Summary:
Autosomal dominant hypocalcemia (ADH) is a rare genetic disorder of calcium metabolism caused by mutations in the CASR gene. It leads to low calcium levels in the blood and may cause symptoms ranging from muscle cramps to neurological problems. Treatment requires careful monitoring to minimize the risk of complications.

Overview

ADH is characterized by:

• Low blood calcium levels (hypocalcemia)
• Inappropriately low or normal parathyroid hormone (PTH) levels

It is inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene from one parent is enough to cause the condition.

Causes and Mechanism

• Gene Mutation: ADH is primarily caused by mutations in the CASR gene, which encodes the calcium-sensing receptor (CaSR).
• Mechanism: The CaSR receptor, found in the parathyroid glands and kidneys, regulates blood calcium levels. Mutations make the receptor overly sensitive to calcium, reducing PTH secretion even when calcium levels are low.
• Effect on Calcium Regulation:
  • Decreased calcium release from bones.
  • Reduced calcium absorption in the intestines.
  • Increased calcium excretion by the kidneys.
    This disrupts the normal feedback loop, resulting in chronic hypocalcemia.

Symptoms

Symptoms vary widely, from asymptomatic cases to severe manifestations, including:

• Muscle Cramps or Spasms (Tetany): Caused by low calcium levels.
• Paresthesia: Tingling or numbness in the hands, feet, or around the mouth.
• Seizures: Severe hypocalcemia may trigger convulsions.
• Neurological Symptoms: Confusion, depression, or irritability.
• Cataracts: Chronic hypocalcemia may lead to the development of cataracts.

Diagnosis

ADH is diagnosed based on:

1. Low Serum Calcium: Confirmed through blood tests.
2. Inappropriately Low or Normal PTH Levels: This paradoxical finding suggests suppressed PTH secretion despite low calcium levels.
3. Genetic Testing: Identification of mutations in the CASR gene confirms the diagnosis.

Differential Diagnosis: ADH can be mistaken for other hypocalcemic conditions, such as hypoparathyroidism, underscoring the importance of genetic testing.

Treatment

Managing ADH is challenging, as standard hypocalcemia treatments carry risks, such as:

• Hypercalciuria (excessive urinary calcium excretion)
• Nephrocalcinosis (calcium deposits in the kidneys)

Key treatment approaches include:

1. Calcium and Vitamin D Supplements:
   • Used cautiously to raise calcium levels while minimizing urinary calcium excretion.
2. Thiazide Diuretics:
   • Reduce calcium excretion in urine, lowering the risk of nephrocalcinosis.
3. Regular Monitoring:
   • Frequent monitoring of blood and urinary calcium levels is essential to adjust treatment and avoid complications.

Prognosis

The prognosis for ADH depends on the severity of symptoms and the effectiveness of treatment.

• With careful monitoring and an individualized approach, most patients can lead a relatively normal life.
• The main challenge is balancing adequate calcium supplementation with the prevention of complications such as kidney damage.

A multidisciplinary approach involving endocrinologists and nephrologists