The LA Experience
and an Ataxia Medical Update
Susan L. Perlman M.D.
Clinical Professor of Neurology
Director, UCLA Ataxia Center
Medical Director, NAF
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Los Angeles is much more than
Hollywood and the Beach Boys
• It started with a seafaring
culture in Southern
California in 8,000 B.C.;
• Incorporated Native
Americans of the Hokan
and Uto-Aztecan cultures,
the Spanish, and
ultimately all the rest of
us;
• And will end when
THE BIG ONE
drops us back into the
sea.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
And I believe it is home to the first Ataxia Center
West of the Mississippi
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
And home to some pretty nice weather
most of the time
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
UCLA ATAXIA/NEUROGENETICS CENTER
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Founded--mid-1970’s as a research clinic for Friedreich’s Ataxia.
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Has a database of over 3000 neurogenetics patients, most with ataxic
disorders, as well as a DNA bank. Works with two tissue banks.
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Evaluates about 75 new ataxia patients each year.
Evaluates asymptomatic individuals at-risk for ataxia.
Provides continuity care for many of these individuals.
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Multidisciplinary model (multi-specialty Physician, Nursing, Social Work,
Psychology, PT, OT, Orthotics, Speech, Nutrition, Genetics).
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Is a member of the Cooperative Ataxia Group (www.cooperative-ataxiagroup.org) and the Collaborative Clinical Research Network for FA, and
collaborates with other “ataxologists” across the USA and around the world.
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Provides educational programs and inservice training, as well as community
outreach through the National Ataxia Foundation (www.ataxia.org) and
Friedreich’s Ataxia Research Alliance (www.curefa.org).
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
UCLA ATAXIA CENTER DEMOGRAPHICS
• Catchment area—
southwestern US, remaining
US, Mexico, Canada, Pacific
Rim, providing great ethnic
and cultural diversity (but
few large pedigrees).
• 40% of cases have either
Friedreich’s ataxia or a
known SCA
• 60% of cases have unknown
genotype or sporadic
presentation, spurring the
search for new genes and
epidemiologic factors
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Ethnic Distribution
African- Middle East /
American Mediterr Hispanic
3%
14%
17%
Asian
14%
Caucasian /
NW Europ
52%
Distribution of Ataxia Syndromes
Friedreich’s
Ataxia
21%
Known
SCA
18%
Other
61%
Distribution of Dominant Cases
SCA3
SCA214%
SCA6
SCA7
11% 5%
10%
SCA1
5%
SCA6
SCA7
Other
SCA1
Other
55%
SCA2
SCA3
UCLA ATAXIA CENTER
1562 PATIENTS SEEN BETWEEN 1995 AND 2005
(CURRENTLY BEING UPDATED)
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GENETIC (Total 656)
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Dominant (329)
SCA1 15
Cadasil 7
SCA2 32
DRPLA 2
SCA3 68
GSS 8
SCA6 34
SPG4 2
SCA7 14
FXTAS 2
SCA8 6
SCA10 2
SCA13 2
SCA14 2
SCA17 3
Known mutation 196
Unknown mutation 129
No one yet with SCA 12
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Recessive (250)
A-T 26
EOCARR 6 (AOA1 1, AOA2 5)
Friedreich’s Ataxia 75 (looks like FA but isn’t 112)
LOFA 14
Confirmed inborn errors 6
Late-onset Tay Sachs 11
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X-linked or Mitochondrial (80)
AMN 10
Rett 2
Pedigree suggests X-linked 8
Confirmed mitochondrial point mutation 6
Looks like mitochondrial but isn’t 54
March 18, 2011
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UNKNOWN GENE/SPORADIC (Total 904)
Adult Arnold-Chiari, CP, other congenital 30
Combined cortical atrophy 14
HSA/HSP 76
Immune-mediated 12
MSA 72
NPH 7
Paraneoplastic 11
Post-infectious 17
PSP 20
Pure cerebellar (ILOCA) 219
SOPCA 97
Retroviral 7
Vascular, post-anoxic, post-trauma 52
With known nutritional/toxic cause 16
With dementia 11
With diabetes insipidus 1
With dizziness, vertigo, episodic 71
With dystonia 17
With myoclonus 32
With neuropathy 51
With spasticity 53
With tremor 14
With white matter changes (not MS or Cadasil) 4
NAF AMM LA CA Bringing the
Ataxia World Together
OUR GOALS HAVE BEEN
TO ANSWER THE QUESTIONS ASKED BY OUR ATAXIA PATIENTS
TO MAXIMIZE THEIR QUALITY OF LIFE
AND TO GET THEM INVOLVED IN RESEARCH
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WHAT DO I HAVE?
