Hypocalcemia, Autosomal Dominant 1 (HYPOC1)

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OMIM 57 601198 Disease Ontology 12 DOID:0090107 DOID:0090109 ICD10 33 E20.8 Orphanet 59 ORPHA263417 ORPHA428 ICD10 via Orphanet 34 E26.8 E20.8

MedGen 42 C3715128 C0342345 CN178679 MeSH 44 D006996 SNOMED-CT via HPO 69 263681008 48638002 76976005 18963009 21061000119107 35489007 78667006 48694002 16386004 281104002 43116000 128613002 246545002 313307000 84757009 91175000 10629009 278040002 56317004 42343007 84114007 21522001 71938000 52008007 271719001 45007003 166690008 43339004 5291005 20165001 190855004 55300003 91019004 274523007 237836003 3006004 102594003 44808001 698247007 39539005 698835006 more UMLS 73 C3715128 C0342345 C4048195 C0020598 more

NIH Rare Diseases : ⁵³ The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 428Disease definitionAutosomal dominant hypocalcemia (AD hypocalcemia) is a disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with abnormally low levels of parathyroid hormone (PTH) and persistant normal or elevated calciuria.EpidemiologyPrevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.Clinical descriptionClinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients (in whom the diagnosis is made by chance during a routine exam) to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures). In addition to hypocalcemia, hypercalciuria or relative hypercalciuria (hypercalciuria within the normal range, but relatively high in the presence of hypocalcemia) is present. Hyperphosphatemia, hypomagnesemia and hypermagnesuria are also common. Nephrocalcinosis and impaired renal function have been reported and cases of AD hypocalcemia with classical features of Bartter syndrome (BS; see this term) have been described (referred to as BS with hypocalcemia; see this term). Serum levels of PTH are normal or low. In addition to regulation by PTH, environmental factors also influence calcium homeostasis and may explain why an initially well-controlled hypocalcemia may become symptomatic at various stages of life.EtiologyAD hypocalcemia is caused by activating mutations of the geneCASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and urinary calcium excretion in response to variations in serum calcium levels. Gain-of-function CASR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal. Activating mutations in GNA11 (19p13.3) have also been described.Diagnostic methodsDiagnosis is made through analysis of calcium levels in the serum and urine and PTH levels, Molecular analysis of CaSR followed by GNA11 confirms diagnosis.Differential diagnosisDifferential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.Antenatal diagnosisAntenatal diagnosis is possible.Genetic counselingGenetic counseling may be proposed but patients should be informed about the wide variability in clinical presentation.Management and treatmentTreatment to normalize calcemia levels should be considered with caution, as any increase in calcium levels (even within the normal range) will be perceived by renal cells as hypercalcemia and lead to increased urinary calcium excretion, and possibly to nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and maintenance of calcium homeostasis, without being iatrogenic. Urine calcium levels should be monitored in order to avoid hypercalciuria rather than adapting treatment towards hypocalcemia. In asymptomatic and mildly symptomatic patients, treatment may not be necessary. Special care must be given to children as chronic hypocalcemia has deleterious effects on intellectual development. Treatment is based on administration of 1-alpha hydroxylated vitamin D (doses ranging from 0.5 to 1.5 micrograms/day in adults; higher doses are sometimes required in children). Careful monitoring of calciuria and regular kidney ultrasound are required. In cases where calcium homeostasis is difficult to achieve, exogenous PTH administered by infusion pump can be proposed.PrognosisThe prognosis is variable, depending on the severity of the hypocalcemia and the possible consequences of inadequate treatment.Visit the Orphanet disease page for more resources.

MalaCards based summary : Hypocalcemia, Autosomal Dominant 1, also known as autosomal dominant hypocalcemia, is related to hypomagnesemia 1, intestinal and hypoparathyroidism, familial isolated, and has symptoms including seizures, carpopedal spasm and muscle cramp. An important gene associated with Hypocalcemia, Autosomal Dominant 1 is CASR (Calcium Sensing Receptor), and among its related pathways/superpathways are CREB Pathway and Neuroscience. Affiliated tissues include kidney, bone and liver, and related phenotypes are emotional lability and depressivity

Disease Ontology : ¹² A metal metabolism disorder characterized by autosomal dominant inheritance of variable degrees of hypocalcemia with normal to low levels of parathyroid hormone.

Genetics Home Reference : ²⁵ Autosomal dominant hypocalcemia is characterized by low levels of calcium in the blood (hypocalcemia). Affected individuals can have an imbalance of other molecules in the blood as well, including too much phosphate (hyperphosphatemia) or too little magnesium (hypomagnesemia). Some people with autosomal dominant hypocalcemia also have low levels of a hormone called parathyroid hormone (hypoparathyroidism). This hormone is involved in the regulation of calcium levels in the blood. Abnormal levels of calcium and other molecules in the body can lead to a variety of signs and symptoms, although about half of affected individuals have no associated health problems.

OMIM : ⁵⁷ Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013). Thakker (2001) noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see 146200). Thakker (2001) suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. (601198)

UniProtKB/Swiss-Prot : ⁷⁵ Hypocalcemia, autosomal dominant 1: A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia.

Clinical features from OMIM:

601198

Search Clinical Trials , NIH Clinical Center for Hypocalcemia, Autosomal Dominant 1

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Search GEO for disease gene expression data for Hypocalcemia, Autosomal Dominant 1.