Caring for Machado-Joseph disease: current understanding and how to help patients

Abstract

Machado-Joseph disease or spinocerebellar ataxia 3 (MJD/SCA3) is a clinically heterogeneous, neurodegenerative disorder characterized by varying degrees of ataxia, ophthalmoplegia, peripheral neuropathy, pyramidal dysfunction and movement disorder. MJD/SCA3 is caused by a CAG repeat expansion mutation in the protein coding region of the ATXN3 gene located at chromosome 14q32.1. Current hypotheses regarding pathogenesis favor the view that mutated ataxin-3, with its polyglutamine expansion, is prone to adopt an abnormal conformation, engage in altered protein-protein interactions and aggregate. Expanded CAG repeat length correlates with the range and severity of the clinical manifestations and inversely correlates with age of disease onset. Though MJD/SCA3 is classically described as affecting the cerebellum, brainstem and basal ganglia, recent neuropathology and neuroimaging series demonstrate involvement of other areas such as the thalamus and cerebral cortex. Clinically, much emphasis has been placed in the description and recognition of the non-motor symptoms observed in these patients, such as pain, cramps, fatigue and depression. Currently, no disease modifying treatment exists for MJD/SCA3. Standard of care includes genetic counseling, exercise/physical therapy programs, and speech and swallow evaluation. Symptomatic treatment for clinical findings such as depression, sleep disorders, parkinsonism, dystonia, cramps, and pain is important to improve the quality of life for those with MJD/SCA3.

Figure 1

Negative inverse correlation between CAG repeat length and age of onset. In this specific sample r= −0.6; p<0.001. Inverse correlation between age of onset and CAG repeat lenght.

Figure 2

MJD patient (age: 54 years; disease duration: 29 years) demonstrates cerebellar and brainstem atrophy. Left: Axial view: atrophy of the cerebellum and cerebellar peduncles. Right: Sagital view: Marked atrophy of the brain stem and cerebellum.