Weihua Meng, Mark J. Adams, Harry L. Hebert, Ian J. Deary, Andrew M. McIntosh, Blair H. Smith, EBioMedicine, Available online 31 January 2018, ISSN 2352-3964, doi:10.1016/j.ebiom.2018.01.023.
Loci associated with broadly-defined headache: Gene FXN, Chromosome 9, Lead SNP rs4596713, P 2.30 × 10− 8, Effective allele T, Minor allele frequency 0.41, Beta− 0.0078, standard error 0.0014.
Friday, February 2, 2018
Neurology Measures in FA Children
February 1, 2018. ClinicalTrials.gov identifier (NCT number): NCT03418740
The purpose of this study is to identify ways to follow progression of Friedreich's Ataxia (FA) and be able to measure changes over time in children with FA. Participants will have biannual visits to observe how the disease progresses over time and determine the rate of progression.
The purpose of this study is to identify ways to follow progression of Friedreich's Ataxia (FA) and be able to measure changes over time in children with FA. Participants will have biannual visits to observe how the disease progresses over time and determine the rate of progression.
Wednesday, January 31, 2018
Common drug review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand
John I. McCormick, L. Diana Berescu and Nabil Tadros; Orphanet Journal of Rare Diseases201813:27 doi:10.1186/s13023-018-0759-9
The positive recommendation rate for CDR reviews of orphan drugs was highest when both clinical and price parameters formed the basis of the assessment. However, there was a change in CDR review policies in 2016, with a dramatic increase in the number of positive recommendations, the majority of which were conditional on a substantial reduction in drug price. This change in CDR recommendations is reflected in the expanded criteria and conditions of drug reimbursement outlined in CADTH’s March 2016 recommendation framework. However, it remains to be seen if this represents a permanent change in how CDR reviews orphan drugs and if this will result in wider and more timely provincial access for orphan drugs for patients throughout Canada.
The positive recommendation rate for CDR reviews of orphan drugs was highest when both clinical and price parameters formed the basis of the assessment. However, there was a change in CDR review policies in 2016, with a dramatic increase in the number of positive recommendations, the majority of which were conditional on a substantial reduction in drug price. This change in CDR recommendations is reflected in the expanded criteria and conditions of drug reimbursement outlined in CADTH’s March 2016 recommendation framework. However, it remains to be seen if this represents a permanent change in how CDR reviews orphan drugs and if this will result in wider and more timely provincial access for orphan drugs for patients throughout Canada.
Monday, January 29, 2018
Late onset friedreich ataxia presented with spastic paraparesis
G. PSIMMENOS, N. Grigoriadis, D. Parisis, T. Afrantou, P. Ioannidis; Thessaloniki/GR; (Poster POD416) EAN Congress 2017 in Amsterdam
We report two cases , a 56 year old male patient and a 29 year old female patient. In both cases examination revealed typical clinical symptoms of the disease such as gait-limb ataxia , impaired tandem gait, severe swaying on testing for Romberg sign. There was no history of weakness or numbness. The uncommon findings in both of them were the exaggerated deep tendon reflexes and that the symptoms appeared at such an advanced age(>26 years old).That was the reason why both patients initially underwent genetic testing for other genetic disorders(spinocerebellar ataxia SCA). Genetic testing disclosed expanded GAA repeat length of FTX gene confirming a diagnosis of FA.
These cases highlight that the existence of increased tendon reflexes, although unusual is not incompatible with FA and thus should not prevent the clinician to consider it as a possible diagnosis when the rest clinical picture, the personal-family history and the neurological signs are in keeping with diagnosis of FA
We report two cases , a 56 year old male patient and a 29 year old female patient. In both cases examination revealed typical clinical symptoms of the disease such as gait-limb ataxia , impaired tandem gait, severe swaying on testing for Romberg sign. There was no history of weakness or numbness. The uncommon findings in both of them were the exaggerated deep tendon reflexes and that the symptoms appeared at such an advanced age(>26 years old).That was the reason why both patients initially underwent genetic testing for other genetic disorders(spinocerebellar ataxia SCA). Genetic testing disclosed expanded GAA repeat length of FTX gene confirming a diagnosis of FA.
