Classical homocystinuria, also known as cystathionine beta-synthase (CBS) deficiency, is a rare inherited metabolic disorder that affects the body's ability to break down certain amino acids, accumulating homocysteine in the blood. This condition is caused by mutations in the CBS gene, which provides instructions for producing the CBS enzyme. The worldwide prevalence of homocystinuria is estimated to range from 1 case per 200.000 population to 1 case per 350.000 population. However, it is most common in New South Wales, Australia (1:60.000), Ireland (1:65.000), Germany (1:17.800) and Qatar (1:1.800).
Classical homocystinuria genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features and aspects of classical homocystinuria include:
- Amino Acid Metabolism: Homocysteine is an amino acid usually broken down in the body through a series of enzymatic reactions. In individuals with classical homocystinuria, the CBS enzyme is deficient, which impairs the conversion of homocysteine to cysteine.
- Accumulation of Homocysteine: The lack of functional CBS enzyme leads to the accumulation of homocysteine in the blood and urine. Elevated levels of homocysteine can cause various health problems.
- Symptoms: Classical homocystinuria can result in a range of symptoms, including intellectual disability, developmental delays, dislocation of the lens in the eye, skeletal abnormalities (such as tall stature and long limbs), and an increased risk of blood clot formation.
- Ocular Involvement: Dislocation of the lens in the eye (ectopia lentis) is a typical and characteristic feature of classical homocystinuria. This can lead to visual impairment.
- Vascular Complications: Elevated homocysteine levels are associated with an increased risk of vascular complications, including blood clots, which may lead to strokes or other cardiovascular issues.
Management of classical homocystinuria typically involves a lifelong low-methionine diet, as methionine is a precursor to homocysteine. Additionally, individuals may receive vitamin B6 (pyridoxine) supplements to support the function of the residual CBS enzyme. Regular monitoring of homocysteine levels and clinical assessments are essential components of care. Supportive care may be provided to address specific symptoms and complications. In some regions, newborn screening programs may identify elevated levels of homocysteine, leading to early detection of classical homocystinuria. Early diagnosis allows for prompt intervention and management. Classical homocystinuria is inherited in an autosomal recessive manner. Both parents must carry a mutated CBS gene for a child to be affected. Genetic counseling is recommended for families affected by classical homocystinuria to understand the inheritance pattern, assess the risk for future generations, and make informed decisions. Management of classical homocystinuria aims to prevent complications and improve the quality of life for affected individuals. Early diagnosis and intervention are crucial for achieving the best possible outcomes.
Homocystinuria due to CBS deficiency follows an autosomal recessive pattern of inheritance. Pathogenic variants in the CBS gene, in homozygosis or compound heterozygosis, can produce symptoms ranging from mild to severe depending on how the variants affect enzyme activity.
The c.919G>A (p.Gly307Ser) variant in the CBS gene is one of the best-known pathogenic variants that has been frequently identified in individuals with homocystinuria, both in homozygosis and compound heterozygosis. Celtic origin mutation accounts for 71% of the alleles associated with the disease in Ireland, 21% in the United Kingdom, and 8% in the United States. The c.919G>A mutation significantly reduces CBS enzyme activity and is more common in patients who do not respond to pyridoxine treatment.
The c.833T>C variant (p.Ile278Thr) is the most common in the United Kingdom and the United States, with an allele frequency of 29% and 18%, respectively. In some countries, e.g., Denmark and the Netherlands, it is the main pathogenic variant associated with this disease. c.833T>C slightly reduces CBS activity, and patients usually respond to treatment with vitamin B6. Individuals who are homozygous for c.833T>C are generally asymptomatic if they have a good diet and tend to be diagnosed in adulthood. Those compound heterozygotes have variable phenotypes, ranging from mild to severe. Another variant associated with response to pyridoxine treatment is c.341C>T (p.Ala114Val).
The pathogenic variant c.1058C>T (p.Thr353Met) has been observed in both homozygous and compound heterozygous patients. The amino acid change that occurs causes a significant reduction in CBS activity.
This test analyzes the 27 most frequent pathogenic mutations of the CBS gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
