Autosomal Dominant Hypocalcemia 1

Mendelian MONDO:0011013 Pathograph 35 Show in embeddings browser Endocrine disorder

Autosomal dominant hypocalcemia type 1 is caused by activating CASR variants that alter calcium-sensing receptor signaling. Inappropriately low or normal PTH despite hypocalcemia reflects a shifted parathyroid response; PTH can be nearly undetectable. Variant-dependent signaling, receptor abundance and tissue context influence the phenotype. Renal calcium loss may be excessive relative to the low circulating calcium even when absolute urine calcium is within its reference range. Overt hypercalciuria is variable and can emerge or worsen when calcium and active vitamin D raise serum calcium. Clinical manifestations range from asymptomatic biochemical findings to seizures, renal calcifications and impaired kidney function. A minority of variants cause an additional Bartter-like salt-wasting phenotype. PTH replacement bypasses deficient hormone secretion, whereas investigational calcilytics inhibit the abnormal receptor signal.

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1
Inheritance
13
Pathophys.
14
Phenotypes
3
Gaps
35
Pathograph
1
Genes
7
Medical Actions
2
Subtypes
2
Trials
1
Models
29
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Usually caused by a heterozygous activating CASR variant, inherited or de novo. Variable expression and parental mosaicism mean that an unaffected parent or absent family history does not exclude ADH1. Rare biallelic cases have also been reported.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:7874174 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation."
States both the dominant mechanism and that heterozygosity is sufficient.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Only one report described a patient with ADH1 with a homozygous CASR variant"
The systematic review identifies an exceptional biallelic case; the usual inheritance remains autosomal dominant.
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Subtypes

2
Isolated autosomal dominant hypocalcemia type 1
The common presentation: hypocalcaemia with inappropriately low PTH and relative hypercalciuria, without a salt-wasting tubulopathy. Severity ranges from an incidental biochemical finding to seizures.
ADH1 with Bartter syndrome type V
Some activating CASR variants additionally cause a Bartter-like salt-wasting tubulopathy with hypokalemic metabolic alkalosis, hyperreninemia and hyperaldosteronism. CaSR-mediated inhibition of renal potassium recycling is a proposed route to impaired thick ascending limb salt transport. The historical label Bartter type V here denotes CASR-related disease; MAGED2-related transient antenatal Bartter syndrome is a different entity.
Show evidence (1 reference)
PMID:12241879 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartter's syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients."
The report establishing that activating CASR alleles can carry a Bartter phenotype alongside ADH1.
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Discussions and Knowledge Gaps

3
Why are symptoms and urinary calcium assessed together when titrating conventional treatment?
INTERPRETATION adh1_calcium_target_is_a_tradeoff
Attached to
pathophysiology#Renal Calcium Wasting treatments#Calcitriol and Calcium Supplementation
PTH deficiency and direct renal CaSR effects can both impair calcium conservation. Baseline renal activation is allele- and calcium-dependent rather than obligatorily maximal in every patient. Raising serum calcium may recruit or worsen renal calcium losses, so symptom relief must be balanced against urine calcium and renal outcomes. This supports individualized targets, not withholding acute calcium treatment or assuming every patient has the same threshold.
Show evidence (3 references)
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment"
The observed harm from raising calcium by the conventional route.
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion."
States the trade-off directly as the motivation for seeking an alternative.
PMID:35313217 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized."
One retrospective patient observation supports treatment dependence, not universal absence of untreated hypercalciuria.
How well can cellular variant assays predict individual calcilytic response?
KNOWLEDGE GAP adh1_in_vitro_activation_does_not_predict_response
Attached to
genetic#CASR treatments#Calcilytic (Negative Allosteric Modulator of the CaSR)
The five-adult NPSP795 study found no significant correlation between its cellular assay readouts and clinical PTH response. Small sample size, brief exposure and within-allele variability limit this negative result. Leu723Arg demonstrates G11-biased signaling in HEK293 cells, while other tested ADH1 variants activate multiple pathways. This establishes possible assay dependence but does not prove that signaling bias caused clinical nonresponse or short stature. Proposed residue contacts and genotype-guided drug selection require further validation.
Show evidence (3 references)
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any..."
The paired result - uniform in vitro behaviour, uncorrelated clinical behaviour - which is the gap itself.
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug."
The authors' own statement of the disconnect, quoted separately from the result that produced it.
PMID:39658204 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs)."
Direct evidence that a variant can be activating for one G-protein route and not others, which is one of the candidate explanations for the assay-to-clinic disconnect.
What does ADH1 need to be distinguished from, and why does the distinction change management?
INTERPRETATION adh1_vs_adh2_and_hypoparathyroidism
Attached to
diagnosis#CASR Sequencing
Low calcium with insufficient PTH occurs in ADH1, other genetic hypoparathyroidism and acquired parathyroid disorders. All may have renal treatment complications; urine calcium alone is not a definitive discriminator. Pathogenic activating CASR variants distinguish ADH1 from GNA11-related ADH2 and from other molecular causes. Activating CaSR autoantibodies are an acquired phenocopy, but a negative CASR test also warrants assessment of other genetic causes, surgery, autoimmunity and magnesium disturbances.
Show evidence (2 references)
PMID:28194447 SUPPORT INDIRECT BACKGROUND Human Clinical
"Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2)."
Defines ADH2 and its relationship to the receptor, which is the basis of the differential.
PMID:20374733 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating autoantibodies, respectively."
The review describes activating autoantibodies as one acquired phenocopy; negative CASR sequencing alone does not establish that diagnosis.
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Pathophysiology

13
Activating CASR Variant
Mechanism confidence: Established
Activating variants are usually heterozygous missense changes, but deletions and a nonsense variant have also been reported. Effects depend on the allele: reduced calcium-response thresholds, constitutive activation, altered G-protein selectivity or increased receptor abundance can contribute. Normal expression and trafficking observed for some variants do not generalize to all ADH1 alleles.
Genetic context CASR hgnc:1514 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CASR (hgnc:1514). hgnc:1514 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: GAIN_OF_FUNCTION
calcium-sensing receptor activity GO:0004930 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcium-sensing receptor activity, annotated with G protein-coupled receptor activity (GO:0004930), qualified as gain of function. GO:0004930 is a molecular function from the Gene Ontology.
Downstream
Increased Calcium-Sensing Receptor Signaling
Show evidence (3 references)
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to..."
The direct measurement of the leftward shift in the dose-response curve, which is the molecular claim this node makes. Graded IN_VITRO because it is a heterologous expression experiment in HEK-293 cells.
PMID:32386559 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The mGoF variants increased total and plasma membrane protein levels"
The two hypocalcemia-associated variants tested in HEK293 cells increased receptor abundance, contradicting a universal normal-expression mechanism.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"There were six deletion variants and one nonsense variant."
The published variant spectrum is predominantly, but not exclusively, missense.
Increased Calcium-Sensing Receptor Signaling
Mechanism confidence: Established
Many ADH1 variants increase signaling at lower extracellular calcium concentrations than wild-type CaSR. This is not a uniform shift of every pathway: Leu723Arg selectively enhanced G11 activation in HEK293 assays while Gq, Gi and Gs responses were unchanged. The molecular contacts proposed to explain that selectivity remain structural predictions.
calcium-sensing receptor signalling GO:0007186 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium-sensing receptor signalling, annotated with G protein-coupled receptor signaling pathway (GO:0007186). GO:0007186 is a biological process from the Gene Ontology.
Downstream
Suppressed Parathyroid Hormone Secretion Increased parathyroid CaSR signaling suppresses PTH release at lower calcium concentrations.
Impaired Renal Tubular Calcium Reabsorption Renal CaSR activation can reduce reabsorption, depending on allele, receptor expression and prevailing calcium. Low serum calcium may limit this branch at baseline.
Impaired Vasopressin-Dependent Water Reabsorption A candidate renal water-handling branch is supported by CaSR knock-in mice; its independent contribution in human ADH1 remains unresolved.
Reduced Renal MicroRNA Repression of CLDN14 Selected activating variants reduce transcription of CLDN14-targeting microRNAs in a heterologous cell model.
Show evidence (2 references)
PMID:7874174 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor."
The heterologous-expression measurement showing increased signalling output for the same calcium stimulus.
PMID:39658204 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling"
This allele-specific cellular result qualifies the common left-shift model.
Suppressed Parathyroid Hormone Secretion
Mechanism confidence: Established
PTH secretion is insufficient for the prevailing hypocalcemia. Measured concentrations may be low, inappropriately normal or nearly undetectable. This biochemical pairing identifies hypoparathyroid physiology but does not by itself distinguish CASR activation from other causes of deficient PTH.
parathyroid chief cell CL:0000446 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves parathyroid chief cell, annotated with chief cell of parathyroid gland (CL:0000446). CL:0000446 is a cell type from the Cell Ontology.
parathyroid hormone secretion GO:0035898 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased parathyroid hormone secretion (GO:0035898). GO:0035898 is a biological process from the Gene Ontology.
Animal models
Nuf mouse (Casr Leu723Gln) Mouse recapitulates Low baseline PTH and an acute PTH rise after calcilytic treatment support suppressed secretion downstream of mutant CaSR.
Downstream
Reduced Circulating Calcium
Renal Calcium Wasting Loss of PTH removes the hormone's own stimulus to distal tubular calcium reabsorption. This is the limb ADH1 shares with every other hypoparathyroidism.
Increased Renal Phosphate Retention Loss of PTH reduces its phosphaturic action, increasing renal phosphate reabsorption.
Hypoparathyroidism The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (1 reference)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"which reduces PTH secretion from parathyroid cells despite low serum calcium levels"
States the parathyroid limb explicitly, including that it operates despite low serum calcium.
Impaired Renal Tubular Calcium Reabsorption
Mechanism confidence: Established
Activated renal CaSR can reduce tubular calcium reabsorption in addition to the loss of PTH-dependent reabsorption. In Nuf Leu723Gln mice, baseline hypocalcemia was associated with unchanged fractional calcium excretion and no increased CLDN14 readout; raising calcium with a vitamin D analog induced renal CaSR-associated changes. A retrospective human A784V case showed a similar treatment-dependent pattern. These observations qualify obligatory baseline renal activation and do not exclude stronger renal effects of other alleles.
calcium ion transport GO:0006816 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion transport (GO:0006816). GO:0006816 is a biological process from the Gene Ontology.
Downstream
Renal Calcium Wasting Reduced tubular reabsorption increases calcium excretion relative to the filtered load.
Show evidence (3 references)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"the presence of CaSRs with increased sensitivity to calcium in the renal tubule also impairs reabsorption of calcium"
Background description of a renal CaSR pathway in addition to PTH-dependent reabsorption; the threshold study below limits generalization to obligatory baseline activation.
PMID:37754292 SUPPORT INDIRECT BACKGROUND Human Clinical
"Gain-of-function CASR variants increase the sensitivity of the CaSR to extracellular calcium, reducing PTH secretion and renal calcium reabsorption and resulting in hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypercalciuria."
States both limbs and, importantly, names hypomagnesaemia among the cardinal biochemical consequences rather than as a Bartter-subtype feature.
PMID:35313217 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels."
The conclusion concerns chronic renal CaSR activation inferred from CLDN14 in one mouse allele; it does not establish the absence of every renal signal.
Impaired Vasopressin-Dependent Water Reabsorption
Mechanism confidence: Provisional
CaSR knock-in mice showed reduced AQP2 abundance, increased AQP2 Ser261 phosphorylation and altered p38MAPK, ATF1 and miR-137 readouts. JTT-305 increased AQP2 abundance and reduced miR-137. These results support a candidate water-handling mechanism; concurrent changes in mineral metabolism and PTH prevent attributing the rescue solely to a direct collecting-duct effect. The pathway has not been demonstrated as the cause of polyuria in human Bartter-like ADH1.
AQP2 hgnc:634 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AQP2 (hgnc:634). hgnc:634 is a gene from the HUGO Gene Nomenclature Committee.
renal water homeostasis GO:0003091 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal water homeostasis (GO:0003091). GO:0003091 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:38367250 SUPPORT DIRECT PRIMARY RESULT Model Organism
"we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved..."
The measured AQP2 defect in a knock-in mouse built to model this disease.
PMID:38367250 SUPPORT DIRECT PRIMARY RESULT Model Organism
"In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice."
Calcilytic treatment reversed AQP2-associated readouts in the mouse model; concurrent systemic changes prevent isolating a direct collecting-duct effect.
Reduced Circulating Calcium
Mechanism confidence: Established
Insufficient PTH action reduces the hormonal support of calcium homeostasis; renal calcium loss may further lower circulating calcium. PTH and calcium must be interpreted together, but the low-calcium state is represented separately from its hormonal cause.
Animal models
Nuf mouse (Casr Leu723Gln) Mouse recapitulates Hypocalcemia and its partial pharmacological correction are observed in the Nuf model.
Downstream
Neuromuscular Irritability Low ionized calcium increases neuromuscular excitability.
Intracranial Calcium Deposition Chronic mineral imbalance accompanies brain calcification, but the site-specific causal intermediates remain unresolved.
Hypocalcemia The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (1 reference)
PMID:31063613 SUPPORT INDIRECT BACKGROUND Human Clinical
"Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria."
The three-part biochemical signature stated compactly in a clinical study of ADH1 patients.
Renal Calcium Wasting
Mechanism confidence: Established
Urine calcium can be inappropriately high relative to hypocalcemia without exceeding the absolute reference range. Loss of PTH action and renal CaSR effects can both contribute, with their relative importance varying by allele and treatment. In a selected literature aggregate, frank hypercalciuria was reported in 34% of 91 patients with pretreatment biochemistry.
Downstream
Renal Calcium Deposition Sustained excess urinary calcium promotes crystal formation and renal deposition through urine supersaturation.
Reduced Circulating Calcium Persistent urinary calcium loss can contribute to negative calcium balance.
Hypercalciuria The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (2 references)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"The combination of both loss of PTH and gain of CaSR activity provides a dual mechanism for hypercalciuria in ADH1"
Names the convergence of the two upstream limbs on this node, which is the reason this entry models them separately.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed."
Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
Increased Renal Phosphate Retention
Mechanism confidence: Established
Reduced PTH action increases renal phosphate reabsorption, contributing to raised serum phosphate.
Downstream
Hyperphosphatemia
Show evidence (1 reference)
PMID:37754292 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Mean blood levels of intact PTH, magnesium, and 1,25-dihydroxy-vitamin D increased, whereas phosphorus levels and tubular reabsorption of phosphate decreased"
Phosphate handling and PTH changed together during encaleret treatment; this does not isolate PTH as the sole mediator.
Neuromuscular Irritability
Mechanism confidence: Established
Reduced ionized calcium increases neuromuscular excitability, contributing to paresthesia, tetany and seizures. Symptoms vary within families, while a larger published-case aggregate associated lower calcium and younger age with more severe symptoms. Persistent epilepsy in individual patients need not track acute calcium changes.
Downstream
Seizures The process contributes to this observed clinical manifestation; occurrence and severity vary.
Tetany The process contributes to this observed clinical manifestation; occurrence and severity vary.
Paresthesia The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (3 references)
PMID:22863393 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Although hypocalcemic patients commonly present with symptoms of neuromuscular irritability with perioral numbers paresthesias, tingling, seizures and, bronchospasm; hypocalcemia may be identified on the biochemical profile of an asymptomatic patient."
Names the syndrome and its manifestations, and records that it may be absent altogether. The source's typo "numbers" for "numbness" is reproduced as published.
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia."
The observation that symptom burden does not track calcium level, measured within a single kindred carrying one variant.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients"
Aggregated published cases show an association that a single kindred cannot exclude.
Renal Calcium Deposition
Mechanism confidence: Established
Renal calcium deposition and urinary stones can accompany hypercalciuria, including during conventional treatment. Selected case series cannot establish a universal untreated course or irreversibility. This renal route is distinct from intracranial calcification.
Downstream
Nephrocalcinosis The process contributes to this observed clinical manifestation; occurrence and severity vary.
Nephrolithiasis The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (1 reference)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"As a result, nephrocalcinosis and nephrolithiasis are more common in subjects with ADH1 than other forms of hypoparathyroidism"
Ties the renal deposits specifically to ADH1's extra renal limb rather than to hypoparathyroidism in general.
Reduced Renal MicroRNA Repression of CLDN14
Mechanism confidence: Provisional
Selected ADH-associated CaSR variants reduce pri-miR-374 transcription in HEK293 cells; miR-9-1 effects vary by variant. Renal antagomir experiments support a pathway in which loss of microRNA repression increases CLDN14. Constitutive activation of this pathway in every untreated ADH1 kidney has not been demonstrated.
Downstream
Increased Renal CLDN14 Expression Reduced microRNA-mediated silencing increases the abundance of the paracellular transport inhibitor.
Show evidence (1 reference)
PMID:25071082 SUPPORT DIRECT PRIMARY RESULT In Vitro
"All three mutations significantly reduced the pri-miR-374 transcript levels by 30% compared with wild-type CaSR"
The ADH variants were expressed in HEK293 cells; this is not a measurement in patient kidneys.
Increased Renal CLDN14 Expression
Mechanism confidence: Provisional
Increased claudin-14 inhibits the cation-permeable claudin pathway in the thick ascending limb. Mouse knockout, antagomir, drug and tubule-perfusion experiments support this route. The HDAC-inhibitor rescue used cinacalcet-treated wild-type mice, rather than a genetic ADH1 mouse; no human efficacy is established.
CLDN14 hgnc:2035 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CLDN14 (hgnc:2035). hgnc:2035 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Renal Tubular Calcium Reabsorption Claudin-14 reduces paracellular cation transport in the thick ascending limb.
Show evidence (1 reference)
PMID:25071082 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the CLDN14 protein level was 3.25-fold higher with anti–miR-374 than scrambled antagomir treatment"
Antagomir-treated wild-type mice test release of CLDN14 repression; these are not CASR knock-in mice.
Intracranial Calcium Deposition
Mechanism confidence: Provisional
Basal ganglia and other intracranial calcifications occur in some patients with chronic mineral imbalance. A direct path from urinary calcium loss to brain deposition is not established; local mechanisms and contributions of hypocalcemia, phosphate balance and treatment remain unresolved.
Downstream
Intracranial Calcification The process contributes to this observed clinical manifestation; occurrence and severity vary.
Show evidence (1 reference)
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"basal ganglia calcification, identified by CT scanning in all five individuals"
Occurrence in the five imaged members of a selected seven-member kindred; not population prevalence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Hypocalcemia 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Endocrine 1
Hypoparathyroidism HP:0000829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoparathyroidism (HP:0000829). HP:0000829 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism."
Establishes the hypoparathyroid phenotype and ADH1's place among its genetic causes.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed."
Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
Eye 1
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Left unconnected: human cases establish occurrence, but the proposed lens mechanism has not been demonstrated in ADH1 patients. Nuf lens opacity did not show substantial lens mineralization.
Show evidence (1 reference)
PMID:35818129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He was diagnosed with congenital cataracts at the age of 14 years."
An observed cataract in an ADH1 patient with long-standing poorly controlled hypocalcaemia.
Genitourinary 4
Hypercalciuria HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33112267 SUPPORT INDIRECT BACKGROUND Human Clinical
"Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism."
States the phenotype and, importantly, that it exceeds that of other hypoparathyroidisms.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed."
Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
Nephrocalcinosis HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Her renal ultrasound at two months of age demonstrated nephrocalcinosis."
Nephrocalcinosis was observed at two months; the infant had already received calcium and calcitriol, so this is not evidence of untreated disease.
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals."
Documents occurrence in the cited report; no disease-wide frequency is inferred.
Nephrolithiasis HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"he continued to have marked hypercalciuria, and he developed multiple, recurrent renal stones. He underwent lithotripsy at the age of 2 years"
Documents stones as a clinical course in an ADH1 patient, with the intervention they required.
Chronic Kidney Disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Left unconnected: the reports establish renal impairment, but do not isolate crystal injury, treatment exposure and other contributors to a single causal route.
Show evidence (1 reference)
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment"
Renal impairment observed in the original ADH1 kindreds, and attributed there to the treatment rather than only to the disease.
Metabolism 4
Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31063613 SUPPORT INDIRECT BACKGROUND Human Clinical
"Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria."
States hypocalcaemia as a defining feature of the ADH1 cohort studied.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed."
Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
Hyperphosphatemia HP:0002905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperphosphatemia (HP:0002905). HP:0002905 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35818129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hypocalcemia, hyperphospheremia, and hypoparathyroidism were clearly evident, and brain computed tomography showed multiple intracranial calcifications"
The biochemical triad as measured in the reported patient. The source spells the finding "hyperphospheremia"; the quote is reproduced as published.
PMID:35879818 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed."
Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
Hypomagnesemia HP:0002917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomagnesemia (HP:0002917). HP:0002917 is a phenotype from the Human Phenotype Ontology.
Renal magnesium handling and possible treatment effects are not resolved into a dedicated causal branch here.
Show evidence (2 references)
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia."
The full biochemical signature in a seven-member kindred, including magnesium and including the observation that PTH is low but detectable.
PMID:37754292 SUPPORT INDIRECT BACKGROUND Human Clinical
"The CaSR primarily regulates parathyroid hormone (PTH) secretion and renal calcium and magnesium reabsorption."
The mechanistic basis - magnesium is handled by the same receptor, so its loss is expected rather than incidental.
Hypokalemia HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Restricted to the Bartter-like phenotype; the general calcium-reabsorption branch does not represent the full salt-transport mechanism.
Show evidence (1 reference)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"which accounted not only for his ADH1 but also type 5 Bartter syndrome with persistent hypokalemia, hypomagnesemia, and polyuria"
An observed Bartter-type-V presentation in a genetically confirmed ADH1 patient, which is why this phenotype is tagged to that subtype.
Musculoskeletal 2
Tetany HP:0001281 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetany (HP:0001281), qualified as temporality recurrent. HP:0001281 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She also experienced frequent episodes of tetany, manifesting as an inability to walk."
A directly observed clinical description of tetany and its functional impact.
Intracranial Calcification Basal ganglia calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135). HP:0002135 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35818129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Computed tomography of the brain revealed multiple intracranial calcifications, and electroencephalography showed extensive epileptic discharges."
Imaging documentation of the intracranial deposits in a genetically confirmed patient.
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"basal ganglia calcification, identified by CT scanning in all five individuals"
Documents occurrence in the cited report; no disease-wide frequency is inferred.
Nervous System 2
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as temporality recurrent. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:35818129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant."
Seizure as the presenting manifestation, attributed to the hypocalcaemia.
Paresthesia HP:0003401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paresthesia (HP:0003401). HP:0003401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16128246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia."
Documents occurrence in the cited report; no disease-wide frequency is inferred.
🧬

