Mannstadt et al. (2013) studied 2 unrelated 4-generation families segregating autosomal dominant hypocalcemia. In the first family, the male proband was diagnosed at 2 years of age with type 1 diabetes mellitus (see 222100), at which time his ... Mannstadt et al. (2013) studied 2 unrelated 4-generation families segregating autosomal dominant hypocalcemia. In the first family, the male proband was diagnosed at 2 years of age with type 1 diabetes mellitus (see 222100), at which time his total calcium level was normal. At 5 years of age, he presented with generalized seizures, some of which were not associated with hypoglycemia; he was treated with carbamazepine for a year and had no recurrences when treatment was discontinued. At 14 years of age, he complained of tremulousness and muscle cramps and was found to be hypocalcemic with inappropriately low parathyroid hormone (PTH) levels. Review of the family history at that time revealed autosomal dominant transmission of hypocalcemia on the maternal side. In the second family, the female proband presented with chronic fatigue and occasional muscle cramps at 20 years of age and was found to have mild hypocalcemia and mild hyperphosphatemia with a low PTH level. Family evaluation revealed 9 additional relatives diagnosed with isolated hypoparathyroidism, all of whom had similarly mild symptoms of hypocalcemia. None of the affected members of either family had a history of mucocutaneous candidiasis, hearing loss, or renal abnormalities, and clinical examination was unremarkable; specifically, there was no evidence for skin changes.
In 8 unrelated patients with hypocalcemia and low or normal serum parathyroid hormone concentrations, who were negative for mutation in the CASR gene (601199), Nesbit et al. (2013) analyzed the candidate gene GNA11 (139313) and identified heterozygosity for ... In 8 unrelated patients with hypocalcemia and low or normal serum parathyroid hormone concentrations, who were negative for mutation in the CASR gene (601199), Nesbit et al. (2013) analyzed the candidate gene GNA11 (139313) and identified heterozygosity for missense mutations in 2 patients (R181Q, 139313.0003; and F341L, 139313.0004). Functional analysis in HEK293 cells stably expressing calcium-sensing receptors demonstrated that the mutant GNA11 proteins induce an enhanced sensitivity to changes in extracellular calcium concentrations, similar to the effects of gain-of-function mutations in CASR reported in autosomal dominant hypocalcemia type 1. One of the mutation-positive patients was asymptomatic, whereas the other reported a 10-year history of occasional paresthesias, muscle cramping, and carpopedal spasm. Other family members were unavailable for study. In a 4-generation family segregating autosomal dominant hypocalcemia mapping to chromosome 19q13.3, Mannstadt et al. (2013) sequenced the candidate gene GNA11 and identified a heterozygous missense mutation (R60C; 139313.0005) that segregated with disease. In an unrelated 4-generation family with hypocalcemia, exome sequencing revealed heterozygosity for a different missense mutation in GNA11 (S211W; 139313.0006) in affected individuals.