Homocystinuria: what is it, symptoms, treatment, prognosis

What is homocystinuria?

Homocystinuria is a rare metabolic disorder characterized by an excess of the homocystine compound in the urine. The condition can be caused by a deficiency of any of several enzymes involved in the conversion of essential amino acid methionine to another amino acid (cysteine), or, less commonly, by disrupting the conversion of the homocysteine ​​compound to methionine. Enzymes are proteins that speed up the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most cases, homocystinuria is caused by a decrease in the activity of an enzyme known as cystathionine beta synthase (CBS).

Babies who develop homocystinuria due to CBS deficiency may not grow or gain weight at the expected rate and may have developmental delays. By about three years of age, additional, more specific symptoms and signs may appear. These may include partial dislocation (subluxation) of the lens of the eye, associated "trembling" (iridodonesis) of the colored area of ​​the eye (iris), severe

myopia and other eye disorders.

Although intelligence may be normal in some cases, many children may suffer from progressive mental retardation. In addition, some people may develop mental disorders and / or episodes of uncontrolled electrical activity in the brain (epilepsy). Patients also tend to be thin and unusually tall; long, slender fingers and toes (arachnodactyly); and elongated arms and legs ("Marfanoid" appearance). In addition, victims may be at risk of developing blood clots that can become lodged in certain large and small blood vessels, which can lead to life-threatening complications.

Homocystinuria due to CSB deficiency is inherited in an autosomal recessive manner. The disorder is caused by changes (mutations) in a gene that regulates the production of the enzyme cystathionine beta synthase.

Signs and symptoms

Symptoms associated with homocystinuria due to CBB deficiency are highly variable. Some affected people may have only very mild signs of the disorder; others can have many different symptoms, including some potentially life-threatening complications. Patients can be divided into two distinct groups:

1. those who respond to therapy with pyridoxine (vitamin B6),
2. and those who do not respond to vitamin B6 therapy.

Typically, people who respond to pyridoxine therapy have a milder form of the disorder, most likely due to residual CBL enzyme activity. In addition, the presence and specific location of blood clots also determines the severity of the associated symptoms in each person.

Babies with homocystinuria due to CBL deficiency are normal at birth, but if left untreated, they will gradually develop various symptoms associated with this disorder. Rapid detection and treatment of homocystinuria due to cystathionine beta synthase deficiency is important to prevent or reduce symptoms associated with the disorder.

Homocystinuria due to cystathionine beta synthase deficiency can potentially affect various organ systems in the body. Four organ systems are most commonly affected:

1. eyes;
2. central nervous system;
3. skeleton;
4. the network of vessels that carry blood and other fluids throughout the body (vascular [circulatory] system).

In some cases, abnormalities affecting the eyes may be the first external sign of homocystinuria. Many people develop a shift in the lens of the eye from the center of the eyeball (ectopia of the lens). Affected children also usually develop severe myopia (myopia) and flutter of the colored part of the eye (iridodonesis). Lens ectopia and myopia usually develop after the first year of life, often by age 10.

Patients with homocystinuria also had other visual impairments. These disorders are less common than lens ectopia and myopia. Such anomalies include

• clouding of the lens of the eye (cataract);
• degeneration of a nerve (optic nerve) that carries signals from the eye to the brain (optic atrophy);
• glaucoma, a condition in which increased pressure in the eye causes characteristic damage to the optic nerve.

Some people may have detachment of a thin layer of nerve cells (retina) that lines the back of the eyes from the underlying supporting tissue (retinal detachment). The retina usually picks up light and converts it into nerve signals, which are then transmitted to the brain via the optic nerve. Retinal detachment can result in blurred vision or floaters in the field of view.

In some young patients, delays in reaching milestones (developmental delays) may be the first noticeable symptom of homocystinuria due to CSB deficiency. Affected children may slowly develop skills in sitting, standing, walking and speaking. Some children have normal intelligence; others have varying degrees of mental retardation. About 20 percent of children with homocystinuria develop epilepsy. Some affected children also have psychiatric problems, including depression, alarming, obsessive compulsive disorder and other behavioral or personality disorders.

Patients with homocystinuria also develop many skeletal abnormalities. Skeletal abnormalities are usually not present at birth and may only appear later in childhood. Common signs include:

• thinning and lengthening of long bones (dolichostenomelia);
• knees curved inward so that they touch when the legs are straight;
• strongly concave feet;
• three-plane spinal deformity (scoliosis);
• deformation of the chest.

Many people with homocystinuria are also at greater risk of developing osteoporosis.

A serious complication of homocystinuria is an increased risk of clots (thrombi) in blood vessels that can rupture and end up in another vessel (thromboembolism). Blood clots can occur at any age. The specific symptoms associated with a thromboembolic complication depend on the exact location of the thrombus and the specific blood vessels and organs that are affected. Thromboembolism can cause serious, life-threatening complications.

Several additional rare features have also been reported in people with homocystinuria due to CSB deficiency, including:

• extremely thin, fragile skin;
• discoloration of the skin (hypopigmentation);
• rash on the cheeks;

Some people may develop fatty changes in the liver, a bulge of part of the intestine through a tear in the abdominal wall (inguinal hernia) or inflammation pancreas (pancreatitis), Is a small organ located behind the stomach that secretes enzymes that enter the intestines and aid digestion. In people with homocystinuria, abnormal curvature of the spine in the front and back has also been reported (kyphosis) and collapse of the lung (spontaneous pneumothorax).

