Benign SLC39A14 Course of <scp>Dystonia‐Parkinsonism</scp> Secondary to Inherited Manganese Accumulation

Namnah, Montaser; Bauer, M; Mor‐Shaked, Hagar; Bressman, Susan; Raymond, Deborah; Ozelius, Laurie J.; Arkadir, David

doi:10.1002/mdc3.12947

Cited by 6 publications

(4 citation statements)

References 5 publications

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“…2,3,[5][6][7][8] Forty-five cases with SLC30A10 4,9-12 and 18 with SLC39A14 mutations have been described. 4,13,14 Treatment comprises chelation with disodium calcium edetate (Na 2 CaEDTA) and iron supplementation. However, Na 2 CaEDTA is not widely available, incurs recurrent expenditure, monthly hospitalization and intravenous access, and therefore, presents several barriers in resource-constrained settings.…”

Section: Discussionmentioning

confidence: 99%

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

Garg

Yoganathan

Shamim

et al. 2022

Movement Disord Clin Pract

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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.

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Section: Discussionmentioning

confidence: 99%

“…In both conditions, pathognomonic magnetic resonance imaging (MRI) features include T1‐weighted hyperintensities in basal ganglia, midbrain, dorsal pons, and medulla with characteristic sparing of the ventral pons 2,3,5–8 . Forty‐five cases with SLC30A10 4,9–12 and 18 with SLC39A14 mutations have been described 4,13,14 …”

mentioning

confidence: 99%

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

Garg

Yoganathan

Shamim

et al. 2022

Movement Disord Clin Pract

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“…Interestingly, Patient 3 variant was classified as a variant of uncertain significance by Clinvar. However, a recent article by Montaser Namnah et al [ 18 ] suggests this to be a pathogenic variant as it is predicted to damage the translated protein, leading to an increased level of manganese as we have seen in our patient. It is not clear yet why this patient presented later in life in comparison to our patient, who presented early childhood with more prominent features.…”

Section: Discussionmentioning

confidence: 43%

Hypermanganesemia with Dystonia Type 2: A Potentially Treatable Neurodegenerative Disorder: A Case Series in a Tertiary University Hospital

et al. 2022

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Importance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.

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“…In both cases, a Lys residue in this position could be detrimental for the correct folding and functioning of the protein. Three more mutations have been found associated with HMNDYT2 (i.e., Arg128Trp [ 111 ], Pro379Leu [ 112 ], Gly356Ser [ 113 ]), but there are no functional studies analysing the effect of these mutations. From a structural viewpoint Arg128Trp could affect the proper folding of the dimeric ECD, while Pro379Leu and Gly356Ser are located at transmembrane helices interfaces and the presence of different residues could affect the helices packing and flexibility ( Figure 5 B).…”

Section: Zip8 and Zip14mentioning

confidence: 99%

Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects

et al. 2023

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Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.

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Benign SLC39A14 Course of Dystonia‐Parkinsonism Secondary to Inherited Manganese Accumulation

Cited by 6 publications

References 5 publications

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

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

Hypermanganesemia with Dystonia Type 2: A Potentially Treatable Neurodegenerative Disorder: A Case Series in a Tertiary University Hospital

Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects

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