A genetic form of severe hypermanganesemia secondary to SLC30A10 mutation has been recently identified [
8]. We reported the clinical course, brain MRI findings, and treatment response of a patient with dystonia, polycythemia, and hypermanganesemia due to this homozygous mutation. This variant is not a novel one and was previously reported by Tuschl et al. [
5] with a CADD score of 28.8. It is not reported in gnomAD (neither homozygous nor heterozygote state) but has been reported once in a heterozygous state in the ExAC database. The protein encoded by SLC30A10 is a significant Mn efflux transporter localized in the cell membrane that decreases cellular Mn levels and protects tissues against its toxicity [
9]. It is highly expressed in the liver, as an important organ in the manganese homeostasis. Liver disease develops with a variable intensity and presents as hepatomegaly, increased serum transaminases, direct hyperbilirubinemia, and cirrhosis. However, it is not pathognomonic of the SLC30A10 mutation syndrome and pure neurological symptoms without hepatic manifestations have been reported [
10]. A recent study showed that severity and age of onset of either neurological or hepatic dysfunction varied even among the same family members [
7]. Mukhitar et al. reported liver dysfunction only in one of the three siblings with SLC30A10 mutation [
3]. Quadri et al. also reported three affected siblings of whom two with severe dystonia did not have hepatic dysfunction while their sister with minor neurological symptoms died due to hepatic involvement [
10]. We did not find any evidence of hepatic involvement in the proband from the disease onset through the following period. The SLC30A10 carrier protein is also highly expressed in the brain, especially in the basal ganglia, where it prevents the neurotoxic effects of manganese excess. The toxic effects of hypermanganesemia are severe and result in cumulative and chronic brain damage [
4]. According to several studies, the most common neurological manifestation of hypermanganesemia is dystonic movement disorder. Tuschl et al. found that most affected individuals, particularly those affected in childhood, had walking difficulties and fine motor impairment due to dystonia [
5]. We found rigidity and dystonia in our patient that resulted in walking difficulties and an unstable high stepping gait, Fine motor dysfunction led to a bad handwriting and dysdiadochokinesis, and tongue dystonia resulted in dysarthria. Gospe et al. reported spastic paraparesis in one patient [
11]. Although cognitive defects and psychological symptoms have been shown in patients with acquired hypermanganesemia [
12], they have not yet been reported in SLC30A10 mutations. Several studies have found that these patients have typical brain MRI findings including symmetric hyperintensities of the basal ganglia and dentate nucleuses on T1- weighted and normal appearance or milder changes as related hypointensities on T2-weighted images [
3‐
5]. This is in contrast to Wilson disease in which a brain MRI often shows basal ganglia hyperintensities on T2-images due to copper deposition [
7]. Brain MRI findings are identical in both acquired and inherited forms of hypermanganesemia [
3].Other inherited syndromes with metal deposition observed on neuroimaging include brain iron accumulation syndromes that cause specific patterns of iron deposition on T2 images, and syndromes of brain calcium storage that present as hyperdensities on a CT scan [
13]. Several laboratory tests help to diagnose inherited hypermanganesemia and to differentiate it from the acquired type and other inherited metal deposition syndromes. The mean serum Mn level in these patients is above 2000 nmol/L while it is lower than 2000 in acquired hypermanganesemia [
13]. Moreover, polycythemia is a general finding in SLC30A10 mutation which serves as an early disease marker [
7]. It may exist prior to neurological symptoms and hence recurrent phlebotomies are often recommended before making a correct diagnosis [
5,
10]. Mn is known to upregulate erythropoietin gene expression, which could be a probable mechanism [
4]. The mean hemoglobin concentration has been reported at 19 g/dl. A few studies have shown increased erythropoietin levels in some affected individuals [
5,
10,
11]. Polycythemia can be corrected by chelation therapy or iron compounds [
5]. Further findings include low serum ferritin and iron levels and increased TIBC. Iron store depletion is due to competitive inhibition of intestinal iron absorption exerted by Mn. The homeostatic mechanism of iron and Mn is closely related due to the same serum binding and transporter proteins [
7]. Iron discharge from intracellular reserves, increased iron uptake, and reduced iron utilization by hypermanganesemia have been proposed as other mechanisms [
14]. Reduced iron stores or polycythemia are not usual findings in acquired hypermanganesemia [
4]. SLC30A10 variations may be the cause of susceptibility of some individuals to Mn toxicity in overexposure situations [
10].
Lifelong chelation therapy combined with iron supplementation is the treatment of choice that should be started as soon as possible [
3,
5,
15]. Intravenous disodium calcium edetate increases urinary excretion of Mn. Iron compounds prevent further intestinal absorption of Mn and can also improve polycythemia. Continuous treatment with edetate can decrease the serum Mn level and resolve brain MRI changes, bringing liver damage to a stop and causing a relative neurological improvement [
4]. However, patients with acquired hypermanganesemia may show variable responses to this treatment [
13]. The patients left untreated may die from cirrhosis or become severely disabled and wheelchair- bound [
13].Similar to other reports, our patient showed a poor therapeutic response to levodopa. There are different reports of the effects of other chelator agents such as D-penicillamine [
3,
4]. Mukhtiar et al. found beneficial effects in one patient with milder symptoms, while Stamelous et al. did not report any responses to D-penicillamine, which was similar to our case [
3]. There is a need for further investigations. Since the disease manifestations are preventable, it is rational for the siblings of a patient to be assessed either by genetic testing or by regular measurement of serum Mn and hemoglobin levels.
In conclusion, we would like to highlight a syndrome caused by SLC30A10 mutation, which, along with the Wilson disease, is the only treatable inherited metal deposition syndrome. It is noticeable that the patient may only exhibit pure neurological symptoms without hepatic manifestations. Early diagnosis and genetic testing are necessary in children with early onset dystonia and typical MRI findings, especially in association with polycythemia and hypermanganesemia. Early treatment might improve the symptoms and prevent the progression of this potentially fatal disease.