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WHAT IS THE CAUSE?
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ARE MY CHILDREN AT RISK?
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WILL IT GET WORSE?
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HOW BAD WILL IT GET? HOW SOON?
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CAN IT BE TREATED?
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CAN IT BE CURED?
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IS THERE ANY RESEARCH BEING DONE? CAN I GET INVOLVED?
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
HOW FAR HAVE WE COME?
QUESTION
1977
2011
What do I have?
10% known
>50% known
Can it be cured?
No
No
Can it be treated? No drugs tested
Rehab helps
Is there research? 223 articles
Are my children
at risk?
March 18, 2011
No gene tests
available
18 drugs tested
(more on the way)
Rehab helps
1342 articles
21 gene tests
available($17K),
more on the way
NAF AMM LA CA Bringing the
Ataxia World Together
1. Diagnosis—Is this Ataxia?
• What are we actually seeing?
• It is important to nail down a phenotype that can be
retrieved (with the patient) as advances are made in
diagnosis and treatment of progressive ataxia.
• The launch of the National Ataxia Registry and
Database will make this easier.
• Patient self-registration at:
https://www.nationalataxiaregistry.org/
• Dr. Subramony is here helping people sign up in the
National Ataxia Registry.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
2. Proper Evaluation—
Everyone Deserves a Screen For
• Neural localization (MRI, ENG, EPs, EMG/NCV)
• Acquired factors--prior illnesses, toxic exposures
or medication (Dilantin, amiodorone)
• Other medical problems—
thyroid dysfunction
low B12 or E
syphilis, EBV, Lyme, HTLV1, HIV
rheumatologic factors
• Immune/paraneoplastic—
anti-GAD, anti-gliadin, anti-thyroid
anti-Yo, Hu, Ri, others; imaging for hidden Ca
• Possible genetic factors—why? Are they treatable? Not yet.
But can aid in prognosis and family counseling if found.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Our Approach to the Adult-onset,
Predominantly Cerebellar Syndromes
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Assign a phenotype by H & P, imaging, electrodx, LP
Obtain a detailed family and environmental history
Rule out known acquired causes.
Consider genetic testing—
Screening for FXTAS, SCA6, FRDA, as well as
SCA1,2, and 3 will identify over 50% of possible
inherited causes and cost less than $3000.
2-5% of sporadic cases turn out to be genetic.
• Establish a treatment plan that includes
symptomatic medication and rehabilitation.
• Help patients find resources and get involved in
research.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Growth of Clinical Research at UCLA (1)
the 1980’s
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1980-82—4 unfortunate publications looking for the cause of Friedreich’s ataxia before we had molecular
genetic technologies to help us
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The rest of the 1980’s not so bad, as we focused on the clinical aspects of FA and related ataxias:
Evoked potential abnormalities in the various inherited ataxias.
Nuwer MR, Perlman SL, Packwood JW, Kark RA.
Ann Neurol. 1983 Jan;13(1):20-7.
Eye movements in Friedreich's ataxia.
Furman JM, Perlman S, Baloh RW.
Arch Neurol. 1983 Jun;40(6):343-6.
Cardiac involvement in Friedreich's ataxia: a clinical study of 75 patients.
Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA.
J Am Coll Cardiol. 1986 Jun;7(6):1370-8.
The mental status of patients with Friedreich's ataxia.
Flood MK, Perlman SL.
J Neurosci Nurs. 1987 Oct;19(5):251-5
Idiopathic central diabetes insipidus followed by progressive spastic cerebral ataxia. Report of four cases.
