Jacobs, H., U. Latza, et al. (2001). "Attitudes of young
patients with Parkinson's disease towards possible presymptomatic and prenatal
genetic testing." Genet Couns 12(1): 55-67.
OBJECTIVE: To evaluate the opinions and attitudes of young patients with
Parkinson's disease (PD) towards possible presymptomatic and prenatal genetic
testing for their illness. Background: With progress in understanding of the
genetic component in the etiology of PD, presymptomatic genetic testing may
become available in subgroups of patients. METHODS: During a survey on
sociodemographic and risk factors 111 PD patients (mean age 45 years: mean age
at PD onset 36 years) were given a questionnaire with six items about possible
presymptomatic and prenatal genetic testing. RESULTS: Fifty-seven patients
(5196) had knowledge about presymptomatic and prenatal testing. Eighty patients
(72%) would take a presymptomatic test, if they had an autosomal dominant form
of PD and if the test were available. The most Important reasons given for
taking the test were planning of partnership (40%) and family (48%). When being
identified as a carrier of a presumed "Parkinson gene", 78 patients (70%) would
decide not to have children. Sixty-three patients (57%) would choose to have
prenatal testing. Attitudes were largely independent of sociodemographic and
disease variables. CONCLUSIONS: When addressed as hypothetical persons at
genetic risk, young patients with PD support possible presymptomatic genetic
testing and, to a lesser extent, prenatal testing. Attitudes and reasons to
participate in such hypothetical testing do not grossly differ from those of
at-risk persons in established single-gene autosomal dominant disorders of late
onset.
Jankovic, J. and R. Tintner (2001). "Dystonia and parkinsonism." 8(2):
109-121.
Parkinsonism and dystonia may coexist in a number of neurodegenerative, genetic,
toxic, and metabolic disorders and as a result of structural lesions in the
basal ganglia. Parkinson's disease (PD) and the 'Parkinson-plus' syndromes (PPS)
account for the majority of patients with the parkinsonism-dystonia combination.
Dystonia, particularly when it involves the foot, may be the presenting sign of
PD or PPS and these disorders should be suspected when adults present with
isolated foot dystonia. Young age, female gender, and long disease duration are
risk factors for PD-related dystonia, but dystonia in patients with PD is
usually related to levodopa therapy. The mechanism of dystonia in PD is not well
understood and the management is often challenging because levodopa and other
dopaminergic agents may either improve or worsen dystonia. Other therapeutic
strategies include oral medications (baclofen, anticholinergics and
benzodiazepines), local injections of botulinum toxin, intrathecal baclofen, and
surgical lesions or high frequency stimulation of the thalamus, globus pallidus,
or subthalamus.
Jeon, B. S., J. M. Kim, et al. (2001). "An apparently sporadic case with parkin
gene mutation in a Korean woman." Arch Neurol 58(6): 988-9.
OBJECTIVE: To report the clinical features and results of iodine I
123-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane (CIT) single photon emission
computed tomography and molecular genetic analysis in a Korean woman with
juvenile Parkinson disease with deletion in exon 4 of the parkin gene. DESIGN:
Case report with molecular genetic analysis. PATIENT AND RESULTS: The patient
had bradykinesia, postural imbalance, and postural tremor since the age of 12
years. She developed wearing off early in the disease course. The
[(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission
computed tomography showed severe reduction of specific striatal CIT binding,
comparable to that of Parkinson disease. The polymerase chain reaction products
from the parkin gene showed homozygous exon 4 deletion. CONCLUSION: In this
sporadic juvenile Parkinson disease case, severe nigrostriatal dopaminergic
damage and homozygous exon 4 deletion in the parkin gene were demonstrated.
Johnson, S. (2001). "Is Parkinson's disease the heterozygote form of Wilson's
disease: PD = 1/2 WD?" Med Hypotheses 56(2): 171-3.
Wilson's disease (WD) patients often present with Parkinson's disease (PD).
Furthermore, most patients with PD have reduced ceruloplasmin, a characteristic
of Wilson's disease. WD is an autosomal recessive disease (requires two faulty
copies of a gene to produce a homozygote individual) that afflicts 1 in 1000
people. However, the number of people with one faulty copy (heterozygotes) is
much larger, probably about 2% of the population. I hypothesize that the large
number of heterozygotes for WD are at greatly increased risk for idiopathic PD,
because these people accumulate free copper in the basal ganglia at a slower
rate than homozygotes, which accounts for the fact that PD usually develops
after 40 years of age. In WD, a ceruloplasmin deficiency results in accumulation
of free Cu in the liver, brain, kidneys, etc. The excess Cu results in impaired
Zn absorption, which would account for the low levels of Zn in the brains of PD
patients. Moreover, the high levels of Fe found in the substantia nigra of PD
patients may perhaps be explained by free Cu binding to iron binding protein-1
(IBP-1), causing it to malfunction and preventing it from detaching itself from
the transferrin receptor (TfR) inhibition gene, resulting in expression of TfR
even when the cell has plenty of Fe. The gradual accumulation of Fe and Cu would
explain the damage inflicted on the substantia nigra by free radicals catalyzed
by these two metals and which is exacerbated by the low levels of CuZnSOD, due
to the Zn deficiency mentioned above. Moreover, if this hypothesis is correct,
then PD could be used to help discover the gene (or genes) responsible for WD
and vice versa. Furthermore, idiopathic PD could be prevented by identifying the
heterozygote individuals and providing them with Zn supplementation, Cu
chelation therapy and phlebotomy to eliminate Fe.
