TRPM6 – Hypomagnesemia with Secondary Hypocalcemia

Hereditary hypomagnesemia with secondary hypocalcemia (HSH; MONDO:0011176) is a rare autosomal recessive disorder presenting in early infancy with refractory seizures, tetany, and growth disturbances due to profound hypomagnesemia and hypocalcemia. Biallelic pathogenic variants in TRPM6 impair intestinal magnesium absorption and renal reabsorption, establishing TRPM6 as the causal gene for HSH (PMID:16107578).

In a multi‐center cohort of 21 unrelated families encompassing 28 affected individuals, mutational analysis identified 37 of 42 expected mutant alleles in TRPM6, including 16 novel stop, frameshift, splice‐site, and exon‐deletion variants. Segregation in consanguineous and multiplex pedigrees consistently supports autosomal recessive inheritance (PMID:16107578).

Variant spectrum is dominated by loss‐of‐function alleles: nonsense (e.g., c.4287C>A (p.Cys1429Ter)), frameshift, canonical and non‐canonical splice‐site mutations, and exon deletions. Missense variants have been reported but uniformly result in channel dysfunction in functional assays.

Functional assays in Xenopus oocytes and HEK293 cells demonstrate that TRPM6 loss‐of‐function variants abolish channel activity and fail to form functional TRPM6/TRPM7 heteromeric complexes at the cell surface, confirming loss of channel function as the pathogenic mechanism (PMID:12032568; PMID:14976260).

No clear genotype–phenotype correlation has been observed with respect to mutation location and clinical severity, underscoring the need for comprehensive sequencing of TRPM6 for accurate diagnosis.

Early genetic diagnosis facilitates prompt initiation of high‐dose oral or intravenous magnesium supplementation, effectively preventing irreversible neurologic damage. Lifelong magnesium replacement remains essential to maintain subnormal serum magnesium and normocalcemia.

Key Take-home: TRPM6 genetic testing is critical for definitive diagnosis of HSH and guides early treatment to avert permanent neurodevelopmental sequelae.

References

• Journal of the American Society of Nephrology • 2005 • Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. PMID:16107578
• Nature genetics • 2002 • Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. PMID:12032568
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. PMID:14976260

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