Advances in Our Understanding of Dystonia—Pathophysiology and Treatment Options
Genetic and Molecular Mechanisms Primary Dystonias Early-onset Torsion Dystonia
Early-onset torsion dystonia (DYT1) is a childhood-onset disease with a mean age of onset of 12 years and onset before age 26 years in almost all clinically ascertained cases, although onset up to age 64 years has been reported. It typically first affects a limb and in approximately 65% of patients progresses over 5–10 years to generalized or multifocal dystonia. It does not commonly affect cranial muscles. It is caused by an in-frame GAG deletion in exon 5 of the DYT1 (TOR1A) gene, which results in the loss of a glutamic acid residue in the C-terminal region of the protein. The mutation is inherited in an autosomal dominant pattern with reduced penetrance of approximately 30%. The reason for reduced penetrance is not known, but it is likely a result of both genetic and environmental factors. Risch et al. identified the first evidence of an intragenic modifier of DYT1 dystonia penetrance, demonstrating a protective effect of the 216H allele in trans with the GAG deletion.5
The precise role of TorsinA, the protein encoded by the DYT1 gene, remains unknown. It is a member of the AAA+ family of proteins (ATPases associated with a variety of cellular activities), chaperone proteins that mediate conformational changes in target proteins and perform a variety of cellular functions. TorsinA is widely distributed in the brain, with intense expression in the substantia nigra dopamine neurons, cerebellar Purkinje cells, thalamus, globus pallidus, hippocampus, and cortex.6–10
It is restricted to neurons in the brain and
in the normal state it localizes to the lumen of the endoplasmic reticulum. Current evidence, including studies using DYT1 patient fibroblasts, indicates that mutant torsinA likely leads to dysfunction of the endoplasmic reticulum and nuclear envelope, resulting in abnormalities in nucleo-cytoskeletal connections and/or protein processing through the secretory pathway.11
Early-onset Torsion Dystonia Animal Models Two types of mouse models of DYT1 have been produced: heterozygous knock-in mice, in which the GAG mutation is introduced into the endogenous mouse torsinA gene, and transgenic mice, in which the human mutant torsinA gene is inserted into the mouse genome and over-expressed via genetic promoters. Neither of these models has overt dystonic features, although they both manifest more subtle motor abnormalities, including hyperactivity and deficits in beam walking.12,13 Another transgenic mouse model has impaired motor-learning in a similar fashion to14
non-manifesting carriers.15
motor sequence learning deficits found in DYT1 Mice that are either homozygous knock-in or
knock-out for the mutation die at birth, whereas a knock-down mouse model in which expression of torsinA is reduced has a phenotype similar to the heterozygous knock-in mice.16
This suggests that the
pathogenic deletion produces a loss of function of TorsinA. The loss of function may be the result of a dominant negative effect, in which the mutant protein interferes with the wild-type protein.
DYT6 Dystonia
DYT6 dystonia is characterized by a relatively early but broad age of onset (mean 16 years, range five to 49 years). The body regions first affected include the arm, cranial muscles (larynx, tongue, and facial muscles), and neck. In contrast to DYT1, onset at the leg is uncommon.
US NEUROLOGY
The dystonia usually progresses, but the degree of progression is variable. For most patients with DYT6 dystonia, disability is due to cranial and cervical dystonia, including significant speech difficulties. As in DYT1, DYT6 is inherited in an autosomal dominant pattern with reduced penetrance. The DYT6 gene, THAP1, is the most recently identified dystonia gene.17
The initial report was of two mutations in the
THAP1 gene causing DYT6 dystonia in five families. Subsequent genetic screening studies in families with early-onset, non-DYT1, non-focal primary dystonia identified 11 additional THAP1 mutations in families of diverse ancestries, suggesting that mutations in THAP1 may underlie a substantial proportion of dystonia in early-onset non-DYT1 families, particularly in those with affected cranial muscles.18,19
The
THAP1 protein is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes. Mutated THAP1 may disrupt DNA binding, resulting in transcriptional dysregulation, although how this disrupts brain function leading to dystonia remains unknown. Determining the specific pathogenic mechanisms of THAP1 mutations and their import in other dystonia populations are important future research goals.
Dystonia Plus Syndromes Dopa-responsive Dystonia
The classic form of dopa-responsive dystonia (DRD/DYT5) is an early-onset dystonia presenting in childhood (five to six years of age) with dystonia of the lower extremities, and a diurnal pattern to the symptoms. Arm dystonia, hyperreflexia, and parkinsonism are other common features. The hallmark feature of this disorder is a dramatic and sustained resolution of dystonia symptoms in response to low-dose levodopa therapy. The autosomal dominant form of DRD is caused by mutations in the GCH1 gene. GCH1 is required for the synthesis of tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme in dopamine synthesis. Penetrance is incomplete and is gender related, with females manifesting dystonia two to four times more frequently than males.20
Over 100 different GCH1
mutations have been identified,21 but GCH1 mutations are not found in approximately 25% of patients with DRD.22
Recessive genetic causes
account for some of the mutation negative cases, but a small proportion of DRD cases remain unexplained.22
There are several autosomal recessive forms of DRD to be found, which are due to varying mutations in genes encoding other enzymes involved in dopamine synthesis, including tyrosine hydroxylase (TH),23
6-pyruvoyltetrahydropterin synthase (6-PTPS),24 reductase.25 and sepiapterin Typically, the clinical picture in these conditions is different
from GCH1 DRD, with infantile-onset severe neurologic symptoms, including hypotonia, severe bradykinesia, drooling, ptosis, miosis, oculogyria, cognitive impairment, and seizures.22
Another important
autosomal recessive cause of the DRD phenotype are mutations in the ‘juvenile’ parkinsonism parkin gene.22,26,27
Generally the presence of early
prominent parkinsonism and severe dyskinesias favors parkin mutations. Myoclonus Dystonia
Myoclonus dystonia (MD) (DYT11 and DYT15) is characterized by prominent early-onset myoclonus with or without dystonia. Symptom onset is typically in the first or second decade, and symptoms tend to plateau in adulthood. The neck and arms are the most commonly
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