Zorzi, G., B. Garavaglia, et al. (2002).
"Frequency of DYT1 mutation in early onset primary dystonia in Italian
patients." Mov Disord17(2): 407-8.
Thirty Italian patients with sporadic, early-onset, primary
dystonia were screened for the DYT1 mutation. Five patients were positive (mean
age at onset, 8 years); two had the typical phenotype, two a generalised
dystonia also involving the cranial muscles, and one a segmental dystonia. In
the other 25 patients (mean age at onset, 7.7 years), dystonia was generalised
in 22 patients and remained segmental in three. Our results indicate the role of
DYT1 mutation in Italian patients and confirm clinical and genetic heterogeneity
of early-onset primary dystonia.
Ziefer, P., J. Leung, et al. (2002). "Molecular
cloning and expression of rat torsinA in the normal and genetically dystonic (dt)
rat." Brain Res Mol Brain Res101(1-2): 132-5.
Deletions within the TOR1A gene cause early-onset (DYT1)
torsion dystonia. We have cloned and sequenced the rat cDNA homologue of TOR1A
and found a 91% identity with the human sequence. Northern blot analysis detects
a single transcript of approximately 1.5 kb. In situ hybridization reveals a
widespread distribution of torsinA mRNA within brain. No mutations were
identified in the coding region of the gene in the genetically dystonic (dt)
rat.
Opal, P., R. Tintner, et al. (2002). "Intrafamilial
phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene
carrier status to dystonic storm." Mov Disord17(2): 339-45.
When primary torsion dystonia is caused by a GAG deletion in
the TOR1A gene (DYT1 dystonia), it typically presents with an early-onset
dystonia involving distal limbs, subsequently spreading to a generalized
dystonia. We describe a large family with an unusually broad variability in the
clinical features of their dystonia both with regard to severity and age of
onset. The proband of this family succumbed in his second decade to malignant
generalized dystonia, whereas other family members carrying the same mutation
are either asymptomatic or display dystonia that may be focal, segmental,
multifocal, or generalized in distribution. One family member had onset of her
dystonia at age 64 years, probably the oldest reported in genetically confirmed
DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes
some families with DYT1 dystonia, suggesting a role for genetic, environmental,
or other modifiers. These findings have implications for genetic testing and
counseling.
O'Riordan, S., D. Cockburn, et al. (2002).
"Primary torsion dystonia due to the Tor1A GAG deletion in an Irish family."
Ir J Med Sci171(1): 31-2.
BACKGROUND: Early, limb-onset primary torsion dystonia (PTD)
is commonly due to a trinucleotide GAG deletion in the TOR1A (DYT1) gene on
chromosome 9q34. The majority of carriers of this mutation conform to a
characteristic phenotype that is similar in different ethnic populations. AIM:
To describe the clinical features of affected members of a large Irish family
with PTD due to the TOR1A deletion. METHODS: Fourteen consenting family members
from three generations were examined according to a standardised protocol.
RESULTS: Five affected individuals were identified. Two had a somewhat atypical
phenotype with focal and segmental upper-limb dystonia without further
progression. CONCLUSION: The authors describe the clinical features of PTD due
to the TOR1A GAG deletion in an Irish family illustrating the presence of
intrafamilial phenotypic variability.
O'Farrell, C., D. G. Hernandez, et al. (2002).
"Normal localization of deltaF323-Y328 mutant torsinA in transfected human
cells." Neurosci Lett327(2): 75-8.
Two mutations in torsinA have been identified to date, both
of which are associated with an autosomal dominant form of early onset-dystonia.
It has been reported previously that expression of the more common mutation, a
deletion of one of a pair of glutamates (deltaE302/303) produces intracellular,
endoplasmic reticulum-derived inclusions in cultured cells. In this study we
have replicated these previous results and have additionally looked at the
localization of the more recently described deltaF323-Y328 mutation. We show
that the localization of this latter mutation is similar to wild type torsinA
and unlike the deltaE302/303 mutation. This data suggests that the formation of
intracellular inclusions is specific to deltaE302/303 and not a property shared
by deltaF323-Y328.
Klein, C. and L. J. Ozelius (2002). "Dystonia:
clinical features, genetics, and treatment." Curr Opin Neurol15(4):
491-7.
PURPOSE OF REVIEW: The present review covers recent advances
in dystonia research related to dystonia genetics and treatment. These have led
to the discovery of novel dystonia genes and loci, to changing classification
schemes, and to the introduction of improved and new treatment options. RECENT
FINDINGS: Currently 13 different forms of dystonia can be distinguished on a
genetic basis (dystonia types 1-13). Recently, a novel gene locus (DYT13) was
detected in a family with segmental dystonia, and the gene causing
myoclonus-dystonia was identified (SGCE). Furthermore, a novel mutation in the
DYT1 gene is associated with a myoclonus-dystonia phenotype. Regarding dystonia
treatment, patients refractory to botulinum toxin type A can now be treated with
botulinum toxin type B. Selective peripheral denervation remains an effective
form of treatment for patients with secondary, but probably not with primary
botulinum toxin treatment failure. Finally, a renaissance of functional surgical
ablative procedures has taken place, with high frequency deep brain stimulation
being introduced in dystonia treatment. Bilateral pallidotomy or pallidal
stimulation may provide major benefit especially in patients with generalized,
disabling dystonia with the most dramatic improvements in dystonia type 1
patients. Neurostimulation may also be effective in primary segmental axial
dystonia, myoclonus-dystonia, and tardive dystonia. SUMMARY: The recent mapping
of additional dystonia gene loci, the identification of novel dystonia genes,
and the characterization of proteins encoded by these genes have enhanced our
understanding of various forms and aspects of the dystonias and have opened up
new avenues for research. Treatment options include both medical and surgical
therapies, with deep brain simulation being the most recent development.
Hjermind, L. E., L. M. Werdelin, et al. (2002).
"Inherited and de novo mutations in sporadic cases of DYT1-dystonia." Eur J
Hum Genet10(3): 213-6.
A study of Danish probands with primary torsion dystonia is
presented. The probands were examined clinically and biochemically to exclude
secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were
performed on 107 probands; and the mutation was detected in three. All three
probands had the classical phenotype of DYT1-dystonia, but only one had a family
history of dystonia. The other two probands had, obviously, sporadic
DYT1-dystonia, one of which was caused by a de novo mutation, while the other
one had a parent being an asymptomatic carrier. De novo mutations in the DYT1
gene are seldom reported although independent founder mutations are known to
have occurred. The frequency of DYT1-dystonia was low in our study even though
several probands had early onset generalised dystonia. None of the probands in
our study with other types of dystonia had the GAG-deletion as reported in other
studies. The difficulties in genetic counselling concerning the heterogeneity of
dystonia exemplified by DYT1-dystonia are outlined.
