Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1
Thomas Cuny1, Pauline Romanet2, Michelle Goldsworthy3
1Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, Service d'Endocrinologie, Marseille, France.
Insights
Familial hypocalciuric hypercalcemia type 1 (FHH-1) patients with a short QT interval may benefit from cinacalcet. This treatment corrected the QT interval and normalized calcium levels in a study of three family members.
Area of Science:
- Endocrinology
- Cardiology
- Genetics
Background:
- Familial hypocalciuric hypercalcemia type 1 (FHH-1) is an autosomal dominant disorder caused by CASR gene mutations, typically presenting with mild hypercalcemia.
- A novel association between FHH-1 and a short QT interval, a condition predisposing to cardiac arrhythmias, is reported.
Purpose of the Study:
- To investigate three FHH-1 patients with a short QT interval.
- To evaluate the efficacy of cinacalcet, a calcimimetic agent, in correcting the short QT interval and abnormal calcium-sensing receptor (CaSR) sensitivity.
Main Methods:
- CASR gene sequencing identified the p.Ile555Thr variant.
- Functional studies in HEK293 cells assessed CaSR variant function and cinacalcet's effects.
- A cinacalcet challenge test involved administering 30 mg cinacalcet and monitoring serum calcium, phosphate, parathyroid hormone, and ECG parameters over 8 hours.
Main Results:
- The identified CaSR variant (p.Ile555Thr) demonstrated loss-of-function characteristics, which were ameliorated by cinacalcet.
- Cinacalcet significantly reduced parathyroid hormone levels within 2 hours and normalized serum calcium and phosphate levels within 8 hours.
- The short QT interval was corrected by cinacalcet and remained normal during 3 months of treatment.
Conclusions:
- FHH-1 patients should be screened for short QT intervals.
- A cinacalcet challenge test can identify patients likely to benefit from this therapeutic intervention.
- This study highlights a potential therapeutic strategy for FHH-1 patients with cardiac complications.
Context:
Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date.
Objective:
Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined.
Methods:
CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed.
Results:
The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment.
Conclusion:
Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment.
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