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What are homocystinurias?

Classical homocystinuria, HCU for short, is a rare metabolic disorder that prevents the normal breakdown of protein. Babies with HCU inherit two faulty copies of the affected gene, one from each parent. With HCU, an enzyme called cystathionine beta-synthase is deficient or missing, leading to problems breaking down the amino acid methionine. This causes methionine and a substance called homocysteine to build up in the body and blood.¹

Genetic mutations in different genes cause most types of HCU. Two of the most common mutations are G307S for B6 non-responders and I278T for the B6 responders. Elevation of homocysteine, however, may be observed in non genetic conditions such as deficiency of vitamin B12.²

The most common type of homocystinuria affects 1:200,000 to 335,000 people worldwide.²

Cystathionine beta-synthase (CBS) deficiency: The most common type and is known as classical homocystinuria. This occurs when the CBS gene produces little to no CBS enzyme or when it produces CBS enzyme that doesn’t work properly. The CBS enzyme requires vitamin B6 to function.

When both parents are carriers, in each pregnancy the risk to the baby is:

• 25% chance (1 in 4) of HCU
• 50% chance (1 in 2) for the baby to be a carrier of HCU
• 25% chance (1 in 4) for the baby to have two working genes and neither have HCU or be a carrier

Signs and symptoms of homocystinuria

The main signs and symptoms of homocystinuria usually develop during childhood, but some people don’t develop any symptoms until into adulthood.

Bones: excessive growth, knock knees, sunken or protruding chest, curvature of the spine and long limbs, fingers and toes, and sometimes scoliosis and osteoporosis.

Eyes: Dislocation of the lenses of the eyes and severe short-sightedness.

Brain: Developmental delays, seizures, learning problems.

Vascular system: Increased risk of blood clots, which can lead to strokes or pulmonary embolisms.²

Diagnosing homocystinuria

HCU is currently included on the newborn screening test (NBS) in most areas.

However, the testing threshold (methionine level) varies from region to region. The NBS screening test measures the amount of some amino acids in the blood. A high level of the amino acids methionine and total homocysteine suggests a baby may have HCU. However, It’s important to remember that newborn screening tests aren’t always accurate, and some people aren’t diagnosed until after symptoms appear.

If a person is recognised as having symptoms of HCU, their healthcare provider should order a homocysteine test (tHcy). A genetic test is needed to confirm an HCU diagnosis. In approximately 10-15% of individuals, treatment with high-dose vitamin B6 alone is sufficient to lower their homocysteine to safer levels. These individuals are called B6-responsive. However, studies from around the world show that nearly half of individuals with the B6 non-responsive form of HCU struggle to achieve levels of homocysteine deemed safe.

Treating homocystinuria

In some babies, homocysteine levels in the blood can be reduced by administering vitamin B6 (also known as pyridoxine), however, not all are responsive to this treatment.¹ If this is unsuccessful, a strict low-protein diet is prescribed, from birth or immediately on diagnosis. This includes a special formula and adapted diet which restricts protein intake and requires strict adherence for optimum outcomes.³ Patients with HCU need regular blood tests to monitor levels of homocysteine in their blood to guide treatment plans.³

Support

For more information about HCU and more support:

HCU Network Australia: Visit hcunetworkaustralia.org.au

HCU Network America: Visit hcunetworkamerica.org

Metabolic Support: Visit metabolicsupport.org

This disease education graphic was created with sponsorship from Travere Therapeutics.

With special thanks to Emeritus Professor Dr. Sufin Yap, honorary consultant paediatrician in metabolic medicine.

References

[1] gov.uk/government/publications/hcu-suspected-description-in-brief/homocystinuria-hcu-detailed-information
[2] my.clevelandclinic.org/health/diseases/25160-homocystinuria
[3] galenmedicalnutrition.com/metabolics/homocystinuria-hcu/

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This digital spotlight has been made possible with financial support from Travere Therapeutics.
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