FAMILIAL HYPOMAGNESEMIA WITH SECONDARY HYPOCALCEMIA CAUSED BY A NOVEL TRPM6 INSERTION: LONG-TERM AND PREGNANCY OUTCOMES

Hypomagnesemia with Secondary Hypocalcemia (HSH) is a rare autosomal-recessive disorder due to TRPM6 dysfunction, causing impaired intestinal magnesium (Mg) absorption and distal tubular reabsorption. Few reports describe the long-term course or pregnancy management of HSH. We report three sisters with lifelong hypomagnesemia/hypocalcemia carrying a novel homozygous TRPM6 insertion and provide integrated biochemical, functional, and genetic characterization.

The eldest and second sisters were evaluated for Mg balance, pregnancy course, and genotype. Renal Mg handling was tested by a Mg-loading protocol (0.5 mmol/L MgSO₄, 0.6 mL/kg over 3 hour). Serum and urinary Mg were measured every 30 min. The ultrafiltrable Mg fraction was 0.7 × plasma [Mg]; magnesium excretion index = U[Mg] × S[Cr]/U[Cr]. Targeted sequencing of 530 renal genes with CNV analysis was performed, variants classified by ACMG guidelines using gnomAD and ToMMo. Ethical approval and informed consent were obtained.

Family summary: The family originated from rural Japan with no consanguinity. All three siblings presented in infancy with seizures, hypomagnesemia, and secondary hypocalcemia. Growth and cognition were normalexcept for short-term ADHD medication in the second sister. None developed nephrocalcinosis, QTc prolongation, or renal dysfunction. The second sister showed the most severe phenotype.
Case 1 (Second sister): She was healthy at birth but developed seizures at 1 month, when laboratory testing revealed hypomagnesemia/hypocalcemia. Seizures ceased after Mg therapy, though she had headaches and polyuria. At 16 years, recurrent seizures led to referral. She exhibited severe hypomagnesemia (0.7mg/dL)/hypocalcemia with elevated FEMg (7.6%) and low urinary Mg (11mg/day), indicating combined intestinal malabsorption and renal loss. In Mg-loading, urinary Mg rose before serum Mg, confirming renal Mg wasting. Mg oxide (MgO)(3 g/day) was continued long-term, maintaining serum Mg 1.0–1.3 mg/dL. She had two term pregnancies (ages 34, 36); the second was complicated by uterine inertia. Mg demand rose during pregnancy; Mg-K aspartate maintained serum Mg 1.4 mg/dL. Both deliveries required MgSO₄ 20 mEq/day. Newborns had normal or transiently low Mg.
Case 2 (Eldest sister): From infancy, she was easily startled and had generalized seizures at 6 months with hypomagnesemia/hypocalcemia which were resolved on Mg therapy. At 18 years, her serum/urinary Mg and Mg-loading test revealed renal and intestinal Mg loss (serum Mg 1.0 mg/dL, FEMg 7.0 %, and urinary Mg 22mg/day). Long-term MgO (1.5 g/day) kept serum Mg 1.4 mg/dL. She had two pregnancies (ages 37, 38): one miscarriage and one preterm birth (35 weeks). Mg demand increased during pregnancy. The second child had Down syndrome with normal Mg.
Genetic findings: Both sisters carried a novel homozygous TRPM6 in-frame insertion (p. Thr696_Tyr697ins8aa), absent from gnomAD and ToMMo. Although classified as a variant of uncertain significance (VUS; ACMG PM2, PM4), its segregation with disease, early-onset phenotype with low PTH, and consistent renal Mg wasting support pathogenicity.

This familial form of HSH caused by a novel TRPM6 insertion shows persistent renal Mg wasting and increased Mg demand during pregnancy. Recognition of this phenotype is essential for lifelong and perinatal management, emphasizing individualized Mg replacement and genetic counseling in TRPM6-related HSH.