Birnbaum DC, Shields D, Lippe B, Perlman S, Phillipart M.
Arch Neurol. 1989 Sep;46(9):1001-3.
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And were able to run early pilot studies of physostigmine as a symptomatic treatment for ataxia:
Double-blind, triple-crossover trial of low doses of oral physostigmine in inherited ataxias.
Kark RA, Budelli MM, Wachsner R.
Neurology. 1981 Mar;31(3):288-92.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Growth of Clinical Research at UCLA (2)
the 1990’s
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The 1990’s:
Saw the beginning of our ongoing collaboration with the Ataxia Telangiectasia
Research Laboratory at UCLA (Dr. Richard Gatti).
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We continued work with neuro-otology and neuro-opthalmology:
Comparison of oculomotor findings in the progressive ataxia syndromes.
Moschner C, Perlman S, Baloh RW.
Brain. 1994 Feb;117 ( Pt 1):15-25.
Ophthalmologic findings in patients with ataxia.
Rabiah PK, Bateman JB, Demer JL, Perlman S.
Am J Ophthalmol. 1997 Jan;123(1):108-17.
Oculomotor phenotypes in autosomal dominant ataxias.
Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW.
Arch Neurol. 1998 Oct;55(10):1353-7.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
•
And finally the scientific revolution, brought about by molecular genetic
technology, opened up the first multi-center collaborations, with Dr. Gomez at
U Minn (after his stint at UCLA), as well as our own UCLA-based
phenotype/genotype studies.
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The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2
trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.
Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM.
Am J Hum Genet. 1997 Apr;60(4):842-50.
Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic
ataxia.
Geschwind DH, Perlman S, Grody WW, Telatar M, Montermini L, Pandolfo M, Gatti
RA.
Neurology. 1997 Oct;49(4):1004-9.
Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype
correlations.
Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM.
Neurology. 1997 Nov;49(5):1247-51.
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March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Growth of Clinical Research at UCLA (3)
2000-2010
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In the new millennium:
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We published our first review of symptomatic treatment for ataxia, based on
our experiences as well as the published experiences of other “ataxologists”.
Cerebellar Ataxia.
Perlman SL.
Curr Treat Options Neurol. 2000 May;2(3):215-224.
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Joined Dr. Dave Lynch’s Collaborative Clinical Research Network for FA.
As well as the Cooperative Ataxia Group under Drs. Ashizawa and Subramony.
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And were finally able to get back into drug trials:
A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia.
Lynch DR, Perlman SL, Meier T.
Arch Neurol. 2010 Aug;67(8):941-7.
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And the pilot study of Varenicline in SCA3 under Dr. Theresa Zesiewicz
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
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Began our collaboration with the neuroimaging groups at UCLA:
Analysis of the brain-stem white-matter tracts with diffusion tensor imaging.
Salamon N, Sicotte N, Alger J, Shattuck D, Perlman S, Sinha U, Schultze-Haakh H,
Salamon G.
Neuroradiology. 2005 Dec;47(12):895-902. Epub 2005 Sep 13.
Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging
findings, and review of the literature.
Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH.
Arch Neurol. 2005 Dec;62(12):1865-9.
Pontine and cerebellar atrophy correlate with clinical disability in SCA2.
Ying SH, Choi SI, Perlman SL, Baloh RW, Zee DS, Toga AW.
Neurology. 2006 Feb 14;66(3):424-6.
White matter fiber tractography and color mapping of the normal human cerebellum
with diffusion tensor imaging.
Salamon N, Sicotte N, Drain A, Frew A, Alger JR, Jen J, Perlman S, Salamon G.
J Neuroradiol. 2007 May;34(2):115-28.
Patterns of fractional anisotropy changes in white matter of cerebellar peduncles
distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia
syndromes.
Prakash N, Hageman N, Hua X, Toga AW, Perlman SL, Salamon N.
Neuroimage. 2009 Aug;47 Suppl 2:T72-81. Epub 2009 May 14
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
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Continued our work with genotype/phenotype:
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SCA8 repeat expansions in ataxia: a controversial association.
Sobrido MJ, Cholfin JA, Perlman S, Pulst SM, Geschwind DH.
