Machado-Joseph disease, also known as spinocerebellar ataxia 3, is a progressive, degenerative nervous system disorder affecting the cerebellum, brain stem, basal ganglia, thalamus and cerebral cortex. It is characterized by varying degrees of motor and non-motor symptoms and is caused by a mutation in the ATXN3 gene located on chromosome 14.
Machado-Joseph disease, also known as spinocerebellar ataxia 3, (MJD/SCA3) is a rare disease characterized by varied phenotypic features and progressive neurodegeneration. It is caused by a trinucleotide repeat expansion (CAG) related to the mutation in the ATXN3 gene located at chromosome 14q32.1 . Clinical presentation consists of motor, as well as, non-motor manifestations. Motor manifestations are noticed initially between the age of 30 and 40 years and they include cerebellar ataxia, gait instability, incoordination of limb movements, and intentional tremor . Spasticity is a common feature with lower limbs being more frequently affected . Later, other motor problems like dysphagia, dysarthria, and truncal ataxia start to develop. Diplopia is a common ocular complaint . Dystonia and parkinsonism are two movement disorders which are frequently noticed in MJD/SCA3 along with peripheral neuropathy, tactile and proprioceptive hypoesthesia   . Non-motor manifestations include chronic pain, cramps, fatigue, sleep disorders, and depression, while autonomic symptoms like nocturia, urinary incontinence, cold intolerance and hypohidrosis may also be present . A majority of MJD/SCA3 patients have excessive daytime sleepiness with impaired nocturnal sleep , insomnia , and restless legs syndrome. Sleep disorders are seen more frequently in older adults with a long-standing disease. About half of the patients complain of chronic pain, especially in the lumbar region . Minor cognitive and behavioral difficulties, but not frank dementia, are noticed in MJD/SCA3 patients .
Three types of MJD/SCA3 have been identified with onset and severity being their differentiating features:
Clinical presentation of MJD/SCA3 resembles other neurologic disorders like Parkinson's disease and multiple sclerosis. Therefore diagnosis based on clinical features, family history, and genetic testing, requires an experienced neurologist for interpretation. A family history of neurological disorders should be inquired about during the preliminary interview. Predictive genetic testing in the absence of symptoms can be performed in suspected cases with a positive family history . During the physical examination, gaze-evoked nystagmus, abnormal saccades, decreased smooth pursuit gain, impaired vestibulo-ocular reflex, and supranuclear vertical gaze palsy may be noticed . Lid retraction and decreased blinking may lead to the appearance of “bulging eyes" which is characteristic of MJD/SCA3 . The diagnostic test to detect MJD/SCA3 is the direct determination of the number of abnormal CAG triplets in the DNA of affected patients using genetic testing which is available in specialized laboratories.
Neuroimaging studies like magnetic resonance imaging (MRI) help to demonstrate the extent of neural degeneration. MRI may be normal in the early stages of MJD/SCA3 but typical findings include brainstem and cerebellar atrophy . Single-photon emission computed tomography (SPECT) studies of the brain have shown poor perfusion in the parietal lobes, inferior portion of the frontal lobes, medial and lateral portions of the temporal lobes, basal ganglia, and cerebellar hemispheres and vermis . Magnetic resonance spectroscopy (MRS) of the deep white matter has demonstrated changes indicative of axonal dysfunction, although MRI in the same study did not reveal any abnormalities .