Chinnery, P. F., P. J. Reading, et al. (2002).
"Late-onset axial jerky dystonia due to the DYT1 deletion." Mov Disord
17(1): 196-8.
We describe a 71-year-old woman who presented to the
neurology department late in life with a jerky axial dystonia due to the DYT1
GAG deletion. She recalled that her symptoms began 62 years prior to study and
remained unchanged for 40 years, illustrating the broad phenotype of DYT1
idiopathic torsion dystonia.
Augood, S. J., Z. Hollingsworth, et al. (2002).
"Dopamine transmission in DYT1 dystonia: a biochemical and autoradiographical
study." Neurology59(3): 445-8.
Indices of dopamine transmission were measured in the
postmortem striatum of DYT1 dystonia brains. A significant increase in the
striatal 3,4-dihydroxyphenylacetic acid/dopamine ratio was found. Quantitative
autoradiography revealed no differences in the density of dopamine transporter
or vesicular monoamine transporter-2 binding; however, there was a trend toward
a reduction in D(1) receptor and D(2) receptor binding. One brain with DYT1
parkinsonism was similarly evaluated and marked reductions in striatal dopamine,
3,4-dihydroxyphenylacetic acid, and homovanillic acid content as well as the
density of binding of all four dopaminergic ligands were measured.
Zimprich, A., M. Grabowski, et al. (2001).
"Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia
syndrome." Nat Genet29(1): 66-9.
The dystonias are a common clinically and genetically
heterogeneous group of movement disorders. More than ten loci for inherited
forms of dystonia have been mapped, but only three mutated genes have been
identified so far. These are DYT1, encoding torsin A and mutant in the
early-onset generalized form, GCH1 (formerly known as DYT5), encoding
GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH,
encoding tyrosine hydroxylase and mutant in the recessive form of the disease.
Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder
characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly
the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp,
occurs in most but not all affected patients and may occasionally be the only
symptom of the disease. In addition, patients often show prominent psychiatric
abnormalities, including panic attacks and obsessive-compulsive behavior. In
most MDS families, the disease is linked to a locus on chromosome 7q21 (refs.
11-13). Using a positional cloning approach, we have identified five different
heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE),
which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed
in all brain regions examined. Pedigree analysis shows a marked difference in
penetrance depending on the parental origin of the disease allele. This is
indicative of a maternal imprinting mechanism, which has been demonstrated in
the mouse epsilon-sarcoglycan gene.
Walker, R. H., M. F. Brin, et al. (2001).
"Distribution and immunohistochemical characterization of torsinA
immunoreactivity in rat brain." Brain Res900(2): 348-54.
A mutation of the DYT1 gene on chromosome 9q34 has recently
been identified as the cause of one form of autosomal-dominantly inherited
dystonia. TorsinA, the protein product of this gene, has homology with the
family of heat shock proteins, and is found in many peripheral tissues and brain
regions. We used a polyclonal antibody to torsinA, developed in our laboratory,
to systematically examine the regional distribution of torsinA in rat brain. We
find that neurons in all examined structures are immunoreactive for this
protein. There is intense immunoreactivity in most neuronal nuclei, with
slightly less labeling of cytoplasm and proximal processes. Terminals also are
labeled, especially in striatum, neocortex and hippocampus. Double-labeling
fluorescence immunohistochemistry using antibodies to neurotransmitters and
other neurochemical markers demonstrated that the majority of neurons of all
studied neurochemical types are immunoreactive for torsinA. Our findings
indicate that torsinA is widely distributed in the central nervous system
implicating additional, localized factors, perhaps within the basal ganglia, in
the development of dystonia. Many other proteins have a similar widespread
distribution, including some which have been implicated in other movement
disorders and neurodegenerative processes, such as parkin, alpha-synuclein,
ubiquitin and huntingtin. The distribution of torsinA in rat brain as
demonstrated by immunohistochemistry contrasts with the results of in situ
hybridization studies of torsinA mRNA in human postmortem brain in which a more
limited distribution was found.
Tuffery-Giraud, S., L. Cavalier, et al. (2001).
"No evidence of allelic heterogeneity in the DYT1 gene of European patients with
early onset torsion dystonia." J Med Genet38(10): E35.
Sharma, N., J. Hewett, et al. (2001). "A close
association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence
resonance energy transfer study." Am J Pathol159(1): 339-44.
TorsinA, a novel protein in which a mutation causes dominant,
early onset torsion dystonia, may serve as a chaperone for misfolded proteins
that require refolding or degradation. It has been hypothesized that misfolded
alpha-synuclein, a protein in which two mutations cause autosomal dominantly
inherited Parkinson's disease, serves as a nidus for the development of a Lewy
body. We hypothesized that torsinA plays a role in the cellular processing of
alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies
and Lewy neurites in the substantia nigra and cortex. Using sensitive
fluorescent resonance energy transfer (FRET) techniques, we find evidence of a
close association between torsinA and alpha-synuclein in Lewy bodies.
Sessa, M., G. Galardi, et al. (2001). "Sporadic
idiopathic cervical dystonia: exclusion of the DYT1 deletion." J Neurol248(9): 812-3.
Misbahuddin, A. and T. T. Warner (2001). "Dystonia:
an update on genetics and treatment." Curr Opin Neurol14(4):
471-5.
Recent years have seen many advances in our understanding of
the genetics of the dystonias, with 13 loci identified to date. The DYT1 gene,
which causes most cases of childhood-onset generalized primary dystonia, was
cloned in 1997, and use of cell models has begun to unravel the role of its
protein (torsinA) in both health and disease. Treatment of more severe dystonia
has been a difficult area, with only limited success from medical therapies.
Recently, there has been increasing interest in the use of globus pallidus deep
brain stimulation and a number of reports have shown promising results.
Matsumoto, S., M. Nishimura, et al. (2001).
"DYT1 mutation in Japanese patients with primary torsion dystonia."
Neuroreport12(4): 793-5.
A GAG deletion at position 946 in the DYT1 gene has been
identified as one of the gene mutations responsible for autosomal dominant
primary torsion dystonia. We examined 178 Japanese patients with various forms
of dystonia, and found the mutation in six patients (3.4%) from three families.
Five of them had early clinical onset (before age 12) with initial involvement
of a limb. To our knowledge, this is the first report of the frequency and the
clinical features of DYT1 mutation in oriental patients, and the clinical
presentation of the mutation in these patients was similar to that of Jewish or
non-Jewish Caucasian patients.
