Homocystinuria

What is Homocystinuria?

Homocystinuria is a genetic disease in which incorrect metabolism of the amino acid methionine causes the amino acid homocysteine to accumulate in the blood and higher levels to be excreted in the urine.

Amino acids are the building blocks of proteins. After eating proteins, the body breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of starvation, amino acids can be redirected to generate energy for the body. Methionine is present in animal and plant proteins, especially sesame seeds, nuts, spinach, mushrooms, broccoli, potatoes, fish and meat. However, homocysteine is produced only by our bodies as part of the processing of methionine. 

Raised homocysteine levels in the blood adversely affect multiple areas of the body including the eye, muscles, connective tissue, brain and blood vessels. The most serious complications are related to the damage to blood vessels. High levels of homocysteine in the blood promote atherosclerosis or ‘hardening’ of the arteries. Besides occurring in individuals with homocystinuria, atherosclerosis is more commonly seen in adults with a history of diabetes, smoking, high blood pressure and high blood levels of ‘bad’ cholesterol. In atherosclerosis, the walls of large and medium arteries become inflamed, less elastic and more likely to form fatty lumps or ‘plaques’. The plaques can block the blood vessels, reducing or preventing blood flow to the organ that the artery supplies. The consequences can be life-threatening. The exact event will depend on the site of the blockage. For example, a heart attack can occur if the obstruction stops blood flow to the heart. Blockage in the deep vein of the leg, pelvis or sometimes the arm can result in deep vein thrombosis (DVT). If the clot from a DVT breaks free, it can travel in the circulation and impede blood supply to the lungs causing pulmonary embolism. Finally, a stroke could occur if the brain is affected. 

How common is homocystinuria?

Worldwide, only 1 in 344,000 people have homocystinuria, making the condition extremely rare. However, some studies suggest the incidence may be higher in Ireland where up to 1 in 65,000 people could be affected.

What causes homocystinuria?

Most commonly, the defective gene in homocystinuria is the one that codes for an enzyme known as cystathionine β-synthase. This enzyme is involved in processing methionine into smaller molecules via a pathway of reactions. When cystathionine β-synthase is deficient, the pathway stops after the production of homocysteine, which is why this molecule accumulates and causes problems.
 
Homocystinuria is recessive in nature, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with homocystinuria. 

What are the symptoms and signs of homocystinuria?

Newborn infants with homocystinuria rarely show any symptoms. Later in infancy, failure to thrive or mildly delayed development may be the only early clues that a problem exists.

As the child grows, other symptoms of homocystinuria begin to show. The pattern and severity of symptoms vary greatly between patients. Characteristic features include increasing visual problems, dislocation of the lens of the eye and glaucoma. Certain physical signs are also indicative, including flushing across the cheeks, chest deformities, curved spine, long limbs, ‘knock knees’, high arches on the feet, spidery fingers, and a tall, thin build. The joints may be tight and the bones less dense than normal due to osteoporosis. There may be evidence of plaque formation in the arteries, although in many cases this produces no symptoms at first. Finally, patients may have a low IQ, have intellectual development difficulties or psychiatric disorders.

How is homocystinuria diagnosed?

Recognising homocystinuria is difficult in infants because many show no symptoms or, if present, early symptoms are vague and could have a number of causes. Visual problems, especially lens dislocation, are usually the main indicators, and a tall, thin build raises suspicion of the condition.
Diagnosis of homocystinuria is confirmed by an amino acid test of the blood and urine, which shows high levels of homocysteine and methionine. Other tests used for diagnosis and evaluation of the condition include genetic testing, liver biopsy and enzyme assays, x-rays, skin biopsies and eye examinations.

In certain countries, homocystinuria is identified through routine newborn screening programmes.

How is homocystinuria treated?

Treatment aims to normalise homocysteine levels. In infants the goal is to reduce the risk of all complications whereas in older individuals the priority is to prevent atherosclerosis-related complications.
Approximately 50% of patients respond to high doses of vitamin B6, also known as pyridoxine. This vitamin is a ‘co-factor’ in methionine metabolism, which means that it is involved in the natural processing of methionine. Supplementation must continue over the long term in those who respond to treatment. Responders to vitamin B6 supplements are also advised to limit their dietary intake of protein.

Non-responders to vitamin B6 are treated with a low-methionine diet. Started early, the diet can reduce the risk of complications and the impact of intellectual disability. It must continue for the individual’s lifetime, and should only begin after consultation with a dietician. Methionine restriction is achieved by limiting the intake of natural proteins in the diet. To prevent malnutrition of other amino acids, a methionine-free amino acid formula is taken. There is a range of general methionine-free powders formulated to meet the nutritional needs of individuals of various ages. These contain a balanced mix of essential and non-essential amino acids, vitamins and minerals, with minimal carbohydrates. Special low-protein food products are also available. 

Most individuals with homocystinuria also require treatment with a drug called trimethylglycine, or betaine. This converts homocysteine to methionine, thus reducing levels of homocysteine in the body. However, this treatment is not suitable for infants.
For some people, supplementation with folic acid and/or vitamin B12 is useful. Like vitamin B6, these are co-factors in methionine metabolism so help correct the abnormal processing. Adding the amino acid cysteine to the diet can also be useful.

Individuals with homocystinuria may also require therapy for the complications of this disease, for example lens replacement surgery and osteoporosis treatment.

Although no cure exists for homocystinuria, long-term treatment to reduce homocysteine levels significantly reduces the risk of life-threatening vascular events. A benefit is seen even if homocysteine levels do not return fully to normal levels.