What are the other Names for this Condition? (Also known as/Synonyms)
- Autosomal Dominant Hypoparathyroidism
- Familial Hypercalciuric Hypocalcemia
- Familial Hypocalcemia
What is Autosomal Dominant Hypocalcemia? (Definition/Background Information)
- Autosomal Dominant Hypocalcemia (ADH) is a genetic disorder that is inherited in an autosomal dominant manner, where one defective copy of either affected gene can cause the disorder if present in all the cells. A family history of the condition is the single major risk factor for developing ADH
- Under normal circumstances, two proteins (CaSR and Gα11) coded by the CASR and GNA11 genes, work together towards calcium homeostasis (equilibrium). CaSR binds calcium and signals to Gα11 to block the release of calcium in the bloodstream, when calcium levels are too high
- However, if either the CaSR or Gα11 genes are mutated, calcium metabolism is affected, which can cause Autosomal Dominant Hypocalcemia. There are two types of ADH:
- Type 1 Autosomal Dominant Hypocalcemia
- Type 2 Autosomal Dominant Hypocalcemia
- The majority of individuals with Autosomal Dominant Hypocalcemia have Type 1 ADH, where the CASR gene is mutated and the CaSR protein is abnormal. This abnormal protein is hyper-sensitive to calcium and sends a signal to Gα11 to block the release of calcium in blood, which can cause the characteristic symptoms of Autosomal Dominant Hypocalcemia
- Mutations in the GNA11 gene, which codes for the Gα11 protein, leads to Type 2 Autosomal Dominant Hypocalcemia. The abnormal Gα11 blocks the release of calcium in the bloodstream, which can lead to a drop in blood calcium levels
- Individuals with Autosomal Dominant Hypocalcemia may be asymptomatic, or may have mild, moderate, or severe symptoms. These symptoms can include abnormal weakness, movement disorders, abnormal sensations, seizures, and the release of excess calcium through urine. Additionally, ADH may also interfere with the balance of other molecules such as phosphates and magnesium
- Since calcium can crystallize within the kidneys, the crystals can form stones and interfere with kidney function. This can cause renal failure, a potential complication of ADH
- The diagnosis of Autosomal Dominant Hypocalcemia can be made accidentally during a routine examination in asymptomatic individuals. In those with ADH symptoms, a physical examination, assessment of family medical history, symptom evaluation, blood and urine tests, and ultrasound imaging studies may be required for diagnosis
- Some of the treatment options for Autosomal Dominant Hypocalcemia include oral or intravenous calcium supplementation, vitamin-D supplements, and parathyroid hormone infusion
- The prognosis of Autosomal Dominant Hypocalcemia is dictated by the type and severity of the symptoms. Delayed or inadequate treatment may lead to kidney failure
Who gets Autosomal Dominant Hypocalcemia? (Age and Sex Distribution)
- The exact prevalence of Autosomal Dominant Hypocalcemia is currently unknown
- It is a congenital disorder, but the age of onset varies; the symptoms may manifest during infancy, childhood, or even later in life
- ADH can affect both male and female genders
- No racial and ethnic group preference is noted
- It is believed that Autosomal Dominant Hypocalcemia may be underdiagnosed, as it may present without significant signs and symptoms in many affected individuals
What are the Risk Factors for Autosomal Dominant Hypocalcemia? (Predisposing Factors)
- Autosomal Dominant Hypocalcemia is a genetic disorder, which means that having a parent with ADH is a chief risk factor for developing the same
It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.
Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.
What are the Causes of Autosomal Dominant Hypocalcemia? (Etiology)
- The majority of Autosomal Dominant Hypocalcemia cases are caused by mutations in the CASR gene and are classified as Type 1 ADH.
- The CASR gene codes for a protein known as the calcium-sensing receptor or CaSR. This protein binds and also initiates a signaling mechanism by activating another protein called Gα11, which blocks release of more calcium in blood
- Gα11 is coded by the gene GNA11. CaSR and Gα11 both cooperatively regulate the calcium levels in blood
- When there is a mutation in the CASR gene, CaSR is rendered hypersensitive to calcium. It then binds to free calcium, even when the circulating levels of the element are low, effectively reducing the amount of calcium in blood
- In a small amount of cases, classified as Type 2 ADH, the GNA11 gene is mutated, causing an overactive Gα11 protein. Even very low levels of calcium can activate Gα11 signaling, such that the signal is sent to the body systems to stop releasing calcium in blood. This keeps the blood calcium levels low
- Mutations in either the CASR or GNA11 genes can cause hypocalcemia, and lead to the characteristic symptoms of the disorder with abnormal muscular function
- Abnormally low levels of calcium in blood can also interfere with the regulation of other important molecules, such as magnesium and phosphate, leading to additional symptoms
- Autosomal Dominant Hypocalcemia is inherited in an autosomal dominant fashion, whereby a single copy of the mutated gene is sufficient to cause the disorder
- In rare cases, individuals with no family history of ADH may develop the condition due to de-novo mutations in CASR or GNA11 genes
Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.