Johnson, S. (2001). "Micronutrient accumulation and depletion in schizophrenia,
epilepsy, autism and Parkinson's disease?" Med Hypotheses 56(5):
641-5.
Zinc has several crucial functions in brain development and maintenance: it
binds to p53, preventing it from binding to supercoiled DNA and ensuring that
p53 cause the expression of several paramount genes, such as the one that
encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP),
which directs embryonic development of the brain cortex, adrenal glands, etc.;
it is required for the production of CuZnSOD and Zn-thionein, which are
essential to prevent oxidative damage; it is required for many proteins, some of
them with Zn fingers, many of them essential enzymes for growth and homeostasis.
For example, the synthesis of serotonin involves Zn enzymes and since serotonin
is necessary for melatonin synthesis, a Zn deficiency may result in low levels
of both hormones. Unfortunately, Zn levels tend to be low when there is excess
Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of
Cu and Cd, and smoking and eating food contaminated with Cd result in high
levels of the latter. Furthermore, ethanol ingestion increases the elimination
of Zn and Mg (which acts as a cofactor for CuZnSOD).Increased Cu levels may also
be found in people with Wilson's disease, which is a rather rare disease.
However, the heterozygote form (only one faulty copy of the chromosome) is not
so rare. Therefore, the developing fetus of a pregnant women who is low in Zn
and high in Cu may experience major difficulties in the early development of the
brain, which may later manifest themselves as schizophrenia, autism or epilepsy.
Similarly, a person who gradually accumulates Cu, will tend to experience a
gradual depletion of Zn, with a corresponding increase in oxidative damage,
eventually leading to Parkinson's disease. Also discussed are the crucial roles
of histidine, histamine, vitamin D, essential fatty acids, vitamin E,
peroxynitrate, etc. in the possible oxidative damage involved in these mental
diseases. Copyright 2001 Harcourt Publishers Ltd.
Jung, Y. and Y. Surh (2001). "Oxidative DNA damage and cytotoxicity induced by
copper-stimulated redox cycling of salsolinol, a neurotoxic
tetrahydroisoquinoline alkaloid." Free Radic Biol Med 30(12):
1407-17.
A series of neurotoxic tetrahydroisoquinoline alkaloids has been detected in
certain regions of mammalian brains. One such dopaminergic
tetrahydroisoquinoline neurotoxin is salsolinol (SAL), which is suspected of
being associated with the etiology of Parkinson's disease and neuropathology of
chronic alcoholism. In the present study, we found that SAL in combination with
Cu(II) induced strand scission in pBR322 and phiX174 supercoiled DNA, which was
inhibited by the copper chelator, reactive oxygen species (ROS) scavengers,
reduced glutathione, and catalase. SAL in the presence of Cu(II) caused
hydroxylation of salicylic acid to produce 2,3- and 2,5-dihydroxybenzoic acids.
Reaction of calf thymus DNA with SAL plus Cu(II) resulted in substantial
oxidative DNA damage as determined by 8-hydroxydeoxyguanosine (8-OH-dG)
formation. Blockade of the dihydroxy functional group of SAL abolished its
capability to yield 8-OH-dG in the presence of Cu(II). The dehydro analog of
SAL, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinoline, produced significantly high
levels of 8-OH-dG when incubated with calf thymus DNA, even in the absence of
Cu(II), which appears to be attributable to the tautomer formation by this
compound. In another experiment, SAL exerted cytotoxicity when treated to rat
pheochromocytoma (PC12) cells. Based on these findings, it seems likely that SAL
undergoes redox cycling in the presence of Cu(II) with concomitant production of
ROS, particularly hydroxyl radical, which could contribute to DNA damaging and
cytotoxic properties of this neurotoxin.
Jung, Y. J., J. Y. Youn, et al. (2001). "Salsolinol, a naturally occurring
tetrahydroisoquinoline alkaloid, induces DNA damage and chromosomal aberrations
in cultured Chinese hamster lung fibroblast cells." Mutat Res 474(1-2):
25-33.
Salsolinol (SAL) is a tetrahydroisoquinoline neurotoxin that has been speculated
to contribute to pathophysiology of Parkinson's disease and chronic alcoholism.
The compound is also found in certain beverages and food stuffs, including soy
sauce, beer and bananas. Despite potential human exposure to SAL and its
endogenous formation, little is known about the genotoxic or carcinogenic
potential of this substance. In the present investigation, SAL induced DNA
damage in cultured Chinese hamster lung (CHL) fibroblasts as assessed by single
cell gel electrophoresis (Comet). CHL cells treated with SAL also exhibited
higher frequencies of chromosomal aberrations than did vehicle-treated controls.
Our recent study has revealed that SAL in combination with Cu(II) causes the
strand scission in phiX174 supercoiled DNA [Neurosci. Lett. 238 (1997) 95]. In
line with this notion, addition of cupric ion potentiated the DNA damaging and
clastogenic activity of SAL. Antioxidant vitamins, such as Vitamin C and Vitamin
E, and reduced glutathione inhibited clastogenicity of SAL, suggesting the
involvement of reactive oxygen species (ROS) in SAL-induced DNA damage and
genotoxicity in CHL cells.