Homocystinuria is a rare disease with two known forms. The more common form affects an individual’s eyesight and is diagnosed in 1 in 200,000-335,000 people worldwide. The rarer form of HCU affects intellectual development and has only been reported a small number of times in the literature.

There is a geographical impact on homocystinuria prevalence, with instances occurring in 1 in 65,000 children in Ireland, 1 in 17,8000 children in Germany, 1 in 6,400 children in Norway, and 1 in 1,800 children in Qatar. The current estimated prevalence of homocystinuria in the US is 1 in 100,000 people, but research is beginning to show that this rare disease is being underdiagnosed in newborns and may have higher occurrences in later childhood.

Homocystinuria (HCU) is a genetic mutation inherited from the parents through the autosomal recessive inheritance pattern. Some common gene inheritance patterns come from the method of inheriting one chromosome from each parent. If a gene is abnormally short, long, or has other mutations that change the DNA code, it will change proteins in the cell that the cell needs to function and will affect the genetic code of the offspring. In autosomal recessive inherited disorders, a mutated gene must be present on both paired chromosomes in order to exhibit a trait in the offspring. This means that both parents need to possess a chromosome with a mutated gene to pass this trait to their children. 

The more common form of homocystinuria is caused by a mutation in the CBS gene, a gene responsible for the production of an enzyme known as cystathionine beta-synthase which breaks down the amino acid homocysteine and converts it to the active molecule cystathionine. This molecule is then used to produce the amino acid methionine for use in the body. Mutations in the CBS gene can prevent homocysteine from being broken down and used properly within the body. This can result in the build-up of potentially toxic by-products in the blood and released into the urine.

Less common causes of homocystinuria are mutations in the genes MTHFR, MTR, MTRR, and MMADHC. These genes also ​​encode enzymes that play a role in converting homocysteine to methionine. Mutations in these genes can lead to more rare forms of homocystinuria as homocysteine builds up in the body. 

Since homocystinuria is present from birth, symptoms may develop immediately or often become present within the first year of life. These can include vision problems, severe short-sightedness (myopia), weakened bones (osteoporosis), bone and joint problems, and an elevated risk of blood clots and stroke. Other physical abnormalities that may lead to a diagnosis of homocystinuria include chest deformities, flushed cheeks, high foot arch, knock knees, long limbs, spidery fingers, tall and lean frame. 

There are less common forms of homocystinuria that may cause intellectual disabilities, deficient weight and height gain, seizures, movement difficulties, and a blood disorder known as megaloblastic anemia that occurs when the individual has a low number of red blood cells combined with larger than normal red blood cells. Additionally, a lack of proper treatment for children with homocystinuria can lead to brain damage and developmental problems. 

A diagnosis of homocystinuria usually occurs within the first 5 days of life by conducting a newborn blood spot test to check amino acid levels. Symptoms will often develop within the first year of life, often consisting of eyesight difficulty, but certain features may occur later in childhood. Doctors may further examine an individual for homocystinuria if they present a combination of the following symptoms: dislocated lens in the eye, curved spine or scoliosis, deformity of the chest.

To confirm a diagnosis of homocystinuria, genetic testing for known gene mutations causing the rare disease must be confirmed. There are other tests that can indicate that a diagnosis of HCU:

1. Newborn blood spot test: Conducted within 5 days of birth, a newborn baby’s heel is pricked to collect drops of blood to conduct a panel of tests. 

2. Amino acid screen of the blood or urine: This tests for elevated levels of methionine and/or homocysteine.

3. Blood tests: Regular blood tests to monitor amino acid levels and diet influence may be necessary for individuals with HCU.

4. Liver biopsy: This involves removing a piece of the liver to examine under a microscope or to conduct other tests. This tests whether the enzymes in the liver are functioning and present in sufficient amounts. 

5. Skeletal x-ray

6. Skin biopsy with a fibroblast culture

7. Ophthalmic exam: This determines if HCU has caused the eye lens to become dislocated and if the individual qualifies for a replacement lens. 

Treatments for homocystinuria can begin as early as diagnosed, with some newborns being treated to prevent complications. Most individuals with HCU are prescribed vitamin B6 (pyridoxine) combined with a special diet to control their high levels of homocysteine. This is effective in about half of cases, with the other half also prescribed a combination of vitamins B6, B9, and B12. Limiting protein intake can also be used in combination with vitamins, avoiding high protein foods such as meat, fish, cheese, eggs, beans, and nuts. For newborn babies, a specialty formula is prescribed with only the vitamins, minerals, and amino acids that their body needs and digests. For children and young adults with homocystinuria, betaine (trimethylglycine) may be administered the clear excess homocysteine from the body. Some individuals also require lens replacement surgery to repair or replace the dislocated eye lens and improve vision problems. In advanced or extreme cases of homocystinuria, individuals with blood clots may be treated with blood thinners or other methods to reduce this health risk.

Early detection and treatment of HCU enables the individual to lead a healthy life, but the treatment must continue lifelong. Individuals who do not monitor or treat their high homocysteine levels in the blood are at an increased risk of developing blood clots. These can potentially be life-threatening as they can lead to stroke and other serious medical problems.

1. https://www.nhs.uk/conditions/homocystinuria/#:~:text=Homocystinuria%20(HCU)%20is%20a%20rare,in%20the%20blood%20and%20urine.

2. https://medlineplus.gov/genetics/condition/homocystinuria/

3. https://www.mountsinai.org/health-library/diseases-conditions/homocystinuria

4. https://www.ncbi.nlm.nih.gov/books/NBK1524/