Dystonia

Characterize dopa-responsive dystonia and name the associated mutations

(AKA DYT5 dystonia). Presents as a generalized dystonia in early childhood, sometimes with a diurnal variation with reduced symptom severity in the morning and progression throughout the day. Sometimes associated with parkinsonian features such as bradykinesia or rigidity. This is the ONE dystonia responsive to therapy with L-dopa. Often misdiagnosed as cerebral palsy. Two genetic causes: autosomal dominant mutation in GTP cyclohydrolase gene (co-factor for tyrosine hydroxylase in DA synthesis)--most common; autosomal recessive mutation in tyrosine hydroxylase gene itself--less common

Define dystonia

A movement disorder with co-contraction of agonist and antagonist muscles resulting in abnormal postures or twisting movements.

What is the most recent model for the pathophysiology of dystonia?

Alteration in the pattern of pallidal-thalamic activities during voluntary movement and abnormal sensory feedback lead to an increase in abnormally synchronous cortical output and thus co-contraction of multiple muscle groups or overactivation of intended muscle groups. In addition, abnormal thalamic activity synchronizes the intended movement as well as unwanted overflow movements in other muscles.

What are the primary pharmacological therapies for dystonia?

Anticholinergics (in high doses), benzodiazepines, baclofen, and tetrabenazine (dopamine-depleting) have had moderate success. Dopa-responsive dystonia (DYT5) is treated with L-dopa. Botulinum toxin is the mainstay of dystonia therapy, whereby it is injected directly into the affected muscles (injections repeated every 3-6 mos., with occasional development of resistance).

List the common focal dystonias

Cervical dystonia (which can include torticollis, anterocollis, retrocollis, laterocollis, or combinations of these movements; may also involve dystonic tremor), blepharospasm, oromandibular dystonia, laryngeal dystonia, and task-specific dystonias.

Compare and contrast childhood-onset dystonia with adult-onset primary dystonia

Childhood-onset dystonia often begins in the lower body and becomes generalized. It is commonly inherited. Adult-onset dystonia often begins as a focal dystonia of the neck or face and can become segmental or mutifocal, but rarely does it generalize. It is commonly sporadic.

What are the surgical therapies for dystonia?

DBS is useful when all other therapies have failed. Unlike with tremor, the electrodes are implanted in the GPi (rather than the thalamus). In further contrast to DBS for tremor, the beneficial effects generally take weeks to manifest.

Characterize secondary dystonia

Dystonia associated with an underlying degenerative disease, lesion, or insult. Examples include stroke, encephalitis, head trauma, toxins, Huntington's disease, Wilson's disease, and PD.

Characterize primary dystonia

Dystonic muscle contractions are the only abnormal finding. No underlying degenerative lesions and no other exogenous causes. If childhood onset, dystonia often begins in the lower body and later becomes generalized--commonly inherited. If adult onset, dystonia often begins as focal dystonia of the neck or face and can become segmental or multi-focal (but rarely generalized)--commonly sporadic.

Describe the pathophysiology of primary dystonias

No clear neurodegenerative processes. Abnormalities are likely subtle mechanistic changes in neuronal signaling and communication. Basal ganglia implicated, with some evidence of reduced output from the GPi, although this is contradicted by symptom improvement following GPi lesioning. Also evidence of cortical dysfunction and abnormal sensory afferent processing.

Define Meige's syndrome

Simultaneous presentation of blepharospasm (dystonic contractions of the peri-ocular muscles) and oromandibular dystonia (contractions of jaw, mouth, or lower face).

Describe DYT1 dystonia

The DYT1 mutation is the most common mutation causing primary dystonia; it is a CAG mutation in the torsin A gene on chromosome 9 (function unknown, although similar in structure to AAA+ ATPases that are molecular chaperones). Torsin A is highly concentrated in SNpc neurons. DYT1 dystonia presents in childhood and generally fits the childhood-onset dystonia model (lower limb dystonia-->generalized). Autosomal dominant inheritance, like most other genetic dystonias.