Hypermanganesemia with dystonia, polycythemia and cirrhosis in 10 patients: Six novel SLC30A10 mutations and further phenotype delineation

Abstract

Biallelic mutations in the SLC30A10 gene cause an inborn error of Mn metabolism characterized by hypermanganesemia, polycythemia, early-onset dystonia, and liver cirrhosis (HMDPC). To-date only 14 families from various ethnic groups have been reported. Here, we describe 10 patients from 7 unrelated Egyptian families with HMDPC. Markedly elevated blood Mn levels, the characteristic basal ganglia hyperintensity on T1W images, and variable degrees of extrapyramidal manifestations with or without liver disease were cardinal features in all patients. Eight patients presented with striking early diseased onset (<2 years). Unexpectedly, early hepatic involvement before the neurological regression was noted in 3 patients. Mutational analysis of SLC30A10 gene revealed six novel homozygous mutations [c.77T>C (p.Leu26Pro), c.90C>G (p.Tyr30*), c.119A>C (p.Asp40Ala), c.122_124delCCT (p.Ser41del), c.780_782delCAT (p.Iso260del) and c.957+1G>C]. Treatment using 2,3 dimercaptosuccinic acid as a manganese chelating agent showed satisfactory results with improvement of biochemical markers, hepatic manifestations and relative amelioration of the neurological symptoms. Our findings present a large cohort of patients with HMDPC from same ethnic group. The majority of our patients showed severe and early presentation with clear phenotypic variability among sibship. Moreover, we extend the phenotypic and mutational spectrum and emphasize the importance of early diagnosis and treatment of this potentially fatal disorder.

We describe 10 patients with hypermanganesemia. polycythemia, early-onset dystonia. and liver cirrhosis syndrome carrying six novel homozygous SLC30A10 mutations. Our patients had a striking early onset of symptoms (<2 years) with unexpected early hepatic involvement before the neurological regression in some patients.

Treatment with DMSA showed satisfactory results and improvement of biochemical markers. hepatic manifestations and relative amelioration of the neurological symptoms.

Thus. we believe that we expanded the mutational spectrum and further delineate the phenotypic spectrum of this very rare inborn error of Mn metabolism.

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