SLC39A8 – SLC39A8-Congenital Disorder of Glycosylation

SLC39A8-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic mutations in the manganese transporter ZIP8. Patients present in infancy with severe neurodevelopmental impairment, seizures, dystonia or dyskinesia, hearing loss and Leigh-like basal ganglia abnormalities. The disorder is biochemically defined by whole blood manganese deficiency and type II transferrin hypoglycosylation detectable by advanced N-glycome mass spectrometry rather than standard transferrin assays.

Genetic evidence includes 11 unrelated probands (2 ([PMID:32852845]), 2 ([PMID:28749473]), 3 ([PMID:34246313]), 2 ([PMID:26637979]), 2 ([PMID:27995398])) with homozygous or compound heterozygous SLC39A8 variants such as c.112G>C (p.Gly38Arg) and c.608T>C (p.Phe203Ser). Segregation analysis confirms pathogenicity in two consanguineous sibships ([PMID:34246313]; [PMID:27995398]).

Functional studies demonstrate that CDG-associated ZIP8 variants abolish Mn2+ uptake, mislocalize to the endoplasmic reticulum and abrogate Mn-dependent β-1,4-galactosyltransferase activity in patient cells and heterologous systems ([PMID:26637979]; [PMID:29453449]). Rescue experiments with oral galactose and high-dose manganese supplementation restore glycosylation profiles and lead to marked clinical improvement in motor function, hearing and biochemical markers ([PMID:28749473]).

Mechanistic data indicate that SLC39A8 deficiency links trace element transport with glycosylation and mitochondrial enzyme function, accounting for both CDG type II and Leigh-like phenotypes. Concordance across genetic, biochemical and therapeutic studies supports a definitive gene-disease relationship.

Key take-home: Biallelic SLC39A8 mutations cause a treatable CDG with manganese supplementation, underscoring the importance of advanced glycomics for accurate diagnosis and management.

References

• Journal of inherited metabolic disease • 2020 • N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency. PMID:32852845
• Genetics in medicine • 2018 • SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy. PMID:28749473
• American journal of human genetics • 2015 • SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation. PMID:26637979
• Scientific reports • 2018 • Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders. PMID:29453449
• Journal of inherited metabolic disease • 2017 • A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. PMID:27995398
• Orphanet journal of rare diseases • 2021 • Clinical, molecular and glycophenotype insights in SLC39A8-CDG. PMID:34246313

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