We thank Tabatabaee et al 1 for their interest in our work and congratulate the authors on reporting five new patients with hypermanganesemia with dystonia (HMNDYT), three of whom had HMNDYT1 and two with HMNDYT2. 1 Similar to our cohort of 27 children, 2 the authors observed a relatively younger age at onset of symptoms in children with SLC39A14 variants (HMNDYT2) compared to HMNDYT1.
We reiterate their observation that polycythemia is an important feature seen only among patients with HMNDYT1 and not in HMNDYT2. Polycythemia is associated with depleted iron stores. It may be a presenting feature, predating the neurological presentation. Moreover, it may rise to impressive levels. Although it may precipitate hyperviscosity syndrome, as was observed in one child in our series (F1), most children were observed to tolerate polycythemia without development of clinical features of hyperviscosity, suggesting the development of adaptive mechanisms. Interestingly, we have observed that polycythemia does not necessarily respond to chelation therapy, as was seen among three patients in our series (F1, F3, and F8) in whom polycythemia worsened despite chelation. We advocate that patients should undergo phlebotomy promptly if they develop clinical features of hyperviscosity. We also suggest that patients should undergo phlebotomy empirically, if the hematocrit level rises beyond 70%.
Individuals with HMNDYT2 lack hepatic dysfunction. SLC39A14 is expressed in hepatocytes and regulates hepatic manganese (Mn) homeostasis. Variants in SLC39A14 prevent Mn absorption by hepatocytes, leading to Mn accumulation in the blood and the brain. 3
Although disodium calcium edetate is the current treatment of choice, the role of oral iron remains interesting. Mn and iron (Fe) share interdependent homeostasis as they use the same metal transporters such as divalent metal transporter 1, transferrin/transferrin receptor complex and ferroportin. Oral iron therapy limits intestinal Mn absorption and has been observed to be useful in reducing dystonia and improving clinical and radiological parameters, either as stand‐alone 4 or in combination with chelation. 5 Oral iron may be a useful addition in disease maintenance and may be explored if disodium calcium edetate is unavailable or refused by the patient. Another important caveat is early initiation of treatment, as delayed onset of treatment may not reverse clinical abnormalities, despite lowering serum manganese level and improving magnetic resonance imaging brain signal change.
We also find appealing the authors’ suggestion that c.1006 > T in the SLC30A10 gene may be a founder‐mutation in our region. Interestingly, our patient F5, who shares this mutation with one of the authors’ patients and three Pakistani patients, hails from Jammu and Kashmir, the northernmost part of India, which lies adjacent to Pakistan.
The unique combination of childhood onset dystonia‐parkinsonism with T1‐weighted hyperintensity in the basal ganglia in the absence of acquired manganese exposure should alert clinicians to the possibility of HMNDYT, particularly if associated with polycythemia. Treatment should be initiated early to minimize neurodegeneration. Longitudinal studies and severity scales are required to inform long‐term outcomes.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.
D.G.: 1A, 1B, 1C, 2A, 2B.
S.S.: 1A, 1B, 2B.
Disclosures
Ethical Compliance Statement: The authors confirm that the approval of an institutional review board and patient consent were not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work.
Financial Disclosures for Previous 12 Months: The authors declare that there are no additional disclosures to report.
References
- 1. Tabatabaee SN, Effatnejad S, Nikkah A, Hashemi N, Alavi A, Lang A, et al. Familial Hypermanganesemia in Iran. Mov Disord Clin Pract 2023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Garg D, Yoganathan S, Shamim U, et al. Clinical profile and treatment outcomes of Hypermanganesemia with dystonia 1 and 2 among 27 Indian children. Mov Disord Clin Pract 2022;9:886–899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Rodichkin AN, Guilarte TR. Hereditary disorders of manganese metabolism: pathophysiology of childhood‐onset dystonia‐parkinsonism in SLC39A14 mutation carriers and genetic animal models. Int J Mol Sci 2022;23(21):12833. 10.3390/ijms232112833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Yapici Z, Tuschl K, Eraksoy M. Hypermanganesemia with dystonia 1: a novel mutation and response to iron supplementation. Mov Disord Clin Pract 2019;7(1):94–96. 10.1002/mdc3.12861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner‐Glindzicz M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia–a new metabolic disorder. J Inherit Metab Dis 2008;31(2):151–163. 10.1007/s10545-008-0813-1. [DOI] [PubMed] [Google Scholar]