Major, T., M. Svetel, et al. (2001). "DYT1
mutation in primary torsion dystonia in a Serbian population." J Neurol248(11): 940-3.
Primary torsion dystonia (PTD) is a clinically and
genetically heterogeneous movement disorder. A GAG deletion at position 946 in
the DYT1 gene is responsible for most cases of autosomal dominant early-onset
PTD. We analysed the DYT1 mutation in 50 patients from a Serbian population,
selected according to the proposed guidelines for diagnostic testing: (a) 38
patients with PTD onset < 26 years, and (b) 12 patients with the disease onset
+/- 26 years, but with at least one affected family member with early-onset
dystonia. Only three apparently sporadic patients among the 50 individuals
tested were positive for the GAG deletion in the DYT1 gene: one with typical,
generalized, one with long-lasting, non-progressive segmental, and one with
multifocal dystonia. Molecular analysis of relatives in 2 families revealed that
the lack of family history was due to reduced penetrance.
Leung, J. C., C. Klein, et al. (2001). "Novel
mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and
polymorphisms in dystonia and early onset parkinsonism." Neurogenetics
3(3): 133-43.
Dystonia is a movement disorder involving sustained muscle
contractions and abnormal posturing with a strong hereditary predisposition and
without a distinct neuropathology. In this study the TOR1A (DYT1) gene was
screened for mutations in cases of early onset dystonia and early onset
parkinsonism (EOP), which frequently presents with dystonic symptoms. In a
screen of 40 patients, we identified three variations, none of which occurred in
EOP patients. Two infrequent intronic single base pair (bp) changes of unknown
consequences were found in a dystonia patient and the mother of an EOP patient.
An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient
with early onset dystonia and myoclonic features. This deletion would remove 6
amino acids close to the carboxy terminus, including a putative phosphorylation
site of torsinA. This 18-bp deletion is the first additional mutation, beyond
the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is
associated with a distinct type of early onset dystonia.
Konakova, M., D. P. Huynh, et al. (2001).
"Cellular distribution of torsin A and torsin B in normal human brain." Arch
Neurol58(6): 921-7.
BACKGROUND: Early-onset torsion dystonia is a hyperkinetic
movement disorder caused by a deletion of 1 glutamic acid residue in torsin A
protein, a novel member of the AAA family of adenosine triphosphatases. No
mutation has been found so far in the closely related torsin B protein. Little
is known about the molecular basis of the disease, and the cellular functions of
torsin proteins remain to be investigated. OBJECTIVE: To study the regional,
cellular, and subcellular distribution of the torsin A and torsin B proteins.
METHODS: Expression of torsin proteins in the central nervous system was
analyzed by Western blot analysis and immunohistochemistry in human postmortem
brain tissues. RESULTS: We generated polyclonal antipeptide antibodies directed
against human torsin A and torsin B proteins. In Western blot analysis of normal
human brain homogenates, the antibodies specifically recognized 38-kd endogenous
torsin A and 62-kd endogenous torsin B. Absorption controls showed that labeling
was blocked by cognate peptide used for immunization. Immunolocalization studies
revealed that torsin A and torsin B were widely expressed throughout the human
central nervous system. Both proteins displayed cytoplasmic distribution,
although torsin B localization in some neurons was perinuclear. Strong labeling
of neuronal processes was detected for both proteins. CONCLUSIONS: Torsin A and
torsin B have similar distribution in the central nervous system, although their
subcellular localization is not identical. Strong expression in neuronal
processes points to a potential role for torsin proteins in synaptic
functioning.
Konakova, M. and S. M. Pulst (2001). "Immunocytochemical
characterization of torsin proteins in mouse brain." Brain Res922(1):
1-8.
Early-onset torsion dystonia is a hyperkinetic movement
disorder caused by a deletion of one glutamic acid residue in torsinA, a novel
member of the AAA-family of ATPases. No mutation has been found so far in the
closely related torsinB protein. Little is known about the molecular basis of
the disease, and the cellular functions of torsin proteins remain to be
investigated. We generated polyclonal anti-peptide antibodies directed against
human torsinA and torsinB proteins. In Western blot analysis of mouse brain
homogenates, the antibodies specifically recognized 33 kDa endogenous torsinA
and 52 kDa endogenous torsinB. Absorption controls showed that labeling was
blocked by cognate peptide used for immunization. Immunolocalization studies
revealed that torsinA and torsinB were widely expressed throughout the mouse
central nervous system. Both proteins were detected in the majority of neurons
in nearly all regions. The proteins displayed cytoplasmic distribution, although
in some types of neurons localization was perinuclear. Strong labeling of
neuronal processes and fibers was detected for both proteins. TorsinA and
torsinB have similar CNS distribution, although some differences were observed.
Widespread expression suggests that these proteins may play an essential role in
normal neuronal functions. The localization of torsinA and torsinB
immunoreactivity in neuronal processes points to a potential role for torsin
proteins in synaptic functioning.
Bressman, S. B., S. Fahn, et al. (2001). "The
DYT1 mutation and nonfamilial primary torsion dystonia." Arch Neurol
58(4): 681-2.
Breakefield, X. O., C. Kamm, et al. (2001). "TorsinA:
movement at many levels." Neuron31(1): 9-12.
TorsinA is the causative protein in the human neurologic
disease early onset torsin dystonia, a movement disorder involving dysfunction
in the basal ganglia without apparent neurodegeneration. Most cases result from
a dominantly acting three-base pair deletion in the TOR1A gene causing loss of a
glutamic acid near the carboxyl terminus of torsinA. Torsins are members of the
AAA(+) superfamily of ATPases and are present in all multicellular organisms.
Initial studies suggest that torsinA is an ER protein involved in chaperone
functions and/or membrane movement.
Basham, S. E. and L. S. Rose (2001). "The
Caenorhabditis elegans polarity gene ooc-5 encodes a Torsin-related protein of
the AAA ATPase superfamily." Development128(22): 4645-56.