Neurology. 2001 Oct 9;57(7):1310-2.
Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.
Figueroa KP, Chan P, Schöls L, Tanner C, Riess O, Perlman SL, Geschwind DH, Pulst SM.
Arch Neurol. 2001 Oct;58(10):1649-53.
The SCA12 mutation as a rare cause of spinocerebellar ataxia.
Cholfin JA, Sobrido MJ, Perlman S, Pulst SM, Geschwind DH.
Arch Neurol. 2001 Nov;58(11):1833-5.
Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations.
Kerber KA, Jen JC, Perlman S, Baloh RW.
J Neurol Sci. 2005 Nov 15;238(1-2):41-5. Epub 2005 Aug 16. Review.
Depressive and memory symptoms as presenting features of spinocerebellar ataxia.
McMurtray AM, Clark DG, Flood MK, Perlman S, Mendez MF.
J Neuropsychiatry Clin Neurosci. 2006 Summer;18(3):420-2.
Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.
Fogel BL, Perlman S.
Neurology. 2006 Dec 12;67(11):2083-4.
A family with combined mutations of the hemophilia A and X-linked adrenoleukodystrophy genes.
Fogel BL, Young P, Thompson AR, Perlman S.
Neurogenetics. 2008 Jul;9(3):215-8. Epub 2008 May 15.
Aberrant splicing of the senataxin gene in a patient with ataxia with oculomotor apraxia type 2.
Fogel BL, Lee JY, Perlman S.
Cerebellum. 2009 Dec;8(4):448-53.
Candidate Screening of the TRPC3 Gene in Cerebellar Ataxia.
Becker EB, Fogel BL, Rajakulendran S, Dulneva A, Hanna MG, Perlman SL, Geschwind DH, Davies KE.
Cerebellum. 2011 Feb 16.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Clinical Studies We are Currently Doing
at UCLA
1. Clinical Research Consortium for Spinocerebellar Ataxias [CRC-SCA] to Study
Natural History and Genetic Modifiers in Spinocerebellar Ataxias [SCA]--Natural
History Study for SCA1, 2, 3, and 6 only.
Not a drug trial. All ages and levels of disability. Visits every 6 months for 2 years. No
travel reimbursement.
2. Clinical Outcome Measures in Friedreich Ataxia--Natural History Study for
Friedreich's Ataxia.
Not a drug trial. All ages and levels of disability. Visits once a year. Some travel
reimbursement.
3. Molecular Genetic Studies in Diseases of the Brain Affecting Movement and
Balance--one visit for anyone with any type of ataxia, all ages and levels of disability.
Not a drug trial. A neurological history and exam plus blood draw will be done. No
travel reimbursement.
4. Benefits of Hydrotherapy Versus Conventional Physical Therapy in the
Treatment of Friedreich Ataxia--open to Friedreich's ataxia patients 18 years of age
and older who are still ambulatory (with or without assistive devices) and can come in
for physical therapy 3 mornings per week for 1 to 3 months. No travel reimbursement.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
The Geschwind Lab for Basic Research
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Dr. Daniel Geschwind is the Gordon and Virginia MacDonald Distinguished
Chair in Human Genetics and is a professor of neurology and psychiatry at
the UCLA School of Medicine. He is director of the Neurogenetics Program
and the Center for Autism Research and Treatment (CART) and co-director
of the Center for Neurobehavioral Genetics at UCLA.
