Abstract
Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed.
Highlights
Spinocerebellar ataxias (SCAs) are autosomal dominant inherited ataxias, which constitute a heterogeneous group of typically late-onset, progressive, and often fatal neurodegenerative disorders, characterized by progressive cerebellar dysfunction, variably associated with other symptoms of the central and peripheral nervous systems [1,2,3]
The availability of a molecular test has allowed a thorough identification of cases, changing the initial geographic distribution pattern of Machado-Joseph Disease (MJD), initially thought to be related with the Portuguese discoveries and currently known to be present in many ethnic backgrounds [12], with strong geographic variation
Flores Island, while GGC was found in the families from São Miguel Island. These results indicated that two distinct mutational events accounted for the presence of MJD in the Azorean Islands and in families of Azorean extraction, a fact previously evidenced by studies based on the genealogical reconstruction of affected families [95,96]
Summary
Spinocerebellar ataxias (SCAs) are autosomal dominant inherited ataxias, which constitute a heterogeneous group of typically late-onset, progressive, and often fatal neurodegenerative disorders, characterized by progressive cerebellar dysfunction, variably associated with other symptoms of the central and peripheral nervous systems [1,2,3]. The identification of MJD’s causative gene allowed the direct detection of the mutation, enabling the molecular diagnosis of the disease [101] It allowed worldwide molecular studies about MJD, leading, as previously referred, to a distribution of cases that was clearly different from the initial scenario, obtained exclusively by clinical criteria [113]. The first problem was the occurrence of intermediate size alleles, for which it is still not possible to determine whether they are associated with a phenotype or not [32] To minimize this constrain, clinical and molecular analysis, including the determination of CAG repeat length and the establishment of intragenic haplotypes, of large pedigrees of the affected families, is essential. Much is still needed to transpose those allelespecific silencing strategies to effective treatment of patients, but good perspectives are foreseen in the future
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