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Neurodegenerative Disorders
Neurodegenerative disorders are among the most common to
affect us as we age. They include, but are not limited to, Alzheimer's
disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS, Lou
Gehrig's disease), and Multiple Sclerosis (MS). All of these disorders
are genetic, in part. We have focused on a number of diseases with a strong
genetic basis. By cloning genes causing strongly genetic forms of
neurodegenerative disease, we hope to better help affected individulas and
to gain insights into neurodegeneration more globally.
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Autosomal Dominant Leukodystrophy
(ADLD) Leukodystrophy
refers to a group of genetic disorders that are characterized by the imperfect
development or maintenance of the white matter (myelin sheath covering nerve
fibers in the brain). Adult-onset autosomal dominant leukodystrophy (ADLD), is a
slowly progressive, neurological disorder characterized by symmetrical
widespread myelin loss in the CNS. The ADLD phenotype is similar to that of
chronic progressive multiple sclerosis (MS). It is characterized by development
of autonomic dysfunction e.g. (low blood pressure, incontinence, and blurred
vision). In contrast to MS patients, ADLD sufferers experience earlier autonomic
dysfunction. CT scans/MRIs of ADLD patients illustrate the widespread
symmetrical demyelination that occurs, as opposed to the asymmetrical
demyelination exhibited in MS. In addition, large families segregating a highly
penetrant autosomal dominant MS allele have not been described.
Our
Research
Linkage analysis
has already localized ADLD to chromosome 5q31 and we hope to isolate the ADLD
gene through fine genetic mapping. ADLD represents a model for monogenic
demyelination, and identification of the ADLD gene and its encoded protein could
provide further insight into the molecular mechanisms of myelin assembly and
maintenance. Therefore the study of this disorder could enhance our
understanding of the pathogenesis of non-Mendelian demyelinating diseases such
as MS and may provide novel therapeutic targets for development of new
treatments.
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Spinocerebellar Ataxia 4
& 7 (SCA4, SCA7)
The
hereditary ataxias are a group of genetic disorders producing slowly
progressive incoordination of gait and often associated with poor
coordination of hands, speech, and eye movements. Ataxia may result from
dysfunction of the cerebellum and its associated systems, lesions in the
spinal cord, peripheral sensory loss, or any combination of these three
conditions. In some families with SCA, there is an associated retinal or
peripheral nerve degeneration that can lead to blindness or neuropathy which
is the case in SCA7 and SCA4 respectively. SCA4 is distinct from other SCAs
because the neuropathy is frequently the earliest sign of the disease and is
always found in affected individuals. Patients with SCA4 may not be able to
sense their position when they have their eyes closed resulting in
unsteadiness. Reflexes are absent in many patients and there is decreased
sensation to touch.
Our
Research
All
but two of the genes predisposing individuals to SCA that have been
identified so far are caused by polyglutamine tract expansions. In
individuals with expanded alleles, CAG repeat length correlates with disease
progression and severity. These findings have led to the hypothesis that
expanded polyQ tracts may be toxic to cells in the CNS. The disease-causing
gene for SCA4 has been linked to chromosome 16q22.1 and we are working very
hard to clone the gene.
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Parkinson’s Disease
Parkinson’s
disease (PD) is a slowly progressive, chronic neurological condition that
affects a small area of the brain, the midbrain. Degeneration of cells in this
region of the brain results in a reduction of the chemical dopamine. A decrease
in dopamine produces signs of Parkinson's disease that may include a resting
tremor of one or both hands, slowness of body movement, rigidity of limbs, and
gait or balance problems. Most people who develop Parkinson's disease have
"Idiopathic Parkinson's Disease" meaning that the cause of the disease is
unknown. Once considered non-genetic in etiology, within certain families there
are multiple individuals with Parkinson’s disease. This suggests that the
disease may be genetically inherited in those families.
Our
Research
By studying
families affected by Parkinson’s disease, we hope to localize and eventually
clone the disease-causing gene for Parkinson’s disease. This approach will not
only facilitate a greater understanding of this disease but hopefully provide
greater insight into the genetic of neurodegeneration in general.
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Participate in a Research Study
For our neurodegenerative studies, we are
currently enrolling participants affected by ADLD and
SCA 4.
As an initial screening
process, you will be asked about your
medical history. These questions are used to determine if you would be a
good candidate for our studies. Dr. Ptacek will review your information and
determine your eligibility for participation.
Participants will
then sign consent forms detailing the study objectives, UCSF health privacy
policy, and procedures and donate either a blood or saliva sample for DNA
extraction. We may also request clinical files or other medical
records.
We would
truly appreciate hearing from you if you feel you have any of these
neurological
disorders and are interested in participating in
our studies.
Please
refer to our
Contact Page for more
instructions.
We are currently not
enrolling participants for the other neurodegenerative disorders.
However, we may
open enrollment in the future. If you would like to be
contacted in the future for our circadian studies,
please contact our clinical coordinators with your
information. Please refer to the
Contact Page for more
information.
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Publications
1. Lamin B1
duplications cause autosomal dominant leukodystrophy. Nat Genet. 2006 Oct;
38(10):1114-23.
2. The dominant form of
vanishing white matter-like leukoencephalopathy represents autosomal
dominant leukodystrophy. Ann Neurol. 2006 Feb;59(2):434.
3.
Clinical feature profile of spinocerebellar ataxia type 1-8 predicts
genetically defines subtypes. Mov Disord. 2005 Nov;20(11):1405-12.
4. A novel
central nervous system-enriched spinocerebellar ataxia type 7 gene product.
Arch Neurol. 2003 Nov; 20(11):1405-12.
5. Genomic
context drives SCA 7 CAG repeat instability, while expressed SCA 7 cDNAs are
intergenerationally and somatically stable in transgenic mice. Hum Mol
Genet. 2003 Jan 1;12(1):21-50
6.
Channelopathies: episodic disorders of the nervous system. Epilepsia.
2001;42 Suppl 5:35-43.
7.
Autosomal dominant
spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical
description and genetic localization to chromosome 16q22.1.
8. Retinal degeneration
characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet.
1995 May;10(1):89-93.
9. An expanded CAG repeat
sequence in spinocerebellar ataxia type 7. Genome Res. 1996
Oct;6(10):965-71.
10. Analysis of the dynamic
mutation in the SCA7 gene shows marked parental effecs of CAG repeat
transmission. Hum Mol Genet. 1998 Mar;7(3):525-32.
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