Dystonia, Juvenile-Onset

A number sign (#) is used with this entry because of evidence that juvenile-onset dystonia (DJO) is caused by heterozygous mutation in the beta-actin gene (ACTB; 102630) on chromosome 7p22. One such family has been reported.

Clinical Features

Gearing et al. (2002) reported the cases of male twins with the onset at age 12 years of rapidly progressive, dopa-unresponsive generalized dystonia. They found extensive neurologic involvement of the cortex and basal ganglia of a novel type suggesting that these identical twins suffered from a degenerative disorder not previously characterized. The dystonic manifestations in adolescence were heralded by early bulbar signs that suggested a widespread disorder. The twins were born with cleft lip and palate requiring multiple repairs. They were small for age, and their limbs were small in relation to the rest of their bodies. Skeletal abnormalities included high foreheads, hypoplastic scapulas, and externally rotated hips. By age 10 years, they began developing kyphoscoliosis and severe antecolis. Achalasia presented at age 2 years, requiring surgical repair in 1 twin. One twin developed spontaneous cataracts, aggravated later by trauma; by age 10 years, he was blind in 1 eye and had limited vision in the other. Vision in the other twin was not affected. Sensorineural hearing loss in both twins resulted in functional deafness by age 4 years, significantly affecting their speech development. Cognition was mildly subnormal but stable until the last few years. Genetic, metabolic, and imaging studies ruled out known causes of dystonia. Death occurred at ages 21 and 22 years.

Neuropathologic Findings

The brains of the twins reported by Gearing et al. (2002) were macroscopically unremarkable. The most striking findings on microscopic examination were (1) eosinophilic, rod-like cytoplasmic inclusions in neocortical and thalamic neurons that were actin depolymerizing factor/cofilin-immunoreactive but only rarely actin-positive; and (2) abundant eosinophilic spherical structures in the striatum that were strongly actin- and actin depolarizing factor/cofilin-positive. Gearing et al. (2002) stated that aggregation of actin had not previously been reported as the predominant feature in any neurodegenerative disease. They suggested that this neuropathologic change associated with dystonia may represent a new degenerative mechanism involving actin. Since actin is a ubiquitous constituent of the cytoskeletal system the presence of congenital anomalies and developmental abnormalities may be explained by systemic involvement.

Molecular Genetics

In the monozygotic twins reported by Gearing et al. (2002), Procaccio et al. (2006) identified a heterozygous missense mutation, arg183 to trp (102630.0001), in the beta-actin gene as the cause of the neurologic syndrome.