxin in vitro have been investigated. Purified recombinant yeast frataxin homolog Yfh1 binds two Cu(II) ions with a Kd1(CuII) of 1.3 x 10-7 M and a Kd2(CuII) of 3.1 x 10-4 M and a single Cu(I) ion with a higher affinity than for Cu(II) (Kd(CuI) = 3.2 x 10-8 M). Mn(II) forms two complexes with Yfh1 (Kd1(MnII) = 4.0 x 10-8 M; Kd2(MnII) = 4.0 x 10-7 M). Cu and Mn bind Yfh1 with higher affinities than Fe(II). It is established for the first time that the mechanisms of the interaction of iron and copper with frataxin are comparable and involves three kinetic steps. The first step occurs in the 50-500 ms range and corresponds to a first metal uptake. This is followed by two other kinetic processes which are related to a second metal uptake and/or to a change in the conformation leading to thermodynamic equilibrium. Frataxin deficient Δyfh1 yeast cells exhibited a marked growth defect in the presence of exogenous Cu or Mn. Mitochondria from Δyfh1 strains accumulated also higher amounts of copper, suggesting a functional role of frataxin in vivo in copper homeostasis

http://jnnp.bmj.com/content/88/5/e1.58

Peripheral nerve ultrasound in friedreich’s ataxia

1. Eoin Mulroy1,
2. Luciana Pelosi2,
3. Purwa Joshi3,
4. Ruth Leadbetter3,
5. Miriam Rodrigues1,
6. Stuart Mossman2,
7. Richard Roxburgh1

Author affiliations

1. Department of Neurology, Auckland City Hospital, Auckland, New Zealand 2. Department of Neurology and Clinical Neurophysiology, Bay of Plenty District Health Board, Tauranga, New Zealand 3. Capital and Coast District Health Board, Wellington, New Zealand

Abstract

Objectives To investigate peripheral nerve ultrasound findings in patients with Friedreich’s ataxia (FRDA) and their relationship to the complex neuropathology of the somatosensory system in this condition.

Methods The ultrasound cross-sectional area of median and ulnar nerves at mid-forearm and mid-humerus level of eight non-diabetic FRDA patients (confirmed by GAA triplet expansion of the frataxin gene) were compared with eight age- and gender-matched healthy controls and with a reference population. All patients had sensory neuropathy with reduced or absent sensory action potentials on electrophysiological tests.

Results The mean cross-sectional area of the FRDA patient group was significantly larger than that of the healthy control group at all sites (p<0.05) with maximal differences at mid-humerus level. Seven of the eight FRDA patients had cross-sectional area measurements>2 SDs above our reference mean at one or more sites.

Conclusions The ultrasound finding of enlarged peripheral nerves in FRDA patients points to a structural abnormality at peripheral nerve level. This contrasts with the reduced cross-sectional area seen in the cerebellar ataxia, neuronopathy, vestibular areflexia syndrome (CANVAS) which is thought to be due to a pure sensory ganglionopathy (Pelosi et al, Muscle Nerve 2017, in press). While the specific pathophysiology in FRDA is unknown, nerve enlargement suggests, in agreement with recent neuropathological studies, that axonal loss from dorsal root ganglionopathy is not the sole mechanism underlying sensory neuropathy of FRDA. Myelin and/or stromal abnormality at peripheral nerve level may play a significant role.

http://onlinelibrary.wiley.com/wol1/doi/10.1111/jnp.12125/abstract

Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests

1. Francesco Saccà^*,
2. Teresa Costabile,
3. Filomena Abate,
4. Agnese Liguori,
5. Francesca Paciello,
6. Chiara Pane,
7. Anna De Rosa,
8. Fiore Manganelli,
9. Giuseppe De Michele and
10. Alessandro Filla

AbstractIntroduction

Despite neurological patients show frequent physical impairment, timed neuropsychological tests do not take this into account during scoring procedures.

Objective

We propose a normalization method based on the PATA Rate Task (PRT) and on the nine-hole pegboard test (9HPT) as a measure of dysarthria and upper limb dysfunction.

Methods

We tested 65 healthy controls on timed neuropsychological tests (Attentional Matrices [AM], Trail Making Test, Symbol Digit Modalities Test, Verbal Fluencies) to determine the time spent on phonation or on hand movement during test execution. We developed correction formulas to normalize test times considering the patient’s PRT/9HPT, their normality limits, and the test timing. We tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment.

Results

In healthy controls, phonation or hand movement is 13.5–61.7% of total test time. In FRDA patients, the effect of normalization improved all test results (range: 0.51–48.4%; p < .001). FRDA patients had worst scores in all tests when compared to controls, and the difference remained significant after correction except for the AM. At the individual level, the normalization method improved equivalent scores with fever patients showing impaired scores after correction.

Conclusions

We propose an innovative normalization method to reduce the impact of neurological disability on timed neuropsychological tests. This could be easily integrated in a clinical setting, as it requires a simple preliminary test with the PRT and 9HPT.

https://link.springer.com/article/10.1007%2Fs00455-017-9804-4

Dysphagia in Friedreich Ataxia

• Authors
• Authors and affiliations
• Megan J. Keage
• Martin B. Delatycki
• Isabelle Gupta
• Louise A. Corben
• Adam P. Vogel

Abstract

The objective of the study was to comprehensively characterise dysphagia in Friedreich ataxia (FRDA) and identify predictors of penetration/aspiration during swallowing. We also investigated the psychosocial impact of dysphagia on individuals with FRDA. Sixty participants with FRDA were screened for dysphagia using a swallowing quality of life questionnaire (Swal-QOL) and case history. Individuals reporting dysphagia underwent a standardised oromotor assessment (Frenchay Dysarthria Assessment, 2, FDA-2) and videofluoroscopic study of swallowing (VFSS). Data were correlated with disease parameters (age at symptom onset, age at assessment, disease duration, FXN intron 1 GAA repeat sizes, and Friedreich Ataxia Rating Scale (FARS) score). Predictors of airway penetration/aspiration were explored using logistic regression analysis. Ninety-eight percent (59/60) of participants reported dysphagia, of whom 35 (58.3%) underwent FDA-2 assessment, and 38 (63.3%) underwent VFSS. Laryngeal, respiratory, and tongue dysfunction was observed on the FDA-2. A Penetration–Aspiration Scale score above 3 (deemed significant airway compromise based on non-clinical groups) was observed on at least one consistency in 13/38 (34.2%) participants. All of those who aspirated (10/38, 26.3%) did so silently, with no overt signs of airway entry such as reflexive cough. Significant correlations were observed between dysphagic symptoms and disease duration and severity. No reliable predictors of penetration or aspiration were identified. Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA.