|
http://www.medicalnewstoday.com/articles/185939.php
A New Proposal For Achieving Neuronal
Regeneration
Main Category: Neurology / Neuroscience
Also Included In: Biology / Biochemistry; Clinical Trials / Drug Trials
Article Date: 20 Apr 2010 - 2:00 PDT
Over the past four years, in the installations
of the Faculty of Medicine, University of Cadiz, a group of researchers, headed
by Doctor Carmen Estrada, has been studying neurogenesis the process of forming
new neurons from mother cells in the adult mammal brain. The purpose of this
research project is to contribute to the knowledge of this process with the
object of finding some additional mechanism that would facilitate the treatment
of pathologies of the central nervous system (CNS) that are suffered in
consequence of neuronal death. In other words, this work concerns diseases of
huge personal and socioeconomic implication, such as Alzheimer's, Parkinson's
and amyotrophic lateral sclerosis (ELA), and the consequences of cerebrovascular
accidents and neuronal loss from severe cranial shock.
The investigations carried out in the area of Physiology of the Faculty of
Medicine have made sufficient advances that the UCA has now applied for a patent
on the use of specific agents, inhibitors of the action of the protein ADAM-17,
for the preparation of a drug to increase the neuronal regeneration of the
central nervous system.
To appreciate the importance of this patent, it should be understood that in the
brain there are two types of cells: neurons and glial cells. Contrary to popular
belief, the glial cells constitute the majority cellular type within the central
nervous system. However it is the activity of the neurons that underlies the
mental functions, some of which give rise to our consciousness in the form of
sensations, emotions, memories, thoughts and decisions. The glia constitute
tissue whose principal functions are those of support, and essentially they
enable the neurons to perform their activity with exceptional efficacy.
"When a lesion is suffered and both types of cell are lost, the neural mother
cells that reside in the adult brain are activated. These mother cells multiply
by dividing and take on the role of new glial cells but not of new neurons. We
have demonstrated that this limitation is due to the activity of a protein with
enzymatic activity (i.e. an enzyme) known as ADAM-17. When we block the activity
of this enzyme in neural mother cells in vitro, more neurons and fewer glial
cells are generated (which is contrary to the normal effect of the enzyme).
Furthermore, we have also confirmed that, in the brain zone where damage has
taken place, there is an increased presence of the protein ADAM-17, which in the
normal undamaged brain is either not present at all or, if so, only in very
small amounts. Specifically, ADAM-17 is produced in the mother cells that are
dividing and multiplying around the lesion, and is the factor responsible for
the formation of new glial cells but not neurons. For this reason we think that
the inhibition of ADAM-17 will facilitate the emergence of new neurons and thus
facilitate the recovery of the lesion", explains Doctor Carmen Estrada, of the
Faculty of Medicine.
To enable this process to take place "one of the alternatives that could
contribute to resolving, or at least to alleviating, the clinical problems
presented by diseases and injuries that involve neuronal loss, is the
transplanting of mother cells that could help to form new neurons once exposed
to the micro-environment of the appropriate nervous tissue". However, to do this,
we have to modify the non-neurogenic niche of the lesioned zone and convert it
into a neurogenic niche in which both the endogenous and the transplanted mother
cells can become mature and functioning neurons". In other words, "a cellular
therapy would have to be applied to the tissue through the implanting of mother
cells in the lesioned zone simultaneously with treatment to inhibit ADAM-17
which would encourage these transplanted cells to transform themselves into
neurons", adds Doctor Carmen Castro, one of the researchers who has worked on
the development of this patent.
"The ideal is to be able to find a potential drug that would serve to annul the
activity of ADAM-17 but that would not have secondary effects in humans; this is
an objective that several pharmaceutical laboratories are currently working
towards".
From in vitro to in vivo research.
To date, the experiments carried out have been done in vitro, since "we are
faced with the problem that we have not yet obtained a drug that inhibits
ADAM-17, and so the work has been done with an interference RNA", states Carmen
Estrada. However, "to take the research forward to the in vivo stage,
interference RNA cannot be used because the techniques for its application in
experimentation animals are not yet very well-developed". This is something that,
in recent weeks, has been resolved by these researchers, and the team is already
working on a new way to carry out the in vivo work. These advances suggest that
at least four more years of research are needed.
A team of six persons has worked on this complex and important project. Having
explained what has been achieved to date, the researchers want to clarify that
the next objective of the group is to demonstrate that the inhibition of ADAM-17
in vivo really does facilitate the generation of new neurons and so helps the
brain to recover from a lesion. Thus, if a specific inhibitor of ADAM-17 that
does not have adverse secondary effects in humans could be found, a drug could
be developed that would inhibit the process of glial differentiation and enhance
neuronal differentiation, during the process of cell regeneration either from
the individual's own (endogenous) neural mother cells, or from transplanted
cells, or from both, in cases of lesions of the central nervous system.
If all this works, in the not-too-distant future, there should be a clinical
application in humans affected by a lesion of the central nervous system (of the
brain or the spinal cord). In addition, the possibility would be opened for the
employment of transplants of neural mother cells. A new proposal for
facilitating neuronal regeneration.
Source: Universidad de Cádiz
http://www.curefa.org/_pdf/FARAchantixPRapril9-2010.pdf
Important Clinical Trial Update - “Double-Blind,
Randomized, Placebo-Controlled Pilot
Study of Varenicline in the Treatment of Friedreich’s Ataxia”
Springfield, VA - April 12, 2010
In June 2009, the Friedreich’s Ataxia Research Alliance (FARA) announced the
launch of a
clinical trial of varenicline (Chantix®) to investigate both safety and
potential efficacy in improving
neurological symptoms such as balance, coordination and sensory perception in a
diverse group
of adults diagnosed with Friedreich’s ataxia. This pilot study was initiated
based on case reports
indicating that uncoordinated movements (ataxia) and balance problems in
patients with various
forms of ataxia had improved significantly when the individuals were taking
Chantix. The double
blind, randomized, placebo-controlled pilot study has been led by principal
investigator Dr.
Theresa Zesiewicz, Professor of Neurology at the University of South Florida
College of
Medicine, and co-investigator Dr. David Lynch, Associate Professor of Neurology
and Pediatrics
at Children’s Hospital of Philadelphia. Chantix® is approved by the U.S. Food
and Drug
Administration to help cigarette smokers stop smoking.
The Data Safety Monitoring Board (DSMB) responsible for monitoring the progress
and
associated risk/benefits of the study convened April 7th 2010 to review the data
collected to date.
Following that review, the DSMB recommended that the study be stopped as a
result of concerns
regarding safety and intolerability and insufficient evidence of efficacy.
Twenty six subjects had
been enrolled into the trial. The primary concern among those who were withdrawn
was a
worsening of gait and imbalance. FARA, the study sponsor, and the study
investigators have
decided to act upon the DSMB recommendation. Therefore, no further subjects will
be enrolled
and all current subjects in both the double blind and open label periods are
being instructed to
discontinue the study drug. Of note, this DSMB recommendation and this decision
by FARA and
the investigators pertain solely to this study, which involved only subjects
with Friedreich’s ataxia.
At this time, the study investigators and subjects continue to be blinded
regarding each subject’s
treatment assignment as data collection is ongoing and subjects are still being
evaluated and
scheduled for final study visits. Once all of the final visits have been
completed and data
collected, the study team will be able to analyze the data and share the
complete results. We all
anxiously await this full review and FARA will keep the entire Friedreich’s
ataxia community
informed, as new information and analyses become available.
FARA would like to thank and recognize the study investigators, DSMB and, most
especially, the
patients who participated in the study. FARA remains committed to exploring this
type of
therapeutic approach for Friedreich’s ataxia. As mentioned above, the study team
still needs to
analyze the study data and issue a complete report, which we are confident will
provide important
details and insights. In addition, the initial case reports on which this pilot
study was based
opened an exciting new avenue of research investigating neurotransmission and
improvement of
nervous system function in Friedreich’s ataxia. We believe that further basic
investigation of this
area will lead to new studies in the future that will provide hope for a variety
of methods of
improvement of nervous system function in Friedreich’s ataxia.
About Friedreich’s Ataxia (FA)
FA is an aggressive neurodegenerative disease that debilitates people of all
ages, robbing them
of their ability to walk, see, speak and hear and cutting short their life
expectancies. Currently,
there is no cure or treatment for FA. Although rare, FA is the most prevalent
inherited ataxia,
affecting about one in every 50,000 people in the United States.
About Friedreich's Ataxia Research Alliance (FARA)
FARA advances research for Friedreich's Ataxia (FA) and is dedicated to curing
FA.
Founded in 1998 by FA parents and patients, FARA is a nonprofit, 501c3, whose
mission is
directing and funding research through a remarkable level of collaboration among
the
patient, medical and scientific communities. FARA funded research is bringing
promising
treatments forward fueling confidence in the ability to slow, stop and reverse
this disease for
patients living with FA today. http://www.CureFA.org
Contact
Jennifer Farmer
Executive Director, Friedreich's Ataxia Research Alliance
(484) 875-3015
jen.farmer@curefa.org
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBD-4YVRRSF-9&_user=10&_coverDate=05%2F31%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a7f82f3ff8a
3e08147ec9074e3104ae2
Intermediate-Dose Idebenone and Quality of Life
in Friedreich Ataxia
John F. Brandsema MD*, Derek Stephens MSc†, Jessica Hartley MSc‡ and Grace Yoon
MD*, ‡, ,
† Department of Child Health Evaluative Sciences, The Hospital for Sick Children,
University of Toronto, Toronto, Canada
‡ Division of Clinical and Metabolic Genetics, Department of Paediatrics, The
Hospital for Sick Children, University of Toronto, Toronto, Canada
* Division of Neurology, The Hospital for Sick Children, University of Toronto,
Toronto, Canada
Received 6 October 2009; accepted 4 January 2010. Available online 15 April
2010.