The PAR proteins are required for polarity and asymmetric
localization of cell fate determinants in C. elegans embryos. In addition,
several of the PAR proteins are conserved and localized asymmetrically in
polarized cells in Drosophila, Xenopus and mammals. We have previously shown
that ooc-5 and ooc-3 mutations result in defects in spindle orientation and
polarity in early C. elegans embryos. In particular, mutations in these genes
affect the re-establishment of PAR protein asymmetry in the P(1) cell of
two-cell embryos. We now report that ooc-5 encodes a putative ATPase of the Clp/Hsp100
and AAA superfamilies of proteins, with highest sequence similarity to Torsin
proteins; the gene for human Torsin A is mutated in individuals with early-onset
torsion dystonia, a neuromuscular disease. Although Clp/Hsp100 and AAA family
proteins have roles in diverse cellular activities, many are involved in the
assembly or disassembly of proteins or protein complexes; thus, OOC-5 may
function as a chaperone. OOC-5 protein co-localizes with a marker of the
endoplasmic reticulum in all blastomeres of the early C. elegans embryo, in a
pattern indistinguishable from that of OOC-3 protein. Furthermore, OOC-5
localization depends on the normal function of the ooc-3 gene. These results
suggest that OOC-3 and OOC-5 function in the secretion of proteins required for
the localization of PAR proteins in the P(1) cell, and may have implications for
the study of torsion dystonia.
Shashidharan, P., B. C. Kramer, et al. (2000). "Immunohistochemical
localization and distribution of torsinA in normal human and rat brain."
Brain Res853(2): 197-206.
Dystonia is a disease of basal ganglia function, the
pathophysiology of which is poorly understood. Primary torsion dystonia is one
of the most severe types of inherited dystonia and can be transmitted in an
autosomal dominant manner. Recently, one mutation causing this disorder was
localized to a gene on chromosome 9q34, designated DYT1, which encodes for a
novel protein termed torsinA. The role of this protein in cellular function, in
either normal or dystonic individuals is not known. We have developed a
polyclonal antibody to torsinA and report its localization and distribution in
normal human and rat brain. We demonstrate that torsinA is widely expressed in
brain and peripheral tissues. Immunohistochemical studies of normal human and
rat brain reveal the presence of torsinA in the dopaminergic neurons of the
substantia nigra pars compacta (SNc), in addition to many other regions,
including neocortex, hippocampus, and cerebellum. Labeling is restricted to
neurons, as shown by double-immunofluorescence microscopy, and is present in
both nuclei and cytoplasm. An ATP-binding property for torsinA has been
suggested by its homology to ATP-binding proteins; this was confirmed by
enrichment of torsinA in ATP-agarose affinity-purified fractions from tissue
homogenates. An understanding of the role of torsinA in cellular function and
the impact of the mutation (deletion of a glutamic acid at residue 303) is
likely to provide insights into the etiopathogenesis of primary dystonia.
Shashidharan, P., P. F. Good, et al. (2000).
"TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease." Brain
Res877(2): 379-81.
Parkinson's disease (PD) is a neurodegnerative disorder that
is pathologically characterized by the presence of Lewy bodies in the brain. We
show that Lewy bodies in PD are strongly immunoreactive for torsinA, the protein
product of the DYT1 gene, which is associated with primary generalized dystonia.
In the substantia nigra, torsinA immunoreactivity is localized to the periphery
of Lewy bodies, whereas, in cortical Lewy bodies it is uniformly distributed.
The significance of this finding is unknown, but may implicate torsinA in
neuronal dysfunction that occurs in PD as well as in primary dystonia.
Nomura, Y., T. Ikeuchi, et al. (2000). "Two
phenotypes and anticipation observed in Japanese cases with early onset torsion
dystonia (DYT1) - pathophysiological consideration." Brain Dev22
Suppl 1: S92-101.
Early onset torsion dystonia (DYT1) is a dominantly inherited
dystonia caused by a deletion of three bases, GAG, coding glutamic acid, in
chromosome 9q34. The protein coded by this gene was named as torsin A. DYT1 is
common among the Ashkenazi Jewish population, but has been thought to be rare
among Japanese. Among the idiopathic torsion dystonias being followed in this
clinic, we found five families with DYT1 by gene analysis. This is the first
report of genetically proven Japanese DYT1.The clinical features of five proband
cases were divided into two types. One type is postural dystonia with marked
trunkal torsion, and the other is action dystonia associated with violent
dyskinetic movements. The affected family members in the upper generations
presented with focal or segmental dystonia; it was postural dystonia of the legs
in the former, and writer's cramp or tremor of the arms in the latter families.
There was an asymptomatic carrier in the upper generation. Anticipation in the
age of onset and severity of the disease was observed in all families. Medical
treatment, including anticholinergics and levodopa, did not show apparent
effects, while stereotactic thalamotomy to the nucleus ventralis lateralis (VL)
or ventralis intermedius (Vim), with or without posterior ventral pallidotomy,
were effective with action dystonia, but not postural dystonia. This study
suggests the existence of at least two phenotypes in DYT1, in which different
pathways of the basal ganglia are involved.
Markova, E. D., P. A. Slominskii, et al. (2000).
"[Molecular-genetic analysis of torsion dystonia in Russia]." Genetika
36(7): 952-8.
For the first time in Russia, analysis of the GCH-I and DYT1
genes was carried out for the purpose of direct DNA diagnostics in families with
various forms of hereditary torsion dystonia (TD). Four new missense mutations
(Met102Lys, Thr94Lys, Cys141Trp, and Ser176Thr) in the GCH-I gene were found in
patients with dopa-responsive dystonia (DRD), testifying to a genetic
heterogeneity of this clinical form of TD. The distribution of the major del GAG
mutation in exon 5 of the DYT1 gene was studied in patients with
non-dopa-responsive dystonia (NDRD). In total, the mutation was found in 68% of
the patients. The frequency of this mutation in Ashkenazi Jews with NDRD was
100% (twice higher than in Slavonic families), suggesting the founder effect
reported for NDRD in this ethnic group. Mutations of the GCH-I and DYT1 genes
were also found in patients with atypical and questionable cases of TD, which
are difficult to diagnose with methods other than DNA analysis. The data
obtained made it possible to extend the spectrum of clinical signs of DRD and
NDRD and to revise the views on true penetrance of the corresponding mutant
genes, which is important for medical genetic counseling in affected families.
Lichter, D. G. and A. E. Lang (2000). "To test
or not to test? That is the question (with a twist)." Neurology54(9):
1718-9.
Kustedjo, K., M. H. Bracey, et al. (2000).
"Torsin A and its torsion dystonia-associated mutant forms are lumenal
glycoproteins that exhibit distinct subcellular localizations." J Biol Chem275(36): 27933-9.
Early-onset torsion dystonia is an autosomal dominant
hyperkinetic movement disorder that has recently been linked to a 3-base pair
deletion in the DYT1 gene. The DYT1 gene encodes a 332-amino acid protein,
torsin A, that bears low but significant homology to the Hsp100/Clp family of
ATPase chaperones. The deletion in DYT1 associated with torsion dystonia results
in the loss of one of a pair of glutamic acid residues residing near the C
terminus of torsin A (DeltaE-torsin A). At present, little is known about the
expression, subcellular distribution, and/or function of either the torsin A or
DeltaE-torsin A protein. When transfected into mammalian cells, both torsin A
and DeltaE-torsin A were found to behave as lumenally oriented glycoproteins.