Genetic Associations

1
CASR
Gene: CASR hgnc:1514 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CASR (hgnc:1514). hgnc:1514 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:20374733 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Heterozygous loss-of-function mutations cause familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong mild hypercalcemia is generally asymptomatic. Homozygous inactivating mutations give rise to neonatal severe hyperparathyroidism (NSHPT) with extreme hypercalcemia and marked..."
The full allelic series in one passage, which is what places ADH1 at the gain-of-function end of a graded dosage relationship rather than treating it as an isolated phenotype.
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease."
Establishes the allelic spectrum and its cosegregation across six kindreds.
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"There was significant variability in response clinically across genotypes."
Documents variable short-term calcilytic response in five participants; it does not establish a genotype-based severity or drug-response prediction rule.
+ 1 more reference
💊

Medical Actions

7
Calcitriol and Calcium Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Active vitamin D, with calcium supplementation when needed, can relieve symptomatic hypocalcemia. Treatment is titrated to symptoms and urinary calcium rather than routinely normalizing serum calcium, because raising calcium can aggravate renal losses. Some asymptomatic patients within an individualized target range and without hypercalciuria can be monitored without medication. Recommendations are based largely on small ADH1 studies and broader hypoparathyroidism practice.
Mechanism Target:
BYPASSES Reduced Circulating Calcium — Raises circulating calcium without correcting CASR activation or restoring endogenous PTH secretion.
Show evidence (2 references)
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment."
The observed treatment-associated renal harm supports cautious titration and urinary-calcium monitoring; this quotation does not establish calcitriol efficacy.
PMID:39607645 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In asymptomatic patients without hypercalciuria we recommend not to commence medical treatment if serum calcium is within the target range"
The proposed approach is conditional on symptoms, urine calcium and the target range; it is not a blanket recommendation to leave hypocalcemia untreated.
Recombinant Human PTH(1-84)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: recombinant parathyroid hormone NCIT:C62555 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant parathyroid hormone (NCIT:C62555). NCIT:C62555 is a therapeutic agent from the NCI Thesaurus.
Platform: Peptide
Historical ADH1 evidence includes an uncontrolled three-child series with improved calcium balance and reduced calcium/calcitriol requirements. Regimens were individualized; one child required twice-daily dosing on several days each week, and another comparison followed prior PTH(1-34), limiting attribution. These reports do not establish prevention or reversal of renal calcifications. Takeda announced discontinuation of NATPAR/NATPARA manufacturing at the end of 2024, so this evidence should not imply routine current availability.
Mechanism Target:
BYPASSES Suppressed Parathyroid Hormone Secretion — Supplies exogenous PTH activity downstream of suppressed secretion; it does not restore endogenous PTH release or correct the CASR variant.
Show evidence (2 references)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol."
The result, with its own scope stated - three subjects, compared against conventional therapy rather than against a control arm.
url:https://www.takeda.com/en-us/newsroom/statements/2022/takeda-to-discontinue-manufacturing-of-natpar-natpara/ SUPPORT DIRECT BACKGROUND Other
"at the end of 2024 due to unresolved supply issues"
The manufacturer announcement limits present availability; the clinical case-series evidence is historical.
Palopegteriparatide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: palopegteriparatide CHEBI:759036 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses palopegteriparatide (CHEBI:759036). CHEBI:759036 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
A long-acting PTH(1-34) prodrug approved by the FDA for adult hypoparathyroidism. ADH1-specific evidence remains limited: a broader pivotal trial included very few ADH1 patients, and a 2026 report described off-label treatment of one 16-year-old. Tetany resolved, calcium and phosphate balance improved, and active vitamin D and calcium were stopped while low-dose hydrochlorothiazide, magnesium and potassium continued. Urinary calcium improved in the reported follow-up, but persistent hypocalcemia and hyperphosphatemia and the uncontrolled design limit claims of complete correction or renal protection. Pediatric efficacy and long-term safety are not established.
Mechanism Target:
BYPASSES Suppressed Parathyroid Hormone Secretion — Provides sustained exogenous PTH activity without restoring the suppressed endogenous secretion.
Show evidence (3 references)
PMID:42388864 SUPPORT INDIRECT BACKGROUND Human Clinical
"Evidence on the use of long-acting PTH analogs in pediatric ADH1 remains scarce."
The authors describe the limited pediatric evidence base. This background statement supports the caution about generalizing from a single case, rather than an efficacy estimate.
url:https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-yorvipath SUPPORT DIRECT BACKGROUND Other
"approved for the treatment of hypoparathyroidism in adults"
The FDA indication is adult hypoparathyroidism; the pediatric case is off-label.
PMID:42388864 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At the final maintenance dose, both alfacalcidol and calcium supplementation were successfully discontinued."
The one-patient result is supported alongside continued low-dose thiazide use; clinical benefit does not establish renal protection.
Thiazide Diuretic
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: thiazide diuretic NCIT:C49185 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses thiazide diuretic (NCIT:C49185). NCIT:C49185 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
An adjunct to reduce urinary calcium in selected patients, often combined with a low-sodium diet when blood pressure permits. Monitor potassium, magnesium and blood pressure. Proposed ADH1 recommendations advise against thiazides in Bartter-like disease with hypokalemia and in pre-existing hypomagnesemia or high urinary magnesium losses.
Mechanism Target:
MODULATES Renal Calcium Wasting — Increases distal tubular calcium reabsorption, opposing the renal limb at its output rather than at its cause.
Show evidence (2 references)
PMID:22863393 SUPPORT DIRECT REVIEW SYNTHESIS Other
"In the long-term management of hypoparathyroidism thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor."
The review supports thiazide use as an adjunct; this is not a genotype-stratified comparative trial and the ADH1-specific contraindications remain important.
PMID:39607645 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"We recommend against the use of thiazides in ADH1 patients with Bartter-like syndrome with hypokalemia"
The authors propose ADH1-specific care recommendations from limited studies; this caveat restricts thiazide use.
Calcilytic (Negative Allosteric Modulator of the CaSR)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: encaleret CHEBI:749959 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses encaleret (CHEBI:749959). CHEBI:749959 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Investigational negative allosteric modulators reduce CaSR signaling. A three-day NPSP795 study in five adults increased PTH without significant improvement in ionized calcium or fractional calcium excretion. An uncontrolled encaleret phase 2b study in 13 adults improved serum calcium and hypercalciuria over 24 outpatient weeks. The 2026 CALIBRATE conference report adds randomized phase 3 evidence: at week 24, 75.6% of encaleret participants achieved both blood and urine calcium targets, compared with 19% in the concurrent standard-care group. The primary comparison was separately within the encaleret arm against its own pretreatment standard-care period (75.6% versus 4.4%). These are biochemical endpoints reported in a conference abstract; long-term kidney protection is not established. FDA accepted the encaleret application in July 2026, with approval still pending at review. AXT914 and related quinazolinones have preclinical evidence, not established clinical ADH1 efficacy.
Mechanism Target:
INHIBITS Increased Calcium-Sensing Receptor Signaling — Reduces abnormal CaSR signaling; sensitivity and pharmacological response can vary across alleles and compounds.
Show evidence (7 references)
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1."
Direct evidence of increased PTH in five adults over three days supports pharmacological proof of concept; it does not establish sustained biochemical correction or clinical benefit.
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Fractional excretion of calcium (FECa) trended down but not significantly so."
The negative result on the renal endpoint in the earlier compound, quoted separately so the limitation is recorded structurally rather than only in prose.
PMID:37754292 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Encaleret corrected hypocalcemia and reduced hypercalciuria during the inpatient periods and the 24-week outpatient period."
The uncontrolled 13-adult study improved both endpoints. This does not establish superiority over all PTH-based approaches.
+ 4 more references
Teriparatide (PTH 1-34)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: teriparatide CHEBI:135983 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses teriparatide (CHEBI:135983). CHEBI:135983 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Off-label PTH(1-34), by repeated injection or pump, has been studied in small ADH1 cohorts. A retrospective six-patient series reported fewer seizures during infusion compared with prior conventional treatment. Mixed-etiology hypoparathyroidism trials contain small ADH1 subgroups and do not establish uniform normalization of urinary calcium or prevention of renal disease.
Mechanism Target:
BYPASSES Suppressed Parathyroid Hormone Secretion — Replaces PTH action downstream of deficient secretion.
Show evidence (1 reference)
PMID:39607645 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"SC PTH1-34 infusion reduced the number of seizures from 2 to 0.01 per month"
The review summarizes a retrospective six-patient ADH1 cohort; this was not a randomized comparison.
Acute Intravenous Calcium
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcium gluconate CHEBI:3309 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium gluconate (CHEBI:3309). CHEBI:3309 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Severe symptomatic hypocalcemia may require intravenous calcium with cardiac and biochemical monitoring. Acute stabilization is distinct from long-term attempts to normalize calcium, which can worsen urinary calcium losses.
Mechanism Target:
BYPASSES Reduced Circulating Calcium — Provides calcium during acute symptomatic decompensation.
Show evidence (1 reference)
PMID:39607645 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"IV calcium gluconate should be administered under cardiac monitoring"
The recommendation applies to acute severe hypocalcemia, not routine correction of chronic asymptomatic biochemical values.
🔬

