Clinical Profile and Treatment Outcomes of Hypermanganesemia with Dystonia 1 and 2 among 27 Indian Children

Abstract

Background Hypermanganesemia with dystonia 1 and 2 (HMNDYT1 and 2) are rare, inherited disorders of manganese transport. Objectives We aimed to describe clinical, laboratory features, and outcomes among children with HMNDYT. Methods We conducted a retrospective multicenter study involving tertiary centers across India. We enrolled children between 1 month to 18 years of age with genetically confirmed/clinically probable HMNDYT. Clinical, laboratory profile, genetic testing, treatment details, and outcomes scored by treating physicians on a Likert scale were recorded. Results We enrolled 27 children (19 girls). Fourteen harbored SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset (1.3 [interquartile range (IQR), 0.7–5.5] years) versus SLC30A10 cohort (2.0 [IQR, 1.5–5.1] years). The most frequent neurological features were dystonia (100%; n = 27), gait abnormality (77.7%; n = 21), falls (66.7%; n = 18), and parkinsonism (59.3%; n = 16). Median serum manganese (Mn) levels among SLC39A14 (44.9 [IQR, 27.3–147.7] mcg/L) cohort were higher than SLC30A10 (29.4 [17.1–42.0] mcg/L); median hemoglobin was higher in SLC30A10 (16.3 [IQR, 15.2–17.5] g/dL) versus SLC39A14 cohort (12.5 [8.8–13.2] g/dL). Hepatic involvement and polycythaemia were observed exclusively in SLC30A10 variants. A total of 26/27 children underwent chelation with disodium calcium edetate. Nine demonstrated some improvement, three stabilized, two had marked improvement, and one had normalization. Children with SLC39A14 mutations had poorer response. Two children died and nine were lost to follow‐up. Conclusions We found female predominance. Children with SLC39A14 mutations presented at younger age and responded less favorably to chelation compared to SLC30A10 mutations. There is emerging need to better define management strategies, especially in low resource settings.

Hereditary Disorders of Manganese Metabolism: Pathophysiology of Childhood-Onset Dystonia-Parkinsonism in SLC39A14 Mutation Carriers and Genetic Animal Models

“…More recently, a new genetic form of dystonia-parkinsonism associated with high blood and brain Mn concentrations has been described [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These cases are the result of inherited, autosomal recessive, loss-of-function mutations of the metal ion efflux and influx transporter genes SLC30A10 and SLC39A14 , respectively [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These new clinical cases have provided a wealth of new knowledge on the metabolism and neurotoxicology of Mn [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

“…These cases are the result of inherited, autosomal recessive, loss-of-function mutations of the metal ion efflux and influx transporter genes SLC30A10 and SLC39A14 , respectively [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These new clinical cases have provided a wealth of new knowledge on the metabolism and neurotoxicology of Mn [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

“…This specificity of tissue expression is hypothesized to be central to the function of the protein and its role in maintaining Mn homeostasis in the body. Mutations in SLC39A14 result in Mn accumulation due to a lack of Mn absorption from the peripheral circulation and subsequent accumulation in the brain [ 6 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Although the cases of mutations in SLC39A14 are rare, most mutations appear to affect the first ~150 amino acid residues of SLC39A14.…”

“…Since 2016, an increasing number of clinical reports have described a progressive childhood-onset dystonia-parkinsonism resulting from inherited, autosomal recessive, loss-of-function mutations of the SLC39A14 gene [ 6 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. The timeline of most recent and significant discoveries can be found in Figure 2 .…”

“…SLC39A14 encodes for a metal ion influx transporter of the same name. Originally, SLC39A14 was studied as a zinc (Zn) transporter; however, most recent studies and clinical cases indicate a major role in Mn transport and homeostasis [ 6 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In addition to Mn and Zn transport, SLC39A14 can also transport iron (Fe) and cadmium.…”