Immunofluorescence studies revealed that torsin A localized to a diffuse network
of intracellular membranes displaying significant co-immunoreactivity for the
endoplasmic reticulum resident protein BiP, whereas DeltaE-torsin A resided in
large spheroid intracellular structures exclusive of BiP immunoreactivity. These
results initially suggested that DeltaE-torsin A might exist as insoluble
aggregates. However, both torsin A and DeltaE-torsin A were readily solubilized
by nonionic detergents, were similarly accessible to proteases, and displayed
equivalent migration patterns on sucrose gradients. Collectively, these data
support that both the wild type and torsion dystonia-associated forms of torsin
A are properly folded, lumenal proteins of similar oligomeric states. The
potential relationship between the altered subcellular distribution of
DeltaE-torsin A and the disease-inducing phenotype of the protein is discussed.
Kamm, C., M. Naumann, et al. (2000). "The DYT1
GAG deletion is infrequent in sporadic and familial writer' s cramp." Mov
Disord15(6): 1238-41.
A 3-base pair (GAG) deletion in the DYT1 gene has recently
been found to be responsible for most cases of early-onset primary generalized
dystonia. In some cases, this mutation has been associated with writer's cramp.
To determine the frequency of this mutation in a larger series of patients, we
examined 44 index patients with sporadic or familial (seven patients) writer's
cramp for the presence of the DYT1 GAG deletion, including eight patients with
segmental dystonia involving at least one upper limb. We found the mutation in
none of these index patients, which confirms that isolated writer's cramp is
only in rare cases a phenotypic manifestation of this mutation, even if a
positive family history of writer's cramp is present.
Hewett, J., C. Gonzalez-Agosti, et al. (2000).
"Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane
inclusions in cultured neural cells." Hum Mol Genet9(9): 1403-13.
Early-onset torsion dystonia is a hereditary movement
disorder thought to be caused by decreased release of dopamine into the basal
ganglia, without apparent neuronal degeneration. Recent cloning of the gene
responsible for this disease, TOR1A (DYT1), identified the encoded protein,
torsinA, as a member of the AAA+ superfamily of chaperone proteins and revealed
highest levels of expression in dopaminergic neurons in human brain. Most cases
of this disease are caused by a deletion of one glutamic acid residue in the
C-terminal region of the protein. Antibodies generated against torsinA revealed
expression of a predominant immunoreactive protein species similar to the
predicted size of 37.8 kDa in neural, glial and fibroblastic lines by western
blot analysis. This protein is N-glycosylated with high mannose content and not,
apparently, phosphoryl-ated. Overexpression of torsinA in mouse neural CAD cells
followed by immunocytochemistry, revealed a dramatically different pattern of
distribution for wild-type and mutant forms of the protein. The wild-type
protein was found throughout the cytoplasm and neurites with a high degree of
co-localization with the endoplasmic reticulum (ER) marker, protein disulfide
isomerase. In contrast, the mutant protein accumulated in multiple, large
inclusions in the cytoplasm around the nucleus. These inclusions were composed
of membrane whorls, apparently derived from the ER. If disrupted processing of
the mutant protein leads to its accumulation in multilayer membranous structures
in vivo, these may interfere with membrane trafficking in neurons.
Friedman, J. R., C. Klein, et al. (2000). "The
GAG deletion of the DYT1 gene is infrequent in musicians with focal dystonia."
Neurology55(9): 1417-8.
Coubes, P., A. Roubertie, et al. (2000).
"Treatment of DYT1-generalised dystonia by stimulation of the internal globus
pallidus." Lancet355(9222): 2220-1.
In seven selected patients with dystonia musculorum
deformans-1 generalised dystonia (DYT1), continuous bilateral stimulation of the
globus pallidus internus was associated with substantial improvement of dystonia
and functional disability.
Bressman, S. B., C. Sabatti, et al. (2000). "The
DYT1 phenotype and guidelines for diagnostic testing." Neurology54(9):
1746-52.
OBJECTIVE: To develop diagnostic testing guidelines for the
DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary
torsion dystonia (PTD) populations and to determine the range of dystonic
features in affected DYT1 deletion carriers. METHODS: The authors screened 267
individuals with PTD; 170 were clinically ascertained for diagnosis and
treatment, 87 were affected family members ascertained for genetic studies, and
10 were clinically and genetically ascertained and included in both groups. We
used published primers and PCR amplification across the critical DYT1 region to
determine GAG deletion status. Features of dystonia in clinically ascertained
(affected) DYT1 GAG deletion carriers and noncarriers were compared to determine
a classification scheme that optimized prediction of carriers. The authors
assessed the range of clinical features in the genetically ascertained
(affected) DYT1 deletion carriers and tested for differences between AJ and NJ
patients. RESULTS: The optimal algorithm for classification of clinically
ascertained carriers was disease onset before age 24 years in a limb
(misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although
application of this classification scheme provided good separation in the AJ
group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it
was less specific in discriminating NJ carriers from noncarriers (sensitivity,
94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset
gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43%
in NJ). Among genetically ascertained carriers, onset up to age 44 years
occurred, although the great majority displayed early limb onset. There were no
significant differences between AJ and NJ genetically ascertained carriers,
except that a higher proportion of NJ carriers had onset in a leg, rather than
an arm, and widespread disease. CONCLUSIONS: Diagnostic DYT1 testing in
conjunction with genetic counseling is recommended for patients with PTD with
onset before age 26 years, as this single criterion detected 100% of clinically
ascertained carriers, with specificities of 43% to 63%. Testing patients with
onset after age 26 years also may be warranted in those having an affected
relative with early onset, as the only carriers we observed with onset at age 26
or later were genetically ascertained relatives of individuals whose symptoms
started before age 26 years.
Brassat, D., A. Camuzat, et al. (2000).
"Frequency of the DYT1 mutation in primary torsion dystonia without family
history." Arch Neurol57(3): 333-5.
