We aimed to describe the clinical, laboratory and genetic profile of children with inherited hypermanganesemia (IH).

IH is a rare autosomal recessive disorder of manganese (Mn) transport, characterized by two phenotypes due to mutations in SLC30A10 and SLC39A14 genes. There are around 50 cases reported worldwide.

We conducted a multicentric retrospective study across 11 centers in India. We collected data pertaining to clinical, laboratory profile and treatment outcomes among children between 1 month-18 years of age with genetically confirmed/ clinically probable IH.

We enrolled 27 children from 20 families (19 girls). Fourteen harboured the SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset [1.6 (IQR 0.7-5.8) years] versus the SLC30A10 cohort [2.9 (IQR 1.6-4.5) years]. The most frequent neurological features were dystonia (100%), gait abnormality (77.8%; n=21), falls (66.7%; n=18) and Parkinsonism (59.3%; n=16). Eight demonstrated typical ‘cock-walk’ gait. Median blood Mn levels among the SLC39A14 [101.8 (IQR 28.5-200.0) mcg/L] were higher than the SLC30A10 cohort [34.0 (23.9-100.0) mcg/L]. Median hemoglobin was higher in the SLC30A10 [16.1 (IQR 15.2-17.5) g/dL] versus SLC39A14 cohort [11.7 (IQR 8.8-13.2) g/dL]. Hepatic involvement and polycythemia were observed among the SLC30A10 cohort only. MRI brain universally showed T1 hyper-intensities in basal ganglia, basal pons and cerebellar white matter. The SLC39A14 cohort had more severe disease evidenced by higher proportions of generalized dystonia, dependent ambulation and blood Mn levels. All children underwent chelation with disodium-calcium edetate. Children with SLC39A14 mutations had poorer response, scored by treating physicians on a Likert scale. Eight children were lost to follow-up.

We describe the largest pediatric cohort of IH till date. Children with SLC39A14 mutations were younger, had more severe disease and responded less favorably to chelation versus children with SLC30A10 mutations. There is emerging need to better define management strategies for these children.