A new treatable genetic disorder of manganese metabolism causing dystonia‐parkinsonism and cirrhosis: The “New” Wilson's disease?

Manganese (Mn) intoxication (manganism) causing dystoniaparkinsonism, often accompanied by psychiatric features, has been described in relation to several etiologies: Mn environmental overexposure, for example, in miners; in chronic liver disease from the failure of manganese hepatic clearance; in individuals receiving parenteral nutrition; and in drug addicts exposed to ephedrine-containing potassium permanganate. However, an autosomal-recessive dystonic syndrome from hypermanganesemia has been previously recognized, where the above-mentioned causes have been excluded, suggesting a genetic disorder of Mn metabolism. Recently, 2 independent reports published in the American Journal of Human Genetics described that homozygous mutations in the SLC30A10 gene, on chromosome 1q41– q42, which encodes for a Mn transporter, are responsible for a syndrome of dystonia-parkinsonism, hypermanganesemia, cirrhosis, and polycythemia. The authors carried out homozygosity mapping and functional studies in 10 families, and the 20 affected members were found to have mutations in the SLC30A10 gene. In 8 families, the 17 affected members presented with young-onset (2–14 years) generalized dystonia, whereas in 1 family, the affected member had paraparesis and no dystonia. Interestingly, in 1 family from Italy the 2 affected members presented with late-onset (ages 47 and 57 years) asymmetric parkinsonism and early postural instability. This exciting discovery is clinically important for a number of reasons. First, this disorder is potentially treatable, and therefore the diagnosis should not be missed. Treatment with chelation therapy (calcium sodium edetate and oral iron) can prevent the fatal consequences of cirrhosis but also alleviates disability, as several patients had become wheelchair bound when untreated and improved considerably after treatment. Thus, this disorder, along with Wilson’s disease, is the only potentially treatable inherited metal storage disorder described to date. Second, it would be interesting to investigate patients with manganism attributed to other causes, for mutations or polymorphisms in this gene that may explain why some individuals may be more prone to developing manganism than others when overexposed to Mn. Additional individuals and families need to be investigated.