Summaries of the four Keynote Presentations

Contributed by Jim Campbell, Synapse Newsletter (visit http://www.synapsepls.org/current.html to see the current issue of Synapse)

John K. Fink, MD; University of Michigan (SPF Medical Advisory and recipient of SPF Research Awards)

Molecular Processes Underlying HSP

Dr. Fink is a Professor of Neurology at the University of Michigan where he directs the neurogenetic disorders program. He studies genes that cause these disorders, recently identifying two genes that cause forms of HSP and is developing animal models of these disease, a pathway toward finding a cure. He has been the scientific medical advisor for the Spastic Paraplegia Foundation since the beginning and played a major role in getting us started. He is a recipient of a Spastic Paraplegia Foundation research award in 2003 and again in 2006.

Dr. Fink is excited to be a part of a new research agenda. Whereas five years ago medicine had no idea of causes, now 33 types of HSP have been identified. He’s recently found a family with dominantly inherited PLS. In his Power Point presentation, he explained that the primary motor cortex in front of middle gray matter ribbon contains nerve cell bodies. The white matter beneath contains nerve cell axons which go to axon terminals.

Each axon is surrounded by a myelin sheath. A single axon of .5 meters extends all the way through the spinal cord where the lower motor neuron continues. Axonal transport propagates through microtubules both via nerve impulses and molecules. The microtubules are constantly replaced/refreshed. Enzymes cleave to the microtubules.

Chemicals transfer signals across synapse or space. In ALS it has been found that surrounding cell health is import to maintain health of the motor neuron. In PLS and most HSP, distal axonopathy degeneration is now thought to be at distal end of axon at lower terminals (not a myelin problem). He said that proteins are involved in creating axonal abnormalities. He is now questioning an apparent dichotomy: are the diseases primarily ones of degeneration, or, are they developmental disorders at onset of nerve development. If the latter is true, minor symptoms might be diagnosed much earlier, maybe at early stages of development.

Peter Hedera , MD; Vanderbilt University (recipient of SPF Research Award)

Using Worms, Flies and Fish in Search of a Cure

Dr. Hedera is at Vanderbilt as an assistant professor of neurology. His research is on the genetics and molecular biology of HSP. He is a recipient of a Spastic Paraplegia Foundation research award.

Dr. Hedera explained that these are exciting times - when you answer one question, it creates hundreds more. If we can shut off genes to stop protein production, we may help unravel many questions and hopefully slow progression. He has found similar function of some genes in worms, flies, fish and humans. Since the life span of these lower life forms is short, he can quickly find if he's on a wrong track. Furthermore the worms and fish are transparent, so he can see what is going on within them. His slides with worms in motion showing disease progression made clear to all how his study works. Eventually promising leads will be tried in higher vertebrates.

Mary Kay Floeter; MD; National Institutes of Health

Primary Lateral Sclerosis: Lessons from Patients

Dr. Floeter is Chief, EMG section and the Chief of the Human Spinal Physiology Unit (the research unit of the EMG section) and the Deputy Clinical Director of NINDS. NINDS is one of the Institutes at NIH. The work she has been doing on PLS is within the research unit NINDS started in 1999 to define PLS by physician referral of patients. Her work is devoted to:

• Defining the clinical features of PLS
• Analysis of the epidemiology and environmental risks
• Analysis of genetics of patients

She went on to discuss each point in detail. About 3% of ALS patients have PLS. That means there are 600-1800 in USA, and 50-75 new patients per year. Earlier this year Michael Strong's group published a paper which compared ALS and PLS. The medial life expectancy with ALS is 3 years; with PLS it is greater than 20 years. Stiffness presented in 47% with PLS vs 4 % with ALS. Muscle atrophy presented in 2% of PLS vs 100% with ALS. 77% who developed LMN signs did so by 4 yrs. after symptom onset.