Idebenone has been used as therapy for Friedreich ataxia for more than a decade.
Although several studies have assessed the influence of therapy on neurologic or
cardiac function, there is a paucity of data surrounding patient-reported
outcome measures. In an observational study of the effect of intermediate-dose
idebenone (20 mg/kg per day) on quality of life and neurologic function measures,
seven patients with Friedreich ataxia were assessed using the Pediatric Quality
of Life Inventory, the International Cooperative Ataxia Rating Scale, and an
Activities of Daily Living Scale before initiation of idebenone therapy and
after 1 year of therapy. Physical scores on the Pediatric Quality of Life
Inventory were universally worse after 1 year, and correlated with decreased
activities of daily living scores. Despite worsening physical scores, there was
a trend toward improved total, emotional, social, and school components of
quality of life scores after 1 year of idebenone therapy. There was no
statistically significant change in Pediatric Quality of Life Inventory scores
between baseline and 1 year of idebenone therapy. Functional ability, as
measured by activities of daily living scores, appeared to have the most
influence on the perception of physical quality of life, which may be important
in planning future therapeutic trials.
Communications should be addressed to: Dr. Yoon; Divisions of Neurology and
Clinical and Metabolic Genetics; Department of Paediatrics; The Hospital for
Sick Children; 555 University Ave.; Toronto, ON M5G 1X8, Canada.
--------------------------------------------------------------------------------
Pediatric Neurology
Volume 42, Issue 5, May 2010, Pages 338-342
http://www.ncbi.nlm.nih.gov/pubmed/20393584?dopt=Abstract
Can J Physiol Pharmacol. 2010 Mar;88(3):187-96.
Iron redistribution as a therapeutic strategy for treating diseases of localized
iron accumulation.
Kakhlon O, Breuer W, Munnich A, Cabantchik ZI.
Department of Biological Chemistry, Alexander Silberman Institute of Life
Sciences, The Hebrew University of Jerusalem, Safra Campus at Givat Ram,
Jerusalem 91904, Israel.
Abstract
Defective iron utilization leading to either systemic or regional
misdistribution of the metal has been identified as a critical feature of
several different disorders. Iron concentrations can rise to toxic levels in
mitochondria of excitable cells, often leaving the cytosol iron-depleted, in
some forms of neurodegeneration with brain accumulation (NBIA) or following
mutations in genes associated with mitochondrial functions, such as ABCB7 in X-linked
sideroblastic anemia with ataxia (XLSA/A) or the genes encoding frataxin in
Friedreich's ataxia (FRDA). In anemia of chronic disease (ACD), iron is withheld
by macrophages, while iron levels in extracellular fluids (e.g., plasma) are
drastically reduced. One possible therapeutic approach to these diseases is iron
chelation, which is known to effectively reduce multiorgan iron deposition in
iron-overloaded patients. However, iron chelation is probably inappropriate for
disorders associated with misdistribution of iron within selected tissues or
cells. One chelator in clinical use for treating iron overload, deferiprone (DFP),
has been identified as a reversed siderophore, that is, an agent with iron-relocating
abilities in settings of regional iron accumulation. DFP was applied to a cell
model of FRDA, a paradigm of a disorder etiologically associated with cellular
iron misdistribution. The treatment reduced the mitochondrial levels of labile
iron pools (LIP) that were increased by frataxin deficiency. DFP also conferred
upon cells protection against oxidative damage and concomitantly mediated the
restoration of various metabolic parameters, including aconitase activity.
Administration of DFP to FRDA patients for 6 months resulted in selective and
significant reduction in foci of brain iron accumulation (assessed by T2* MRI)
and initial functional improvements, with only minor changes in net body iron
stores. The prospects of drug-mediated iron relocation versus those of chelation
are discussed in relation to other disorders involving iron misdistribution,
such as ACD and XLSA/A.
Verified by S. Andrea Hospital, April 2010
|
S. Andrea Hospital
|
|
S. Andrea Hospital |
|
NCT01104649 |
The
hereditary cerebellar ataxias include diverse neurodegenerative
disorders. Hereditary ataxias can be divided into autosomal dominant
ataxias (ADCAs), autosomal recessive ataxias (ARCAs), X-linked, and
mitochondrial ataxias on the basis of mode of inheritance. The key
feature in all these disorders is ataxia typically characterised by
poor balance, hand incoordination, postural or kinetic tremor,
dysarthria and dysphagia.