BACKGROUND: Idiopathic torsion dystonia is a clinically and
genetically heterogeneous movement disorder. A GAG deletion at position 946 of
the DYT1 gene was the first mutation found, in early-onset dystonia, with an
autosomal dominant transmission and reduced penetrance. OBJECTIVE: To evaluate
the frequency of the DYT1 mutation in patients with idiopathic torsion dystonia
but without a family history. DESIGN: Prospective cohort study. SETTING: Four
botulinum toxin clinics in the Paris, France, area. PATIENTS: A French
population of 100 patients with dystonia. MAIN OUTCOME: Frequency of the DYT1
mutation tested by polymerase chain reaction and enzyme restriction analysis for
the 946 GAG deletion, and genotype-to-phenotype correlation. RESULTS: Only 5
mutation carriers were identified, 4 of whom were part of a group of 10 patients
with generalized dystonia. Onset was between ages 5 and 12 years as in typical
early-onset dystonia. All 4 patients had cranial muscle involvement, which is
atypical for DYT1 mutation carriers. One had segmental dystonia. Molecular
analysis of relatives in 2 families demonstrated that the lack of family history
was due to reduced penetrance. CONCLUSIONS: For accurate diagnosis and genetic
counseling, screening for the DYT1 deletion is of great interest in cases with
generalized dystonia without a family history. In other cases, positive results
are rare.
Valente, E. M., S. Povey, et al. (1999).
"Detailed haplotype analysis in Ashkenazi Jewish and non-Jewish British dystonic
patients carrying the GAG deletion in the DYT1 gene: evidence for a limited
number of founder mutations." Ann Hum Genet63 ( Pt 1): 1-8.
The DYT1 gene on human chromosome 9q34 appears to be
responsible for most cases of early onset primary torsion dystonia (PTD) both in
Ashkenazi Jewish (AJ) and in non-Jewish patients. Previous haplotype analysis in
a 2 cM region surrounding the DYT1 gene showed that a single founder mutation
(DYT1AJ) was responsible for most cases of early onset PTD in the North American
AJ population and refined the most likely location of the gene to a 150 kb
interval between the marker loci D9S2161 and D9S63. Recently, the majority of
cases of early onset PTD in both AJ and non-Jewish patients were found to carry
a unique 3-bp (GAG) deletion in the coding region of the DYT1 gene. This
deletion appears to have arisen more than once, suggesting independent
mutational events. In this study, we analysed the haplotypes surrounding DYT1 in
9 AJ and 15 non-Jewish British patients carrying the GAG deletion in the DYT1
gene. We found that all AJ British patients carried the same haplotype as the
North American Jews, sustaining the theory that the current British AJ community
descends from the same small group of individuals as the North American Jewry.
Furthermore, in the non-Jewish British patients, only a limited number of
distinct founder mutations was observed. This supports the hypothesis that the
GAG deletion in the DYT1 gene is not a very frequent mutation, and that it has
arisen only a limited number of times throughout the centuries.
Slominsky, P. A., E. D. Markova, et al. (1999).
"A common 3-bp deletion in the DYT1 gene in Russian families with early-onset
torsion dystonia." Hum Mutat14(3): 269.
Hereditary torsion dystonia represent a clinically and
genetically heterogeneous group of movement disorders. The most severe and
frequent form of hereditary torsion dystonia is early-onset generalized
dystonia, DYT1. The DYT1 gene (Ozelius et al., 1997) encodes an ATP-binding
protein torsin A. A unique 3-bp deletion (GAG) was found in the heterozygous
state in almost all patients with early-onset dystonia from different
populations. We observed 39 patients with early-onset generalized torsion
dystonia belonging to 22 families from Russia. Seven families were of Ashkenazi
Jewish (AJ) ethnic background, and other patients originated from the Slavonic
population of Russia. The GAG deletion was identified in 24 affected persons
from 15 families (68.2% of the families studied). In all the 7 families of AJ
origin the disease was found to be caused by the deletion. In Slavs, the
deletion was identified in 8 of 15 families (53%). In two deletion-positive
families we observed the co-occurrence of typical early-onset generalized
dystonia and atypical phenotypes-either isolated postural hand tremor or
stutter.
Ozelius, L. J., C. E. Page, et al. (1999). "The
TOR1A (DYT1) gene family and its role in early onset torsion dystonia."
Genomics62(3): 377-84.
Most cases of early onset torsion dystonia are caused by a
3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2),
resulting in loss of a glutamic acid in the carboxy terminal of the encoded
protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located
adjacent to each other on human chromosome 9q34. Both genes comprise five
similar exons; each gene spans a 10-kb region. Mutational analysis of most of
the coding region and splice junctions of TOR1A and TOR1B did not reveal
additional mutations in typical early onset cases lacking the GAG deletion (N =
17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal
region (N = 5), or in a representative Ashkenazic Jewish individual with late
onset dystonia, who shared a common haplotype in the 9q34 region with other late
onset individuals in this ethnic group. A database search revealed a family of
nine related genes (50-70% similarity) and their orthologues in species
including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least
four of these genes occur in the human genome. Proteins encoded by this gene
family share functional domains with the AAA/HSP/Clp-ATPase superfamily of
chaperone-like proteins, but appear to represent a distinct evolutionary branch.
Nomura, Y. (1999). "[Early-onset torsion
dystonia linked to chromosome 9q34: DYT1]." Ryoikibetsu Shokogun Shirizu(27
Pt 2): 139-43.
Leube, B., K. R. Kessler, et al. (1999).
"Phenotypic variability of the DYT1 mutation in German dystonia patients."
Acta Neurol Scand99(4): 248-51.
Primary dystonia is a clinically and genetically
heterogeneous movement disorder characterized by sustained involuntary muscle
contractions causing repetitive movements and/or abnormal postures. Recently,
the gene locus (DYT1) and mutation responsible for a substantial number of cases
suffering from early-onset primary dystonia was described. Here we report 2
German families and 1 sporadic patient with early-onset dystonia due to the DYT1
mutation in order to illustrate the variability of clinical manifestation within
this molecularly defined entity. We demonstrate that writer's cramp or focal
cervical dystonia is a clinical presentation of DYT1 as well as generalized
dystonia.
Lebre, A. S., A. Durr, et al. (1999). "DYT1
mutation in French families with idiopathic torsion dystonia." Brain
122 ( Pt 1): 41-5.
A GAG deletion at position 946 in DYT1, one of the genes
responsible for autosomal dominant idiopathic torsion dystonia (ITD), has
recently been identified. We tested 24 families and six isolated cases with ITD
and found 14 individuals from six French families who carried this mutation,
indicating that 20% of the affected families carried the DYT1 mutation. Age at
onset was always before 20 years (mean, 9+/-4 years). Interestingly, the site of
onset was the upper limb in all but one patient. Dystonia was generalized in
seven patients and remained focal or segmental in three patients. The absence of
common haplotypes among DYT1 families suggests that at least six independent
founder mutations have occurred. In addition, one Ashkenazi Jewish family
carried the common haplotype described previously in Ashkenazi Jewish patients,
but it was absent in the other family. Moreover, the dystonia remained focal in
the latter family when compared with the usual generalized phenotype in patients
with the common Ashkenazi Jewish haplotype. This indicates that there are at
least two founder mutations in this population.
