SLC39A8 Deficiency: Biochemical Correction and Major Clinical Improvement by Manganese Therapy

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2017 Jul 28

PMID 28749473

Citations 33

Authors

Julien H Park

Max Hogrebe

Manfred Fobker

Renate Brackmann

Barbara Fiedler

Janine Reunert

Stephan Rust

Konstantinos Tsiakas

Rene Santer

Marianne Gruneberg

Thorsten Marquardt

Affiliations

Soon will be listed here.

Abstract

PurposeSLC39A8 deficiency is a severe inborn error of metabolism that is caused by impaired function of manganese metabolism in humans. Mutations in SLC39A8 lead to impaired function of the manganese transporter ZIP8 and thus manganese deficiency. Due to the important role of Mn as a cofactor for a variety of enzymes, the resulting phenotype is complex and severe. The manganese-dependence of β-1,4-galactosyltransferases leads to secondary hypoglycosylation, making SLC39A8 deficiency both a disorder of trace element metabolism and a congenital disorder of glycosylation. Some hypoglycosylation disorders have previously been treated with galactose administration. The development of an effective treatment of the disorder by high-dose manganese substitution aims at correcting biochemical, and hopefully, clinical abnormalities.MethodsTwo SCL39A8 deficient patients were treated with 15 and 20 mg MnSO/kg bodyweight per day. Glycosylation and blood manganese were monitored closely. In addition, magnetic resonance imaging was performed to detect potential toxic effects of manganese.ResultsAll measured enzyme dysfunctions resolved completely and considerable clinical improvement regarding motor abilities, hearing, and other neurological manifestations was observed.ConclusionHigh-dose manganese substitution was effective in two patients with SLC39A8 deficiency. Close therapy monitoring by glycosylation assays and blood manganese measurements is necessary to prevent manganese toxicity.

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References

Marquardt T, Luhn K, Srikrishna G, Freeze H, Harms E, Vestweber D . Correction of leukocyte adhesion deficiency type II with oral fucose. Blood. 1999; 94(12):3976-85. View

Boycott K, Beaulieu C, Kernohan K, Gebril O, Mhanni A, Chudley A . Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. Am J Hum Genet. 2015; 97(6):886-93. PMC: 4678439. DOI: 10.1016/j.ajhg.2015.11.002. View

Zeevaert R, de Zegher F, Sturiale L, Garozzo D, Smet M, Moens M . Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165. JIMD Rep. 2013; 8:145-52. PMC: 3565624. DOI: 10.1007/8904_2012_172. View

Fujishiro H, Yano Y, Takada Y, Tanihara M, Himeno S . Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells. Metallomics. 2012; 4(7):700-8. DOI: 10.1039/c2mt20024d. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

Kuhn N, Ward S, Leong W . Submicromolar manganese dependence of Golgi vesicular galactosyltransferase (lactose synthetase). Eur J Biochem. 1991; 195(1):243-50. DOI: 10.1111/j.1432-1033.1991.tb15700.x. View

Horning K, Caito S, Tipps K, Bowman A, Aschner M . Manganese Is Essential for Neuronal Health. Annu Rev Nutr. 2015; 35:71-108. PMC: 6525788. DOI: 10.1146/annurev-nutr-071714-034419. View

Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello M, Bowman A . Manganese homeostasis in the nervous system. J Neurochem. 2015; 134(4):601-10. PMC: 4516557. DOI: 10.1111/jnc.13170. View

Tuschl K, Clayton P, Gospe Jr S, Gulab S, Ibrahim S, Singhi P . Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012; 90(3):457-66. PMC: 3309187. DOI: 10.1016/j.ajhg.2012.01.018. View

10.

Niehues R, Hasilik M, Alton G, Korner C, Koch H, Zimmer K . Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest. 1998; 101(7):1414-20. PMC: 508719. DOI: 10.1172/JCI2350. View

11.

Wild M, Luhn K, Marquardt T, Vestweber D . Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs. 2002; 172(3):161-73. DOI: 10.1159/000066968. View

12.

Etzioni A, Frydman M, Pollack S, Avidor I, Phillips M, Paulson J . Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med. 1992; 327(25):1789-92. DOI: 10.1056/NEJM199212173272505. View

13.

Foulquier F, Amyere M, Jaeken J, Zeevaert R, Schollen E, Race V . TMEM165 deficiency causes a congenital disorder of glycosylation. Am J Hum Genet. 2012; 91(1):15-26. PMC: 3397274. DOI: 10.1016/j.ajhg.2012.05.002. View

14.

Crossgrove J, Zheng W . Manganese toxicity upon overexposure. NMR Biomed. 2004; 17(8):544-53. PMC: 3980863. DOI: 10.1002/nbm.931. View

15.

Riley L, Cowley M, Gayevskiy V, Roscioli T, Thorburn D, Prelog K . A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. J Inherit Metab Dis. 2016; 40(2):261-269. DOI: 10.1007/s10545-016-0010-6. View

16.

Nelson K, Golnick J, Korn T, Angle C . Manganese encephalopathy: utility of early magnetic resonance imaging. Br J Ind Med. 1993; 50(6):510-3. PMC: 1035477. DOI: 10.1136/oem.50.6.510. View

17.

Ng B, Buckingham K, Raymond K, Kircher M, Turner E, He M . Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet. 2013; 92(4):632-6. PMC: 3617373. DOI: 10.1016/j.ajhg.2013.03.012. View

18.

Achouitar S, Mohamed M, Gardeitchik T, Wortmann S, Sykut-Cegielska J, Ensenauer R . Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression. J Inherit Metab Dis. 2011; 34(4):923-7. PMC: 3232068. DOI: 10.1007/s10545-011-9325-5. View

19.

Potelle S, Morelle W, Dulary E, Duvet S, Vicogne D, Spriet C . Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis. Hum Mol Genet. 2016; 25(8):1489-500. DOI: 10.1093/hmg/ddw026. View

20.

Aschner M, Aschner J . Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain Res Bull. 1990; 24(6):857-60. DOI: 10.1016/0361-9230(90)90152-p. View