The causes of homocystinuria are rooted in inherited genetic mutations that disrupt the normal breakdown of methionine, an essential amino acid. These mutations affect enzymes responsible for converting methionine into other compounds, leading to a harmful buildup of homocysteine in the body. High homocysteine levels damage blood vessels and connective tissue, resulting in serious complications if left untreated.
CBS Deficiency – The Most Common Cause
The most frequent cause of homocystinuria is a deficiency of cystathionine beta-synthase (CBS). This enzyme helps convert homocysteine into cystathionine. When CBS is faulty or absent, homocysteine accumulates in the blood and tissues, causing widespread damage to organs.
Homocystinuria is an autosomal recessive disorder, meaning a child must inherit two defective copies of the gene—one from each parent—to develop the disease. Carriers with only one defective copy typically show no symptoms but can pass the mutation on. If both parents are carriers, each pregnancy carries a 25% risk of producing an affected child.
Other Genetic Causes
While CBS deficiency accounts for most cases, other rare enzyme defects can also cause homocystinuria:
- MTHFR Deficiency
Methylenetetrahydrofolate reductase (MTHFR) helps remethylate homocysteine into methionine. A defect here leads to high homocysteine and low methionine, often with neurological symptoms. - Vitamin B12 Metabolism Defects
Genes like MMACHC and MTRR affect the body’s ability to process vitamin B12, which is essential for homocysteine metabolism. These forms usually present early in life and may be more severe. - Methionine Synthase Deficiency
This enzyme is also involved in the remethylation pathway. Its deficiency results in high homocysteine and low methionine, sometimes with megaloblastic anaemia and neurological problems.
Although all these variants raise homocysteine levels, they differ in severity and treatment response. For example, some CBS-deficient patients respond to high doses of vitamin B6 (pyridoxine), while those with B12-related defects need hydroxocobalamin injections.
Role of Genetic Variability and Environment
Not all mutations in the same gene cause equal damage. Some allow partial enzyme activity, leading to milder symptoms, while others completely block function, causing severe disease. Nutritional deficiencies, such as low intake of folate, B6, or B12, can make symptoms worse in genetically susceptible individuals.
Screening and Genetic Testing
Newborn screening detects many cases by identifying elevated methionine levels in dried blood spots. However, this method can miss non-CBS forms, so additional homocysteine testing is often needed. Genetic testing confirms the diagnosis, identifies carriers, and helps predict treatment response.
Summary
The causes of homocystinuria involve inherited enzyme deficiencies affecting methionine metabolism. Understanding the underlying mutation is key to effective treatment and family planning. Genetic counselling is strongly recommended for affected families, and early detection remains the best way to prevent complications.
