Manganese transport disorder: Novel SLC30A10 mutations and early phenotypes

Abstract

Our findings expand the mutational and clinical spectra of this recently recognized disorder. An early diagnosis is warranted, because treatment with manganese-chelating agents, iron supplementation, or their combination might improve symptoms and prevent progression of this otherwise potentially fatal disease. © 2015 International Parkinson and Movement Disorder Society.

Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

“…Based on these preliminary data, we consider Mn concentrations lower than 0.3 mM and higher than 1 mM to be relatively low and relatively high, respectively. Importantly, embryos exposed to 1 mM MnCl 2 developed dark-colored brain and liver tissues (S1B and S1C Fig), suggesting that these two organs are sensitive to Mn exposure in zebrafish just like humans [22,23,26]. …”

“…Patients with HMDPC develop a wide range of liver complications, including steatosis, hepatomegaly, hepatic fibrosis, and—ultimately—cirrhosis [23,26]. We therefore examined whether our mutant zebrafish develop a similar hepatic phenotype.…”

“…Specifically, autosomal recessive mutations in the SLC30A10 gene, which encodes a key Mn exporter [21], have been linked to HMDPC [22–24]. To date, 28 affected individuals in 14 families have been described [25,26]. The majority of these 28 patients presented with dystonia (25 patients) or spastic paraparesis (one patient); the remaining two patients developed late-onset parkinsonism [26].…”

“…To date, 28 affected individuals in 14 families have been described [25,26]. The majority of these 28 patients presented with dystonia (25 patients) or spastic paraparesis (one patient); the remaining two patients developed late-onset parkinsonism [26]. However, the mechanism by which SLC30A10 contributes to Mn homeostasis, and the underlying pathological processes associated with SLC30A10 mutations, are unknown.…”

“…Although chelation therapy improves the neurological symptoms, reduces serum Mn accumulation, and prevents further hepatic pathology [18,28], it has the disadvantage of requiring strict monitoring of other essential minerals, including zinc, copper, and selenium [22]. Moreover, intravenous EDTA-CaNa 2 and close patient monitoring are generally not available in most regions with inadequate medical resources [26]. Chelation therapy also requires lifelong treatments of at least two 5-day courses per month, and once treatment has begun, reducing and/or stopping treatment can cause the patient’s condition to worsen [29].…”