Thi Hong Lien Han, Jean-Michel Camadro, Renata Santos, Emmanuel Lesuisse, Jean Michel El Hage Chahine and Nguyêt Thanh Ha-Duong; Metallomics, 2017, Accepted Manuscript. DOI:10.1039/C7MT00031F
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.
Wednesday, May 10, 2017
Tuesday, May 9, 2017
Peripheral nerve ultrasound in friedreich’s ataxia
Eoin Mulroy, Luciana Pelosi, Purwa Joshi, Ruth Leadbetter, Miriam Rodrigues, Stuart Mossman, Richard Roxburgh; J Neurol Neurosurg Psychiatry 2017;88:e1. doi:10.1136/jnnp-2017-316074.59
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.
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.
Monday, May 8, 2017
Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency
Abela L, Spiegel R, Crowther LM, Klein A, Steindl K, Papuc SM, Joset P, Zehavi Y, Rauch A, Plecko B, Simmons TL. PLoS ONE 12(5): e0176363. Doi:10.1371/journal.pone.0176363
Neurotoxicity induced by mitochondrial oxidative stress has been demonstrated for several neurodegenerative disorders. Furthermore, reduced aconitase activity has been found in Huntington disease, progressive supranuclear palsy, Friedreich ataxia and Alzheimer’s disease.
We demonstrate that metabolome profiling is a powerful tool to characterize disease mechanisms and pathogenicity of mutations.
Neurotoxicity induced by mitochondrial oxidative stress has been demonstrated for several neurodegenerative disorders. Furthermore, reduced aconitase activity has been found in Huntington disease, progressive supranuclear palsy, Friedreich ataxia and Alzheimer’s disease.
We demonstrate that metabolome profiling is a powerful tool to characterize disease mechanisms and pathogenicity of mutations.
Sunday, May 7, 2017
Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests
Saccà, F., Costabile, T., Abate, F., Liguori, A., Paciello, F., Pane, C., De Rosa, A., Manganelli, F., De Michele, G. and Filla, A. Journal of Neuropsychology. doi: 10.1111/jnp.12125
We tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment. 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 Attentional Matrices. At the individual level, the normalization method improved equivalent scores with fever patients showing impaired scores after correction.
We tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment. 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 Attentional Matrices. At the individual level, the normalization method improved equivalent scores with fever patients showing impaired scores after correction.
Friday, May 5, 2017
Dysphagia in Friedreich Ataxia
Megan J. Keage, Martin B. Delatycki, Isabelle Gupta, Louise A. Corben, Adam P. Vogel; Dysphagia (2017). doi:10.1007/s00455-017-9804-4
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. 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. No reliable predictors of penetration or aspiration were identified.
Thursday, May 4, 2017
Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy
Gregory M. Enns and Tina M. Cowan; Journal of Clinical Medicine 2017, 6(5), 50; doi:10.3390/jcm6050050
“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function. The lack of validated, widely available, and objective markers of mitochondrial function makes this state-of-the-art of mitochondrial medicine in the 21st century somewhat discouraging.
Dysfunction of the mitochondrial electron transport chain is associated with redox imbalance and abnormally low GSH levels in primary genetic mitochondrial disorders, as well as conditions associated with secondary mitochondrial impairment, such as organic acidemias, Friedreich ataxia, Alzheimer disease, Parkinson disease, amyotropic lateral sclerosis, and Rett syndrome.
Friedreich ataxia patients also have evidence of redox abnormalities and mitochondrial dysfunction. A study of 14 unrelated Friedreich ataxia patients measured total and free GSH concentrations in erythrocytes by HPLC. Patients had a significant reduction of free glutathione levels, although total glutathione levels were comparable to controls. Friedreich ataxia patients were also found to have a significant increase in glutathione bound to hemoglobin in erythrocytes. Glutathione homeostasis was, therefore, considered to be impaired in Friedreich ataxia, raising the possibility that free radicals play a role in disease pathophysiology.
“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function. The lack of validated, widely available, and objective markers of mitochondrial function makes this state-of-the-art of mitochondrial medicine in the 21st century somewhat discouraging.
Dysfunction of the mitochondrial electron transport chain is associated with redox imbalance and abnormally low GSH levels in primary genetic mitochondrial disorders, as well as conditions associated with secondary mitochondrial impairment, such as organic acidemias, Friedreich ataxia, Alzheimer disease, Parkinson disease, amyotropic lateral sclerosis, and Rett syndrome.
Friedreich ataxia patients also have evidence of redox abnormalities and mitochondrial dysfunction. A study of 14 unrelated Friedreich ataxia patients measured total and free GSH concentrations in erythrocytes by HPLC. Patients had a significant reduction of free glutathione levels, although total glutathione levels were comparable to controls. Friedreich ataxia patients were also found to have a significant increase in glutathione bound to hemoglobin in erythrocytes. Glutathione homeostasis was, therefore, considered to be impaired in Friedreich ataxia, raising the possibility that free radicals play a role in disease pathophysiology.
Monday, May 1, 2017
The new top 10 most expensive drugs on the planet
Endpoints News. by John Carroll
April 28, 2017 07:38 AM
¨5. Actimmune $572,292¨
Company: Horizon
Category: Rare disease – orphan drug
(Interferon gamma 1-b)
Approved for severe, malignant osteopetrosis and chronic granulomatous disease, rare genetic diseases, Actimmune noted last last year that the drug failed a Phase III for Friedreich’s ataxia. Horizon obtained a separate orphan drug designation for the drug when it decided to mount the study.
April 28, 2017 07:38 AM
¨5. Actimmune $572,292¨
Company: Horizon
Category: Rare disease – orphan drug
(Interferon gamma 1-b)
Approved for severe, malignant osteopetrosis and chronic granulomatous disease, rare genetic diseases, Actimmune noted last last year that the drug failed a Phase III for Friedreich’s ataxia. Horizon obtained a separate orphan drug designation for the drug when it decided to mount the study.
Sunday, April 30, 2017
Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells
Kevin Kemp Rimi Dey, Amelia Cook, Neil Scolding, Alastair Wilkins; Cerebellum (2017). doi:10.1007/s12311-017-0860-y
The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich’s ataxia.
The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich’s ataxia.
Saturday, April 29, 2017
Frataxin Deficiency Impairs Mitochondrial Biogenesis in Cells, Mice and Humans
Mittal J. Jasoliya, Marissa Z. McMackin, Chelsea K. Henderson, Susan L. Perlman, Gino A. Cortopassi; Hum Mol Genet 2017 ddx141. doi: 10.1093/hmg/ddx141
We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency.
We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency.
Friday, April 28, 2017
Dimethyl Fumarate Mediates Nrf2-dependent Mitochondrial Biogenesis in Mice and Humans
Genki Hayashi, Mittal Jasoliya, Francesco Saccà, Chiara Pane, Alessandro Filla, Angela Marsili, Giorgia Puorro, Roberta Lanzillo, Vincenzo Brescia Morra, Gino Cortopassi; Hum Mol Genet 2017 ddx167. doi: 10.1093/hmg/ddx167
The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
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