Abstract Autosomal dominant hypocalcemia type 1 (ADH1) is a disorder of extracellular calcium homeostasis caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR). Over 35% of ADH1 patients have intracerebral calcifications predominantly affecting the basal ganglia. The clinical consequences of such calcifications remain to be fully characterized, although the majority of patients with these calcifications are considered to be asymptomatic. We report a 20-year-old female proband with a severe form of ADH1 associated with recurrent hypocalcemic and hypercalcemic episodes, persistent childhood hyperphosphatemia, and a low calcium/phosphate ratio. From the age of 18 years, she had experienced recurrent myoclonic jerks affecting the upper limbs that were not associated with epileptic seizures, extra-pyramidal features, cognitive impairment, or alterations in serum calcium concentrations. Computerised tomography (CT) scans revealed calcifications of the globus pallidus regions of the basal ganglia bilaterally, and also the frontal lobes at the grey-white matter junction, and posterior horn choroid plexuses. The patient’s myoclonus resolved following treatment with levetiracetam. CASR mutational analysis identified a reported germline gain-of-function heterozygous missense mutation, c.2363T>G; p.(Phe788Cys), which affects an evolutionarily conserved phenylalanine residue located in transmembrane domain helix 5 of the CaSR protein. Analysis of the cryo-electron microscopy CaSR structure predicted the wild-type Phe788 residue to form interactions with neighbouring phenylalanine residues, which likely maintain the CaSR in an inactive state. The p.(Phe788Cys) mutation was predicted to disrupt these interactions, thereby leading to CaSR activation. These findings reveal myoclonus as a novel finding in an ADH1 patient with intracerebral calcifications.
Journal of the Endocrine Society
The Endocrine Society