Klein, C., J. Friedman, et al. (1999). "Genetic
testing for early-onset torsion dystonia (DYT1): introduction of a simple
screening method, experiences from testing of a large patient cohort, and
ethical aspects." Genet Test3(4): 323-8.
Early-onset, generalized primary torsion dystonia (PTD) is an
autosomal dominantly inherited disorder, characterized by involuntary movements
and abnormal postures. The majority of cases are caused by a 3-bp deletion in
the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We
developed a simple, reliable, and cost-effective, PCR-based screening method for
this mutation. Testing results from a cohort of 550 cases, including patients
with different forms of dystonia and unclassified movement disorders, revealed
that 72.2% of the patients with typical early-onset generalized PTD carried the
GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental
dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of
the patients with an unclassified movement disorder were GAG positive. Our
results confirm a genotype/phenotype correlation in early-onset PTD and show
that application of strict clinical criteria leads to accurate prediction of
carrier status in more than two-thirds of patients with this type of dystonia.
Currently, we suggest that testing be recommended in individuals with age of
onset of dystonia below 30 years and/or a positive family history of early-onset
PTD. Testing is not recommended in patients with onset of symptoms after 30
years or in asymptomatic individuals under the age of 18.
Kamm, C., E. Castelon-Konkiewitz, et al. (1999).
"GAG deletion in the DYT1 gene in early limb-onset idiopathic torsion dystonia
in Germany." Mov Disord14(4): 681-3.
We examined 57 patients with idiopathic torsion dystonia
(ITD) for the 3-bp GAG deletion in the DYT1 gene on human chromosome 9q34. Three
of five patients with early limb-onset ITD, one of them with a positive family
history, tested positive for the mutation, as did one young patient with
multifocal dystonia and a short course of the disease. Two patients with
early-onset generalized dystonia beginning in the cervical muscles, as well as
five other patients with multifocal, 14 patients with segmental, and 30 patients
with focal cervical dystonia did not carry the mutation. This suggests that the
GAG deletion is responsible for a major portion of cases of typical early
limb-onset dystonia, but not for other types of dystonia, in our population.
Ikeuchi, T., T. Shimohata, et al. (1999). "A
case of primary torsion dystonia in Japan with the 3-bp (GAG) deletion in the
DYT1 gene with a unique clinical presentation." Neurogenetics2(3):
189-90.
Augood, S. J., D. M. Martin, et al. (1999).
"Distribution of the mRNAs encoding torsinA and torsinB in the normal adult
human brain." Ann Neurol46(5): 761-9.
To gain insight into the neural pathways involved in the
pathogenesis of DYT1 dystonia, we have mapped the cellular expression of the
mRNA encoding torsinA and the closely related family member, torsinB, in normal
adult human brain. Here, we report an intense expression of torsinA mRNA in the
substantia nigra pars compacta dopamine neurons, the locus ceruleus, the
cerebellar dentate nucleus, Purkinje cells, the basis pontis, numerous thalamic
nuclei, the pedunculopontine nucleus, the oculomotor nucleus, the hippocampal
formation, and the frontal cortex. Within the caudateputamen, the cellular
expression of torsinA mRNA was heterogeneous; a moderate signal was found
overlying large cholinergic neurons, and most striatal neurons exhibited only a
very weak signal. A moderate signal was detected in numerous midbrain and
hindbrain nuclei. A weak cellular signal was detected in neurons of the globus
pallidus and subthalamic nucleus. In marked contrast to torsinA, no specific
mRNA signal was detected for torsinB. That torsinA mRNA is enriched in several
basal ganglia nuclei, including the dopamine neurons in the substantia nigra, is
intriguing since it suggests that DYT1 dystonia may be associated with a
dysfunction in dopamine transmission.
Valente, E. M., T. T. Warner, et al. (1998).
"The role of DYT1 in primary torsion dystonia in Europe." Brain121 (
Pt 12): 2335-9.
Primary torsion dystonia (PTD) is a clinically and
genetically heterogeneous movement disorder. DYT1 on chromosome 9q34 was the
first PTD gene to be mapped. A 3-bp (GAG) deletion in this gene was reported to
account for almost all early limb-onset generalized PTD. No relationship has
been found with DYT1 in patients with prominent craniocervical involvement. To
elucidate the DYT1-associated phenotype, we analysed the DYT1 mutation in 150
PTD patients, either sporadic or index cases from small PTD families. Twenty-two
patients were positive for the GAG deletion in the DYT1 gene. Fifteen of them
presented with the typical DYT1 phenotype (early, limb-onset generalized
dystonia without spread to craniocervical muscles), four had limb-onset dystonia
with spread to craniocervical muscles, two patients had arm-onset segmental
dystonia and one had focal right-arm dystonia. One-hundred and twenty-eight
patients were negative for the DYT1 mutation. Forty-six of them had segmental
dystonia and 59 had focal dystonia. The other 23 patients presented with
generalized dystonia, either with craniocervical involvement (13 patients) or
without spread to the craniocervical region (typical DYT1 phenotype-10
patients). These data confirm the importance of the GAG deletion in European
cases of PTD, and indicate phenotypic and genotypic heterogeneity.
Ozelius, L. J., J. W. Hewett, et al. (1998).
"The gene (DYT1) for early-onset torsion dystonia encodes a novel protein
related to the Clp protease/heat shock family." Adv Neurol78:
93-105.
Muller, U., D. Steinberger, et al. (1998).
"Clinical and molecular genetics of primary dystonias." Neurogenetics
1(3): 165-77.
Primary dystonias are movement disorders with dystonia as a
major symptom. They are frequently inherited as Mendelian traits. There are at
least eight clinically distinct autosomal dominant and two X-linked recessive
forms. In addition, pedigree analyses suggest the occurrence of an autosomal
recessive variant. The clinical classification is increasingly being replaced by
a genetic one. To date gene loci have been identified in at least six autosomal
dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia
(18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22),
dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic
choreoathetosis (2q25-q33; 1p21-p13.3). Gene loci in the X-linked recessive
forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism
syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental
retardation. The disease genes have been identified in two autosomal dominant
forms and in one X-linked recessive form. Mutations in a gene coding for an
ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the
GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In
sensorineural deafness, dystonia, and mental retardation, mutations were found
in the gene DDP coding for a polypeptide of unknown function. This article
reviews the clinical and molecular genetics of primary dystonias, critically
discusses present findings, and proposes referring to the known forms, most of
which can be distinguished by genetic criteria, as dystonias 1-12.
