Clicking on the above image will take you to our page with more information on HCU Network America's Race for Research and CanPKU+  partnership in this activity. You will be able to  donate Canadian Dollars to CanPKU+ and we will ONLY use these donations for HCU Research.

About Homocystinuria (HCU)

The basics:

Homocystinuria (HCU) is a rare, inherited metabolic disorder that affects the body’s ability to process certain amino acids—most notably methionine. It is caused by a deficiency in the enzyme cystathionine beta-synthase (CBS), which is needed to convert homocysteine into cystathionine. When this enzyme doesn’t function properly, homocysteine and methionine build up in the blood and urine, potentially causing serious health problems.

There are several types of homocystinuria, but the most common form is classical HCU, caused by a mutation in the CBS gene. This form is inherited in an autosomal recessive pattern—meaning both parents must carry and pass on a copy of the defective gene.

If left untreated, elevated homocysteine can damage blood vessels and connective tissue and lead to complications such as:

• Intellectual and developmental delays

• Eye problems (including severe nearsightedness, lens dislocation, and glaucoma)

• Skeletal abnormalities (such as long limbs and scoliosis)

• Increased risk of blood clots (which can lead to strokes or pulmonary embolisms)

HCU is typically diagnosed in infancy through newborn screening in some jurisdictions, although in Canada, screening is not consistent across provinces and territories. As a result, many people with HCU are not diagnosed until symptoms appear—often in childhood or adolescence.

Symptoms

HCU presents differently depending on the individual's mutation and responsiveness to vitamin B6 (pyridoxine). Some individuals are diagnosed early, while others may remain undiagnosed for years. Symptoms can vary in severity and may include:

• Developmental delay or intellectual disability

• Eye problems (e.g., lens dislocation, severe nearsightedness)

• Marfanoid body habitus (tall, thin build with long limbs)

• Skeletal issues (e.g., osteoporosis, scoliosis)

• Seizures

• Behavioural or psychiatric concerns

• Blood clots, even in children and young adults

The risk of thrombosis (blood clots) increases with age and can be life-threatening if not properly managed.

Diagnosis

Diagnosis typically involves a combination of blood and urine tests that measure levels of homocysteine and methionine. A positive newborn screen (where available) is followed up with confirmatory tests, including:

• Plasma total homocysteine (tHcy)

• Plasma amino acids (notably elevated methionine)

• Genetic testing to identify mutations in the CBS gene

• Enzyme activity assays in cultured fibroblasts (in some cases)

Treatment

Management of HCU aims to lower homocysteine levels and prevent complications. Treatments depend on whether the individual is B6-responsive (meaning their body can use vitamin B6 to increase CBS enzyme activity).

Common treatments include:

• Vitamin B6 (pyridoxine): High doses may be effective for responsive individuals

• Betaine: Helps lower homocysteine levels through alternative pathways

• Folate and vitamin B12 supplements: Support homocysteine metabolism

• Low-methionine diet: Requires restricting high-protein foods and supplementing with specialized medical foods and formulas

• Regular blood monitoring: To assess homocysteine, methionine, and other nutrient levels

Early and aggressive treatment can prevent many complications of HCU, especially when initiated before symptoms appear.

Medical Advances

Researchers are exploring gene therapy and enzyme replacement therapy as long-term solutions for classical HCU. Studies in mouse models have shown promise for adeno-associated virus (AAV)-based gene therapy to deliver functional CBS genes (Jung et al., 2021). Additional research is also underway to better understand the neurological effects of elevated homocysteine and improve treatment adherence in adolescents and adults.

Prognosis

With early diagnosis and lifelong management, many people with HCU can live healthy, active lives. However, undiagnosed or poorly managed HCU can lead to serious complications—particularly blood clots and progressive neurological symptoms.

Multidisciplinary care, including support from metabolic dietitians, neurologists, geneticists, and ophthalmologists, is essential for best outcomes.

Resources of Information:

• Mudd, S. H., et al. (2001). “Homocystinuria due to cystathionine beta-synthase deficiency: The effect of betaine treatment.” Molecular Genetics and Metabolism, 74(1–2), 57–63.

• Yap, S., & Naughten, E. R. (1998). “Pyridoxine-unresponsive homocystinuria: early detection and treatment with a methionine-restricted diet.” Archives of Disease in Childhood, 78(2), 131–136.

• Huemer, M., et al. (2021). “Newborn screening for homocystinuria in Europe—survey results.” Molecular Genetics and Metabolism Reports, 27, 100743.

• Morris, A. A. M. (2006). “Cystathionine beta-synthase deficiency: Clinical course, pathophysiology, and treatment.” Current Opinion in Pediatrics, 18(6), 657–662.

• Jung, J. H., et al. (2021). “Gene therapy for classical homocystinuria in a murine model.” Nature Communications, 12(1), 3844. 

• Office of Rare Diseases Research, Genetic and Rare Diseases Information Center (GARD):  https://rarediseases.info.nih.gov/diseases/7320/homocystinuria

• HCU Network America: https://hcunetworkamerica.org