To date
no treatment has been shown to slow progression of the disease and
symptomatic therapies are limited to few options that are partially
effective.
Purkinje
cells project inhibitory signals to the deep cerebellar nuclei(DCN)
which have a critical role in cerebellar function and motor
performance. DCN neurons fire spontaneously in the absence of
synaptic input from Purkinje neurons and modulation of the DCN
response by Purkinje input is believed to be responsible for
coordination of movement, while uncontrolled spontaneous firing of
DCN neurons may underlay cerebellar ataxia. Recent studies have
demonstrated that small-conductance calcium-activated potassium (SK)
channels inhibitor are able to increase DCN firing rate. Since SK
channels are critical regulators of DCN firing rate, SK openers such
as the drug riluzole may reduce neuronal hyperexcitability and
thereby be useful in the therapy of cerebellar ataxia.
On this
base the investigators published a pilot study in patients with
chronic cerebellar ataxia (Ristori et al., Neurology 2010)
investigating safety and efficacy of riluzole or placebo
administration for 8 weeks. The results demonstrated a significative
improvement in International Cooperative Ataxia Rating Scale (ICARS)
global score after four weeks and after 8 weeks in the riluzole arm.
The
present protocol is aimed at verifying the safety and efficacy of
riluzole administration for a longer period, in a larger sample size
of patients, with more stringent diagnostic criteria (hereditary
cerebellar ataxia), respect to the above pilot study. Sixty patients
will be enrolled in a double-blind, placebo-controlled trial. By
central randomisation, patients will take 50 mg of riluzole or
placebo twice daily for 12 months. Treatment effects will be
assessed by comparing the ICARS and Scale for the Assessment and
Rating of Ataxia (SARA) before treatment and during therapy at
months 3, 6, 9 ,12.
Cerebellar Ataxia
|
Drug:
riluzole
Other: Placebo comparator
|
Phase
II
Phase III
|
| Study
Type: |
Interventional
|
| Study
Design: |
Allocation: Randomized
Control: Placebo Control
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment |
|
Official Title: |
Efficacy of Riluzole in Hereditary
Cerebellar Ataxia: a Randomized Double-blind
Placebo-controlled Trial. |
Primary Outcome Measures:
-
Scale for the assessment and rating of ataxia (SARA) [ Time Frame: 12
months ] [ Designated as safety issue: No ]
Improvement in ataxia
Secondary Outcome Measures:
| Estimated
Enrollment: |
60 |
| Study Start
Date: |
April 2010 |
| Estimated
Study Completion Date: |
May 2012 |
| Estimated
Primary Completion Date: |
January 2012 (Final data collection date
for primary outcome measure) |
| Riluzole:
Experimental
|
Drug:
riluzole
Study drug will be
orally dispensed in doses of 50 mg twice daily for
12 months.
|
| placebo:
Placebo Comparator
|
Other:
Placebo comparator
Study drug will be
orally dispensed in doses of 50 mg twice daily for
12 months.
|
| Ages Eligible for Study:
|
18
Years to 70 Years |
| Genders Eligible for
Study:
|
Both |
| Accepts Healthy
Volunteers:
|
No |
Inclusion
Criteria:
-
Clinical or genetic diagnosis of hereditary cerebellar ataxia
Exclusion
Criteria:
-
Concomitant experimental therapy for ataxia
-
Serious systemic illnesses
-
Pregnancy
Please refer to this study by its
ClinicalTrials.gov identifier: NCT01104649
|
Center for Experimental
Neurological Therapies (CENTERS), S. Andrea Hospital, II Faculty
of Medicine, "Sapienza" University of Rome |
|
Rome, Italy, 00139 |
|
Contact: Giovanni Ristori, MD
+390633776044
giovanni.ristori@uniroma1.it |
|
Contact: Silvia Romano, MD,
PhD +390633776044
silvia.romano@uniroma1.it |
S. Andrea Hospital
|
Principal Investigator: |
Silvia Romano, MD, PhD |
Center for Experimental Neurological
Therapies
(CENTERS), S. Andrea Hospital, II Faculty
of Medicine,
"Sapienza" University of Rome |
Additional Information:
Publications:
Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali
M, Pontieri FE,
Vanacore N, Salvetti M. Riluzole in cerebellar ataxia: a
randomized, double-blind,
placebo-controlled pilot trial. Neurology. 2010 Mar
9;74(10):839-45.