The Geschwind laboratory is working to improve our understanding of
human neuropsychiatric diseases, such as autism and neurodegenerative
diseases, and their relationship to the range of normal human higher
cognitive function. We use a combination of genetic, functional genomic and
neurobiological methods in our work--frequently in collaboration with other
laboratories or disciplines. Our methodological focus involves the
application of network analyses and systems biology, which offer the
promise of integration of multiple levels of data, connecting molecular
pathways to nervous system function in health and disease.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Partners in Clinical Neurogenetics Research
at UCLA
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Daniel Geschwind, M.D., Ph.D., Neurogenetics Program Director (Molecular Genetics, DNA bank)
Susan Perlman, M.D., Ataxia Clinic Director (Ataxia Database, Drug Trials)
Robert Baloh, M.D. (Neuro-Otology)
George Bartzokis, M.D. (Neuroimaging, Biomarkers)
Yvette Bordelon, M.D., Ph.D. (Huntington’s disease, Biomarkers, Drug Trials)
Stephen Cederbaum, M.D. (Medical Genetics, Metabolic Disorders)
Giovanni Coppola, M.D. (Molecular Genetics)
Brent Fogel, M.D., Ph.D. (Molecular Genetics, DNA bank)
Ming Guo, M.D., Ph.D. (Drosophila)
Michelle Hamilton, M.D., Juan Alejos, M.D. (Cardiology)
Joanna Jen, M.D., Ph.D. (Episodic Ataxias, Drug Trials)
Arik Johnson, Psy.D. (Psychology)
Catherine Mamah, M.D. (Molecular Genetics)
William Oppenheim, M.D. (Orthopedics)
Noriko Salamon, M.D. (Neuroradiology)
Eric Wexler, M.D., Ph.D. (Psychiatry)
Ernest Wright D.Sc., Ph.D, Vladimir Kepe Ph.D,, Jorge Barrio Ph.D. (Neuroimaging, Biomarkers)
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GlennyJane Gabriel — Clinic Coordinator (310) 825-3370
Tarshiah Nulliah— Ataxia Research Coordinator (310) 206-8153
Barbara Fallick, MSW — Social Work Coordinator (310) 794-1225
Michelle Fox, M.S. — Genetic Counselor (310) 206-6581
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New Patient Appointments — (310) 794-1195 and follow the menu
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Goals for Future Clinical Trials at UCLA
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A longitudinal natural history study for people with non-genetic ataxia
or less common genetic ataxias.
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An epidemiologic study of environmental and lifestyle factors that can
influence the cerebellum and progression of ataxia.
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More Drug trials—pilot or Phase I, II, or III
for the SCAs
for Friedreich’s ataxia
for Ataxia Telangiectasia
for other recessive ataxias
for non-genetic ataxia
for Multiple System Atrophy
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Our clinical neurogenetic research team is eager to push forward with
these important projects, together with all our colleagues here and
around the world. We need each other and WE NEED YOU.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Upcoming Ataxia Medical Update
Diagnosis, Symptomatic Treatment, Disease-Modifying Therapy, Resources
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You will be hearing a lot more about advances in all areas of ataxia over the rest of the convention and in
the Birds of a Feather sessions:
The rest of Friday morning:
9:45 a.m. ............ Melinda Guttry, PT & Jacquelyn Glenn, OTR ......OT/PT for Ataxia
10:40 a.m. .......... Anne Lefton, CCC-SLP ......................................... Speech & Swallowing
11:20 a.m. ........... Al LaSpada, MD, PhD, FACMG ............................ Poly Q SCAs/SCA7
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Saturday
8:30 a.m. ............ Jamie Hoffman, CTRS ............................ Adaptive Recreation, What You CAN DO!
8:55 a.m. ............ Richard Ivry, PhD ....................
