Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3, is characterized by remarkable clinical heterogeneity. We present a MJD family in which variable phenotypes were noted in affected members, including one presenting predominantly with spastic paraparesis. A review of the literature revealed that MJD with the initial presentation of spastic paraparesis is more frequently observed in cases of eastern Asian origin who carry a greater CAG expansions in the ATXN3 gene. A greatly expanded allele in ATXN3 combined with an eastern Asian genetic background is associated with a phenotype of spastic paraparesis in MJD.

A young Chinese male patient was identified as homozygous for Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3. This patient had a 4-year medical history mainly presenting severe ataxia, abnormal eye movement and pyramidal signs. Magnetic resonance imaging of the brain and cervical spinal cord revealed no obvious abnormality despite the severe symptoms and the findings of an electromyogram. However, brainstem auditory evoked potential indicated peripheral impairment and visual evoked potential indicated central impairment of his visual pathways. Molecular diagnosis revealed the pattern of CAG repeat units of this patient was 71/71. This case demonstrates that homozygosity for MJD enhances the clinical severity of the disease, which suggests that genetic education is of great importance.

BACKGROUND: Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson\'s disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNA(Gln) T4336C).
METHODS: Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients.
CONCLUSIONS: The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD.

Polyglutamine (polyQ) diseases are a group of nine neurodegenerative disorders caused by an unstable CAG expansion in the codifying region of their respective associated genes. However, each polyQ disease displays a different symptomatic and pathoanatomic profile and the proteins involved share no homology outside the polyQ tract. This suggests that the other regions of the proteins and the cellular functions they mediate are important in defining disease progression and specificity. Machado-Joseph disease (MJD), the most common form of spinocerebellar ataxia worldwide, is a progressive and ultimately fatal neurodegenerative disorder caused by polyQ expansion in ataxin-3 (atx3), a conserved and ubiquitous protein known to bind polyubiquitin chains and to function as a deubiquitinating enzyme. Atx3 has been linked to protein homeostasis maintenance, transcription, cytoskeleton regulation and myogenesis, but its precise biologic function remains a mystery, limiting the understanding of the mechanisms by which the mutated protein leads to the selective neuronal death profile observed in MJD patients. A number of recent evidence support the idea that the toxic entities behind neuronal demise may be either the dysfunctional expanded atx3 or the soluble amyloid-like oligomers formed by self-assembly of the aggregation-prone mutated protein. Expanded atx3 pathogenicity is likely the result of a series of events implicating both atx3 dysfunction and aggregation, possibly involving both full-length atx3 and polyQ-containing fragments that may act as seeds for protein aggregation. A deeper understanding of polyQ protein biology, the way the expansion alters their features, and the consequences of these changes for cell functioning and survival are sure to be of critical importance for developing future treatment of polyQ diseases.

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We report a 61-year-old woman with Machado-Joseph disease (MJD) presenting with pure cerebellar ataxia. The patient exhibited an unsteady gait at the age of 51 years. She was admitted to our hospital at the age of 61 years. Her older brother had been diagnosed as having spinocerebellar degeneration (SCD). Our patient showed gaze-evoked nystagmus, wide-based gait, slight lack of coordination of the four extremities, mildly ataxic speech and slight decrease in the bilateral Achilles tendon reflexes. Babinski\'s sign was absent. Sensory impairments were not present and muscle tone and muscle strength were normal. There was no autonomic dysfunctions. MRI revealed moderate atrophy of the cerebellum and pons. We performed gene analysis of SCD using white blood cells from the patient, and the analysis showed 70 CAG repeats in the MJD1 gene, which is an abnormally high number of repeats. Compared with three reported cases of MJD presenting pure cerebellar ataxia, only our patient showed a nasal voice. The number of CAG repeats in the MJD1 gene of our patients was the most prolonged of the four cases. MJD should be considered in patients with familial SCD even if their neurological signs and symptoms outside the cerebellum are not obvious.