She then discussed the physiology of upper motor neurons. She outlined three clinical subtypes: ascending, multifocal, and sporadic parparesis. From 300 initial contacts, 100 records were screened, 63 were evaluated, and 45 fit the above criteria. The median onset is 45-50 years; patients have a normal life span; the fastest deterioration occurs in 1-2 years for ascending. Of the 45, 33 had symptom onset in legs (ascending). In the current study of possible cognitive difficulties study 30 patients and 30 controls is the goal.>When looking at epidemiology and environmental risks, so far there is no good correlation with risk factors. The depression found in many patients probably preceded disease onset.
She hopes to challenge SP to survey our membership to help advance the work with scientists.

Richard Bedlack, M.D., Ph.D.: Director of MDA/ALS Clinic, Duke University

Barriers to Treating Patients with PLS…and ways around them

Dr. Bedlack is an Associate Professor of Neurology at Duke, and director of their ALS clinic. He is also Chief of Neurology at the Durham VA Medical Center. He is involved in clinical trials of new treatments, as well as epidemiology (the study of disease in populations of people) and is studying the causes of motor neuron diseases, to learn how they might be stopped.

Dr. Bedlack began his talk by comparing PLS to ALS. They are alike in many ways, but there are no therapies for disease modification or symptomatic therapies for PLS. Published articles are 133-PLS/761-ALS. Relevant therapies are 1-PLS/50-ALS.

Another barrier is the cumbersome diagnosis procedure. MRIs, EMGs and other tests can’t prove a diagnosis. Since PLS appears to be a progressive upper motor neuron disease involving multiple body parts, in order to prove that no other process is involved, one must wait 4 years from symptom onset for a definitive diagnosis.

The next barrier for research is the rarity. Only 2-5% of MND diagnoses are PLS. There is a lack of preclinical models; we don't know cause or pathophysiology; molecular targets have not been identified; there is no good animal model like there is for ALS; there are no validated measures over time. He next discussed how to get around these barriers:

• Continued searching for an imaging or electrodiagnositic test
• Look for a biomarker in blood or spinal fluid
• Micro array genomic screens
• More published articles such as the one in “Lancet Neurology” April, 2007
• Analyze protein signals in PLS vs. normal controls
• Compare PLS with ALS data base as controls early on
• Accept that it’s either ALS or PLS (lump them together)
• VA has113 PLS confirmed patients
• Make use of the ALS Registry
• Make use of preclinical ideas from other diseases
• Chronicle patient experience, variability of symptoms and progression rate
• Use micro array to detect differences in protein signals
• Borrow outcome measures yield

Dr. Bedlack is now conducting a Levetiracetam study with 20 patients with progressive UMN diseases. He has also submitted a grant proposal to SP Foundation - protein biomarkers ALS vs PLS and patients with fast vs. slow progression using the VA registry. He is hoping the study might yield microbilecular targets.

Spastic Paraplegia Foundation, Inc.
Hall of Fame
2002-2007

As the Spastic Paraplegia Foundation celebrates five years, we want to recognize those who have made significant contributions of time and talent to SPF. The following people were nominated to the Hall of Fame. Thanks to those listed and the many other people who have supported our mission and worked to make SPF the success that it is today.
 

In the Beginning

John Fink, MD
Shellie Fischer
Kathi Geisler
Mark Weber, Esq.

Shakers & Movers

Betsy Baquet 
Thurza Campbell
Marlene Doolen
Mark Dvorak
Linda Gentner
Ronnie Grove
Jane Anne King
Annette Lockwood
Sue Meholick
The Milbourne Family
Don Wilson
Sarah Witt

Behind the Scenes

Anna Bonanni
Doug Brand
Flora Brand
Frank Davis
David Lewis
Martha Nance, MD
Nancy Shaidnagle
Cheryl Schumer
John Swain   

Never to be Forgotten

Dean Bathalter
Kay Bell
Warren Cave
Alexander Grossbier
Gerry Leary
Havel Lewis
Frank Reyerse
William Swain
Thom Twichell
Jeannie Young
Emma Yugo