Biochemical Markers

3
Serum ionised calcium (Decreased)
Context: Ionized calcium or albumin-adjusted total calcium is interpreted with simultaneous PTH. Ionized calcium is the receptor ligand; total calcium requires consideration of albumin and clinical context.
Pathograph Readouts
Readout Of Reduced Circulating Calcium Negative Diagnostic
Measures circulating calcium, not receptor sensitivity directly.
Show evidence (1 reference)
PMID:31063613 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation."
Uses ionised calcium as the monitored analyte in an ADH1 study, which is the measurement this readout names.
Intact parathyroid hormone (Decreased)
Context: A low or reference-range PTH is inappropriate in hypocalcemia. This pairing supports deficient PTH physiology but does not uniquely diagnose ADH1.
Pathograph Readouts
Readout Of Suppressed Parathyroid Hormone Secretion Negative Diagnostic
Reports the parathyroid limb of the receptor lesion.
Show evidence (1 reference)
PMID:31063613 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels."
The treatment study measures circulating PTH as a pharmacodynamic endpoint; support for its diagnostic interpretation is indirect.
Urinary calcium excretion (Increased)
Context: Measure 24-hour calcium excretion or an age-appropriate spot calcium:creatinine ratio and interpret against serum calcium, kidney function, age and treatment. Relative calcium wasting and frank hypercalciuria are distinct.
Pathograph Readouts
Readout Of Renal Calcium Wasting Positive Monitoring
Reports the renal limb, and tracks whether treatment is aggravating it.
Show evidence (1 reference)
PMID:33112267 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year."
Urinary calcium used as the monitored endpoint that determined whether the treatment change was working.
🔬

Diagnosis

3
Paired Serum Calcium and Intact PTH
Measure ionized or albumin-adjusted calcium together with intact PTH, phosphate, magnesium and renal function. Inappropriately low or normal PTH supports hypoparathyroid physiology; the finding is not specific to CASR activation. Urinary calcium informs phenotype and treatment risk.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:8813042 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor."
This clinical pattern prompted investigation of CASR in selected families; it is not a specific diagnostic test by itself.
CASR Sequencing
A pathogenic or likely pathogenic activating CASR variant in the appropriate clinical context establishes ADH1. A VUS or a loss-of-function CASR variant does not. If testing is nondiagnostic, assess GNA11-related ADH2, other genetic hypoparathyroidism, acquired causes and magnesium disturbances; negative CASR sequencing alone does not establish an activating autoantibody disorder.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35818129 SUPPORT INDIRECT BACKGROUND Human Clinical
"It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney."
Identifies CASR as the gene to sequence and states both tissues in which the receptor acts.
Renal and Mineral Surveillance
Assess serum calcium, phosphate, magnesium, creatinine and vitamin D status, and urinary calcium during follow-up and after treatment changes. Renal imaging evaluates nephrocalcinosis or stones. Monitoring intensity depends on symptoms, biochemical stability, age, treatment and kidney function; published ADH1 schedules are proposed practice recommendations rather than validated outcome-based protocols.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39607645 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"serum calcium should be remeasured within days after adjustments in medical treatment."
The review discusses broader hypoparathyroidism monitoring recommendations and the need for closer ADH1 assessment.
📊

Prevalence

1
DiscovEHR cohort from one US healthcare system, predominantly of northern European ancestry
Point Prevalence 3.9 per 100,000 1–9 per 100,000
Estimated from two unrelated genetically and functionally supported cases among 51,289 sequenced participants. Three carriers included a related pair before deduplication. This is a cohort genetic-prevalence estimate, not worldwide diagnosed-case prevalence; very few cases and incomplete clinical phenotyping limit precision and generalizability.
Show evidence (1 reference)
PMID:32386559 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Two unrelated individuals with ADH1 yielded a prevalence of 3.9 per 100,000."
The primary healthcare-cohort analysis supports the bounded estimate.
🔬

Clinical Trials

2
NCT04581629 PHASE_II COMPLETED
Completed open-label encaleret dose-ranging phase 2 study with 13 adults. The published letter describes 24 outpatient weeks after inpatient dose-ranging; it does not establish comparative efficacy or long-term renal protection. Completion status checked against ClinicalTrials.gov in September 2026.
Target Phenotypes: Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology. Hypercalciuria HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04581629 SUPPORT DIRECT BACKGROUND Human Clinical
"The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1)."
The registry describes study design and intended population; it is not evidence of a positive outcome.
NCT05680818 PHASE_III ACTIVE_NOT_RECRUITING
CALIBRATE is an open-label randomized encaleret versus standard-care study in ADH1, with 67 participants. The registry lists active, not recruiting in September 2026, despite completion of the primary endpoint period. Conference results distinguish a primary within-encaleret comparison against baseline standard care from concurrent between-arm comparisons; extension follow-up remains ongoing.
Show evidence (2 references)
clinicaltrials:NCT05680818 SUPPORT DIRECT BACKGROUND Human Clinical
"The primary purpose of the study is to understand the effectiveness, safety, and tolerability of encaleret"
The registry describes study design and intended population; it is not evidence of a positive outcome.
DOI:10.1093/ejendo/lvag096.130 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"More participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges compared to those randomized to SoC"
Concurrent randomized biochemical comparison at week 24: 45 encaleret participants and 21 standard-care participants assessed. Conference abstract evidence is distinct from a complete trial report and from the primary within-person comparison.
🐁

Animal Models

1
Nuf mouse (Casr Leu723Gln)
The Nuf Leu723Gln allele arose in an isopropyl methane sulfonate mutagenesis screen for lens abnormalities. Heterozygotes and homozygotes develop low calcium and PTH; homozygotes have more severe manifestations. Baseline hypercalciuria is not reproduced reliably. It is one allele-specific model, not the complete human spectrum. The original pathology study found ectopic mineralization mainly in homozygotes; lens opacities reflected fiber damage without substantial lens mineralization. Cataracts are therefore not treated as a readout of renal calcium deposition.
Species
Mouse
Genotype
Casr Leu723Gln (Nuf), heterozygous and homozygous
Publication
PMID:33103030
Pathograph links
Suppressed Parathyroid Hormone Secretion recapitulates fidelity: moderate Low baseline PTH and an acute PTH rise after calcilytic treatment support suppressed secretion downstream of mutant CaSR.
Limitations: One allele, acute dosing and different drug exposures limit comparison with the human NPSP795 study. Mouse blood calcium improved without reaching untreated wild-type levels; neither this endpoint nor PTH directly measures receptor EC50.
Readouts
Plasma PTH response to calcilytic
Direction: RESTORED
Interpretation: PTH increased acutely after CaSR antagonism, providing a hormonal output readout rather than a direct receptor sensitivity assay.
Show evidence (1 reference)
PMID:33103030 SUPPORT DIRECT PRIMARY RESULT Model Organism
"NPSP795 significantly increased plasma PTH concentrations in a dose-dependent manner with the 30 mg/kg dose causing a maximal (≥10-fold) rise in PTH."
The dose-response measurement behind this readout.
Reduced Circulating Calcium recapitulates fidelity: moderate Hypocalcemia and its partial pharmacological correction are observed in the Nuf model.
Limitations: Short-term single-dose mouse results do not establish equivalent human dosing, complete correction or durable renal benefit.
Readouts
Plasma adjusted-calcium response to calcilytic
Direction: INCREASED
Interpretation: Calcium rose after a single dose but remained below untreated wild-type values. This integrated endpoint does not resolve direct renal and PTH-mediated contributions.
Show evidence (1 reference)
PMID:33103030 SUPPORT DIRECT PRIMARY RESULT Model Organism
"NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L"
The measured calcium correction in the heterozygous mouse.
Show evidence (1 reference)
PMID:33103030 SUPPORT DIRECT PRIMARY RESULT Model Organism
"NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L"
The measured calcium correction in the heterozygous mouse.
Show evidence (2 references)
PMID:33103030 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Nuf mice, which have hypocalcemia in association with a gain-of-function CaSR mutation, Leu723Gln"
Establishes the model's genotype and that it reproduces the hypocalcaemic phenotype.
PMID:15347804 SUPPORT DIRECT PRIMARY RESULT Model Organism
"were treated with isopropyl methane sulfonate and bred so that spermatogonial stem cells were sampled."
The original strain report records induced mutagenesis rather than spontaneous origin.
{ }