Note: Some individuals may have low levels of parathyroid hormone in combination with Autosomal Dominant Hypocalcemia, and rarely with Bartter syndrome (termed Bartter syndrome type V).
What are the Signs and Symptoms of Autosomal Dominant Hypocalcemia?
The main symptoms of Autosomal Dominant Hypocalcemia include:
- Carpopedal spasms, or muscle spasms in hands and feet
- Asthenia: Feeling unnaturally tired or weak
- Parasthesia: Sensations of tingling or prickling
- Muscle cramps
- Neuromuscular irritability, or the twitching of nerves and muscles
- Seizures, more commonly in infancy and childhood
- Hypercalciuria, which is an increased calcium excretion in urine
- Nephrocalcinosis, or increased calcium in the kidneys
- Hyperphosphatemia (elevated phosphate levels in blood)
- Hypermagnesuria (increased magnesium in urine)
- Hypomagnesemia (low levels of magnesium in blood)
- Kidney stones
- Kidney malfunction
Many individuals with Autosomal Dominant Hypocalcemia may remain asymptomatic; although, such individuals can still develop symptoms during the course of their lives. A few affected children may show symptoms only during an illness or fever. The type and severity of symptoms may vary considerably among those affected.
How is Autosomal Dominant Hypocalcemia Diagnosed?
The diagnosis of Autosomal Dominant Hypocalcemia is made through:
- A physical examination
- An evaluation of family medical history
- An assessment of symptoms
- Blood test to check for the level of calcium in serum
- Urine test for checking calcium levels in urine
- Urine test to check parathyroid hormone, which can help rule out hypoparathyroidism. Hypoparathyroidism is often characterized by abnormal calcium metabolism
- Imaging studies of the kidneys to check for damage to the organ
- Tests to check for Bartter syndrome, which is characterized by salt-wasting
- Prenatal genetic testing of fetal cells, in case of a family history of ADH
Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.
What are the possible Complications of Autosomal Dominant Hypocalcemia?
Some potential complications of Autosomal Dominant Hypocalcemia include:
- Damaged kidneys and impaired renal function due to increased calcium in urine. This can lead to the development of kidney stones
- Calcium deposits in the brain, in areas (such as the basal ganglia) that help control muscle movement
- Rarely, the affected individuals may have severe symptoms in combination with Bartter syndrome, referred to as Autosomal Dominant Hypocalcemia with Bartter syndrome (or Bartter syndrome type V)
How is Autosomal Dominant Hypocalcemia Treated?
The treatment options for Autosomal Dominant Hypocalcemia may include:
- Oral calcium supplements with mild symptoms
- Intravenous calcium infusion for patients with many and/or major symptoms: The calcium levels in blood are carefully monitored, since the kidney cells may perceive the influx of calcium as hypercalcemia and excrete more calcium in urine
- Magnesium infusion, if the individual is having hypomagnesemia (magnesium deficiency in blood)
- Vitamin D supplementation in combination with calcium supplements
- Infusion of parathyroid hormone to regulate calcium levels in blood, in case the above methods are not successful
Note: Asymptomatic individuals (those in whom the disorder is suspected due to a family history of ADH) may not require any treatment. However, a close monitoring of such individuals may be necessary.
How can Autosomal Dominant Hypocalcemia be Prevented?
- Currently, there are no specific methods or guidelines to prevent Autosomal Dominant Hypocalcemia, since it is a genetic condition
- Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
- If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
- Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Autosomal Dominant Hypocalcemia
- Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended
What is the Prognosis of Autosomal Dominant Hypocalcemia? (Outcomes/Resolutions)
- The prognosis of Autosomal Dominant Hypocalcemia is reported to be dictated by the type and severity of symptoms in the affected individuals
- Individuals with mild signs and symptoms of ADH have better prognosis than those with severe conditions
- Delay or insufficiency in treatment may lead to kidney malfunction and consequent renal failure
Additional and Relevant Useful Information for Autosomal Dominant Hypocalcemia:
Variation in clinical presentation in Autosomal Dominant Hypocalcemia, ranging from asymptomatic hypocalcemia to childhood hypocalcemic seizures, seems to be typical for the disorder and is currently, an unexplained feature of this condition.