Causes

Homocystinuria due to CSB deficiency is caused by changes (mutations) in a gene that regulates the production of the enzyme cystathionine beta synthase. Gene mutations Cbs can lead to a decrease in the activity of the enzyme cystathione beta-synthase, which is involved in the conversion of the essential amino acid methionine to another amino acid (cysteine). Enzyme deficiency leads to an increase in the level of methionine and homocystine in biological fluids, a decrease in the concentration of cysteine, as well as the characteristic symptoms and physical signs observed in individuals with homocystinuria. According to research, more than 160 different gene mutations Cbs have been identified in people with the disorder, many of which affect only one or a small number of affected families (births).

This mutation is inherited in an autosomal recessive manner. Recessive genetic disorders occur when a person inherits an abnormal gene from each parent. If a person receives one normal gene and one abnormal gene for a disease, the person will be a carrier of the disease, but usually asymptomatic. The risk that two carrier parents will both pass on the abnormal gene and therefore infect the baby is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with each pregnancy. The probability for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected populations

Homocystinuria due to CSB deficiency is a rare disease that affects men and women in equal proportions. Population studies show that the worldwide incidence of homocystinuria in the general population is 1 in 344,000 people. In some countries, the prevalence may be higher. In Ireland, the prevalence is estimated at 1 in 65,000 people. In Germany, the prevalence was estimated at 1 in 17,500. Several studies in four European countries have suggested that the prevalence of homocystinuria due to CSF ​​deficiency ranges from 1 in 6400 to 1 in 20,000.

Homocystinuria was first described in the medical literature as an overt disorder in 1962.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of homocystinuria. Comparisons can be useful for differential diagnosis.

• Marfan syndrome Is a genetic disorder that affects connective tissue, the material between the cells of the body that gives the tissues their shape and strength. Connective tissue lines the entire body, and many organ systems are affected in people with Marfan syndrome. Most often, the cardiovascular, skeletal and ocular systems are affected. The main symptoms include overgrowth of the long bones of the arms and legs, curvature of the spine (scoliosis), deformation of the chest wall, dislocation of the lens of the eye, myopia, enlargement (aneurysm) and degeneration of the main artery that carries blood away from the heart, mitral valve prolapse and backflow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait. Defects or abnormalities (mutations) in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome and related disorders.

The characteristic finding of homocystinuria (elevated levels of homocystine or methionine in the body) can be caused by defects other than CSB deficiency. Homocystinuria can also be caused by other defects in the breakdown (metabolism) of methionine, such as a deficiency methylenetetrahydrofolate reductase (MTHFR) or insufficient production (synthesis) of vitamin B12 (cobalamin) due to reconversion defects (remethylation) of homocysteine ​​to methionine.

Diagnostics

The diagnosis of homocystinuria can be suspected on the basis of characteristic features. The diagnosis can be confirmed by careful clinical evaluation, a detailed history of the patient, and various specialized examinations. Tests can be used to confirm the diagnosis of homocystinuria and can detect elevated plasma or urine levels of homocystine, methionine, or homocysteine. Studies are conducted to determine the levels of the enzyme cystathionine beta synthase in specific cells or tissues of the body.

Homocystinuria can also be diagnosed with neonatal screening.

Standard treatments

Treatment of homocystinuria due to CBL deficiency aims to prevent or reduce the symptoms usually associated with the disorder by controlling the level of homocystine in the liquid part of the blood (plasma). Treatment may include pyridoxine therapy (vitamin B6), a diet restricting protein and methionine, betaine therapy, and folate (vitamin B9) or cobalamin (vitamin B12).

Affected people may first undergo a pyridoxine response assessment. In about 50 percent of people, pyridoxine therapy is effective in lowering the levels of homocystine and methionine in the body. To determine if a person is responding to pyridoxine therapy, folate (folate) levels must be normal and some people may need folate supplementation.

There is debate in the medical community about whether individuals responding to pyridoxine therapy need additional treatment. Some doctors suggest that such people should also eat a diet low in protein and methionine, or receive additional betaine treatment (see table). Below).

Individuals who are not diagnosed with homocystinuria prior to childhood or adolescence, or individuals who do not respond to pyridoxine therapy, require a restricted diet low in protein and methionine. People on this diet require an additional methionine-free formula to provide them with other essential amino acids. Low protein and low methionine diet when started in infancy before any complications occurred, was effective in preventing or delaying the onset of symptoms.

A diet low in protein and low in methionine can be combined with cysteine ​​supplements. Cysteine ​​is an amino acid that is often low in people with homocystinuria due to CSB deficiency. When methionine is broken down (metabolized), it produces cystine. Since people with homocystinuria cannot break down methionine properly, this can cause low cysteine ​​levels in some people.

When people who do not respond to pyridoxine therapy are diagnosed later in childhood or adolescence, adherence to dietary restrictions is often difficult. The diet is usually poorly tolerated when given to people diagnosed in childhood or adolescence.

Individuals with homocystinuria, especially those who do not respond to pyridoxine therapy, can be treated with betaine, which can be used to lower homocystine levels in the body. Betaine is often used as an adjunct to low protein and methionine medication.

The specific symptoms of homocystinuria are treated appropriately. For example, lens ectopia or certain skeletal malformations can be treated surgically. However, affected persons who undergo any kind of surgery must undergo it with special caution, as homocystinuria due to CSB deficiency may increase the risk of postoperative thromboembolic events complications.

Forecast

Lowering blood homocysteine ​​levels, either through diet, supplementation, or both, can prevent symptoms. With treatment, people with the most severe form of homocystinuria may have normal growth and development. Some may have eye problems or blood clots that need to be monitored. Blood clots (thrombi) can be serious and cause damage to organs.

Treatment for mild forms of homocystinuria may depend on clinical symptoms and blood homocysteine ​​levels.