How Cerebellar Dysfn Affects Motor Control
9:20 a.m. ............ Joel Gottesfeld, PhD ............................... HDAC Inhibitors in FRDA
9:45 a.m. ............ Vikram Shakkottai, MD, PhD .................. Clinical Trials and Natural History Study
10:10 a.m. .......... Theresa Zesiewicz, MD, FAAN ............... Analysis of Chantix Clinical Trial
10:35 a.m. .......... Clive Svendsen, PhD .............................. Stem Cell Research for Ataxia
11:00 a.m. .......... Henry Paulson, MD, PhD ........................ Research Update
2:00 p.m. ............ Christopher Gomez, MD, PhD ................ Medication for Ataxia Symptoms
2:25 p.m. ............ S.H. Subramony, MD .............................. National Ataxia Registry
2:50 p.m. ............ Ralph Miller .............................................. Wheelchair Yoga
3:15 p.m. ............ Arnie Gruetzmacher, CFP ....................... Financial Planning
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Sunday
9:00 a.m. ............ Sid Gilman, MD .......................................Sporadic Ataxia and MSA Research
9:25 a.m. ............ Una Lee, MD ........................................... Management of Neurogenic Bladder
9:50 a.m. ............ Joanna Jen, MD, PhD ............................. Management of Dizziness in Ataxia
10:15 a.m. .......... Jon Rodis, MBA .......................................Applying for Social Security Disability
10:40 a.m. .......... Brent Fogel, MD, PhD ............................. Recessive & Paraneoplastic Ataxia
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March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
And with the Internet,
you can become the teachers
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http://www.ncbi.nlm.nih.gov for PubMed and OMIM
http://www.neuro.wustl.edu/neuromuscular
http://www.geneclinics.org
http://www.curefa.org
http://www.ataxia.org
http://cooperative-ataxia-group.org/
http://www.eurosca.org/
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
A Brief Literature Search
for the past 10 years in humans (double the numbers if you include animal studies)
http://www.ncbi.nlm.nih.gov for PubMed
and www.clinicaltrials.gov for Clinical Trials
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Spinocerebellar ataxia—--2486 articles
Multiple system atrophy--1903 articles
Friedreich’s ataxia-------- 619 articles
Sporadic ataxia------------ 375 articles
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Spinocerebellar ataxia—----44 clinical studies
Multiple system atrophy—-35 clinical studies
(fluoxetine, lithium, IVIG, stem cells, riluzole, rasagiline, minocycline)
(14 dealing with low blood pressure)
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Friedreich’s ataxia------------19 clinical studies
Sporadic ataxia------------------4 clinical studies
(coQ10, Riluzole, IVIG-all completed)
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Parkinson’s disease--------30,022 articles
746 clinical studies
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
First Thing To Remember
• Everything we are doing with the genetic and
non-genetic ataxias can be applied to the
other genetic and non-genetic brain diseases
and vice versa.
• This includes research about normal nerve
cell functioning, nerve cell sensitivities,
nerve cell death, “normal aging”, and
environmental and lifestyle factors that
influence the brain.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
COOPERATIVE ATAXIA GROUP
founded in 2002 for the development of natural history studies and therapeutic trials in ataxia
* T Ashizawa,
S H Subramony
Laura Ranum, Mike Waters
SCA10
University of Florida,
Gainesville
Sue Perlman
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Kathleen Poston
UCLA
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Stanford University
*Louis Ptacek SCA7
University of San
Francisco
Thomas Bird
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Thomas Crawford
AT
University of Washington
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Johns Hopkins University
Gail Kang
Stefan Pulst
SCA2
University of Utah
John Day, Khalif Bushara
SCA5, 8; Gluten Ataxia
University of Minnesota
University of Rochester
NY
Kurt Fischbeck
NINCDS
(Bernard Ravina)
* Andrew McGarry
* Jeremy Schmahmann
Mass General
Sid Gilman MSA
Hank Paulson SCA3
University of Michigan
Chris Gomez
SCA6
University of Chicago
Mark Hallett
NINCDS
Robert Herndon
Univ of Mississippi
Al La Spada SCA7
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Ja-Shin Lou
UCSD
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University of Oregon
Dave Lynch, Rob Wilson
Friedreich’s ataxia
University of Pennsylvania
* Pietro Mazzoni
Columbia University
MSA
Lew Sudarsky
Brigham and Womens
George Wilmot
Emory
* Joseph Savitt
Johns Hopkins
Sarah Ying
Theresa Zesiewicz
Huda Zoghbi
SCA1
University of South Florida
Baylor
East Coast 13
Middle America 4
West Coast 6
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
We need enough sites to run all the
clinical trials barreling toward us
• Clinical Trials