| Responsible Party: |
Center for Experimental Neurological Therapies (CENTERS) (
Ristori Giovanni ) |
| Study ID Numbers: |
FARM7KAJM7 |
| Study First Received: |
April
7, 2010 |
| Last Updated: |
April
14, 2010 |
| ClinicalTrials.gov
Identifier: |
NCT01104649
History of Changes |
| Health Authority: |
Italy:
Ethics Committee |
Keywords provided by S. Andrea Hospital:
Spinocerebellar
ataxia
Friedreich ataxia
|
http://www.babelfamily.org/en/latestataxianews/732-dna-transfer-prevents-mitochondrial-disease-in-humans
Credit: Australian Science
Media Centre
By Clive Cookson, FT.com Science
Editor
Published: April 14 2010
Scientists have for the first
time transferred DNA between
human eggs. The success at
Newcastle University opens the
door to a powerful but
potentially controversial form
of “germ-line gene therapy”,
which would prevent the
transmission of some inherited
diseases.
The Newcastle team aims to stop
mothers passing on defective
“mitochondrial DNA”. This
genetic material controls
mitochondria, microscopic energy-producing
bodies often called the cell’s
batteries.
Prof. Doug Turnbull
About one child in 200 is born
with harmful mutations in the
mitochondrial genes. Usually
this causes only mild effects,
but about one in 6,500 children
develops severe mitochondrial
disease; symptoms include
muscular weakness, heart or
liver failure, blindness and
neurological problems.
The research, published in the
journal Nature involved
extracting the two “pronuclei” –
the nuclear DNA from mother and
father – from a newly fertilised
human egg. The pronuclei were
inserted into a fertilised donor
egg whose own nuclear material
had been removed.
The resulting fertilised egg
contains the parents’ nuclear
DNA but mitochondria from the
egg donor. “What we’ve done is
like changing the battery on a
laptop,” said Doug Turnbull, the
project leader
http://www3.interscience.wiley.com/journal/123350434/abstract?CRETRY=1&SRETRY=0
Coenzyme Q10-responsive ataxia: 2-Year-treatment follow-up
Merce Pineda, MD, PhD 1 2, Raquel Montero, PhD 2 3, Asuncion Aracil,
MD 1 2, Mar M. O'Callaghan, MD 1 2, Ana Mas, MD 4, Carmen Espinos,
PhD 2, Dolores Martinez-Rubio, BS 2 5, Francesc Palau, MD, PhD 2 5,
Placido Navas, PhD 2 6, Paz Briones, PhD 2 7, Rafael Artuch, MD, PhD
2 3 *
1Department of Pediatric Neurology, Hospital Sant Joan de Déu,
Barcelona, Spain
2Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),
ISCIII, Spain
3Department of Clinical Biochemistry, Hospital Sant Joan de Déu,
Barcelona, Spain
4Department of Pharmacy, Hospital Sant Joan de Déu, Barcelona, Spain
5Genetics and Medicine Molecular Unit, Instituto de Biomedicina de
Valencia-CSIC, Valencia, Spain
6Centro Andaluz de Biología del Desarrollo, Universidad Pablo de
Olavide, Sevilla, Spain
7Institut de Bioquímica Clínica, Hospital Clinic and CSIC,
Barcelona, Spain
email: Rafael Artuch (rartuch@hsjdbcn.org)
*Correspondence to Rafael Artuch, Department of Clinical
Biochemistry, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu,
2, 08950 Esplugues, Barcelona, Spain
Potential conflict of interest: Nothing to report.
Funded by:
Fondo de Investigación Sanitaria; Grant Number: FIS PI080663,
PI080307
Instituto de Salud Carlos III (ISCIII, MICIN, Spain)
Keywords
coenzyme Q10 deficiency • mitochondrial disorders • ataxia •
cerebellum • pediatric patients
Abstract
We assessed the clinical outcome after coenzyme Q10 (CoQ10) therapy
in 14 patients presenting ataxia classified into two groups
according to CoQ10 values in muscle (deficient or not). We performed
an open-label prospective study: patients were evaluated clinically
(international cooperative ataxia rating scale [ICARS] scale, MRI,
and videotape registration) at baseline and every 6 months during a
period of 2 years after CoQ10 treatment (30 mg/kg/day). Patients
with CoQ10 deficiency showed a statistically significant reduction
of ICARS scores (Wilcoxon test: P = 0.018) after 2 years of CoQ10
treatment when compared with baseline conditions. In patients
without CoQ10 deficiency, no statistically significant differences
were observed in total ICARS scores after therapy, although 1
patient from this group showed a remarkable clinical amelioration.