Source YAML

click to show 
name: Autosomal Dominant Hypocalcemia 1
creation_date: "2026-08-28T16:30:00Z"
category: Mendelian
description: >-
  Autosomal dominant hypocalcemia type 1 is caused by activating CASR variants that alter calcium-sensing
  receptor signaling. Inappropriately low or normal PTH despite hypocalcemia reflects a shifted parathyroid
  response; PTH can be nearly undetectable. Variant-dependent signaling, receptor abundance and tissue
  context influence the phenotype. Renal calcium loss may be excessive relative to the low circulating
  calcium even when absolute urine calcium is within its reference range. Overt hypercalciuria is variable
  and can emerge or worsen when calcium and active vitamin D raise serum calcium. Clinical manifestations
  range from asymptomatic biochemical findings to seizures, renal calcifications and impaired kidney function.
  A minority of variants cause an additional Bartter-like salt-wasting phenotype. PTH replacement bypasses
  deficient hormone secretion, whereas investigational calcilytics inhibit the abnormal receptor signal.
disease_term:
  preferred_term: autosomal dominant hypocalcemia 1
  term:
    id: MONDO:0011013
    label: autosomal dominant hypocalcemia 1
synonyms:
- ADH1
- HYPOC1
- autosomal dominant hypocalcemia type 1
- CASR autosomal dominant hypocalcemia
- hypocalcemia, autosomal dominant 1, with Bartter syndrome
parents:
- Endocrine disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Usually caused by a heterozygous activating CASR variant, inherited or de novo. Variable expression
    and parental mosaicism mean that an unaffected parent or absent family history does not exclude ADH1.
    Rare biallelic cases have also been reported.
  evidence:
  - reference: PMID:7874174
    reference_title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.
    explanation: States both the dominant mechanism and that heterozygosity is sufficient.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only one report described a patient with ADH1 with a homozygous CASR variant
    explanation: The systematic review identifies an exceptional biallelic case; the usual inheritance remains autosomal dominant.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
has_subtypes:
- name: Isolated ADH1
  display_name: Isolated autosomal dominant hypocalcemia type 1
  description: >-
    The common presentation: hypocalcaemia with inappropriately low PTH and
    relative hypercalciuria, without a salt-wasting tubulopathy. Severity ranges
    from an incidental biochemical finding to seizures.
- name: Bartter type V
  display_name: ADH1 with Bartter syndrome type V
  description: >-
    Some activating CASR variants additionally cause a Bartter-like salt-wasting tubulopathy with hypokalemic
    metabolic alkalosis, hyperreninemia and hyperaldosteronism. CaSR-mediated inhibition of renal potassium
    recycling is a proposed route to impaired thick ascending limb salt transport. The historical label
    Bartter type V here denotes CASR-related disease; MAGED2-related transient antenatal Bartter syndrome
    is a different entity.
  evidence:
  - reference: PMID:12241879
    reference_title: Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartter's syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients.
    explanation: The report establishing that activating CASR alleles can carry a Bartter phenotype alongside ADH1.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
pathophysiology:
- name: Activating CASR Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Activating variants are usually heterozygous missense changes, but deletions and a nonsense variant
    have also been reported. Effects depend on the allele: reduced calcium-response thresholds, constitutive
    activation, altered G-protein selectivity or increased receptor abundance can contribute. Normal expression
    and trafficking observed for some variants do not generalize to all ADH1 alleles.
  genetic_context:
    gene:
      preferred_term: CASR
      term:
        id: hgnc:1514
        label: CASR
    functional_impact_category: GAIN_OF_FUNCTION
  molecular_functions:
  - preferred_term: calcium-sensing receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  downstream:
  - target: Increased Calcium-Sensing Receptor Signaling
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor.
    explanation: The direct measurement of the leftward shift in the dose-response curve, which is the molecular claim this node makes. Graded IN_VITRO because it is a heterologous expression experiment in HEK-293 cells.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The mGoF variants increased total and plasma membrane protein levels
    explanation: The two hypocalcemia-associated variants tested in HEK293 cells increased receptor abundance, contradicting a universal normal-expression mechanism.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were six deletion variants and one nonsense variant.
    explanation: The published variant spectrum is predominantly, but not exclusively, missense.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Increased Calcium-Sensing Receptor Signaling
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Many ADH1 variants increase signaling at lower extracellular calcium concentrations than wild-type
    CaSR. This is not a uniform shift of every pathway: Leu723Arg selectively enhanced G11 activation
    in HEK293 assays while Gq, Gi and Gs responses were unchanged. The molecular contacts proposed to
    explain that selectivity remain structural predictions.
  biological_processes:
  - preferred_term: calcium-sensing receptor signalling
    modifier: INCREASED
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
  downstream:
  - target: Suppressed Parathyroid Hormone Secretion
    description: Increased parathyroid CaSR signaling suppresses PTH release at lower calcium concentrations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Impaired Renal Tubular Calcium Reabsorption
    description: Renal CaSR activation can reduce reabsorption, depending on allele, receptor expression and prevailing calcium. Low serum calcium may limit this branch at baseline.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Impaired Vasopressin-Dependent Water Reabsorption
    description: A candidate renal water-handling branch is supported by CaSR knock-in mice; its independent contribution in human ADH1 remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Renal MicroRNA Repression of CLDN14
    description: Selected activating variants reduce transcription of CLDN14-targeting microRNAs in a heterologous cell model.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25071082
      reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: All three mutations significantly reduced the pri-miR-374 transcript levels by 30% compared with wild-type CaSR
      explanation: The ADH variants were expressed in HEK293 cells; this is not a measurement in patient kidneys.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:7874174
    reference_title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor.
    explanation: The heterologous-expression measurement showing increased signalling output for the same calcium stimulus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39658204
    reference_title: An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling
    explanation: This allele-specific cellular result qualifies the common left-shift model.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Suppressed Parathyroid Hormone Secretion
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PTH secretion is insufficient for the prevailing hypocalcemia. Measured concentrations may be low,
    inappropriately normal or nearly undetectable. This biochemical pairing identifies hypoparathyroid
    physiology but does not by itself distinguish CASR activation from other causes of deficient PTH.
  cell_types:
  - preferred_term: parathyroid chief cell
    term:
      id: CL:0000446
      label: chief cell of parathyroid gland
  biological_processes:
  - preferred_term: parathyroid hormone secretion
    modifier: DECREASED
    term:
      id: GO:0035898
      label: parathyroid hormone secretion
  downstream:
  - target: Reduced Circulating Calcium
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Renal Calcium Wasting
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of PTH removes the hormone's own stimulus to distal tubular calcium
      reabsorption. This is the limb ADH1 shares with every other
      hypoparathyroidism.
  - target: Increased Renal Phosphate Retention
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of PTH reduces its phosphaturic action, increasing renal phosphate reabsorption.
  - target: Hypoparathyroidism
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism.
      explanation: Establishes the hypoparathyroid phenotype and ADH1's place among its genetic causes.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which reduces PTH secretion from parathyroid cells despite low serum calcium levels
    explanation: States the parathyroid limb explicitly, including that it operates despite low serum calcium.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Impaired Renal Tubular Calcium Reabsorption
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Activated renal CaSR can reduce tubular calcium reabsorption in addition to the loss of PTH-dependent
    reabsorption. In Nuf Leu723Gln mice, baseline hypocalcemia was associated with unchanged fractional
    calcium excretion and no increased CLDN14 readout; raising calcium with a vitamin D analog induced
    renal CaSR-associated changes. A retrospective human A784V case showed a similar treatment-dependent
    pattern. These observations qualify obligatory baseline renal activation and do not exclude stronger
    renal effects of other alleles.
  biological_processes:
  - preferred_term: calcium ion transport
    modifier: DECREASED
    term:
      id: GO:0006816
      label: calcium ion transport
  downstream:
  - target: Renal Calcium Wasting
    description: Reduced tubular reabsorption increases calcium excretion relative to the filtered load.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the presence of CaSRs with increased sensitivity to calcium in the renal tubule also impairs reabsorption of calcium
    explanation: Background description of a renal CaSR pathway in addition to PTH-dependent reabsorption; the threshold study below limits generalization to obligatory baseline activation.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gain-of-function CASR variants increase the sensitivity of the CaSR to extracellular calcium, reducing PTH secretion and renal calcium reabsorption and resulting in hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypercalciuria.
    explanation: States both limbs and, importantly, names hypomagnesaemia among the cardinal biochemical consequences rather than as a Bartter-subtype feature.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35313217
    reference_title: Differential parathyroid and kidney Ca(2+)-sensing receptor activation in autosomal dominant hypocalcemia 1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels.
    explanation: The conclusion concerns chronic renal CaSR activation inferred from CLDN14 in one mouse allele; it does not establish the absence of every renal signal.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
- name: Impaired Vasopressin-Dependent Water Reabsorption
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    CaSR knock-in mice showed reduced AQP2 abundance, increased AQP2 Ser261 phosphorylation and altered
    p38MAPK, ATF1 and miR-137 readouts. JTT-305 increased AQP2 abundance and reduced miR-137. These results
    support a candidate water-handling mechanism; concurrent changes in mineral metabolism and PTH prevent
    attributing the rescue solely to a direct collecting-duct effect. The pathway has not been demonstrated
    as the cause of polyuria in human Bartter-like ADH1.
  genes:
  - preferred_term: AQP2
    term:
      id: hgnc:634
      label: AQP2
  biological_processes:
  - preferred_term: renal water homeostasis
    modifier: DECREASED
    term:
      id: GO:0003091
      label: renal water homeostasis
  evidence:
  - reference: PMID:38367250
    reference_title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation.
    explanation: The measured AQP2 defect in a knock-in mouse built to model this disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:38367250
    reference_title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice.
    explanation: Calcilytic treatment reversed AQP2-associated readouts in the mouse model; concurrent systemic changes prevent isolating a direct collecting-duct effect.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Reduced Circulating Calcium
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Insufficient PTH action reduces the hormonal support of calcium homeostasis; renal calcium loss may
    further lower circulating calcium. PTH and calcium must be interpreted together, but the low-calcium
    state is represented separately from its hormonal cause.
  downstream:
  - target: Neuromuscular Irritability
    description: Low ionized calcium increases neuromuscular excitability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Intracranial Calcium Deposition
    description: Chronic mineral imbalance accompanies brain calcification, but the site-specific causal intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypocalcemia
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31063613
      reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria.
      explanation: States hypocalcaemia as a defining feature of the ADH1 cohort studied.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria.
    explanation: The three-part biochemical signature stated compactly in a clinical study of ADH1 patients.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Renal Calcium Wasting
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Urine calcium can be inappropriately high relative to hypocalcemia without exceeding the absolute
    reference range. Loss of PTH action and renal CaSR effects can both contribute, with their relative
    importance varying by allele and treatment. In a selected literature aggregate, frank hypercalciuria
    was reported in 34% of 91 patients with pretreatment biochemistry.
  downstream:
  - target: Renal Calcium Deposition
    description: Sustained excess urinary calcium promotes crystal formation and renal deposition through urine supersaturation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Reduced Circulating Calcium
    description: Persistent urinary calcium loss can contribute to negative calcium balance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hypercalciuria
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism.
      explanation: States the phenotype and, importantly, that it exceeds that of other hypoparathyroidisms.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The combination of both loss of PTH and gain of CaSR activity provides a dual mechanism for hypercalciuria in ADH1
    explanation: Names the convergence of the two upstream limbs on this node, which is the reason this entry models them separately.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed.
    explanation: Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Increased Renal Phosphate Retention
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced PTH action increases renal phosphate reabsorption, contributing to raised serum phosphate.
  downstream:
  - target: Hyperphosphatemia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mean blood levels of intact PTH, magnesium, and 1,25-dihydroxy-vitamin D increased, whereas phosphorus levels and tubular reabsorption of phosphate decreased
    explanation: Phosphate handling and PTH changed together during encaleret treatment; this does not isolate PTH as the sole mediator.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
- name: Neuromuscular Irritability
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced ionized calcium increases neuromuscular excitability, contributing to paresthesia, tetany
    and seizures. Symptoms vary within families, while a larger published-case aggregate associated lower
    calcium and younger age with more severe symptoms. Persistent epilepsy in individual patients need
    not track acute calcium changes.
  evidence:
  - reference: PMID:22863393
    reference_title: Hypoparathyroidism.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although hypocalcemic patients commonly present with symptoms of neuromuscular irritability with perioral numbers paresthesias, tingling, seizures and, bronchospasm; hypocalcemia may be identified on the biochemical profile of an asymptomatic patient.
    explanation: Names the syndrome and its manifestations, and records that it may be absent altogether. The source's typo "numbers" for "numbness" is reproduced as published.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia.
    explanation: The observation that symptom burden does not track calcium level, measured within a single kindred carrying one variant.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients
    explanation: Aggregated published cases show an association that a single kindred cannot exclude.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  downstream:
  - target: Seizures
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35818129
      reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant.
      explanation: Seizure as the presenting manifestation, attributed to the hypocalcaemia.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Tetany
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: She also experienced frequent episodes of tetany, manifesting as an inability to walk.
      explanation: A directly observed clinical description of tetany and its functional impact.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Paresthesia
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16128246
      reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia.
      explanation: Documents occurrence in the cited report; no disease-wide frequency is inferred.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Renal Calcium Deposition
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Renal calcium deposition and urinary stones can accompany hypercalciuria, including during conventional
    treatment. Selected case series cannot establish a universal untreated course or irreversibility.
    This renal route is distinct from intracranial calcification.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As a result, nephrocalcinosis and nephrolithiasis are more common in subjects with ADH1 than other forms of hypoparathyroidism
    explanation: Ties the renal deposits specifically to ADH1's extra renal limb rather than to hypoparathyroidism in general.
    quote_role: BACKGROUND
    directness: INDIRECT
  downstream:
  - target: Nephrocalcinosis
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Her renal ultrasound at two months of age demonstrated nephrocalcinosis.
      explanation: Nephrocalcinosis was observed at two months; the infant had already received calcium and calcitriol, so this is not evidence of untreated disease.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Nephrolithiasis
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: he continued to have marked hypercalciuria, and he developed multiple, recurrent renal stones. He underwent lithotripsy at the age of 2 years
      explanation: Documents stones as a clinical course in an ADH1 patient, with the intervention they required.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Reduced Renal MicroRNA Repression of CLDN14
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Selected ADH-associated CaSR variants reduce pri-miR-374 transcription in HEK293 cells; miR-9-1 effects vary by variant. Renal antagomir experiments support a pathway in which loss of microRNA repression increases CLDN14. Constitutive activation of this pathway in every untreated ADH1 kidney has not been demonstrated.
  evidence:
  - reference: PMID:25071082
    reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: All three mutations significantly reduced the pri-miR-374 transcript levels by 30% compared with wild-type CaSR
    explanation: The ADH variants were expressed in HEK293 cells; this is not a measurement in patient kidneys.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Increased Renal CLDN14 Expression
    description: Reduced microRNA-mediated silencing increases the abundance of the paracellular transport inhibitor.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25071082
      reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the CLDN14 protein level was 3.25-fold higher with anti–miR-374 than scrambled antagomir treatment
      explanation: Antagomir-treated wild-type mice test release of CLDN14 repression; these are not CASR knock-in mice.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Increased Renal CLDN14 Expression
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Increased claudin-14 inhibits the cation-permeable claudin pathway in the thick ascending limb. Mouse knockout, antagomir, drug and tubule-perfusion experiments support this route. The HDAC-inhibitor rescue used cinacalcet-treated wild-type mice, rather than a genetic ADH1 mouse; no human efficacy is established.
  genes:
  - preferred_term: CLDN14
    term:
      id: hgnc:2035
      label: CLDN14
  evidence:
  - reference: PMID:25071082
    reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the CLDN14 protein level was 3.25-fold higher with anti–miR-374 than scrambled antagomir treatment
    explanation: Antagomir-treated wild-type mice test release of CLDN14 repression; these are not CASR knock-in mice.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Impaired Renal Tubular Calcium Reabsorption
    description: Claudin-14 reduces paracellular cation transport in the thick ascending limb.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Intracranial Calcium Deposition
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Basal ganglia and other intracranial calcifications occur in some patients with chronic mineral imbalance. A direct path from urinary calcium loss to brain deposition is not established; local mechanisms and contributions of hypocalcemia, phosphate balance and treatment remain unresolved.
  evidence:
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: basal ganglia calcification, identified by CT scanning in all five individuals
    explanation: Occurrence in the five imaged members of a selected seven-member kindred; not population prevalence.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Intracranial Calcification
    description: The process contributes to this observed clinical manifestation; occurrence and severity vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35818129
      reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Computed tomography of the brain revealed multiple intracranial calcifications, and electroencephalography showed extensive epileptic discharges.
      explanation: Imaging documentation of the intracranial deposits in a genetically confirmed patient.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
phenotypes:
- category: Biochemical
  name: Hypocalcemia
  description: >-
    Low ionized or albumin-adjusted serum calcium is the characteristic biochemical finding. It may be
    asymptomatic or severe; treatment and the timing of measurement influence individual values.
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria.
    explanation: States hypocalcaemia as a defining feature of the ADH1 cohort studied.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed.
    explanation: Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Endocrine
  name: Hypoparathyroidism
  description: >-
    PTH is insufficient for the simultaneous calcium level and may be inappropriately normal, low or nearly
    undetectable.
  phenotype_term:
    preferred_term: Hypoparathyroidism
    term:
      id: HP:0000829
      label: Hypoparathyroidism
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism.
    explanation: Establishes the hypoparathyroid phenotype and ADH1's place among its genetic causes.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed.
    explanation: Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Renal
  name: Hypercalciuria
  description: >-
    Calcium excretion may be excessive relative to hypocalcemia while remaining within its absolute reference
    range. Frank hypercalciuria varies and may emerge or worsen with treatment.
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism.
    explanation: States the phenotype and, importantly, that it exceeds that of other hypoparathyroidisms.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed.
    explanation: Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Renal
  name: Nephrocalcinosis
  description: >-
    Renal calcium deposition occurs in some patients, including infants receiving calcium and active vitamin
    D. Stability in short case-series follow-up does not establish irreversibility.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her renal ultrasound at two months of age demonstrated nephrocalcinosis.
    explanation: Nephrocalcinosis was observed at two months; the infant had already received calcium and calcitriol, so this is not evidence of untreated disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals.
    explanation: Documents occurrence in the cited report; no disease-wide frequency is inferred.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Renal
  name: Nephrolithiasis
  description: >-
    Renal stones have been reported, including recurrent stones requiring intervention in individual severely
    affected children.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he continued to have marked hypercalciuria, and he developed multiple, recurrent renal stones. He underwent lithotripsy at the age of 2 years
    explanation: Documents stones as a clinical course in an ADH1 patient, with the intervention they required.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Seizures
  description: >-
    Hypocalcaemic seizures, which may be the presenting event in infancy and can
    be mistaken for primary epilepsy when the calcium is not measured.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: RECURRENT
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant.
    explanation: Seizure as the presenting manifestation, attributed to the hypocalcaemia.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Tetany
  description: >-
    Carpopedal spasm and involuntary muscle contraction, reported as episodic and
    disabling in poorly controlled patients.
  phenotype_term:
    preferred_term: Tetany
    term:
      id: HP:0001281
      label: Tetany
    temporality: RECURRENT
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She also experienced frequent episodes of tetany, manifesting as an inability to walk.
    explanation: A directly observed clinical description of tetany and its functional impact.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Intracranial Calcification
  description: >-
    Basal ganglia and other intracranial calcifications have been documented; progression on serial imaging
    is reported in individual cases.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Computed tomography of the brain revealed multiple intracranial calcifications, and electroencephalography showed extensive epileptic discharges.
    explanation: Imaging documentation of the intracranial deposits in a genetically confirmed patient.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: basal ganglia calcification, identified by CT scanning in all five individuals
    explanation: Documents occurrence in the cited report; no disease-wide frequency is inferred.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Biochemical
  name: Hyperphosphatemia
  description: >-
    Raised serum phosphate accompanying the low PTH, part of the standard
    hypoparathyroid biochemistry.
  phenotype_term:
    preferred_term: Hyperphosphatemia
    term:
      id: HP:0002905
      label: Hyperphosphatemia
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypocalcemia, hyperphospheremia, and hypoparathyroidism were clearly evident, and brain computed tomography showed multiple intracranial calcifications
    explanation: The biochemical triad as measured in the reported patient. The source spells the finding "hyperphospheremia"; the quote is reproduced as published.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35879818
    reference_title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed.
    explanation: Selected published cases with pretreatment biochemistry; these proportions are not unselected population penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Biochemical
  name: Hypomagnesemia
  description: >-
    Low serum magnesium can accompany ADH1 with or without the Bartter-like phenotype; it is not present
    in every patient.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  evidence:
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia.
    explanation: The full biochemical signature in a seven-member kindred, including magnesium and including the observation that PTH is low but detectable.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CaSR primarily regulates parathyroid hormone (PTH) secretion and renal calcium and magnesium reabsorption.
    explanation: The mechanistic basis - magnesium is handled by the same receptor, so its loss is expected rather than incidental.
    quote_role: BACKGROUND
    directness: INDIRECT
  notes: Renal magnesium handling and possible treatment effects are not resolved into a dedicated causal branch here.
- category: Neurologic
  name: Paresthesia
  description: >-
    Perioral numbness, tingling and other paresthesias can accompany hypocalcemia.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia.
    explanation: Documents occurrence in the cited report; no disease-wide frequency is inferred.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Renal
  name: Chronic Kidney Disease
  description: >-
    Renal impairment is a potentially serious complication, particularly in patients with hypercalciuria
    and treatment exposure. Broad hypoparathyroidism cohorts do not provide an ADH1-specific frequency.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment
    explanation: Renal impairment observed in the original ADH1 kindreds, and attributed there to the treatment rather than only to the disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: 'Left unconnected: the reports establish renal impairment, but do not isolate crystal injury, treatment exposure and other contributors to a single causal route.'
- category: Ophthalmologic
  name: Cataract
  description: >-
    Lens opacity has been reported in individual ADH1 patients. Its disease-wide frequency and exact mechanism
    are not established.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was diagnosed with congenital cataracts at the age of 14 years.
    explanation: An observed cataract in an ADH1 patient with long-standing poorly controlled hypocalcaemia.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: 'Left unconnected: human cases establish occurrence, but the proposed lens mechanism has not been demonstrated in ADH1 patients. Nuf lens opacity did not show substantial lens mineralization.'
- category: Renal
  name: Hypokalemia
  subtype: Bartter type V
  description: >-
    Part of the salt-wasting tubulopathy seen with the Bartter-type-V alleles,
    alongside hypomagnesaemia and polyuria.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which accounted not only for his ADH1 but also type 5 Bartter syndrome with persistent hypokalemia, hypomagnesemia, and polyuria
    explanation: An observed Bartter-type-V presentation in a genetically confirmed ADH1 patient, which is why this phenotype is tagged to that subtype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: Restricted to the Bartter-like phenotype; the general calcium-reabsorption branch does not represent the full salt-transport mechanism.
genetic:
- name: CASR
  gene_term:
    preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
  relationship_type: CAUSATIVE
  notes: >-
    Most reported pathogenic variants are heterozygous missense changes, distributed across extracellular,
    transmembrane and intracellular domains. Deletions, a nonsense variant, parental mosaicism and a rare
    homozygous case have also been reported. Variant-specific expression and signaling effects matter;
    a five-person NPSP795 study did not establish a reliable relationship between cellular assays and
    clinical drug response. Loss-of-function CASR variants usually cause the opposite calcium phenotype
    and should not be interpreted as ADH1 merely because the gene matches.
  evidence:
  - reference: PMID:20374733
    reference_title: Calcium-sensing receptor and associated diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Heterozygous loss-of-function mutations cause familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong mild hypercalcemia is generally asymptomatic. Homozygous inactivating mutations give rise to neonatal severe hyperparathyroidism (NSHPT) with extreme hypercalcemia and marked skeletal changes. Heterozygous activating mutations of the CASR cause autosomal dominant hypocalcemia (ADH) that may be asymptomatic or present with seizures in the neonatal period or childhood or later in life.
