Introduction:
The role of ions and minerals is essential to maintain various physiologic functions. One of the most important ions is calcium. Calcium ions maintain various functions like muscle contraction, neurotransmission, and blood coagulation. The parathyroid hormone maintains the level of calcium ions. Any problem regarding this hormone is responsible for an imbalance in calcium ion functioning. Autosomal dominant hypoparathyroidism or autosomal dominant hypocalcemia is one such disorder that disrupts the functioning of the parathyroid hormone and is responsible for calcium imbalance.
What Is Hypoparathyroidism?
The parathyroid gland is one of the most important glands of the human body. This gland is located just behind the thyroid gland at the bottom of the neck. Chief cells of the parathyroid gland produce parathyroid hormone. This hormone plays a crucial role in calcium ion balance. In the kidney, this hormone is responsible for increased calcium ions reabsorption and decreased phosphate ions absorption. In the bone, this hormone is associated with the differentiation of osteoblasts (bone-forming cells) and osteoclasts (cells associated with bone resorption). As s result, the release of the calcium ion from the bone is regulated. Parathyroid hormone synthesizes vitamin D and the absorption of calcium ions from the small intestine. The hypofunction of the parathyroid gland is known as hypoparathyroidism. Various conditions like surgical excision of the parathyroid glands, auto-immune diseases, and metabolic disorders can cause this. The genetic cause of hypoparathyroidism is known as isolated familial hypoparathyroidism. Autosomal dominant hypoparathyroidism belongs to this group only.
What Is Autosomal Dominant Hypoparathyroidism?
Familial isolated hypoparathyroidism has three types: dominant, recessive, and X-linked trait. It is a rare condition that affects only 1 in 1000000 individuals. The dominant type of hypoparathyroidism can be divided into three types. These are:
1. Autosomal-Dominant Hypocalcemia Type 1 - This is caused by abnormal signaling of the CASR gene on chromosome 3q21. This mutation causes suppression of the secretion of parathyroid hormone. In this condition, the serum calcium level is low. But the level of phosphate in the blood remains high. The amount of calcium excreted from urine also increased in this condition. Another variation of this condition is Bartter syndrome type V. In this condition, the serum calcium level is also low. Additionally, serum potassium and magnesium levels remain low in this condition. This condition leads to metabolic alkalosis, which disrupts the body's acid-base balance.
2. Autosomal-Dominant Hypocalcemia Type 2 - This is caused by the mutation of the alpha subunit of guanine nucleotide-binding protein G11 on chromosome 19p13. This mutation causes disruption of signaling to the PTH and CASR gene. Another type of this condition is caused by a mutation of glial cells missing-2 gene or GCM2 gene on chromosome 6p24.2. These genes are responsible for the development and functioning of the parathyroid gland. As a result of the mutation, the development and functioning of the gland are impaired.
3. Autosomal-Dominant Hypocalcemia Type 3: This is caused by a mutation of the P2S1 gene. This gene is associated with the regulation of CASR gene functioning. Mutation of the PTH gene is responsible for another type of familial hypoparathyroidism. This mutation disrupts the protein chain formation of the parathyroid hormone. Thus, defective formation of the parathyroid hormone takes place.
What Is the Mechanism of Autosomal Dominant Hypoparathyroidism?
The main cause of familial hypocalciuric autosomal dominant hypoparathyroidism is the inactivation of calcium-sensing receptors (CASR). These receptors are G-protein coupled glycoproteins that detect the level of calcium in the blood. It is expressed in tissues like kidneys, skeletal muscles, and parathyroid glands. This gene regulates the ion channels and maintains various functions like chemotaxis, proliferation, and differentiation. Through these actions, it maintains the calcium balance.
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This gene maintains the release of the parathyroid hormone and the proliferation of the chief cells.
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In the kidneys, this gene is present in the basolateral membrane of the cortical thick ascending limb of Henle's loop (u-shaped part of the nephron). Here it is responsible for the reabsorption of calcium and inhibits phosphate reabsorption.
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Also, these genes activate vitamin D, which is responsible for calcium absorption.
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In the bones, these genes are expressed in osteoblasts and osteoclasts and cause calcium release from the bone.
CASR maintains the parathyroid gland's set point for the secretion of parathyroid hormone. In the autosomal dominant type 1, the mutation causes decreased secretion of the parathyroid hormone and alteration of this set point. As a result, the excretion of calcium through urine is increased. Mutation of protein G11 is responsible for improper signaling to the CASR and disrupts its function. GCM2 genes are responsible for various functions and the development of the parathyroid gland. Mutation of these causes impaired DNA binding of the cells and loss of nuclear localization (a type of cellular signal). This causes decreased secretion of parathyroid hormone.
What Are the Clinical Features of Autosomal Dominant Hypoparathyroidism?
Patients develop mild symptoms in these cases. These are:
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Mild fatigue and weakness.
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Difficulty in movement, a history of frequent headaches, pain in the joints, and muscle pain.
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Abdominal cramps.
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Polyuria or increased volume of the urine.
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Polydipsia or increased urge of thrust.
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Developmental delays and temporary skeletal structures can be found. This is mainly seen in type 2 conditions.
On examination following things can be diagnosed:
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Chondrocalcinosis - Deposition of calcium crystals in the cartilage, which causes cartilage mineralization.
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Osteomalacia - The increased softness of the bones characterized by the presence of a small fracture line.
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Renal Stones - Renal stones and calcification are common in type 1 conditions. In severe cases, renal failure can be observed.
How to Treat of Autosomal Dominant Hypoparathyroidism?
If the patient is asymptomatic, no treatment is necessary. For moderate to severely symptomatic cases following treatment is observed:
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The application of thiazide diuretics lowers urinary calcium.
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Injection of parathyroid hormone can also be given to check the calcium level.
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Molecule allosteric modulators of the CASR, like Cinacalcet, help to activate CASR.
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Vitamin D supplements can be given.
Conclusion:
Autosomal dominant hypothyroidism is an extremely rare condition. This condition affects the secretion of parathyroid hormone levels and alters the calcium ion balance in the body. As a result, neuromuscular problems are noticed. In severe cases, renal failure may occur. Early diagnosis of pathological conditions can help cure this condition.
