LAUSR

We read with interest the recent report of Garg et al on familial hypermanganesemia. They reported 27 cases of hypermanganesemia with mutations in SLC30A10 and SLC39A14. In this regard, we wish to present and compare our similar cases, which are the first series from Iran. Familial hypermanganesemia is a recessive disorder of manganese metabolism, secondary to three known genetic transportopathies (SLC39A8, SLC301A10, and SLC39A14). Three cases in our series had a mutation in SLC30A10 and two, had a mutation in SLC39A14. The core feature in cases with SLC30A10 mutation was dystonia, splenomegaly, and polycythemia, whereas with SLC39A14 psychomotor retardation, spasticity, and dystonia were the main clinical manifestations (Table 1 and Videos 1–3). Our cases with SLC30A10 mutation were older at presentation (mean age, 11.3 years [vs. 5.5 in Indian cases]) than the patients with SLC39A14 (1.5 years [vs. 2.3 in the Indian cases]). Magnetic resonance imaging (MRI) findings play an important role in the diagnosis of hypermanganesemia. Brain MRI features in both groups of our patients were similar comprising hyperintensity of globus pallidus, putamen, caudate, substantia nigra, subthalamic, and dentate nuclei on T1 weighted sequences. (Fig. S1). Blood manganese concentration was elevated in all our cases. Affected cases with SLC30A10 mutation have usually polycythemia and it serves as an early disease marker; it may exist before neurological symptoms. Therefore, polycythemia and depleted iron stores should prompt SLC30A10 analysis; these features have not been observed in cases of environmental manganese toxicity. In contrast, individuals with SLC39A14 mutation do not develop polycythemia or abnormal liver tests. The diagnosis is suggested by characteristic clinical features, brain MRI findings, elevated blood manganese, and confirmed by the identification of SCL30A10 or SCL39A14 mutations. Patients 3 to 5 carried the same mutation in the SCL30A10 gene. They came from a province in southeastern Iran, Sistan-Baluchestan. This mutation has already been reported in three Pakistani siblings and in one of the Indian cases, F5. Although very similar to our case, the F5 case had parkinsonism, normal liver function tests, and manganese level, which were unlike our three patients. Because of the proximity of Sistan-Baluchestan to Pakistan (which is India’s neighbor and was part of it decades ago), it is suggested that c.1006C > T may be a founder mutation in this area. Patient two had a mutation similar to one of the patients in the Indian series, F13. The clinical features of F13 were generalized dystonia and brisk reflexes, whereas our patient had dystonia in limbs, psychomotor retardation, and axial hypotonia. Treatment with intravenous ethylenediaminetetraacetic acid increases the urinary excretion of manganese, can ameliorate neurologic symptoms, and stabilize blood manganese levels and liver disease. We started this treatment in all our cases with some improvement and stabilization of the disease course. In conclusion, hypermanganesemia is a treatable inherited metal deposition syndrome. Early diagnosis and treatment may improve the symptoms and prevent their progression.