    explanation: The full allelic series in one passage, which is what places ADH1 at the gain-of-function end of a graded dosage relationship rather than treating it as an isolated phenotype.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease.
    explanation: Establishes the allelic spectrum and its cosegregation across six kindreds.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was significant variability in response clinically across genotypes.
    explanation: Documents variable short-term calcilytic response in five participants; it does not establish a genotype-based severity or drug-response prediction rule.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27617113
    reference_title: Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected.
    explanation: A clinically and biochemically normal parent mosaic for the proband's variant - the concrete case behind the inheritance block's claim that an absent family history does not argue against the diagnosis, and a warning that parental testing can mislead.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
biochemical:
- name: Serum ionised calcium
  presence: Decreased
  context: >-
    Ionized calcium or albumin-adjusted total calcium is interpreted with simultaneous PTH. Ionized calcium
    is the receptor ligand; total calcium requires consideration of albumin and clinical context.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Reduced Circulating Calcium
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Measures circulating calcium, not receptor sensitivity directly.
    evidence:
    - reference: PMID:31063613
      reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation.
      explanation: Uses ionised calcium as the monitored analyte in an ADH1 study, which is the measurement this readout names.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Intact parathyroid hormone
  presence: Decreased
  context: >-
    A low or reference-range PTH is inappropriate in hypocalcemia. This pairing supports deficient PTH
    physiology but does not uniquely diagnose ADH1.
  biomarker_term:
    preferred_term: Parathyroid Hormone
    term:
      id: NCIT:C41027
      label: Parathyroid Hormone
  readouts:
  - target: Suppressed Parathyroid Hormone Secretion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the parathyroid limb of the receptor lesion.
    evidence:
    - reference: PMID:31063613
      reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels.
      explanation: The treatment study measures circulating PTH as a pharmacodynamic endpoint; support for its diagnostic interpretation is indirect.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Urinary calcium excretion
  presence: Increased
  context: >-
    Measure 24-hour calcium excretion or an age-appropriate spot calcium:creatinine ratio and interpret
    against serum calcium, kidney function, age and treatment. Relative calcium wasting and frank hypercalciuria
    are distinct.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Renal Calcium Wasting
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Reports the renal limb, and tracks whether treatment is aggravating it.
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year.
      explanation: Urinary calcium used as the monitored endpoint that determined whether the treatment change was working.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
prevalence:
- population: DiscovEHR cohort from one US healthcare system, predominantly of northern European ancestry
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.9
  notes: Estimated from two unrelated genetically and functionally supported cases among 51,289 sequenced participants. Three carriers included a related pair before deduplication. This is a cohort genetic-prevalence estimate, not worldwide diagnosed-case prevalence; very few cases and incomplete clinical phenotyping limit precision and generalizability.
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two unrelated individuals with ADH1 yielded a prevalence of 3.9 per 100,000.
    explanation: The primary healthcare-cohort analysis supports the bounded estimate.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
diagnosis:
- name: Paired Serum Calcium and Intact PTH
  description: >-
    Measure ionized or albumin-adjusted calcium together with intact PTH, phosphate, magnesium and renal
    function. Inappropriately low or normal PTH supports hypoparathyroid physiology; the finding is not
    specific to CASR activation. Urinary calcium informs phenotype and treatment risk.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor.
    explanation: This clinical pattern prompted investigation of CASR in selected families; it is not a specific diagnostic test by itself.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: CASR Sequencing
  description: >-
    A pathogenic or likely pathogenic activating CASR variant in the appropriate clinical context establishes
    ADH1. A VUS or a loss-of-function CASR variant does not. If testing is nondiagnostic, assess GNA11-related
    ADH2, other genetic hypoparathyroidism, acquired causes and magnesium disturbances; negative CASR
    sequencing alone does not establish an activating autoantibody disorder.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney.
    explanation: Identifies CASR as the gene to sequence and states both tissues in which the receptor acts.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Renal and Mineral Surveillance
  description: Assess serum calcium, phosphate, magnesium, creatinine and vitamin D status, and urinary calcium during follow-up and after treatment changes. Renal imaging evaluates nephrocalcinosis or stones. Monitoring intensity depends on symptoms, biochemical stability, age, treatment and kidney function; published ADH1 schedules are proposed practice recommendations rather than validated outcome-based protocols.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:39607645
    reference_title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: serum calcium should be remeasured within days after adjustments in medical treatment.
    explanation: The review discusses broader hypoparathyroidism monitoring recommendations and the need for closer ADH1 assessment.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
treatments:
- name: Calcitriol and Calcium Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Active vitamin D, with calcium supplementation when needed, can relieve symptomatic hypocalcemia.
    Treatment is titrated to symptoms and urinary calcium rather than routinely normalizing serum calcium,
    because raising calcium can aggravate renal losses. Some asymptomatic patients within an individualized
    target range and without hypercalciuria can be monitored without medication. Recommendations are based
    largely on small ADH1 studies and broader hypoparathyroidism practice.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  target_mechanisms:
  - target: Reduced Circulating Calcium
    treatment_effect: BYPASSES
    description: >-
      Raises circulating calcium without correcting CASR activation or restoring endogenous PTH secretion.
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment.
    explanation: The observed treatment-associated renal harm supports cautious titration and urinary-calcium monitoring; this quotation does not establish calcitriol efficacy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39607645
    reference_title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In asymptomatic patients without hypercalciuria we recommend not to commence medical treatment if serum calcium is within the target range
    explanation: The proposed approach is conditional on symptoms, urine calcium and the target range; it is not a blanket recommendation to leave hypocalcemia untreated.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Recombinant Human PTH(1-84)
  therapeutic_modality: PEPTIDE
  description: >-
    Historical ADH1 evidence includes an uncontrolled three-child series with improved calcium balance
    and reduced calcium/calcitriol requirements. Regimens were individualized; one child required twice-daily
    dosing on several days each week, and another comparison followed prior PTH(1-34), limiting attribution.
    These reports do not establish prevention or reversal of renal calcifications. Takeda announced discontinuation
    of NATPAR/NATPARA manufacturing at the end of 2024, so this evidence should not imply routine current
    availability.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant parathyroid hormone
      term:
        id: NCIT:C62555
        label: Recombinant Parathyroid Hormone
  target_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    treatment_effect: BYPASSES
    description: >-
      Supplies exogenous PTH activity downstream of suppressed secretion; it does not restore endogenous
      PTH release or correct the CASR variant.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.
    explanation: The result, with its own scope stated - three subjects, compared against conventional therapy rather than against a control arm.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.takeda.com/en-us/newsroom/statements/2022/takeda-to-discontinue-manufacturing-of-natpar-natpara/
    reference_title: Takeda to Discontinue Manufacturing of NATPAR® / NATPARA® for Patients with Hypoparathyroidism at the End of 2024
    supports: SUPPORT
    evidence_source: OTHER
    snippet: at the end of 2024 due to unresolved supply issues
    explanation: The manufacturer announcement limits present availability; the clinical case-series evidence is historical.
    quote_role: BACKGROUND
    directness: DIRECT
- name: Palopegteriparatide
  therapeutic_modality: PEPTIDE
  description: >-
    A long-acting PTH(1-34) prodrug approved by the FDA for adult hypoparathyroidism. ADH1-specific evidence
    remains limited: a broader pivotal trial included very few ADH1 patients, and a 2026 report described
    off-label treatment of one 16-year-old. Tetany resolved, calcium and phosphate balance improved, and
    active vitamin D and calcium were stopped while low-dose hydrochlorothiazide, magnesium and potassium
    continued. Urinary calcium improved in the reported follow-up, but persistent hypocalcemia and hyperphosphatemia
    and the uncontrolled design limit claims of complete correction or renal protection. Pediatric efficacy
    and long-term safety are not established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: palopegteriparatide
      term:
        id: CHEBI:759036
        label: palopegteriparatide
  target_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    treatment_effect: BYPASSES
    description: >-
      Provides sustained exogenous PTH activity without restoring the suppressed endogenous secretion.
  evidence:
  - reference: PMID:42388864
    reference_title: 'Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Evidence on the use of long-acting PTH analogs in pediatric ADH1 remains scarce.
    explanation: The authors describe the limited pediatric evidence base. This background statement supports the caution about generalizing from a single case, rather than an efficacy estimate.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: url:https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-yorvipath
    reference_title: 'Drug Trials Snapshots: YORVIPATH | FDA'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: approved for the treatment of hypoparathyroidism in adults
    explanation: The FDA indication is adult hypoparathyroidism; the pediatric case is off-label.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:42388864
    reference_title: 'Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the final maintenance dose, both alfacalcidol and calcium supplementation were successfully discontinued.
    explanation: The one-patient result is supported alongside continued low-dose thiazide use; clinical benefit does not establish renal protection.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Thiazide Diuretic
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An adjunct to reduce urinary calcium in selected patients, often combined with a low-sodium diet when
    blood pressure permits. Monitor potassium, magnesium and blood pressure. Proposed ADH1 recommendations
    advise against thiazides in Bartter-like disease with hypokalemia and in pre-existing hypomagnesemia
    or high urinary magnesium losses.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: thiazide diuretic
      term:
        id: NCIT:C49185
        label: Thiazide Diuretic
  target_mechanisms:
  - target: Renal Calcium Wasting
    treatment_effect: MODULATES
    description: >-
      Increases distal tubular calcium reabsorption, opposing the renal limb at its
      output rather than at its cause.
  evidence:
  - reference: PMID:22863393
    reference_title: Hypoparathyroidism.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In the long-term management of hypoparathyroidism thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor.
    explanation: The review supports thiazide use as an adjunct; this is not a genotype-stratified comparative trial and the ADH1-specific contraindications remain important.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:39607645
    reference_title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We recommend against the use of thiazides in ADH1 patients with Bartter-like syndrome with hypokalemia
    explanation: The authors propose ADH1-specific care recommendations from limited studies; this caveat restricts thiazide use.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Calcilytic (Negative Allosteric Modulator of the CaSR)
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational negative allosteric modulators reduce CaSR signaling. A three-day NPSP795 study in
    five adults increased PTH without significant improvement in ionized calcium or fractional calcium
    excretion. An uncontrolled encaleret phase 2b study in 13 adults improved serum calcium and hypercalciuria
    over 24 outpatient weeks. The 2026 CALIBRATE conference report adds randomized phase 3 evidence: at
    week 24, 75.6% of encaleret participants achieved both blood and urine calcium targets, compared with
    19% in the concurrent standard-care group. The primary comparison was separately within the encaleret
    arm against its own pretreatment standard-care period (75.6% versus 4.4%). These are biochemical endpoints
    reported in a conference abstract; long-term kidney protection is not established. FDA accepted the
    encaleret application in July 2026, with approval still pending at review. AXT914 and related quinazolinones
    have preclinical evidence, not established clinical ADH1 efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: encaleret
      term:
        id: CHEBI:749959
        label: encaleret
  target_mechanisms:
  - target: Increased Calcium-Sensing Receptor Signaling
    treatment_effect: INHIBITS
    description: >-
      Reduces abnormal CaSR signaling; sensitivity and pharmacological response can vary across alleles
      and compounds.
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1.
    explanation: Direct evidence of increased PTH in five adults over three days supports pharmacological proof of concept; it does not establish sustained biochemical correction or clinical benefit.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fractional excretion of calcium (FECa) trended down but not significantly so.
    explanation: The negative result on the renal endpoint in the earlier compound, quoted separately so the limitation is recorded structurally rather than only in prose.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Encaleret corrected hypocalcemia and reduced hypercalciuria during the inpatient periods and the 24-week outpatient period.
    explanation: The uncontrolled 13-adult study improved both endpoints. This does not establish superiority over all PTH-based approaches.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our study, encaleret appeared to restore physiologic mineral homeostasis in 13 participants with ADH1. This molecularly targeted approach, pending further studies, may establish calcilytics as a potential treatment for ADH1.
    explanation: The authors interpret biochemical changes in an uncontrolled 13-adult study. The quotation supports a potential targeted treatment, without establishing comparative efficacy or long-term kidney protection.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:40086735
    reference_title: Characterization of quinazolinone calcilytic therapy for autosomal dominant hypocalcemia type 1 (ADH1).
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: were shown to bind at a common region within the CaSR transmembrane domain, which is also an ADH1 mutational hotspot
    explanation: Docking based on existing cryo-EM structures predicts overlapping binding regions; it is not a direct quinazolinone-binding structure or clinical response result.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: DOI:10.1093/ejendo/lvag096.130
    reference_title: 'OC10.1 - ECE_3948 - Encaleret restores mineral homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): primary results from the phase 3 CALIBRATE trial'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: More participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges compared to those randomized to SoC
    explanation: 'Concurrent randomized biochemical comparison at week 24: 45 encaleret participants and 21 standard-care participants assessed. Conference abstract evidence is distinct from a complete trial report and from the primary within-person comparison.'
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
    reference_title: https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
    supports: SUPPORT
    evidence_source: OTHER
    snippet: FDA has accepted for filing its New Drug Application (NDA) for encaleret
    explanation: The July 2026 company filing documents regulatory review, not approval or an independent efficacy assessment.
    quote_role: BACKGROUND
    directness: DIRECT
- name: Teriparatide (PTH 1-34)
  therapeutic_modality: PEPTIDE
  description: Off-label PTH(1-34), by repeated injection or pump, has been studied in small ADH1 cohorts. A retrospective six-patient series reported fewer seizures during infusion compared with prior conventional treatment. Mixed-etiology hypoparathyroidism trials contain small ADH1 subgroups and do not establish uniform normalization of urinary calcium or prevention of renal disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: teriparatide
      term:
        id: CHEBI:135983
        label: teriparatide
  target_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    treatment_effect: BYPASSES
    description: Replaces PTH action downstream of deficient secretion.
  evidence:
  - reference: PMID:39607645
    reference_title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SC PTH1-34 infusion reduced the number of seizures from 2 to 0.01 per month
    explanation: The review summarizes a retrospective six-patient ADH1 cohort; this was not a randomized comparison.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Acute Intravenous Calcium
  therapeutic_modality: SMALL_MOLECULE
  description: Severe symptomatic hypocalcemia may require intravenous calcium with cardiac and biochemical monitoring. Acute stabilization is distinct from long-term attempts to normalize calcium, which can worsen urinary calcium losses.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcium gluconate
      term:
        id: CHEBI:3309
        label: calcium gluconate
  target_mechanisms:
  - target: Reduced Circulating Calcium
    treatment_effect: BYPASSES
    description: Provides calcium during acute symptomatic decompensation.
  evidence:
  - reference: PMID:39607645
    reference_title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IV calcium gluconate should be administered under cardiac monitoring
    explanation: The recommendation applies to acute severe hypocalcemia, not routine correction of chronic asymptomatic biochemical values.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
clinical_trials:
- name: NCT04581629
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Completed open-label encaleret dose-ranging phase 2 study with 13 adults. The published letter describes
    24 outpatient weeks after inpatient dose-ranging; it does not establish comparative efficacy or long-term
    renal protection. Completion status checked against ClinicalTrials.gov in September 2026.
  target_phenotypes:
  - preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  - preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: clinicaltrials:NCT04581629
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).
    explanation: The registry describes study design and intended population; it is not evidence of a positive outcome.
    quote_role: BACKGROUND
    directness: DIRECT
- name: NCT05680818
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: CALIBRATE is an open-label randomized encaleret versus standard-care study in ADH1, with 67 participants. The registry lists active, not recruiting in September 2026, despite completion of the primary endpoint period. Conference results distinguish a primary within-encaleret comparison against baseline standard care from concurrent between-arm comparisons; extension follow-up remains ongoing.
  evidence:
  - reference: clinicaltrials:NCT05680818
    reference_title: 'CALIBRATE: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1)'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary purpose of the study is to understand the effectiveness, safety, and tolerability of encaleret
    explanation: The registry describes study design and intended population; it is not evidence of a positive outcome.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: DOI:10.1093/ejendo/lvag096.130
    reference_title: 'OC10.1 - ECE_3948 - Encaleret restores mineral homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): primary results from the phase 3 CALIBRATE trial'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: More participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges compared to those randomized to SoC
    explanation: 'Concurrent randomized biochemical comparison at week 24: 45 encaleret participants and 21 standard-care participants assessed. Conference abstract evidence is distinct from a complete trial report and from the primary within-person comparison.'
    quote_role: PRIMARY_RESULT
    directness: DIRECT
animal_models:
- name: Nuf mouse (Casr Leu723Gln)
  species: Mouse
  genotype: Casr Leu723Gln (Nuf), heterozygous and homozygous
  publication: PMID:33103030
  description: >-
    The Nuf Leu723Gln allele arose in an isopropyl methane sulfonate mutagenesis screen for lens abnormalities.
    Heterozygotes and homozygotes develop low calcium and PTH; homozygotes have more severe manifestations.
    Baseline hypercalciuria is not reproduced reliably. It is one allele-specific model, not the complete
    human spectrum. The original pathology study found ectopic mineralization mainly in homozygotes; lens
    opacities reflected fiber damage without substantial lens mineralization. Cataracts are therefore
    not treated as a readout of renal calcium deposition.
  modeled_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Low baseline PTH and an acute PTH rise after calcilytic treatment support suppressed secretion downstream
      of mutant CaSR.
    limitations: >-
      One allele, acute dosing and different drug exposures limit comparison with the human NPSP795 study.
      Mouse blood calcium improved without reaching untreated wild-type levels; neither this endpoint
      nor PTH directly measures receptor EC50.
    readouts:
    - name: Plasma PTH response to calcilytic
      target: Suppressed Parathyroid Hormone Secretion
      direction: RESTORED
      interpretation: >-
        PTH increased acutely after CaSR antagonism, providing a hormonal output readout rather than a
        direct receptor sensitivity assay.
      evidence:
      - reference: PMID:33103030
        reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: NPSP795 significantly increased plasma PTH concentrations in a dose-dependent manner with the 30 mg/kg dose causing a maximal (≥10-fold) rise in PTH.
        explanation: The dose-response measurement behind this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
  - target: Reduced Circulating Calcium
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Hypocalcemia and its partial pharmacological correction are observed in the Nuf model.
    limitations: Short-term single-dose mouse results do not establish equivalent human dosing, complete correction or durable renal benefit.
    readouts:
    - name: Plasma adjusted-calcium response to calcilytic
      target: Reduced Circulating Calcium
      direction: INCREASED
      interpretation: >-
        Calcium rose after a single dose but remained below untreated wild-type values. This integrated
        endpoint does not resolve direct renal and PTH-mediated contributions.
      evidence:
      - reference: PMID:33103030
        reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L
        explanation: The measured calcium correction in the heterozygous mouse.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:33103030
      reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L
      explanation: The measured calcium correction in the heterozygous mouse.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:33103030
    reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Nuf mice, which have hypocalcemia in association with a gain-of-function CaSR mutation, Leu723Gln
    explanation: Establishes the model's genotype and that it reproduces the hypocalcaemic phenotype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:15347804
    reference_title: Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: were treated with isopropyl methane sulfonate and bred so that spermatogonial stem cells were sampled.
    explanation: The original strain report records induced mutagenesis rather than spontaneous origin.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
discussions:
- discussion_id: adh1_calcium_target_is_a_tradeoff
  kind: INTERPRETATION
  attaches_to:
  - pathophysiology#Renal Calcium Wasting
  - treatments#Calcitriol and Calcium Supplementation
  prompt: Why are symptoms and urinary calcium assessed together when titrating conventional treatment?
  rationale: >-
    PTH deficiency and direct renal CaSR effects can both impair calcium conservation. Baseline renal
    activation is allele- and calcium-dependent rather than obligatorily maximal in every patient. Raising
    serum calcium may recruit or worsen renal calcium losses, so symptom relief must be balanced against
    urine calcium and renal outcomes. This supports individualized targets, not withholding acute calcium
    treatment or assuming every patient has the same threshold.
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment
    explanation: The observed harm from raising calcium by the conventional route.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion.
    explanation: States the trade-off directly as the motivation for seeking an alternative.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:35313217
    reference_title: Differential parathyroid and kidney Ca(2+)-sensing receptor activation in autosomal dominant hypocalcemia 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized.
    explanation: One retrospective patient observation supports treatment dependence, not universal absence of untreated hypercalciuria.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- discussion_id: adh1_in_vitro_activation_does_not_predict_response
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#CASR
  - treatments#Calcilytic (Negative Allosteric Modulator of the CaSR)
  prompt: How well can cellular variant assays predict individual calcilytic response?
  rationale: >-
    The five-adult NPSP795 study found no significant correlation between its cellular assay readouts
    and clinical PTH response. Small sample size, brief exposure and within-allele variability limit this
    negative result. Leu723Arg demonstrates G11-biased signaling in HEK293 cells, while other tested ADH1
    variants activate multiple pathways. This establishes possible assay dependence but does not prove
    that signaling bias caused clinical nonresponse or short stature. Proposed residue contacts and genotype-guided
    drug selection require further validation.
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters.'
    explanation: The paired result - uniform in vitro behaviour, uncorrelated clinical behaviour - which is the gap itself.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug.
    explanation: The authors' own statement of the disconnect, quoted separately from the result that produced it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39658204
    reference_title: An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs).
    explanation: Direct evidence that a variant can be activating for one G-protein route and not others, which is one of the candidate explanations for the assay-to-clinic disconnect.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- discussion_id: adh1_vs_adh2_and_hypoparathyroidism
  kind: INTERPRETATION
  attaches_to:
  - diagnosis#CASR Sequencing
  prompt: What does ADH1 need to be distinguished from, and why does the distinction change management?
  rationale: >-
    Low calcium with insufficient PTH occurs in ADH1, other genetic hypoparathyroidism and acquired parathyroid
    disorders. All may have renal treatment complications; urine calcium alone is not a definitive discriminator.
    Pathogenic activating CASR variants distinguish ADH1 from GNA11-related ADH2 and from other molecular
    causes. Activating CaSR autoantibodies are an acquired phenocopy, but a negative CASR test also warrants
    assessment of other genetic causes, surgery, autoimmunity and magnesium disturbances.
  evidence:
  - reference: PMID:28194447
    reference_title: Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2).
    explanation: Defines ADH2 and its relationship to the receptor, which is the basis of the differential.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:20374733
    reference_title: Calcium-sensing receptor and associated diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating autoantibodies, respectively.
    explanation: The review describes activating autoantibodies as one acquired phenocopy; negative CASR sequencing alone does not establish that diagnosis.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
references:
- reference: PMID:7874174
  title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
- reference: PMID:8813042
  title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
- reference: PMID:12241879
  title: Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.
- reference: PMID:20374733
  title: Calcium-sensing receptor and associated diseases.
- reference: PMID:39658204
  title: An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.
- reference: PMID:40086735
  title: Characterization of quinazolinone calcilytic therapy for autosomal dominant hypocalcemia type 1 (ADH1).
- reference: PMID:28194447
  title: Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
- reference: PMID:31063613
  title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
- reference: PMID:33103030
  title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
- reference: PMID:33112267
  title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
- reference: PMID:15347804
  title: Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification.
- reference: PMID:16128246
  title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
- reference: PMID:22863393
  title: Hypoparathyroidism.
- reference: PMID:25071082
  title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
- reference: PMID:27617113
  title: Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
- reference: PMID:35818129
  title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.'
- reference: PMID:37754292
  title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
- reference: PMID:38367250
  title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
- reference: PMID:42388864
  title: 'Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.'
- reference: clinicaltrials:NCT04581629
  title: A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
- reference: DOI:10.1093/ejendo/lvag096.130
  title: 'OC10.1 - ECE_3948 - Encaleret restores mineral homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): primary results from the phase 3 CALIBRATE trial'
- reference: PMID:32386559
  title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
- reference: PMID:35313217
  title: Differential parathyroid and kidney Ca(2+)-sensing receptor activation in autosomal dominant hypocalcemia 1.
- reference: PMID:35879818
  title: 'Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.'
- reference: PMID:39607645
  title: 'Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.'
- reference: clinicaltrials:NCT05680818
  title: 'CALIBRATE: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1)'
- reference: url:https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-yorvipath
  title: 'Drug Trials Snapshots: YORVIPATH | FDA'
- reference: url:https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
  title: https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
- reference: url:https://www.takeda.com/en-us/newsroom/statements/2022/takeda-to-discontinue-manufacturing-of-natpar-natpara/
  title: Takeda to Discontinue Manufacturing of NATPAR® / NATPARA® for Patients with Hypoparathyroidism at the End of 2024
updated_date: '2026-09-23T00:00:00Z'
📚