Klein, C., M. F. Brin, et al. (1998). "De novo
mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with
early-onset dystonia." Hum Mol Genet7(7): 1133-6.
The DYT1 gene recently has been cloned and shown to contain a
three nucleotide (GAG) deletion responsible for most cases of autosomal dominant
early-onset torsion dystonia. This deletion results in the loss of one of a pair
of glutamic acids in a conserved region of a novel ATP-binding protein
(torsinA). Previous haplotype analysis revealed that this same deletion had
arisen at least two different times in history, suggesting independent
mutational events. This deletion is the only sequence change found thus far to
be associated uniquely with the disease status, regardless of ethnic origin.
Here we describe two patients with typical early-onset torsion dystonia of
Swiss-Mennonite and non-Jewish Russian origin, respectively, that both carry
this same mutation as a de novo GAG deletion. This finding proves that this 3 bp
deletion in the DYT1 gene is indeed a mutation that causes early-onset torsion
dystonia. The DYT1 mutation is one of the rare examples of the same recurrent
mutation causing a dominantly inherited condition. The sequence surrounding the
GAG deletion contains an imperfect 24 bp tandem repeat, suggesting a possible
mechanism for the high frequency of this mutation.
Klein, C., L. J. Ozelius, et al. (1998). "Search
for a founder mutation in idiopathic focal dystonia from Northern Germany."
Am J Hum Genet63(6): 1777-82.
Both the discovery of the DYT1 gene on chromosome 9q34 in
autosomal dominant early-onset torsion dystonia and the detection of linkage for
one form of adult-onset focal dystonia to chromosome 18p (DYT7) in a family from
northern Germany provide the opportunity to further investigate genetic factors
in the focal dystonias. Additionally, reports of linkage disequilibrium between
several chromosome 18 markers and focal dystonia, both in sporadic patients from
northern Germany and in members of affected families from central Europe suggest
the existence of a founder mutation underlying focal dystonia in this
population. To evaluate the role of these loci in focal dystonia, we tested 85
patients from northern Germany who had primary focal dystonia, both for the GAG
deletion in the DYT1 gene on chromosome 9q34 and for linkage disequilibrium at
the chromosome 18p markers D18S1105, D18S1098, D18S481, and D18S54. None of
these patients had the GAG deletion in the DYT1 gene. Furthermore,
Hardy-Weinberg analysis of markers on 18p in our patient population and in 85
control subjects from the same region did not support linkage disequilibrium.
Taken together, these results suggest that most cases of focal dystonia in
patients of northern German or central European origin are due neither to the
GAG deletion in DYT1 nor to a proposed founder mutation on chromosome 18p but
must be caused by other genetic or environmental factors.
Eidelberg, D., J. R. Moeller, et al. (1998).
"Functional brain networks in DYT1 dystonia." Ann Neurol44(3):
303-12.
Early-onset idiopathic torsion dystonia (ITD) is an autosomal
dominant hyperkinetic movement disorder with incomplete penetrance, associated
with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine
the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7
nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with
[18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1
dystonia is mediated by the expression of two independent regional metabolic
covariance patterns. The first pattern, identified in an analysis of
nonmanifesting gene carriers was designated movement free (MF). This abnormal
pattern was characterized by increased metabolic activity in the lentiform
nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in
DYT1 carriers with and without clinical manifestations and persisted in DYT1
dystonia patients in whom involuntary movements were suppressed by sleep. The
second pattern, identified in an analysis of affected gene carriers with
sustained contractions at rest, was designated movement related (MR). This
pattern was characterized by increased metabolic activity in the midbrain,
cerebellum, and thalamus. The expression of the MR pattern was increased in
waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who
were unaffected or who had dystonia only on action, as well as normal controls.
MR subject scores declined significantly with sleep in affected DYT1 patients
but not in normal controls. These findings indicate the penetrance of the DYT1
gene is considerably greater than previously assumed. ITD is mediated through
the interaction of functional brain networks relating separately to gene status
and to abnormal movement.
Eidelberg, D. (1998). "Abnormal brain networks
in DYT1 dystonia." Adv Neurol78: 127-33.
Brice, A. (1998). "[Genetics of extrapyramidal
diseases]." Rev Neurol (Paris)154(11): 739-42.
Bressman, S. B. (1998). "Dystonia." Curr Opin
Neurol11(4): 363-72.
Many different disorders have dystonia as the only or primary
sign. The list of causes for dystonia increases yearly and now includes three
mapped loci for primary torsion dystonia, although other susceptibility genes
are suspected. Study of one of these primary torsion dystonia loci (DYT1) has
culminated in the cloning of a gene which codes for a novel protein, torsin A.
Physiological and positron emission tomography analyses suggest that dystonia
results from impaired inhibition at cortical and subcortical levels; these
physiological changes may in turn be due to striatal dysfunction and a mismatch
or imbalance between the direct and indirect pathways. Future study of normal
and mutant torsin A, as well as the identification of other primary torsion
dystonia genes, should help elucidate the mechanisms underlying dystonia.
Bressman, S. B., D. de Leon, et al. (1998). "The
role of the DYT1 gene in secondary dystonia." Adv Neurol78:
107-15.
Bird, T. D. (1998). "Penetrating observations of
dystonia." Ann Neurol44(3): 299-300.
Augood, S. J., J. B. Penney, Jr., et al. (1998).
"Expression of the early-onset torsion dystonia gene (DYT1) in human brain."
Ann Neurol43(5): 669-73.
Early-onset torsion dystonia, an autosomal dominant disease
associated with the DYT1 locus on 9q34, is the most frequent genetic form of
dystonia. Recent work has revealed that the causative mutation in most cases is
deletion of a glutamate residue from the carboxy terminal of torsinA, a 332
amino acid protein encoded by the DYT1 gene. To gain insight into how deletion
of a single amino acid can produce such a profound movement disorder, we have
mapped the expression of the DYT1 gene in normal human postmortem brain. DYT1
mRNA is highly enriched in the dopamine neurons of the substantia nigra pars
compacta. Intense expression was also found in the cerebellum and hippocampal
subfields. The prominent expression of the DYT1 gene within the substantia nigra
pars compacta, which provides dopaminergic innervation to the basal ganglia,
implicates a disturbance of dopaminergic function in the pathophysiology of
early-onset torsion dystonia.
