The Pathogenesis of Machado Joseph Disease: A High Manganese/Low Magnesium Initiated CAG Expansion Mutation in Susceptible Genotypes?

Abstract

The origin of the progressive spinocerebellar ataxic disorder 'Machado Joseph Disease (MJD)' has been attributed solely to an expansion mutation resulting from an autosomal dominant inheritance of an unstable CAG repeat in chromosome 14q32.1 of the MJD gene that encodes for the synthesis of ataxin 3. The faulty gene has purportedly been disseminated since the Middle Ages into Azorean, Dutch and Makassan communities by an international trading community based in NE-central Portugal. However, following improvements in MJD surveillance, the MJD afflicted families that have been identified in increasing numbers of familial clusters of MJD being discovered around the world--e.g. in Aboriginal, Yemenite, Asian and Japanese populations--cannot be connected back to the original Portuguese founder families, but rather implicates an environmental factor, superimposed on a genetic flaw. An analytical study of the isolated ecosystems supporting both the Portuguese and non-Portuguese MJD affected communities demonstrates a common abnormal hallmark of high manganese (Mn)/low magnesium (Mg) status, suggesting that this aberrant mineral ratio inactivates the Mn/Mg catalyzed endonuclease 1 enzyme in the biosystems of those who are dependent upon these ecosystems. Endonuclease activity is crucial for protecting against the expansion/contraction of the trinucleotide repeats in the genes that encode for proteins such as Ataxin 3--the 'mutant' chaperone protein that hallmarks the central nervous system (CNS) of MJD sufferers. It is proposed that MJD, and possibly the other more common expansion mutation diseases such as Friedrich's Ataxia and Huntingdon's Chorea, are multifactorial diseases caused by a hitherto unrecognised autosomal dominant inherited failure to regulate Mn/Mg metabolism in populations living in high Mn/low Mg ecosystems. Mg supplementation of the 'at risk' populations during the 'in utero' developmental stages could be all that is required to maintain healthy endonuclease turnover, thereby protecting MJD susceptible genotypes against this fatal, progressive neurodegenerative disease.

A Comprehensive Review of Spinocerebellar Ataxia Type 2 in Cuba

“…The endogamous and closed cycle marriages of Holguin people living during the XVII century, in combination with putative restricted environmental factors, limited the SCA2 to this province [8]. A similar explanatory mechanism has been proposed for SCA3 founders in Azoreans [25].…”

Trace Elements in Volcanic Environments and Human Health Effects

“…Mn toxicity affects the central nervous system and can cause tremors, muscle spasms, tinnitus, and hearing loss [101,102]. Mn toxicity can also cause "manganism," a neurodegenerative disease with symptoms that resemble Parkinson's disease [104] and "Machado Joseph Disease (MJD)," a progressive spinocerebellar ataxic disorder [105].…”

“…The most noteworthy aspect of the Mn concentration in the volcanic soils of São Miguel island is that all the volcanic regions have concentrations above the estimated background mean of the European soils (524 mg/kg) [24] and that in most grazing sites the measured concentrations were higher than 900 mg/kg (upper limit threshold) [Linhares et al (unpublished data)]. Considering that high concentrations of Mn can be associated with the Machado Joseph disease [105,108], this scenario undertakes a singular meaning in the Azorean context. There are two major ancestral origins: (1) a worldwide-spread haplotype, TTACAC or the Joseph lineage, and (2) a more recent one, GTGGCA or the Machado lineage, seen mostly in Portuguese people [109,110], being associated with families with MJD from the Portuguese Azorean islands of Flores and São Miguel (respectively, the birthplace of the Joseph and the Machado kindreds).…”

“…In 2004, Purdey [105] established a common abnormal hallmark of high manganese (Mn)/low magnesium (Mg) status and suggested that this aberrant mineral ratio inactivates the Mn/Mg catalyzed endonuclease-1 enzyme. The high Mn/low Mg rate observed in all volcanic regions of São Miguel Island reinforces the need for further studies in these elements as they are intimately related to MJD.…”

Arab gene geography: From population diversities to personalized medical genomics

“…27 On the contrary, some other disorders from the region have possibly spread out to geographically distant locations under this Portuguese influence as demonstrated in the increasing evidence noted with regard to the world distribution of Machado-Joseph disease. 70,71 During the 13 th -19 th centuries CE, Ottomans controlled much of the lands surrounding the Mediterranean then expanded their influence to cover all the Arabian Peninsula and further contributed to the enrichment of the genetic pool in the region. 72 After the 19 th century, areas of the Maghreb were colonized by France, Spain and Italy while the Levant, Egypt, and the Arabian Peninsula where colonized by France and England.…”