Biochemical diagnosis of CoQ10 deficiency was a useful tool for the
selection of patients who are good candidates for treatment as all
of them responded to therapy. However, the remarkable clinical
response in 1 case without CoQ10 deficiency highlights the
importance of treatment trials for identification of patients with
CoQ10-responsive ataxia. © 2010 Movement Disorder Society
http://www3.interscience.wiley.com/journal/123342199/abstract
Analysis of the factors influencing the cardiac phenotype in
Friedreich's ataxia
Bheeshma Rajagopalan, FRCP 1, Jane M. Francis, DCR(R) 2, Fraser
Cooke, MRCP 1, L. V. Prasad Korlipara, MRCP 3, Andrew M. Blamire,
PhD 1, Anthony H.V. Schapira, FMedSci 3, Jason Madan, MSc 4, Stefan
Neubauer, FRCP 2, J. Mark Cooper, PhD 3 *
1Nuffield Department of Medicine, Department of Biochemistry,
University of Oxford, Oxford, UK
2University of Oxford Centre for Clinical Magnetic Resonance
Research, Oxford, UK
3Clinical Neurosciences, Institute of Neurology, UCL, London, UK
4Health Economics and Decision Science, ScHARR, University of
Sheffield, Sheffield, UK
email: J. Mark Cooper (j.cooper@medsch.ucl.ac.uk)
*Correspondence to J. Mark Cooper, Department of Clinical
Neurosciences, UCL Institute of Neurology, Rowland Hill Street,
London, NW3 2PF, United Kingdom
Potential conflict of interest: Nothing to report.
Funded by:
Ataxia UK and the Medical Research Council
Keywords
cardiomyopathy • genetics • magnetic resonance imaging •
Friederich's ataxia
Abstract
Friedreich's ataxia (FRDA) has been associated with both cardiac
hypertrophy and to a lesser degree dilated cardiomyopathy. We have
conducted a cross sectional magnetic resonance imaging (MRI) study
of 25 patients with clinically and genetically confirmed FRDA and 24
healthy controls to analyse how disease parameters influence cardiac
features in FRDA. MR cine imaging in the long and short axis planes
was performed alongside clinical assessments. LV mass was most
pronounced in FRDA patients with a larger genetic mutation (GAA1
repeats >600), earlier age of onset (<16years) and a shorter disease
duration (<15 years). LV mass decreased with longer disease duration
(>15 years), and independent of GAA1 repeat size and age of onset,
suggesting cardiac thinning occurred with prolonged disease. Heart
function was lower in patients with larger GAA1 repeat number and
longer disease duration. Consequently, cardiac hypertrophy was more
marked in FRDA patients with a larger GAA1 repeat number and younger
age of onset, while prolonged disease duration was associated with
lower LV mass and decreased heart function. It is important not only
to understand the biochemical basis for these cardiac changes but
also allow for these changes when assessing the effect of treatment
of FRDA patients. © 2010 Movement Disorder Society
http://www.jci.org/articles/view/41615
http://www3.interscience.wiley.com/journal/123338415/abstract
Long intronic GAA repeats causing Friedreich ataxia impede
transcription elongation
Tanel Punga, Marc Bühler *
Friedrich Miescher Institute for Biomedical Research, Basel,
Switzerland
email: Marc Bühler (marc.buehler@fmi.ch)
*Correspondence to Marc Bühler, Tel: +41 61 6960438; Fax: +41 61 697
39 76
Keywords
epigenetics • Friedreich ataxia (FRDA) • heterochromatic gene
silencing • histone modification • triplet repeat expansion disorder
(TRED)
Abstract
Friedreich ataxia is a degenerative disease caused by deficiency of
the protein frataxin (FXN). An intronic expansion of GAA triplets in
the FXN-encoding gene, FXN, causes gene silencing and thus reduced
FXN protein levels. Although it is widely assumed that GAA repeats
block transcription via the assembly of an inaccessible chromatin
structure marked by methylated H3K9, direct proof for this is
lacking. In this study, we analysed different histone modification
patterns along the human FXN gene in FRDA patient-derived
lymphoblastoid cell lines. We show that FXN mRNA synthesis, but not
turnover rates are affected by an expanded GAA repeat tract.
Importantly, rather than preventing transcription initiation, long
GAA repeat tracts affect transcription at the elongation step and
this can occur independently of H3K9 methylation. Our data
demonstrate that finding novel strategies to overcome the
transcription elongation problem may develop into promising new
treatments for FRDA.
http://www.ncbi.nlm.nih.gov/pubmed/20413654?dopt=AbstractPlus&holding=f1000,f1000m,isrctn
Hum Mol Genet. 2010 Apr 22.
Understanding the molecular mechanisms of Friedreich Ataxia to
develop therapeutic approaches.
Schmucker S, Puccio H.