References & Deep Research

References

29
PMID:7874174
Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
No top-level findings curated for this source.
PMID:8813042
A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
No top-level findings curated for this source.
PMID:12241879
Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.
No top-level findings curated for this source.
PMID:20374733
Calcium-sensing receptor and associated diseases.
No top-level findings curated for this source.
PMID:39658204
An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.
No top-level findings curated for this source.
PMID:40086735
Characterization of quinazolinone calcilytic therapy for autosomal dominant hypocalcemia type 1 (ADH1).
No top-level findings curated for this source.
PMID:28194447
Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
No top-level findings curated for this source.
PMID:31063613
Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
No top-level findings curated for this source.
PMID:33103030
Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
No top-level findings curated for this source.
PMID:33112267
Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
No top-level findings curated for this source.
PMID:15347804
Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification.
No top-level findings curated for this source.
PMID:16128246
A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.
No top-level findings curated for this source.
PMID:22863393
Hypoparathyroidism.
No top-level findings curated for this source.
PMID:25071082
Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
No top-level findings curated for this source.
PMID:27617113
Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
No top-level findings curated for this source.
PMID:35818129
Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.
No top-level findings curated for this source.
PMID:37754292
Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
No top-level findings curated for this source.
PMID:38367250
In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
No top-level findings curated for this source.
PMID:42388864
Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.
No top-level findings curated for this source.
clinicaltrials:NCT04581629
A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
No top-level findings curated for this source.
DOI:10.1093/ejendo/lvag096.130
OC10.1 - ECE_3948 - Encaleret restores mineral homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): primary results from the phase 3 CALIBRATE trial
No top-level findings curated for this source.
PMID:32386559
Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.
No top-level findings curated for this source.
PMID:35313217
Differential parathyroid and kidney Ca(2+)-sensing receptor activation in autosomal dominant hypocalcemia 1.
No top-level findings curated for this source.
PMID:35879818
Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.
No top-level findings curated for this source.
PMID:39607645
Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations.
No top-level findings curated for this source.
clinicaltrials:NCT05680818
CALIBRATE: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1)
No top-level findings curated for this source.
No top-level findings curated for this source.
url:https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
https://www.sec.gov/Archives/edgar/data/1743881/000114036126029291/ef20078442_ex99-1.htm
No top-level findings curated for this source.
url:https://www.takeda.com/en-us/newsroom/statements/2022/takeda-to-discontinue-manufacturing-of-natpar-natpara/
Takeda to Discontinue Manufacturing of NATPAR® / NATPARA® for Patients with Hypoparathyroidism at the End of 2024
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review CASR-related hypocalcemia against full-text mechanisms, cohort denominators and treatment evidence · 2026-09-23T05:44:13Z · View source

Reviewed the entire disorder entry and OpenScientist deep-research narrative/citation artifact. Eligibility checks found no REVIEW history event and no overlapping open PR; inherited CASR-related disease is within the resumed scope excluding infectious/environmental diseases and poisonings. Corrected universal normal-expression/trafficking and uniform left-shift claims using primary variant-expression and G11-biased signaling experiments. Recovered the key renal/parathyroid threshold study: chronic renal activation was not obligatory at baseline in Nuf mice or the studied human case, and treatment-dependent renal effects must not be generalized across alleles. Split renal from intracranial deposition, separated the water-handling branch, and represented the microRNA/CLDN14 steps with their actual cell and pharmacological mouse evidence. AQP2 drug rescue does not isolate direct renal effects from concurrent mineral/PTH changes. Removed unsupported frequency bands derived from single families or broader hypoparathyroidism cohorts, while preserving bounded published-case denominators. Corrected cohort genetic prevalence, differential diagnosis, PTH replacement as bypass rather than restoration of secretion, thiazide caveats, and Nuf induced origin and partial treatment response. Updated treatment evidence through September 2026. Distinguished five-person NPSP795 proof of concept, uncontrolled 13-adult encaleret results, three-child PTH(1-84) experience and the off-label pediatric palopegteriparatide case. The CALIBRATE conference abstract reports both the primary within-encaleret baseline comparison and a separate concurrent randomized comparison; biochemical improvement is not proof of long-term renal protection. Official FDA, SEC/company and Takeda records establish adult palopegteriparatide approval, pending encaleret review and historical NATPAR/NATPARA supply limitations. Registry API records confirmed phase 2 completion and ongoing phase 3 extension status. Source consumption: full cached scientific bodies, pertinent methods/results/discussion and main captions of PMID35313217, 35879818, 32386559, 39607645, 39658204, 15347804, 31063613, 33103030, 25071082, 40086735, 33112267, 37754292, 42388864 and 35818129; pertinent methodology, population tables and limitations of the broader renal systematic review PMID33599907; complete cited primary/review abstracts where no full text was cached. Regenerated PMID35313217 to recover full text. Inspected publisher Table 1 for PMID42388864, including the 16-month urine collection footnote despite its placement under a 12-month column. The continued thiazide and uncontrolled design constrain interpretation. Read the complete CALIBRATE conference abstract and official regulatory/manufacturer documents. Separate supplementary files were not independently retrieved; no conclusions depend on inaccessible supplementary-only numerical data. Reference caches were generated only through the repository fetcher; the frozen dataset blob was not accessed. Deep-research completeness assessment: phenotypes adequate with bounded ascertainment and no invented population penetrance; subtypes adequate for isolated and Bartter-like presentations; mechanisms adequate after renal threshold, expression and biased-signaling corrections; treatments/trials adequate after phase 3 update and missing acute/PTH(1-34)/monitoring care; genetics adequate with non-missense variants, mosaicism and rare biallelic exception; biomarkers/diagnostics adequate with paired interpretation and nonspecificity; high-value references consumed and report errors corrected; overall adequate. Proposed extra-organ mechanisms and genotype-guided drug selection remain research questions. The report's wrong MONDO/cell identifiers were not imported. Current preflight flagged PTH as a rival gene, but PTH is a central hormone/therapeutic mechanism here; GNA11/OMIM615361 appears only as the appropriate ADH2 differential. GeneReviews and StatPearls checks found no matching chapter in the current index. Independent-review follow-up removed four retired PARTIAL-grade rationales and stated their actual evidence limits, expanded the reused conference evidence without a YAML alias, added OLS-verified drug agents, and distinguished renal phosphate retention from its serum phenotype. Hypomagnesemia and hypokalemia remain unlinked rather than adding unsupported causal edges. The SEC reference title retains the fetcher-generated URL because title validation requires the cached title; the document heading is not the HTML title. Validation: schema, ontology terms and 102/102 cached quotations passed on the substantive draft; entity references and causal targets resolve, and model readouts were checked against their link targets. Final formatting, evidence hygiene and history validation are recorded with the published PR. No merge was performed.

Cite the CLDN14 descriptor rather than leaving it on a deep-research lead · 2026-08-28T18:00:11Z · View source

PR review flagged as non-blocking that the CLDN14 gene descriptor on the renal node had no citation - its only source was the deep-research report, which this entry's own notes say are leads rather than evidence. Fixed rather than left, because an uncited gene assertion is worse than an extra review cycle. PMID:25071082 is ADH1-specific, shows that ADH receptor variants repress miR-9 and miR-374 and thereby lift the brake on claudin-14, and reports an HDAC-inhibitor rescue in cell and animal models. The node description now states the route and its evidential strength. Snippets 67 to 69, all verified.