These cases highlight that the existence of increased tendon reflexes, although unusual is not incompatible with FA and thus should not prevent the clinician to consider it as a possible diagnosis when the rest clinical picture, the personal-family history and the neurological signs are in keeping with diagnosis of FA
Early onset Friedreich Ataxia without cardiomyopathy
O. Rujan, I. BURAGA, A. Enachi, I. Ionescu, C. Baetu; Bucharest/RO; (Poster POD163) EAN Congress 2017 in Amsterdam
There is a very important clinical distinction between classic FA and its variants, which consists in the absence of kyphoscoliosis and heart disease (a frequent component) which gives the latter group a better prognosis. Our case shows that an early onset of FA doesn’t necessarily mean the patient will develop cardiomyopathy.
Our patient is a 25 year old female whose symptoms were onset at the age of 3 years old and consisted of ataxia of gait, difficulties in standing steadily and in running. The clinical features progressed slowly and now she presents: gait and limb ataxia, the lower limb reflexes are preserved, Romberg sign is present, a rhythmic tremor of the head and upper limbs (more visible during emotional stress), horizontal nystagmus, the speech is slow, slurred and explosive, pes cavus and hammertoes.
This case has some particularities: the early onset of the symptoms, a very slow progression, the preserved lower limb reflexes and the absence of cardiomyopathy.
There is a very important clinical distinction between classic FA and its variants, which consists in the absence of kyphoscoliosis and heart disease (a frequent component) which gives the latter group a better prognosis. Our case shows that an early onset of FA doesn’t necessarily mean the patient will develop cardiomyopathy.
Our patient is a 25 year old female whose symptoms were onset at the age of 3 years old and consisted of ataxia of gait, difficulties in standing steadily and in running. The clinical features progressed slowly and now she presents: gait and limb ataxia, the lower limb reflexes are preserved, Romberg sign is present, a rhythmic tremor of the head and upper limbs (more visible during emotional stress), horizontal nystagmus, the speech is slow, slurred and explosive, pes cavus and hammertoes.
This case has some particularities: the early onset of the symptoms, a very slow progression, the preserved lower limb reflexes and the absence of cardiomyopathy.
Autosomal-recessive cerebellar ataxias
Brent L. Fogel, Handbook of Clinical Neurology, Elsevier, Volume 147, 2018, Pages 187-209, ISSN 0072-9752, ISBN 9780444632333, Doi:10.1016/B978-0-444-63233-3.00013-0.
The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.
The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.
Wednesday, January 24, 2018
Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases
Susan Stein, Elizabeth Bogard, Nicole Boice, Vivian Fernandez, Tessa Field, Alan Gilstrap, Susan R. Kahn, Jane Larkindale and Toni Mathieson; Orphanet Journal of Rare Diseases 201813:18 doi:10.1186/s13023-018-0761-2
Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Patient advocacy organizations may play a major role by positively influencing research and development, clinical trials, and regulations. Thus, collaboration among patient advocacy organizations and industry is essential to bring new therapeutics to patients.
Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Patient advocacy organizations may play a major role by positively influencing research and development, clinical trials, and regulations. Thus, collaboration among patient advocacy organizations and industry is essential to bring new therapeutics to patients.
Thursday, January 18, 2018
Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat
Li Liande, Shen Xiulong, Liu Zhongtian, Norrbom Michaela, Prakash Thazha P., O'Reilly Daniel, Sharma Vivek K., Damha Masad J., Watts Jonathan K., Rigo Frank, and Corey David R.. January 2018, ahead of print.doi:10.1089/nat.2017.0703
Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.
Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.
Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich’s ataxia fibroblasts
De Samber B, Meul E, Laforce B, De Paepe B, Smet J, De Bruyne M, et al. (2018). PLoS ONE 13(1): e0190495. doi:10.1371/journal.pone.0190495
Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.
Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.
Wednesday, January 17, 2018
Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression
Jan Ježek, Katrina F. Cooper and Randy Strich; (Review) Antioxidants 2018, 7(1), 13; doi: 10.3390/antiox7010013
Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.
Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.
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