CYP24A1

CYP24A1 encodes the enzyme responsible for breaking down active vitamin D, ensuring calcium balance and preventing hypercalcemia. 

Mutations in CYP24A1 disrupt this process, leading to excessive calcium absorption, kidney complications, and disorders such as idiopathic infantile hypercalcemia (IIH1) and recurrent kidney stones in adults.

What is CYP24A1?

The CYP24A1 gene encodes 25-hydroxyvitamin D3-24-hydroxylase, a mitochondrial cytochrome P450 enzyme responsible for vitamin D degradation. This enzyme helps maintain calcium homeostasis by inactivating excess vitamin D, preventing hypercalcemia and hypercalciuria. 

Without proper CYP24A1 function, vitamin D metabolism becomes dysregulated, leading to excessive calcium absorption, elevated serum calcium levels, and renal complications.

CYPD24A1 in Vitamin D Metabolism

CYP24A1 functions within the vitamin D pathway by counterbalancing the activation process. 

In the liver, CYP2R1 converts vitamin D into 25-hydroxyvitamin D (25(OH)D), which is then activated in the kidneys by CYP27B1, producing 1,25-dihydroxyvitamin D (1,25(OH)₂D or calcitriol), the active hormone. 

CYP24A1 is responsible for degrading these active vitamin D metabolites through hydroxylation, preventing excessive calcium absorption from the intestines, and reducing bone resorption. This regulatory process helps maintain a stable calcium balance and prevents complications such as nephrocalcinosis and kidney damage. 

CYP24A1 expression is upregulated by 1,25(OH)₂D as a feedback mechanism to prevent vitamin D toxicity, while parathyroid hormone (PTH) normally suppresses CYP24A1, ensuring sufficient vitamin D activation when calcium levels are low.

Mutations in CYP24A1

Loss-of-function mutations in CYP24A1 impair its ability to degrade active vitamin D, leading to persistent calcitriol activity, increased calcium absorption, and hypercalcemia. 

Biallelic (homozygous or compound heterozygous) mutations cause Idiopathic Infantile Hypercalcemia Type 1 (IIH1), a severe early-onset disorder marked by excessive calcium levels and renal complications. 

Meanwhile, monoallelic (heterozygous) mutations may contribute to milder hypercalcemia, kidney stones, or nephrocalcinosis, particularly when vitamin D intake is high. While some heterozygous carriers remain asymptomatic, others develop chronic calcium-related disorders.

Conditions Associated with CYP24A1 Mutations

The following conditions are associated with mutations in CYP24A1:

Idiopathic Infantile Hypercalcemia Type 1

Idiopathic Infantile Hypercalcemia Type 1 (IIH1) is one of the primary conditions linked to CYP24A1 mutations. Infants with IIH1 typically present with unexplained hypercalcemia, vomiting, poor feeding, and failure to thrive. 

Key biochemical markers of IIH1 include elevated serum calcium and 1,25(OH)₂D, suppressed PTH, and hypercalciuria, which can lead to nephrocalcinosis. While hypercalcemia often resolves with age, nephrocalcinosis can persist and increase the risk of chronic kidney disease (CKD) later in life.

Adult-Onset Hypercalcemia and Kidney Disease

CYP24A1 mutations can also cause adult-onset hypercalcemia and kidney disease, presenting as recurrent kidney stones, nephrocalcinosis, and chronic kidney disease. 

Due to their high calcium levels, these individuals may be misdiagnosed with primary hyperparathyroidism or vitamin D toxicity. Symptoms often worsen with vitamin D supplementation, high dietary calcium intake, or tanning bed use.

Other Associated Conditions

Beyond hypercalcemia, CYP24A1 overexpression has been implicated in cancer, chronic kidney disease (CKD), and metabolic disorders. In several malignancies, including prostate, breast, lung, and colon cancers, excessive CYP24A1 activity leads to vitamin D resistance, potentially contributing to tumor progression. 

Similarly, increased CYP24A1 activity in CKD and diabetic nephropathy exacerbates vitamin D deficiency, worsening disease outcomes. Bone and mineral disorders are also associated with CYP24A1 dysfunction, as excessive vitamin D degradation can impair calcium metabolism, leading to osteoporosis, fractures, and hypophosphatemia.

Who Should Get CYP24A1 Tested?

Testing for CYP24A1 mutations or dysregulation may be appropriate in:

• Unexplained hypercalcemia (particularly with normal or low parathyroid hormone levels).
• Recurrent kidney stones or nephrocalcinosis with no clear metabolic explanation.
• Suspected vitamin D metabolism disorders, including vitamin D toxicity or paradoxical vitamin D deficiency symptoms.
• Individuals with a family history of CYP24A1-related disorders.
• Patients presenting with calcium imbalance symptoms such as fatigue, bone pain, muscle weakness, and polyuria.

Test Procedure and Interpretation

Testing for CYP24A1 is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CYP24A1 genetic testing are considered to be without mutations that can alter the activity of the CYP24A1 proteins.

Clinical Implications of Positive CYP24A1 Mutations

The clinical implications of a positive CYP24A1 mutation test result will vary by individual, although CYP24A1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms.

Patients or practitioners with questions about the clinical implications of CYP24A1 mutations should seek further assessment with a genetic counselor or expert. 

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