IGBMC (Institut de Génétique et de Biologie Moléculaire et
Cellulaire), 1 rue Laurent Fries, BP10142, Illkirch, F-67400 France
;
Abstract
Friedreich ataxia is a neurodegenerative disease caused by reduced
expression of the mitochondrial protein frataxin. The
physiopathological consequences of frataxin deficiency are a severe
disruption of iron sulfur cluster (ISC) biosynthesis, mitochondrial
iron overload coupled to cellular iron dysregulation, and an
increased sensitivity to oxidative stress. Frataxin is a highly
conserved protein which has been suggested to participate in a
variety of different roles associated with cellular iron
homeostasis. The present review discusses recent advances that have
made crucial contributions in understanding the molecular mechanisms
underlying Friedreich ataxia and in advancements towards potential
novel therapeutic approaches. Due to space constraints, this review
will focus on the most commonly accepted and solid molecular and
biochemical studies concerning the function of frataxin and the
physiopathology of the disease. We invite the reader to read the
following reviews to have a more exhaustive overview of the field
(1-4).
http://www.babelfamily.org/en/latestataxianews/721-genetics-telethon-italy-funds-discovery-of-the-cause-of-a-new-form-of-ataxia
Genetics: Telethon Italy Funds Discovery of the Cause of a New Form
of Ataxia
(ANSA) Rome, March 8 -- The genetic defect responsible for a
specific form of hereditary ataxia, SCA28, has been identified. The
term “ataxia”, from the Greek work for “disorder”, indicates a
disturbance in coordination and movements, often associated with
incontinence, difficulty swallowing, and uncontrolled movements of
the limbs, trunk, head, and eyes. The part of the brain involved in
many forms of ataxia is the cerebellum, which normally controls
voluntary movements.
The genetic defect causing SCA28 was discovered in a study conducted
by Franco Taroni, a researcher at Milan’s Carlo Besta Neurological
Institute, in collaboration with Marco Muzi-Falconi of the Research
University of Milan. Funded by the Telethon, the study was published
in the journal Nature Genetics.
Although it is often a result of infection, toxic exposure, or
radiation, ataxia can also be of a genetic origin, as is true for
SCA28. These cases are called hereditary ataxias, and it’s estimated
that in Italy some 5,000 individuals are affected, some with
childhood-onset ataxias, and others with adult-onset ataxias, but
always with a progression of symptoms over time. Although the
various forms have essentially the same symptoms, the different
hereditary ataxias are caused by a variety of genetic defects.
SCA28 is a newly discovered form of ataxia, which Taroni diagnosed
for the first time in the world in an Italian family. This form is
inherited, like many of the hereditary ataxias, in an autosomal
dominant pattern: it will appear in an individual who receives just
one defective copy of the relevant gene from either of the parents,
who each contribute two copies of every gene. The parent
contributing the defective gene is also affected by the disease,
since it only requires one copy of the defective gene to be affected;
however, symptoms often do not appear until middle age, after an
affected parent has already had children.
In studying the DNA of several patients who had an undiagnosed or
unspecified form of ataxia (which is true for about half of those
affected with an hereditary ataxia), the Milanese researchers were
able first to locate the gene involved, then to precisely identify
it and to define the specific alterations responsible for the
disease. The gene involved in SCA28 is called the AFG3L2 gene.
The Milanese group’s work has an immediate impact in the diagnostic
field, which is particularly important in the case of a group of
diseases caused by such a diversity of genetic defects. Looking
ahead, the researchers’ next step will be to look further into the
mechanism of SCA28. Franco Taroni’s work is also supported by Auchan.
About Telethon Italy see:
http://www.telethon.it/english/default.aspx
Telethon Italy fundraising depends primarily on a solidarity
marathon presented on RAI TV channels in December: in 2008-2009,
33.4 million Euros were raised.
http://www.ncbi.nlm.nih.gov/pubmed/20424464?dopt=Abstract
Dysarthria in Friedreich's ataxia: a perceptual analysis.
Folker J, Murdoch B, Cahill L, Delatycki M, Corben L, Vogel A.
School of Health and Rehabilitation Science, The University of
Queensland, Brisbane, Qld., Australia. j.folker@uq.edu.au
Abstract
The aims of this study were to: (1) evaluate the perceptual speech
dimensions, speech intelligibility and dysarthria severity of a
group of individuals diagnosed with Friedreich's ataxia (FRDA); (2)
determine the presence of subgroups within FRDA dysarthria; (3)
investigate the relationship between the speech outcome and the
clinical factors of disease progression. The study included 38
individuals (21 female, 17 male) with a confirmed diagnosis of FRDA.
A group of 20 non-neurologically impaired individuals served as
controls. Perceptual analysis, investigating 30 different dimensions
of speech, was conducted on a speech sample obtained from each
participant. In addition, the Assessment of Intelligibility of
Dysarthria Speech was administered. All FRDA participants presented
with dysarthria with severities ranging from mild to moderate.
