SLC30A10 – Cirrhosis-Dystonia-Polycythemia-Hyper­manganesemia Syndrome

SLC30A10 encodes a cell-surface manganese efflux transporter whose biallelic loss-of-function causes autosomal recessive hypermanganesemia with dystonia 1 (also known as cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome) (MONDO_0013208). Affected individuals present in early childhood with hypermanganesemia, secondary polycythemia, progressive motor neurodegeneration, extrapyramidal features, and hepatic dysfunction with elevated transaminases.

Autosomal recessive inheritance is supported by multiple case reports: a 3-year-old boy with biallelic SLC30A10 c.392T>G (p.Leu131Arg) (PMID:38283630), a consanguineous Saudi family segregating homozygous c.266T>C (p.Leu89Pro) in two affected siblings (PMID:39064292), and an unrelated pediatric case with a homozygous missense mutation (PMID:40726517). Four probands from three families, including two siblings with confirmed segregation, establish a consistent AR pattern.

All reported pathogenic variants are missense changes within transmembrane or cytoplasmic domains, with evidence for at least one recurrent variant in Middle Eastern populations (c.266T>C (p.Leu89Pro)). No loss-of-function or splice variants have been described in this syndrome. The phenotypic spectrum includes dystonia (HP:0001332), spastic paraparesis (HP:0002313), postural instability (HP:0002172), elevated hepatic transaminases (HP:0002910), and neurodegeneration (HP:0002180).

Functional studies demonstrate that SLC30A10 loss leads to impaired manganese efflux. Structural modeling of the human L349P analogue in MamM revealed cytoplasmic domain folding defects (PMID:27550551). Site-directed mutagenesis in cell lines identified critical residues (Asp-248, His-333, His-350) for Mn transport activity (PMID:27307044). AAV-mediated hepatic expression of human SLC30A10 in Slc30a10-deficient mice restores liver Mn homeostasis, corrects erythrocytosis, and normalizes neurological and transcriptional phenotypes (PMID:38336290).

No studies have refuted the association. The convergence of genetic segregation in families, consistent AR inheritance, and mechanistic functional data supports a loss-of-function model. Early identification via NGS and measurement of serum manganese enables targeted chelation and iron supplementation, reducing Mn burden and preventing irreversible neuro-hepatic damage.

Key Take-home: Genetic testing for SLC30A10 should be prioritized in pediatric patients with unexplained polycythemia and elevated liver enzymes, as timely diagnosis permits effective chelation therapy and prevents progression of neurological and hepatic disease.

References

• Frontiers in pediatrics • 2024 • Case Report: A rare form of congenital erythrocytosis due to SLC30A10 biallelic variants-differential diagnosis and recommendation for biochemical and genetic screening. PMID:38283630
• Journal of clinical medicine • 2024 • Exome Sequence Analysis to Characterize Undiagnosed Family Segregating Motor Impairment and Dystonia. PMID:39064292
• Frontiers in hematology • 2024 • Case Report: Childhood Erythrocytosis due to Hypermanganesemia Caused by Homozygous SLC30A10 Mutation. PMID:40726517
• Scientific reports • 2016 • Disease-Homologous Mutation in the Cation Diffusion Facilitator Protein MamM Causes Single-Domain Structural Loss and Signifies Its Importance. PMID:27550551
• The Journal of biological chemistry • 2016 • Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity. PMID:27307044
• The Journal of biological chemistry • 2024 • AAV-mediated hepatic expression of SLC30A10 and the Thr95Ile variant attenuates manganese excess and other phenotypes in Slc30a10-deficient mice. PMID:38336290

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