Manganese Transport Disorder: Novel SLC30A10 Mutations and Early Phenotypes Marialuisa Quadri, PhD, 1 Mahesh Kamate, MD, DM, 2 Suvasini Sharma, MD, DM, 3 Simone Olgiati, MSc, 1 Josja Graafland, BSc, 1 Guido J. Breedveld, BSc, 1 Indu Kori, MD, 2 Virupaxi Hattiholi, MD, 4 Puneet Jain, MD, DM, 3 Satinder Aneja, MD, 3 Atin Kumar, MD, 5 Parveen Gulati, MD, 6 Medha Goel, MD, 7 Bibek Talukdar, MD, 7 and Vincenzo Bonifati, MD, PhD 1 * 1 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands 2 Department of Paediatrics, KLE University’s Jawaharlal Nehru J N Medical College, Belgaum, India 3 Department of Pedia- trics, Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India 4 Department of Radiology, KLE University’s Jawaharlal Nehru Medical College, Belgaum, India 5 Department of Radiodiagnosis, All India Institute of Medical Scien- ces, New Delhi, India 6 Dr. Gulati Imaging Institute, New Delhi, India 7 Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi, India ABSTRACT Background: SLC30A10 mutations cause an autoso- mal recessive disorder, characterized by hypermanga- nesaemia, polycythemia, early-onset dystonia, paraparesis, or late-onset parkinsonism, and chronic liver disease. This is the first identified inborn error of Mn metabolism in humans, reported in 10 families thus far. Methods: Methods for this study consisted of clinical examination, neuroimaging studies (MRI), serum dos- ages, and SLC30A10 genetic analysis. Results: We describe early disease manifestations (including videos) in 5 previously unreported Indian children, carrying novel homozygous SLC30A10 muta- tions. Gait and speech disturbances, falls, dystonias, and central hypotonia were the presenting neurological features, starting within the first 5 years of life. All chil- dren also had severe hypermanganesemia, polycythe- mia, variable degree of liver disease, and marked brain MRI T1 hyperintensities. Conclusions: 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 pre- vent progression of this otherwise potentially fatal dis- ease. V C 2015 International Parkinson and Movement Disorder Society Key Words: dystonia; genetics; manganese; SLC30A10; metabolic inherited disease The existence of a primary disorder of manganese metabolism in humans was initially suggested by the observation of patients presenting with severe hyper- manganesemia in absence of environmental sources of manganese intoxication as well as in association with polycythemia, liver cirrhosis, and neurological distur- bances, such as dystonia and, in one case, spastic par- aparesis. 1-3 Recently, autosomal-recessive mutations in the SLC30A10 gene have been identified as the disease cause in the above-mentioned and additional patients with similar phenotypes, delineating the first inherited disorder of manganese metabolism. 4,5 The disease is a result of the loss of the function of the protein encoded by SLC30A10, an important and evolutionar- ily conserved manganese transporter. Thus far, 10 families have been reported on, for a total of 20 affected individuals. 4,5 Pathological studies have been reported in one of these. 6 The associated clinical phe- notype is broad and affects multiple organs, but is likely to be still incompletely known. The reported neurological presentations range from early-onset dys- tonias to late-onset parkinsonism. However, detailed clinical descriptions are scarce. In particular, the early symptomatic stages of the disease have been observed in only one case thus far. 3 An early recognition of this disease is essential given that treatment with manga- nese chelation or oral iron supplementation, or their combination, might ameliorate symptoms and prevent progression of an otherwise potentially fatal illness. 7 Here, we describe 5 previously unreported Indian ------------------------------------------------------------ *Correspondence to: Prof. Vincenzo Bonifati, Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Neth- erlands; v.bonifati@erasmusmc.nl Funding agencies: This study was supported by grants from the Sticht- ing ParkinsonFonds (The Netherlands; to V.B.). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online ver- sion of this article. M.Q., M.K., and S.S. contributed equally to this work and should be considered as joint first authors. Received: 1 December 2014; Revised: 15 January 2015; Accepted: 9 February 2015 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26202 BRIEF REPORT Movement Disorders, Vol. 00, No. 00, 2015 1