Cluster analysis revealed 3 subgroups, the first presenting with
mild dysarthric symptoms, the second with increased velopharyngeal
involvement and the third characterized by increased laryngeal
dysfunction. Dysarthria severity showed a significant correlation to
disease duration but to no other clinical measure. The findings
support the notion of subgroups in FRDA dysarthria, representing
distinct impairments of the speech mechanism and perhaps reflective
of differing evolutions beyond the cerebellum. 2010 S. Karger AG,
Basel
Dysarthria in Friedreich's ataxia: a perceptual analysis.
Folker J, Murdoch B, Cahill L, Delatycki M, Corben L, Vogel A.
School of Health and Rehabilitation Science, The University of
Queensland, Brisbane, Qld., Australia. j.folker@uq.edu.au
Abstract
The aims of this study were to: (1) evaluate the perceptual speech
dimensions, speech intelligibility and dysarthria severity of a
group of individuals diagnosed with Friedreich's ataxia (FRDA); (2)
determine the presence of subgroups within FRDA dysarthria; (3)
investigate the relationship between the speech outcome and the
clinical factors of disease progression. The study included 38
individuals (21 female, 17 male) with a confirmed diagnosis of FRDA.
A group of 20 non-neurologically impaired individuals served as
controls. Perceptual analysis, investigating 30 different dimensions
of speech, was conducted on a speech sample obtained from each
participant. In addition, the Assessment of Intelligibility of
Dysarthria Speech was administered. All FRDA participants presented
with dysarthria with severities ranging from mild to moderate.
Cluster analysis revealed 3 subgroups, the first presenting with
mild dysarthric symptoms, the second with increased velopharyngeal
involvement and the third characterized by increased laryngeal
dysfunction. Dysarthria severity showed a significant correlation to
disease duration but to no other clinical measure. The findings
support the notion of subgroups in FRDA dysarthria, representing
distinct impairments of the speech mechanism and perhaps reflective
of differing evolutions beyond the cerebellum. 2010 S. Karger AG,
Basel
http://www3.interscience.wiley.com/journal/123393744/abstract?CRETRY=1&SRETRY=0
Carbamylated erythropoietin increases frataxin
independent from the erythropoietin receptor
Brigitte Sturm*, Melissa Helminger*, Hannes Steinkellner*, Mohammad
Mehdi Heidari*,†, Hans Goldenberg* and Barbara Scheiber-Mojdehkar*
*Medical University of Vienna, Vienna, Austria , † Yazd University,
Yazd, Iran
Correspondence to Barbara Scheiber-Mojdehkar, Department of Medical
Chemistry, Medical University of Vienna, Waehringerstr 10, A-1090
Vienna, Austria. Tel.: 43-1-4277/60891; fax: 43-1-4277/60881;
e-mail: barbara.scheiber-mojdehkar@meduniwien.ac.at
Copyright Journal Compilation © 2010 Stichting European Society for
Clinical Investigation Journal Foundation
KEYWORDS
Carbamylated erythropoietin • erythropoietin receptor • frataxin •
Friedreich's ataxia • nonerythropoietic erythropoietin • recombinant
human erythropoietin
Eur J Clin Invest 2010
ABSTRACT
Background Friedreich's ataxia (FRDA) is a neurodegenerative
disorder caused by decreased expression of the mitochondrial protein
frataxin. Recently we showed in a clinical pilot study in
Friedreich's ataxia patients that recombinant human erythropoietin (rhuEPO)
significantly increases frataxin-expression. In this in vitro study,
we investigated the role of the erythropoietin receptor (EPO-R) in
the frataxin increasing effect of rhuEPO and if non-erythropoietic
carbamylated erythropoietin (CEPO), which cannot bind to the
classical EPO-R increases frataxin expression.
Materials and methods In our experiments human erythroleukaemic K562
cells (+ EPO-R), human monocytic leukemia THP-1 cells (− EPO-R) and
isolated primary lymphocytes from healthy control and FRDA patients
were incubated with different concentrations of rhuEPO or CEPO.
Frataxin-expression was detected by an electrochemical luminescence
immunoassay (based on the principle of an ELISA).
Results We show that rhuEPO increases frataxin-expression in K562
cells (expressing EPO-R) as well as in THP-1 cells (without EPO-R
expression). These results were confirmed by the finding that CEPO,
which cannot bind to the classical EPO-R increased frataxin
expression in the same concentration range as rhuEPO. In addition,
we show that both EPO derivatives significantly increase frataxin-expression
in vitro in control and Friedreich's ataxia patients primary
lymphocytes.
Conclusion Our results provide a scientific basis for further
studies examining the effectiveness of nonerythropoietic derivatives
of erythropoietin for the treatment of Friedreich's ataxia patients.
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Received 30 September 2009; accepted 17 March 2010
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