Homocystinuria is a hereditary defect of metabolism, the primary link of which is a violation of the metabolism of sulfur-containing amino acids, leading to damage to the nervous, musculoskeletal and cardiovascular systems. Homocystinuria is accompanied by mental retardation, convulsive syndrome, lens subluxation, cataract, glaucoma, optic nerve atrophy, chest deformity, scoliosis, arachnodactyly, arterial and venous thrombosis. Diagnosis of homocystinuria includes medical and genetic counseling, biochemical examination of blood and urine, ophthalmological examination, X-ray diagnostics of the bone system. Homocystinuria therapy is carried out taking into account the form of the disease and includes dietary nutrition, intake of B vitamins.
Meaning
Homocystinuria is a genetically determined enzymopathy characterized by a violation of the metabolism of the essential amino acid methionine, an increase in the level of homocystine in biological fluids and tissues, leading to damage to organs and systems. The study of the disease began in 1962. The frequency of homocystinuria in the population is 1 case per 200,000 newborns. The course of homocystinuria is accompanied by neuropsychiatric disorders, ocular pathology, changes in the musculoskeletal system, a tendency to thromboembolism. Due to the variety of consequences of metabolic disorders, homocystinuria is considered from the standpoint of various medical disciplines, mainly genetics, pediatrics, neurology, ophthalmology, orthopedics.
Causes
Homocystinuria is caused by an autosomal recessive type of inheritance. To date, 4 types of metabolic disorders are known that may underlie pathology, and therefore the following biochemical variants of the disease are distinguished:
- Homocystinuria I – is due to the absence or decrease in the activity of the enzyme cystathionine beta synthase (classical homocystinuria).
- Homocystinuria II is caused by the absence or decrease in the activity of the enzyme N5, N10–methylenetetrahydrofolate reductase.
- Homocystinuria III is caused by low activity of the enzyme N5-methylenetetrahydrofolate.
- Homocystinuria IV is caused by the absence or decrease in the activity of the homocysteine transmethylase enzyme caused by a defect in the synthesis of methylcobalamin.
The direct pathogenetic mechanisms of pathology are associated with a violation of the metabolism of the essential amino acid methionine. Metabolic processes are controlled by a number of enzymes, during inactivation of which an enzymatic block occurs: an intermediate product of methionine metabolism, homocystine, accumulates in the blood and tissues, which is excreted in the urine; the content of cystathionine and cystine also decreases. Hypovitaminosis B6 and B12, as well as folic acid, can also serve as a possible cause of metabolic pathway disorders.
High concentrations of methionine and homocystine have a damaging effect on the inner wall of the arteries, which is accompanied by increased platelet aggregation and the creation of conditions for thrombosis. In addition, there is a toxic effect of homocystine on the nervous, connective and other tissues. Depending on the features of pathogenesis, two forms of homocystinuria are distinguished – pyridoxine-dependent (vitamin B6-sensitive) and pyridoxine-resistant (vitamin B6-insensitive), which determines the choice of the method of therapeutic effect on the body.
Symptoms
Manifestations of homocystinuria increase gradually. Children are born without any specific abnormalities. During the first year of life, moderate hypotrophy develops. Attempts to eliminate the lag in weight and height due to the additional introduction of protein in the form of kefir or cottage cheese into the diet only aggravate the course of the disease: body weight deficiency increases, sleep is disturbed, the child becomes irritable and tearful, there is a late closure of the fontanelles, deformities of the limbs, delayed psychomotor development.
Usually, a pronounced homocystinuria clinic develops during the first 10 years of life, but often the diagnosis becomes obvious already in early childhood. By this time, the child has highly specific eye symptoms: subluxation of the lens, pronounced myopia, trembling of the iris (iridodon). Somewhat later, astigmatism, glaucoma, cataracts, retinal detachment, and optic nerve atrophy are added. Homocystinuria is often accompanied by mental retardation, muscle tone disorders, hyperkinesis, convulsive syndrome, behavioral disorders. The lesion of the musculoskeletal system includes keeled deformity of the chest, arachnodactyly, kyphoscoliosis, osteoporosis, curvature of the shins, hollow foot or flat feet, Gothic palate. Almost half of patients with homocystinuria experience arterial thrombosis (occlusion of cerebral, coronary, renal and peripheral vessels), as well as venous thrombosis.
Persons suffering from homocystinuria have certain phenotypic features: tall stature, disproportionate physique (thin elongated limbs and shortened torso), blue eyes, sparse blond hair. They often have erythematous spots in the area of the zygomatic arches, telangiectasia. External manifestations of homocystinuria have a certain similarity with Marfan syndrome, but the latter is not characterized by a decrease in intelligence and a number of other manifestations.
Diagnostics
Patients with suspected homocystinuria should be referred to a medical geneticist for genealogical data analysis and molecular genetic diagnostics. The diagnosis is established by biochemical examination of blood and urine: with homocystinuria, significant amounts of homocystine are detected in urine, blood plasma, and liquor, and an increase in methionine content with a reduced level of cystine. A specific enzymatic defect is detected in skin and liver biopsies.
X-ray examination of the tubular bones and spine reveals systemic osteoporosis. Violations of bioelectric activity of the brain, sometimes of a paroxysmal nature, are recorded on the EEG. Consultation with an ophthalmologist allows you to confirm the disorders characteristic of homocystinuria on the part of the visual system. Also, sick children need to be monitored and evaluated by a pediatrician, neurologist, orthopedist, psychiatrist. Differential diagnosis of homocystinuria is carried out with Marfan syndrome, the consequences of birth trauma and intrauterine infections, and other enzymopathies.
Treatment
The treatment tactics depend on the form of the disease (B6-dependent or B6-resistant) and are in many ways similar to the treatment of phenylketonuria. In the B6-resistant form of homocystinuria, it is necessary to follow a low-protein diet based on limiting the intake of methionine into the body. The diet of patients should consist mainly of plant foods with the exclusion or significant reduction in the use of animal products. To compensate for the need for essential amino acids, special amino acid mixtures devoid of methionine are prescribed (XMET Analog, XMET Maxamum, XMET Maxamaid, XMET Homidon). In B6-dependent homocystinuria, the activity of the enzyme can be activated by prescribing large doses of pyridoxine hydrochloride.
In all forms of homocystinuria, the appointment of folic acid, betaine helps to reduce the level of homocystin in biological fluids. To minimize the risk of thrombosis, constant intake of acetylsalicylic acid in a low dosage is indicated. According to the indications, patients are prescribed hepatoprotectors, nootropics, calcium, iron preparations; massage courses, laser acupuncture and reflexotherapy, physical therapy are conducted.
Prognosis
Detection of the disease at the preclinical stage, early initiation of treatment and adherence to a therapeutic diet can delay or prevent disabling complications (intellectual disabilities, paralysis, optic nerve atrophy, pulmonary heart, severe arterial hypertension, strokes, infarctions of internal organs, etc.). In families where there are carriers of the homocystinuria gene, it is necessary to conduct an invasive prenatal diagnosis with the determination of enzyme activity in the culture of chorionic villi cells or amniotic fluid. In relation to children with homocystinuria, the issues of specialized training, professional orientation, social adaptation, and dispensary supervision of specialists are relevant.