Hyperphenylalaninemia due to GTP cyclohydrolase deficiency

Hyperphenylalaninemia due to GTP cyclohydrolase deficiency is a rare genetic disorder characterized by an elevated level of the amino acid phenylalanine in the blood. This condition is a form of hyperphenylalaninemia, which encompasses a group of disorders that lead to high levels of phenylalanine due to various causes. Hyperphenylalaninemia due to GTP cyclohydrolase deficiency specifically results from mutations in the gene responsible for the production of GTP cyclohydrolase, an enzyme crucial for the biosynthesis of tetrahydrobiopterin (BH4). BH4 is essential for the hydroxylation of phenylalanine to tyrosine, a process that, when impaired, leads to the accumulation of phenylalanine in the body.

Causes

The disorder is caused by mutations in the GCH1 gene, which encodes the enzyme GTP cyclohydrolase. This enzyme is pivotal in the initial step of the biosynthetic pathway of tetrahydrobiopterin (BH4), a cofactor necessary for the metabolism of several amino acids, including phenylalanine. Without functional GTP cyclohydrolase, the synthesis of BH4 is reduced, leading to insufficient metabolism of phenylalanine and its subsequent accumulation.

Symptoms

Symptoms of hyperphenylalaninemia due to GTP cyclohydrolase deficiency can vary widely among affected individuals. Early signs may include intellectual disability, microcephaly (small head size), movement disorders, and psychiatric symptoms. The severity of symptoms often correlates with the levels of phenylalanine in the blood; higher levels are typically associated with more severe symptoms.

Diagnosis

Diagnosis of this condition involves biochemical testing to measure the levels of phenylalanine in the blood. Additionally, the diagnosis can be confirmed through genetic testing to identify mutations in the GCH1 gene. Newborn screening programs in many countries include tests for elevated phenylalanine levels, which can lead to early detection of hyperphenylalaninemia.

Treatment

Treatment for hyperphenylalaninemia due to GTP cyclohydrolase deficiency focuses on dietary management to control phenylalanine intake and pharmacological treatment to supplement BH4 levels. A diet low in phenylalanine can help prevent the accumulation of this amino acid in the blood. In some cases, supplementation with synthetic BH4 is effective in reducing phenylalanine levels and mitigating symptoms.

Prognosis

The prognosis for individuals with hyperphenylalaninemia due to GTP cyclohydrolase deficiency varies. Early diagnosis and treatment can improve outcomes and reduce the risk of severe intellectual and developmental disabilities. However, the effectiveness of treatment can vary among individuals, and some may experience lifelong symptoms despite management efforts.

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