Genes are segments of DNA that provide instructions for building proteins. Occasionally, a change, or mutation, occurs in a gene’s DNA sequence, which can alter these instructions. This article will explore the CBS gene, the effects of its mutations, associated health conditions, and how they are diagnosed and managed.
The Role of the CBS Gene
The CBS gene provides instructions for producing an enzyme called cystathionine beta-synthase. This enzyme is part of the transsulfuration pathway, which processes the essential amino acid methionine. The primary job of the cystathionine beta-synthase enzyme is to convert a substance called homocysteine into another molecule named cystathionine.
This conversion serves two main purposes: it clears excess homocysteine, which can be harmful if it accumulates, and it begins the production of other molecules. The cystathionine is later converted into cysteine, an amino acid used to build proteins and the protective molecule glutathione.
Consequences of CBS Gene Mutations
Over 200 known mutations in the CBS gene can lead to health problems. These changes can result in a cystathionine beta-synthase enzyme that is misshapen, unstable, has reduced activity, or is not produced at all. The direct result of a faulty enzyme is a disruption in its metabolic pathway.
The conversion of homocysteine to cystathionine is impaired, causing homocysteine and its precursor, methionine, to build up in the blood and urine. This accumulation is detrimental to various tissues. Concurrently, the blockage causes a deficiency of molecules that would normally be produced, like cystathionine and cysteine. This dual effect of toxic buildup and substance deficiency underlies the associated health issues.
Health Conditions Linked to CBS Mutations
Severe mutations in both copies of the CBS gene lead to a condition known as classical homocystinuria. While infants with the condition are normal at birth, symptoms often appear during the first few years of life, though diagnosis can occur in adulthood. The effects are progressive and impact multiple organ systems.
Common signs and symptoms include:
- Eye problems, such as severe nearsightedness (myopia) and dislocation of the eye’s lens (ectopia lentis).
- Skeletal abnormalities, including a tall, thin build with long limbs, scoliosis (curvature of the spine), and osteoporosis, which causes brittle bones.
- Central nervous system issues, such as developmental delays, learning problems, intellectual disability, seizures, or psychiatric problems.
- An increased risk of thromboembolism (blood clots), which can form in any blood vessel and lead to a stroke or pulmonary embolism.
Blood clots are a serious complication and a primary cause of early death in untreated individuals.
Diagnosing CBS Gene Mutations
Diagnosis of conditions related to CBS gene mutations often begins with newborn screening. A small blood sample from a newborn’s heel is tested for metabolic disorders, and an elevated methionine level prompts further investigation.
To confirm a diagnosis, biochemical tests are performed on blood and urine. These tests measure the total homocysteine concentration in the plasma, which is markedly increased in affected individuals. An analysis of plasma amino acids also looks for high levels of methionine and low levels of cystathionine. In some cases, the enzyme’s activity can be directly measured using cultured skin cells.
Genetic testing provides the final confirmation by sequencing the CBS gene to identify the specific mutations. Identifying the mutations helps confirm the diagnosis, predict the condition’s potential severity, and guide treatment decisions.
Managing Conditions from CBS Gene Mutations
Management of classical homocystinuria focuses on controlling high homocysteine levels to prevent complications. Treatment is lifelong, tailored to the individual, and involves a healthcare team that includes a metabolic specialist and a dietician.
Vitamin B6 (Pyridoxine) Therapy
A primary treatment is high-dose therapy with pyridoxine (vitamin B6). The enzyme requires B6 to function, and large doses can boost its residual activity in some patients. Individuals are categorized as “B6-responsive” or “B6-non-responsive” based on their reaction to this therapy. Responsive patients have a milder form of the disease.
Dietary Management
For B6-non-responsive or partially responsive individuals, dietary management is necessary. This involves a low-protein diet that restricts methionine intake by avoiding foods like meat, fish, eggs, and dairy. Patients use a special medical formula that provides other amino acids without methionine and is enriched with cysteine to ensure proper nutrition.
Additional Medications and Supplements
Another medication is betaine, which helps lower homocysteine by promoting an alternative metabolic pathway. It is often used for B6-non-responsive patients in combination with diet. Supplementation with folic acid (vitamin B9) and vitamin B12 is also common, as they support homocysteine processing.