Create: Autosomal Dominant Hypocalcemia 1 · 2026-08-28T16:48:24Z · View source

De novo curation of ADH1, MONDO:0011013, as a CASR gain-of-function set-point disorder. The pathograph models the parathyroid and renal limbs as parallel downstream arms of one left-shifted calcium set point, because that convergence is what explains why conventional calcium and calcitriol treatment aggravates the renal lesion rather than relieving it. Twelve references, all located through PubMed and fetched with just fetch-reference; an openscientist deep-research run was commissioned and used as a source of leads for four of them after the independent model had been built. Three snippets initially taken from an abstract-metadata service did not match the fetched cache text word for word and were corrected against the cache. Validated: schema, terms, 44 of 44 reference snippets, plus the duplicate-key, entity-ref, folded-hyphen, snippet-length, title-snippet, snippet-grading and environmental-evidence gates.

OpenScientist ▸
Autosomal Dominant Hypocalcemia 1 (ADH1): Comprehensive Disease Characteristics Report
openscientist-autonomous 21 citations 2026-08-28T16:36:20.952107

Autosomal Dominant Hypocalcemia 1 (ADH1): Comprehensive Disease Characteristics Report

Disease: Autosomal Dominant Hypocalcemia 1 (ADH1) Gene: CASR (calcium-sensing receptor) OMIM: #601198 (phenotype), 601199 (gene) | Orphanet: ORPHA:428 | MONDO: 0008833 | HGNC: 1514 | UniProt: P41180 | Category:* Mendelian (autosomal dominant)

Evidence source note: This report is compiled from disease-level aggregated resources (OMIM, Orphanet, HGNC/UniProt) and primary literature (human clinical case series, in-vitro functional studies, and mouse-model studies), not from individual EHR data. Evidence type is indicated per claim.

Summary

Autosomal Dominant Hypocalcemia type 1 (ADH1; OMIM #601198) is a rare Mendelian endocrine disorder caused by heterozygous gain-of-function (activating) missense mutations in CASR, the gene encoding the calcium-sensing receptor (CaSR), a class C G-protein-coupled receptor on chromosome 3q13.33. The activating mutations "left-shift" the set-point for extracellular calcium sensing — the receptor is triggered at abnormally low calcium concentrations. This single molecular defect produces a dual-organ pathophysiology: in the parathyroid glands the over-active receptor inappropriately suppresses parathyroid hormone (PTH) secretion, producing hypocalcemia with inappropriately low/normal PTH; in the kidney the over-active receptor drives hypercalciuria and impairs urinary concentration. The result is a characteristic biochemical signature of low serum calcium, high phosphate, low-normal magnesium, low PTH, and relative-to-frank hypercalciuria.

Clinically, ADH1 spans a wide severity spectrum, from asymptomatic individuals detected on family screening to neonates and children presenting with seizures, tetany, carpopedal spasm, and paresthesias. Long-term complications are dominated by renal disease (nephrocalcinosis, nephrolithiasis, progressive chronic kidney disease), along with basal ganglia calcification, early cataracts, and cardiac QT prolongation. The central therapeutic dilemma is that conventional treatment (oral calcium plus active vitamin D) corrects hypocalcemia but worsens hypercalciuria and accelerates renal damage — so the guiding principle is to relieve symptoms while keeping serum calcium at the low end of normal, with thiazide diuretics as a useful adjunct.

The field is advancing toward mechanism-matched targeted therapy: calcilytics (negative allosteric CaSR modulators such as NPSP795/SHP635 and encaleret) have raised PTH and serum calcium in ADH1 patients and mouse models, and PTH-replacement approaches (palopegteriparatide) have rescued refractory pediatric cases. The Nuf mouse (Casr p.Leu723Gln) is the principal, faithful animal model. As an autosomal dominant disorder with 50% transmission risk (plus frequent de novo and mosaic events), prevention rests on genetic counseling, cascade testing, and reproductive genetic options. This report synthesizes 11 confirmed findings across 35 reviewed papers into a comprehensive knowledge-base entry.

Key Findings

Finding 1 — Genetic cause: heterozygous activating CASR mutations

ADH1 is caused by heterozygous gain-of-function (activating) missense variants in CASR. More than 400 germline CASR mutations (both loss- and gain-of-function) have been catalogued across the spectrum of calcium homeostasis disorders. In ADH1 specifically, the activating variants lower the EC50 for calcium-dependent G-protein activation, producing a left-shifted set-point so the receptor signals as if calcium is high even when it is low or normal. Inheritance is autosomal dominant, and de novo variants are common (e.g., p.Leu723Arg, p.Leu123Ser). ADH1 is molecularly distinct from ADH2, caused by gain-of-function variants in GNA11 (encoding Gα11, the CaSR's signaling partner).

"Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2)." — PMID: 39658204

"It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium." — PMID: 34160437

"the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ homeostasis" — PMID: 31189130

Finding 2 — Biochemical and clinical phenotype

The cardinal biochemistry of ADH1 is hypocalcemia (e.g., serum calcium 1.53–1.85 mmol/L), inappropriately low/normal PTH, hyperphosphatemia, hypomagnesemia, and relative-to-frank hypercalciuria. Clinical features include neuromuscular irritability (paresthesias, carpopedal spasm, tetany) and seizures, which are frequently the presenting feature in infancy and childhood. Complications include nephrocalcinosis/nephrolithiasis, basal ganglia calcification, and early cataracts. A key feature is variable expressivity: symptom severity is not tightly correlated with the degree of hypocalcemia. A severe subset manifests a Bartter-like (type V) salt-wasting phenotype.

"Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia. Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia. Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification" — PMID: 16128246

"presented with hypocalcemia, recurrent tetany, seizures, hypercalciuria, nephrocalcinosis, basal ganglia calcifications, and early-onset cataracts" — PMID: 42388864

"Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later" — PMID: 27617113

Suggested HPO terms: Hypocalcemia (HP:0002901), Hypoparathyroidism (HP:0000829), Hyperphosphatemia (HP:0002905), Hypomagnesemia (HP:0002917), Hypercalciuria (HP:0002150), Seizure (HP:0001250), Tetany (HP:0001281), Paresthesia (HP:0003401), Nephrocalcinosis (HP:0000121), Nephrolithiasis (HP:0000787), Basal ganglia calcification (HP:0002135), Cataract (HP:0000518), Prolonged QT interval (HP:0001657).

Finding 3 — The therapeutic dilemma and emerging targeted therapies

Standard-of-care treatment (oral calcium plus active vitamin D — calcitriol or alfacalcidol) corrects hypocalcemia but exacerbates hypercalciuria, promoting nephrocalcinosis and renal impairment. Cautious ("judicious") dosing is therefore recommended. Targeted therapy is emerging on two fronts: calcilytics (negative allosteric CaSR modulators) — NPSP795/SHP635 raised PTH and serum calcium in five ADH1 adults, and JTT-305 reversed renal AQP2 downregulation in CaSR knock-in mice; encaleret is in clinical development. PTH-replacement approaches (palopegteriparatide) resolved symptoms and lowered the calcium-phosphate product in a refractory pediatric case.

"Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635)" — PMID: 31063613

"In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice." — PMID: 38367250

"Optimal management of ADHH is difficult and we recommend judicious treatment to avoid an increased risk of nephrocalcinosis." — PMID: 16128246

Suggested NCIT terms: Calcium (C332), Calcitriol (C376), Vitamin D (C902), Thiazide Diuretic (C29713), Parathyroid Hormone (C2354).

Finding 4 — The Nuf mouse: the principal animal model

The Nuf mouse carries a germline gain-of-function Casr (Gprc2a) missense mutation Leu723Gln (chromosome 16), which lowers the receptor EC50. Both heterozygous and homozygous mice display hypocalcemia, hyperphosphatemia, inappropriately low PTH, ectopic/soft-tissue calcification, and nuclear cataracts — faithfully mirroring human ADH1. The model also revealed additional CaSR-dependent phenotypes, including impaired glucose tolerance and insulin secretion (hyperglycemia) that is rectified by calcilytics. Calcilytics (NPS 2143, NPSP795, and quinazolinones ATF936/AXT914) raise PTH and plasma calcium in Nuf mice; oral AXT914 raised PTH from 23±4 to 104±29 pmol/L (p<0.05).

"Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia." — PMID: 15347804

"Oral administration of 10 mg/kg AXT914 to Nuf mice increased parathyroid hormone to 104 ± 29 pmol/l compared with 23 ± 4 pmol/l for vehicle-treated mice, p < 0.05" — PMID: 40086735

"Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion." — PMID: 28575322

Finding 5 — Dual-organ pathophysiology

Activated CaSR in parathyroid chief cells suppresses PTH secretion at a lowered set-point, producing hypocalcemia with inappropriately low PTH. In the kidney, CaSR overactivity in the thick ascending limb and distal nephron independently increases urinary calcium excretion (hypercalciuria) via Claudin-14 (Cldn14) upregulation, and in the collecting duct impairs the vasopressin–AQP2 axis. CaSR knock-in mice show reduced AQP2 with increased AQP2 phosphorylation at Ser261 through a p38MAPK–ATF1–miR137 pathway, contributing to a urinary concentrating/Bartter-like tendency. The calcilytic JTT-305 reversed this AQP2 downregulation, confirming the mechanism is receptor-driven.

"CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261" — PMID: 38367250

"Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca" — PMID: 35313217

Suggested GO/CL/UBERON terms: GO:0007200 (phospholipase C-activating GPCR signaling), GO:0055074 (calcium ion homeostasis), GO:0038066 (p38 MAPK cascade), CL:0000446 (parathyroid chief cell), CL:1000456 (kidney collecting duct principal cell), UBERON:0001132 (parathyroid gland), UBERON:0002113 (kidney).

Finding 6 — Diagnostic approach

Diagnosis rests on biochemistry plus CASR sequencing. The workup includes serum calcium (low), phosphate (high), magnesium (often low), and PTH (inappropriately low/normal), plus a 24-hour urinary calcium showing relative/frank hypercalciuria. ADH1 is confirmed by identifying a heterozygous activating CASR variant (single-gene test or hypoparathyroidism/mineral gene panel; WES/WGS in undiagnosed cases). Monogenic causes account for only ~5–10% of hypoparathyroidism, so genetic testing is targeted to clinically suspicious cases. Thiazide diuretics enhance renal calcium reabsorption and are of particular benefit in patients with activating CaSR mutations. ADH1 must be distinguished from other hypoparathyroidism etiologies (postsurgical, autoimmune, DiGeorge/22q11 deletion).

"thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor" — PMID: 22863393

"which have a monogenic aetiology in 5%-10% of cases" — PMID: 34935164

"Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder." — PMID: 34935164

Finding 7 — CaSR structure and biased signaling

CaSR (UniProt P41180) is a class C G-protein-coupled receptor functioning as a homodimer with a large Venus flytrap extracellular domain (ECD), a cysteine-rich domain, and a 7-transmembrane domain (TMD). Five cryo-EM structures of near-full-length CaSR show how Ca2+/agonist binding in the ECD is transmitted to the TMD to activate G proteins (Gq/11, Gi), and how allosteric modulators tune this. Activating ADH1 mutations map to regions important for structural integrity, dimerization, and ligand binding; a TMD "hotspot" (e.g., residue 723) is also the common calcilytic-binding pocket. Some variants produce biased signaling — the de novo p.Leu723Arg variant selectively lowers the EC50 for Gα11 activation without affecting Gi/Gq/Gs.

"five cryo-EM structures of the near full-length CaSR have been published, demonstrating how agonist-binding transmits changes in the CaSR extracellular domain to the transmembrane region to activate G proteins, and how allosteric modulators affect these structural dynamics" — PMID: 36707151

"the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner" — PMID: 31189130

"the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins" — PMID: 39658204

"bind at a common region within the CaSR transmembrane domain, which is also an ADH1 mutational hotspot" — PMID: 40086735

Finding 8 — Nosology, identifiers, and inheritance

ADH1 identifiers: OMIM #601198; gene CASR (601199, HGNC:1514, 3q13.33); Orphanet ORPHA:428 ("autosomal dominant hypocalcemia"); MONDO:0008833; MeSH via "Hypocalcemia"/"Receptors, Calcium-Sensing". Synonyms: hypocalcemia autosomal dominant; hypoparathyroidism, familial isolated, autosomal dominant; ADHH (autosomal dominant hypocalcemia with hypercalciuria); familial/sporadic isolated hypoparathyroidism; Bartter syndrome type V (severe subset). Inheritance: autosomal dominant with frequent de novo mutations; germline/gonadal mosaicism has been reported (asymptomatic transmitting parent), producing variable/incomplete expressivity within families. ADH accounts for the majority of genetic isolated hypoparathyroidism; ADH1 (CASR) is far more common than ADH2 (GNA11). ADH2 (OMIM #615361) is caused by gain-of-function GNA11 mutations and is associated with short stature in ~42%* and less consistent hypercalciuria — a key distinguishing feature.

"ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases." — PMID: 39658204

"autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR)" — PMID: 36970776

"Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected." — PMID: 27617113

Finding 9 — Variable onset, allelic spectrum, and phenocopies

Onset is highly variable: ADH may be asymptomatic (detected on family screening or incidental hypocalcemia) or present with seizures in the neonatal period, childhood, or adulthood; severe neonatal cases require IV calcium (e.g., de novo p.Glu228Lys). CASR is a single locus with a graded allelic spectrum: heterozygous loss-of-function → familial hypocalciuric hypercalcemia (FHH1); homozygous LOF → neonatal severe hyperparathyroidism (NSHPT); heterozygous gain-of-function → ADH1. A common polymorphism Ala986Ser (A986S) in the intracellular tail modestly influences serum calcium and can act as a modifier. Acquired activating anti-CaSR autoantibodies produce an autoimmune ADH phenocopy (an important differential). Drug interactions matter clinically: phenobarbital accelerates 1-alfacalcidol metabolism, causing swings between hypo- and hypercalcemia.

"Heterozygous activating mutations of the CASR cause autosomal dominant hypocalcemia (ADH) that may be asymptomatic or present with seizures in the neonatal period or childhood or later in life. Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating autoantibodies, respectively." — PMID: 20374733

"A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals." — PMID: 11013439

"The child presented in the neonatal period with clinical seizures associated with severe hypocalcaemia, hyperphosphataemia, low parathyroid hormone levels and elevated urine calcium:creatinine ratios." — PMID: 25227206

Finding 10 — Prognosis: normal life expectancy but chronic renal morbidity

ADH1 is a chronic, lifelong disorder with generally good survival, but morbidity is driven by renal complications, amplified by both the intrinsic hypercalciuria and by conventional calcium/active-vitamin-D therapy. A systematic review of chronic hypoparathyroidism on conventional therapy reports nephrolithiasis rates up to 36% and nephrocalcinosis up to 38%, with progression to renal insufficiency/CKD. Additional complications include hypocalcemic seizures, basal ganglia (and other ectopic) calcification, cataracts, and QT-prolongation risk. Postsurgical chronic hypoparathyroidism cohorts show elevated renal disease (moderate-to-severe 28.8% vs 5.6%), nephrocalcinosis (59.9% vs 0.6%), and higher mortality (HR ~2.75) versus controls — underscoring the renal/cardiovascular burden of the hypoparathyroid state that ADH1 shares and exacerbates.

"The reported rate of nephrolithiasis was up to 36%, with the lowest rates in studies reporting shorter duration of disease. The rate of nephrocalcinosis was up to 38%." — PMID: 33599907

"a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)" — PMID: 40531442

Finding 11 — Management principles and prevention

Because overtreatment drives renal damage, the guiding therapeutic principle is to relieve symptoms while keeping serum calcium at the low end of normal, using thiazides to blunt hypercalciuria. Human proof-of-concept for mechanism-matched therapy: the calcilytic NPSP795/SHP635 increased PTH in ADH1 patients, and in-vitro assays show variant-specific responsiveness (supporting genotype-guided calcilytic selection); PTH-based therapy (palopegteriparatide) rescued a refractory pediatric case. Prevention is exclusively at the reproductive/clinical level: as an autosomal dominant disorder, each child of an affected parent has a 50% risk; de novo and mosaic events mean absence of family history does not exclude risk. Preventive tools are genetic counseling, cascade testing of relatives, and prenatal/preimplantation genetic testing for a known familial CASR variant. No population-based primary prevention exists.

"Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1." — PMID: 31063613

"also to allow the identification of other family members who may be at risk of disease" — PMID: 34935164

Mechanistic Model / Interpretation

ADH1 is fundamentally a single-gene, gain-of-function signalopathy with a two-organ output. The causal chain:

    Heterozygous activating CASR missense variant (e.g., L723Q, R205C, E228K)
              │
 Left-shifted Ca2+ set-point (↓ EC50 for Ca2+)
              │
  Receptor "reads" normal/low Ca2+ as if it were HIGH
 ┌────────────┴──────────────┐
 ▼                            ▼
       PARATHYROID GLAND                  KIDNEY
    (chief cells, CL:0000446)     (TAL + distal nephron + CD)
 │                            │
      ↓ PTH secretion            ↑ Cldn14 → ↑ urinary Ca2+ excretion
      (inappropriately low)      ↓ AQP2 (p38MAPK-ATF1-miR137)
 │                            │
 ▼                            ▼
      HYPOCALCEMIA               HYPERCALCIURIA + urine-concentration defect
      Hyperphosphatemia          (Bartter-like tendency in severe subset)
 │                            │
 └────────────┬───────────────┘
              ▼
       CLINICAL: seizures, tetany, paresthesias (acute);
       nephrocalcinosis, nephrolithiasis, CKD, basal ganglia
       calcification, cataracts, QT prolongation (chronic)

Upstream vs downstream: The upstream driver is the mutant receptor's shifted set-point. The parathyroid PTH suppression and renal calcium-wasting are parallel, independent downstream arms — a critical insight because it explains why simply raising serum calcium (which further activates the already over-sensitive renal receptor) worsens hypercalciuria. This is the mechanistic root of the treatment dilemma.

Why calcilytics work: By binding the TMD allosteric pocket (which coincides with the ADH1 mutational hotspot around residue 723), calcilytics raise the receptor's EC50 back toward normal, de-repressing PTH and reducing renal calcium wasting simultaneously — addressing both arms at their common origin rather than downstream.

Comparative nosology of CASR dosage:

Genotype Receptor activity Disorder Calcium phenotype
Heterozygous LOF ↓ FHH1 (familial hypocalciuric hypercalcemia) High Ca, low urine Ca
Homozygous LOF ↓↓ NSHPT (neonatal severe hyperparathyroidism) Severe high Ca
Heterozygous GOF ↑ ADH1 Low Ca, high urine Ca
— (GNA11 GOF) ↑ (via Gα11) ADH2 Low Ca, short stature ~42%

Report by Template Section

1. Disease Information

Rare AD form of hypoparathyroidism from activating CASR variants; hypocalcemia with inappropriately low PTH and hypercalciuria. Identifiers: OMIM #601198 (gene 601199), ORPHA:428, MONDO:0008833, HGNC:1514, UniProt P41180; ICD-10 E20.8 / ICD-11 5A50.0 (no ADH1-specific code); MeSH under Hypocalcemia / Receptors, Calcium-Sensing*. Synonyms: ADHH, familial isolated hypoparathyroidism (AD), Bartter syndrome type V (severe subset). Data are from aggregated disease-level resources plus published clinical case series/pedigrees.

2. Etiology

Primary cause is genetic/monogenic — heterozygous activating CASR missense variants (Finding 1). Genetic modifier: A986S (rs1801725) polymorphism. No environmental or infectious causation; environmental modifiers (dietary calcium/vitamin D, phenobarbital) alter severity only. Acquired activating anti-CaSR autoantibodies produce a phenocopy (differential, not etiology). No established protective alleles.

3. Phenotypes

See Finding 2 and the HPO list. Onset neonatal→adult; variable severity/expressivity; chronic lifelong course with episodic acute symptoms (seizures/tetany). QoL impacted by seizures, renal disease, and treatment burden; no ADH1-specific QoL instrument exists.

4. Genetic/Molecular Information

Causal gene CASR (3q13.33). Variant class predominantly heterozygous missense, gain-of-function; TMD hotspot (residue 723); some biased-signaling variants (Findings 1, 7). Classification: functionally validated activating variants are Pathogenic/Likely Pathogenic; novel variants often require in-vitro Ca2+-response assays. Allele frequency: private/rare, essentially absent in gnomAD; many de novo. Germline (with mosaicism reported). Modifier: A986S. No characteristic epigenetic or chromosomal abnormalities.

5. Environmental Information

Not causal. Modifiers of expression only: dietary calcium/vitamin D status; enzyme-inducing drugs (phenobarbital) that alter vitamin-D-analog metabolism. No infectious agents.

6. Mechanism/Pathophysiology

See Mechanistic Model and Finding 5. Pathways: Gq/11–PLC and Gi signaling, p38MAPK–ATF1–miR137 (renal AQP2), Cldn14-mediated renal calcium handling. Protein dysfunction: class C GPCR homodimer biased toward active state (Finding 7). CHEBI: calcium(2+) (CHEBI:29108), phosphate (CHEBI:43474). Immune involvement: none intrinsic.

7. Anatomical Structures Affected

Primary: parathyroid gland (UBERON:0001132), kidney/nephron (UBERON:0002113). Secondary: basal ganglia (UBERON:0002420), ocular lens (UBERON:0000965), soft tissue (ectopic calcification), heart (functional QT). Cells: parathyroid chief cell (CL:0000446), collecting-duct principal cell (CL:1000456), TAL epithelium. Subcellular: plasma membrane (GO:0005886), ER (trafficking). Lateralization: systemic/bilateral. Systems: endocrine, renal/urinary, nervous, cardiac electrophysiology.

8. Temporal Development

Onset congenital/neonatal → adult, or asymptomatic. Pattern chronic/insidious with acute symptomatic episodes. Course lifelong; renal complications slowly progressive. Critical periods: neonatal seizure risk; intercurrent illness, pregnancy, and medication changes; early diagnosis is the key intervention window to avoid overtreatment-related renal damage.

9. Inheritance and Population

Autosomal dominant; frequent de novo; germline/gonadal mosaicism reported (Finding 8). High biochemical penetrance, variable symptomatic expressivity; negative family history does not exclude ADH1. No anticipation, founder effect, or consanguinity role in the classic sense. Epidemiology: rare; precise prevalence not established; ADH is the most common genetic cause of isolated hypoparathyroidism; monogenic causes ~5–10% of all hypoparathyroidism; ADH1 >> ADH2. No strong sex or geographic predilection.

10. Diagnostics

Biochemistry: low Ca, high phosphate, low/normal PTH, often low Mg, high urine Ca (24-h or Ca:creatinine). Imaging: renal ultrasound, brain CT, ECG (QTc); slit-lamp for cataract. Genetic testing: single-gene CASR sequencing or hypoparathyroidism/mineral panel; WES/WGS if undiagnosed; functional assays for VUS. Diagnostic clue: hypoparathyroidism with hypercalciuria. Differential: postsurgical, autoimmune (incl. anti-CaSR autoantibody phenocopy), 22q11.2 deletion, hypomagnesemia-related, pseudohypoparathyroidism, vitamin D disorders, ADH2 (GNA11). Screening: cascade genetic testing; prenatal/PGT for a known variant; no population newborn screening.

11. Outcome/Prognosis

Near-normal life expectancy with treatment; dominant morbidity is renal (nephrocalcinosis up to ~38%, nephrolithiasis up to ~36%, progression to CKD), amplified by intrinsic hypercalciuria and overtreatment (Finding 10). Other complications: seizures, ectopic/basal ganglia calcification, cataracts, QT prolongation. Prognostic factors: cumulative urinary calcium load, treatment approach, disease duration. Established nephrocalcinosis/CKD is not fully reversible — prevention is key.

12. Treatment

Conventional: oral calcium + active vitamin D (calcitriol/alfacalcidol), targeting low-normal serum calcium with judicious dosing; thiazide diuretics (of particular benefit in activating-CaSR patients); magnesium repletion. Targeted: calcilytics (NPSP795/SHP635, NPS 2143, ATF936/AXT914, encaleret) and PTH-replacement (palopegteriparatide, recombinant PTH) (Finding 3). Pharmacogenomics: avoid enzyme inducers (phenobarbital). No approved gene/cell/RNA therapy; surgery not applicable. Personalized medicine: in-vitro variant response can guide calcilytic vs PTH-based choice. NCIT terms listed in Finding 3.

13. Prevention

Primary prevention not possible (germline). Genetic counseling (AD, 50% offspring risk; de novo/mosaicism caveats) and reproductive options (PGT/prenatal testing) are the main tools. Secondary: cascade testing and early biochemical surveillance of relatives. Tertiary (most important): avoid overtreatment, maintain low-normal calcium, monitor 24-h urine calcium and renal imaging, use thiazides/calcilytics/PTH to prevent nephrocalcinosis/CKD. Immunization/public-health/environmental interventions not applicable.

14. Other Species / Natural Disease

Taxonomy: Homo sapiens (NCBI:txid9606); modeled in Mus musculus (NCBI:txid10090). No notable naturally occurring ADH1 in companion animals/wildlife documented. Ortholog: mouse Casr (historically Gprc2a); receptor and its Ca2+-homeostasis role are evolutionarily conserved, so mechanisms translate well to mouse models. Zoonosis/transmission: not applicable.

15. Model Organisms

Principal model — the Nuf mouse (Casr p.Leu723Gln; Finding 4): AD gain-of-function; recapitulates hypocalcemia, hyperphosphatemia, low PTH, ectopic calcification, and cataracts; plus impaired glucose tolerance. CaSR knock-in mice dissect renal AQP2/vasopressin pathology. Cellular/in-vitro: HEK293 expressing WT vs mutant CaSR for intracellular-Ca2+/BRET assays and calcilytic docking. Applications: validating calcilytics, studying biased signaling, renal/pancreatic CaSR biology. Limitations: mouse mineral set-points/lifespan differ; neurological (basal ganglia calcification) features less emphasized. Resource: MGI (mouse Casr).

Evidence Base

PMID Title (abbreviated) Supports finding(s) Evidence type
39658204 Activating CaSR variant with biased signaling F1, F7, F8 Human genetics + in vitro
31189130 CaSR mutation review F1, F7 Review
34160437 p.Arg205Cys ADH1 pedigree F1 Human clinical
16128246 ADHH family, treatment challenges F2, F3, F10, F11 Human clinical
42388864 Palopegteriparatide pediatric ADH1 F2, F3 Human clinical case
27617113 Novel p.Leu123Ser + mosaicism F2, F8 Human clinical
31063613 Calcilytic NPSP795 in ADH1 patients F3, F11 Human clinical trial
38367250 Calcilytic reverses renal AQP2 defect F3, F5 Model organism (KI mouse)
15347804 Nuf mouse cataracts + calcification F4 Model organism
40086735 Quinazolinone calcilytic in Nuf mice F4, F7 Model organism
28575322 Nuf mice hyperglycemia F4 Model organism
35313217 Parathyroid vs kidney CaSR contributions F5 Model organism
22863393 Hypoparathyroidism review (thiazides) F6 Review
34935164 Genetics of calcium/bone disorders F6, F11 Review
36707151 CaSR cryo-EM structures F7 Structural/computational
36970776 GNA11 variants (ADH2) F8 Human genetics
20374733 CaSR-associated diseases + autoantibodies F9 Review
11013439 CASR mutation spectrum + A986S F9 Human genetics
25227206 Neonatal ADH1 + phenobarbital interaction F9 Human clinical
33599907 Renal complications systematic review F10 Systematic review
40531442 Postsurgical hypoparathyroidism outcomes F10 Retrospective cohort

The evidence base is coherent and mutually reinforcing across human clinical, human genetics, model organism, and structural/computational domains. Human genetic studies establish causation (activating CASR variants), the Nuf mouse and CaSR knock-in models provide mechanistic validation and pharmacological proof-of-concept, cryo-EM structures rationalize where mutations and calcilytics act, and clinical/registry studies define the phenotype, therapeutic dilemma, and prognosis. No paper in the reviewed set contradicts the central model.

Supported vs Refuted Hypotheses

Supported (evidence-backed): 1. ADH1 = heterozygous activating CASR variants, left-shifted Ca2+ set-point (gain of function) [PMID 39658204; 34160437]. 2. Phenotype = hypocalcemia + inappropriately low PTH + hypercalciuria + calcification complications [PMID 16128246]. 3. Dual parathyroid + renal CaSR overactivity explains hypocalcemia with hypercalciuria; renal AQP2 pathway involved [PMID 35313217; 38367250]. 4. Calcilytics are mechanism-matched therapy (human n=5 + mouse) [PMID 31063613; 40086735]. 5. Nuf mouse faithfully models the disease [PMID 15347804].

Refuted / not applicable: environmental or infectious causation; loss-of-function/misfolding mechanism (that is FHH/NSHPT); a role for population-based primary prevention.

Limitations and Knowledge Gaps

  1. Epidemiology is poorly quantified. No reliable population prevalence/incidence figures for ADH1 specifically; estimates are extrapolated from the broader hypoparathyroidism population (monogenic ~5–10%). Precise prevalence, incidence, sex ratio, and geographic/ethnic distribution remain gaps.
  2. Penetrance and expressivity are incompletely characterized. Variable expressivity and mosaicism are documented, but formal penetrance estimates by variant are lacking.
  3. Genotype–phenotype correlations are limited. Symptom severity is explicitly not tightly correlated with hypocalcemia degree; systematic variant-level correlation (including biased-signaling variants) is needed.
  4. Targeted therapy evidence is early-stage. Calcilytic human data are limited (n=5 for NPSP795) and PTH-replacement evidence is a single pediatric case. Long-term renal-protective outcomes are not yet established.
  5. Quality-of-life data are essentially absent — no EQ-5D/SF-36/PROMIS data specific to ADH1.
  6. Cross-species natural disease beyond engineered mouse models is not documented.

Proposed Follow-up Experiments / Actions

  1. Assemble a natural-history registry for ADH1 to quantify prevalence, penetrance, age-of-onset distribution, and long-term renal/neurological outcomes, stratified by variant.
  2. Systematic variant-function mapping: couple in-vitro Gq/11/Gi signaling assays with clinical severity to build a genotype–phenotype and calcilytic-responsiveness atlas guiding personalized therapy.
  3. Complete calcilytic clinical development (e.g., encaleret) with renal endpoints (24-h urine calcium, GFR trajectory, nephrocalcinosis imaging) as primary outcomes, not just PTH/serum calcium.
  4. Head-to-head comparison of thiazide + conventional therapy vs calcilytic vs PTH-replacement (palopegteriparatide) on renal protection in ADH1.
  5. Prospective QoL assessment using validated instruments to capture disease and treatment burden.
  6. Mechanistic follow-up on the renal AQP2/Cldn14 axis in patient-derived models (e.g., iPSC-derived kidney organoids carrying ADH1 variants) to validate the p38MAPK–ATF1–miR137 pathway in human cells.

Report compiled from 11 confirmed findings across 35 reviewed papers over 5 investigation iterations. Evidence spans human clinical, human genetics, model organism (Nuf/knock-in mouse), and structural/computational sources. PMIDs cited inline.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 31
Quoted claims found in source 29
Quoted claims not found in source 2
References weighed for topical relevance 21
On topic 17
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:31189130 (abstract only): "the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ homeostasis"
  • closest text in source: "The importance of the CaSR in the regulation of Ca2+ e has been highlighted by the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ e homeostasis"
  • PMID:40531442 (abstract only): "a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)"
  • closest text in source: "a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 28
Resolved 26
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 7
Terms named correctly 4
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:1000456 (2 mentions) - the report calls it "kidney collecting duct principal cell"; CL calls it mesothelial cell of parietal peritoneum

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0007200 (1 mention) - the report calls it "phospholipase C-activating GPCR signaling"; GO calls it phospholipase C-activating G protein-coupled receptor signaling pathway, and lists "PLC-activating GPCR signaling pathway" among its other names
  • CL:0000446 (3 mentions) - the report calls it "parathyroid chief cell"; CL calls it chief cell of parathyroid gland, and lists "parathyroid chief cell" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.