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
NECESSARY COMPONENTS FOR A
SUCCESSFUL CLINICAL TRIAL (besides $)
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Disease mechanism understood
Candidate drugs
Natural history baseline
Rating scales, QOL measures
Biomarkers to speed up the trials
Research centers to do the trials
Patient Registries to find the subjects
Database to keep it all in
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
WHAT WE ALREADY HAVE
• Disease mechanism understood--somewhat
• Candidate drugs— some ideas, need more
• Natural history baseline— being collected
X Rating scales, QOL measures
• Biomarkers — being developed
X Research centers – telemedicine would help
X Patient Registries
X Database to keep it all in
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
“18 Drugs Tested”
(But Almost None in Controlled Trials)
Some Commonly Used Off-Label Ataxia Treatments
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1. ImmunoRx—Corticosteroids
Mycophenolate mofetil (CellCept),
Rituximab (Rituxan)
IVIG, plasmapheresis
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2. Anti-Oxidants
Alpha lipoic acid
Coenzyme Q10
Creatine
L-carnitine
N-acetylcysteine
Omega 3 fish oil/EPA (eicosapentanoic acid)
Selenium
Vitamin E (d-alpha tocopherol succinate)
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3. Ataxia
Acetazolamide
Amantadine
Buspirone
Gabapentin
L-5-OH tryptophan
Thyrotropin releasing hormone
Varenicline
Several others in very small trials based on
animal or in vitro studies
March 18, 2011
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4. Action tremor
Carbamazepine
Clonazepam
Gabapentin
Isoniazid
Levetiracetam
Ondansetron
Primidone
Propranolol
Topiramate
Valproate
Zonisamide
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5. Nystagmus Dizziness
Acetazolamide
Baclofen
3,4-diaminopyridine
Carbamazepine
Clonazepam
Gabapentin
Meclizine
Ondansetron
Promethazine
Valproate
NAF AMM LA CA Bringing the
Ataxia World Together
Brain Stimulation Rather than Drugs
again, very few and small studies
• Deep brain stimulation with implanted
electrodes—used mainly for tremor.
• rTMS—repetitive transcranial magnetic
stimulation over motor cortex and over
cerebellum.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Exercise Always Helps Ataxia
Brain Aerobics
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Treatment Trial Retrospective
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Mov Disord. 2009 Jun 15;24(8):1111-24.
Effectiveness and safety of treatments for degenerative ataxias: a systematic
review.
Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R.
Canary Islands Research and Health Foundation (Fundación Canaria de
Investigación y Salud-FUNCIS), Santa Cruz de Tenerife, Canary Islands, Spain.
matrumar@gobiernodecanarias.org
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The aim of this study was to determine the effectiveness and safety of available
treatment alternatives for degenerative ataxias (DA). We systematically reviewed
studies that assess pharmacological, rehabilitative, or psychological treatments in
patients with DA. Twenty-five studies were included
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Most studies were of small sample sizes, wide age variations, and low scientific
validity.
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Availability of quality studies to evaluate the safety and efficacy of treatments for most
DA is scarce. Further investigations with improved trial designs are necessary.
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BUT THE PROCESS CAN SEEM OVERWHELMING.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
TYPES OF CLINICAL TRIALS
TYPE
# SUBJECTS LENGTH
AIM OF STUDY
N of 1
1
Ongoing
Do I get better or stop getting
worse on this drug?
Pilot
Up to 20
All get drug
Weeks to
months
Is a larger study worth doing,
will there be problems?
Phase 1
20-80 normal or patient
in groups of 3
2 years
Escalating doses to learn side
effects, safety, best dose
Phase 2
20-300
Placebo and
drug groups
2 years
To assess potential for good
effects, as well as side effects.
Also designed as “futility”
study—to show a drug doesn’t
not work(fewer subjects, less$)
Phase 3
300-3000
Placebo and
drug groups
3-5 years
To prove efficacy
May include crossover design,
open extension trial
Phase 4
100’s-1000’s
Open drug use
Ongoing
To find out more about the
effects of an approved drug.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
OFFICIAL PIPELINE FOR NEW DRUGS
Up to 15 years and $500-700million
to get to market
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Discovery—clinicians and
scientists working out the cause of
the disease, the “dominos” that fall
over, and targeted candidate drugs.
Preclinical testing—test tube and
animal studies.
Phase I—dosing, safety
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Phase II—safety, possible efficacy
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Phase III—efficacy
FDA Approval
Phase IV--Post-marketing studies
for long-term side-effects and good
effects.
