Date Published: June 27, 2013
Publisher: Public Library of Science
Author(s): Aasef G. Shaikh, David S. Zee, Allen S. Mandir, Howard M. Lederman, Thomas O. Crawford, Natasha M. Maurits.
Ataxia-telangiectasia is known for cerebellar degeneration, but clinical descriptions of abnormal tone, posture, and movements suggest involvement of the network between cerebellum and basal ganglia. We quantitatively assessed the nature of upper-limb movement disorders in ataxia-telangiectasia. We used a three-axis accelerometer to assess the natural history and severity of abnormal upper-limb movements in 80 ataxia-telangiectasia and 19 healthy subjects. Recordings were made during goal-directed movements of upper limb (kinetic task), while arms were outstretched (postural task), and at rest. Almost all ataxia-telangiectasia subjects (79/80) had abnormal involuntary movements, such as rhythmic oscillations (tremor), slow drifts (dystonia or athetosis), and isolated rapid movements (dystonic jerks or myoclonus). All patients with involuntary movements had both kinetic and postural tremor, while 48 (61%) also had resting tremor. The tremor was present in transient episodes lasting several seconds during two-minute recording sessions of all three conditions. Percent time during which episodic tremor was present was greater for postural and kinetic tasks compared to rest. Resting tremor had higher frequency but smaller amplitude than postural and kinetic tremor. Rapid non-rhythmic movements were minimal during rest, but were triggered during sustained arm postures and goal directed arm movements suggesting they are best considered a form of dystonic jerks or action myoclonus. Advancing age did not correlate with the severity of involuntary limb movements. Abnormal upper-limb movements in ataxia-telangiectasia feature classic cerebellar impairment, but also suggest involvement of the network between the cerebellum and basal ganglia.
Ataxia-telangiectasia (A–T) is a recessively inherited multi-system disorder with prominent neurodegeneration, immunodeficiency, radiosensitivity, and enhanced risk for lymphoreticular malignancy. Pathological studies in A–T have focused predominantly upon abnormalities of the cerebellar cortex, leading early investigators to identify the disorder as a form of cerebellar ataxia, hence its iconic name . Nonetheless, motor abnormalities of putative extra-cerebellar origin in individuals with A–T have been noted from the earliest case reports , . Some of these features, including resting tremor, suggest dysfunction of the basal ganglia. The pathophysiologic basis of other non-rhythmic adventitious movements, such as dystonia and myoclonus could be cerebellar or extra-cerebellar. This uncertainty about the pathophysiology of abnormal motor control is matched by a paucity of literature that quantifies movement disorders in A–T. Measurement of mixed, hyperkinetic movement disorders in A–T might help us to understand their phenomenology, anatomical substrate, and may assist in development of therapeutics. For example, patients with disorders prominently affecting the basal ganglia benefit from a different treatment strategy than those with substantial cerebellar involvement.
Accelerometer recordings were performed on 80 A–T subjects (36 males and 44 females, age range: 5 to 34 years, mean: 13.8 years, median: 12.1 years) and 19 age-matched control subjects. Figure 1 illustrates an example of one A–T subject holding the arms outstretched against gravity (postural task). Intensity of limb movement (y-axis) is plotted against time (x-axis). The trace qualitatively shows slowly modulated drifts but also two forms of superimposed fast movements (Figure 2A). One is non-rhythmic, isolated, and appeared intermittently (Figure 2B, expanded from region of Figure 2A marked as ‘N’) and the other is rhythmic in clusters and appeared episodically (Figure 2C, expanded from region of Figure 2A marked as ‘R’). The non-rhythmic fast movement qualitatively resembled a dystonic jerk or myoclonus, while the episodic rhythmic movements had the quality of tremor. The video clip S1 depicts an example of both types of movements in a patient with A–T.
Progressive degeneration of the cerebellar Purkinje neurons is the hallmark neuropathology of A–T , . Outside of the cerebellum there is no known consistent pathology, though some animal models of A–T suggest an abnormality of dopaminergic neurons within basal ganglia , . The abnormal movements that we have identified in A–T are characterized by features classically associated with abnormalities in the cerebellum, but also by networks connecting cerebellum and the basal ganglia , , .