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To help with promising drugs for serious
diseases with unmet needs:
NIH—Rapid Access to Intervention Development
(RAID)
FDA—Orphan Drug Status
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March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
FUNDING
A PUBLIC-PRIVATE PARTNERSHIP
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Discovery—clinicians and
scientists working out the cause of
the disease, the “dominos” that fall
over, and targeted candidate drugs.
$25-80,000 per yr over many years
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Preclinical testing—test tube and
animal studies.
$100,000 per year for at least 2 yr
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Phase I and Phase II-$500-700,000 per year for 4 yr
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Government
Private research foundations
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Government
Private research foundations
Pharmaceutical companies
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Government
Private research foundations
Pharmaceutical companies
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Pharmaceutical companies
$2-4 million to get to this point
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Phase III—$4-5 million ($10K/subject)
FDA Approval
Post-marketing studies for longterm side-effects and good effects
and possible other uses of the drug.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
The Bottom Line
• Every ataxia patient must participate in
clinical trials.
• Every researcher designing a clinical trial
must make it accessible to all ataxia
patients.
• There will be exceptions to both of these
fiats, but they must be justified.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Every Ataxia Patient Must Participate in
Clinical Trials
1. Registries will enable you to be found.
These are rare diseases with very small
numbers of patients who can participate.
Every person counts.
2. Be knowledgeable about what makes a good
clinical trial—don’t make bad investments.
3. Speak up about the roadblocks to participation.
Become involved in planning the trials.
4. Be prepared to make sacrifices.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Sacrifices
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Time
Money
Confidentiality
Giving up one drug trial to participate in
another.
• Risking receiving a placebo.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
DO WE REALLY NEED PLACEBOS?
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Gold Standard for Phase III clinical trials is the double–blind, placebocontrolled, randomized study.
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The “placebo effect” is very real and ideally accounts for all the other effects
not related to the drug directly.
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Dramatic differences between the placebo and drug groups will usually result
in all subjects being placed on drug before the end of the trial.
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If it would be dangerous for a potential subject to end up on placebo, that
subject would not be enrolled in the study. This includes the subject having to
stop other medications to enter the study.
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Active placebos may be used.
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Use of historical controls or subject acting as own control may require a longer
study to prove benefit of drug.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Every Researcher Designing A Clinical
Trial Must Make It Accessible To All
Ataxia Patients.
• Design trials that can use the fewest patients over the
shortest period of time (this usually means testing better
drugs and using biomarkers).
• What is the rationale for excluding certain patients? Can
those excluded be used in other ways? Parallel or
compassionate studies?
But remember that a patient can participate in only one
trial at a time and that participation in some trials may
permanently disqualify participation in others.
• Reimbursing travel costs is essential for recruitment and
compliance. Telemedicine?
• Don’t expect the patients to make unreasonable
sacrifices.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
Roadblocks for Clinical Researchers
• Picking the right drugs.
• Designing the trial properly—number of patients,
measures/biomarkers, length of study, placebo,
how many sites.
• Getting the FDA to agree.
• Getting funding.
• Finding sites and getting them approved.
• Finding subjects.
• Doing the work in a timely fashion.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
WHAT WE HAVE DONE IN SPITE OF ALL THIS
October 2007----------------------------------------------------Today
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together
THANK YOU
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National Ataxia Foundation—
sponsor of grants for our internal database, our DNA bank, our web-based
database project, and the SCA3 Chantix study.
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The Cooperative Ataxia Group—
sponsor of the grant for the SCA Natural History Study.
NINDS RC1 NS68897 and NIH Office of Rare Diseases Research
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Muscular Dystrophy Association and
Friedreich’s Ataxia Research Alliance—
sponsors of the grant for the collaborative project on “Clinical Outcome
Measures in Friedreich’s Ataxia”.
http://www.curefa.org/registry.html EVERYONE REGISTER!
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The Smith Family Foundation
The Bettencourt Family Foundation
The Norman Lapin Fund
The Mariette Monnier Fund
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And to our patients and their families for their willingness to work with us and
to share with us their ideas and hopes.
March 18, 2011
NAF AMM LA CA Bringing the
Ataxia World Together