Homocystinuria is the name given to a rare, genetic metabolic disorder caused by an enzyme deficiency and characterized by elevated homocysteine concentrations in the blood. As part of early and consistent therapy, homocystinuria can usually be treated well.
What is homocystinuria?
Homocystinuria is the name given to a rare, genetic amino acid metabolism disorder that results from defects in various enzymes involved in methionine (essential amino acid) metabolism. Homocysteine and homocystine represent degradation and intermediate products of this metabolic process, respectively, and are directly metabolized further in healthy individuals. Due to the presence of defective enzymes, this is only possible to a limited extent in those affected by homocystinuria, so that the concentration of homocysteine in the blood and homocystine in the urine is increased. The increased concentration of these amino acids, which are considered toxic, can lead to damage to various organ systems. Eye diseases (lens luxation, myopia, glaucoma), skeletal changes (osteoporosis, marfanoid long-limbedness), damage to the central nervous system (mental and physical retardation, convulsions, cerebrovascular disorders), and the vascular system (thromboembolism, vascular occlusion) are characteristic sequelae of homocystinuria.
Causes
Homocystinuria is due to an autosomal recessive inherited genetic defect that results in deficiency of various enzymes involved in methionine metabolism. Depending on the specific enzyme and subprocess of methionine metabolism affected, three forms of homocystinuria are distinguished. In the more common type I of homocystinuria, there is a deficiency of the enzyme cystathione beta-synthase (CBS), which disturbs the synthesis of cysteine from methionine. As a result, homocysteine accumulates in the blood (hyperhomocysteinemia) and homocystine accumulates in the urine (homocystinuria). Type II homocystinuria is characterized by a deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), which regulates methionine synthesis from homocysteine. This metabolic subprocess is correspondingly disturbed in those affected by type II and, in addition to the accumulation of homocysteine in the serum, can also lead to a methionine deficiency. Type III homocystinuria is characterized by a cobalamin deficiency (coenzyme vitamin B12). Cobalamin is also involved in methionine synthesis from homocysteine, so deficiency can also cause increased homocysteine concentration in the blood and methionine deficiency.
Symptoms, complaints, and signs
Homocystinuria can occur in a variety of forms. Symptoms are varied and differ depending on the stage of life. Before the age of two, signs of the disease occur only in particularly rare cases. Apart from characteristic laboratory findings, newborns with homocystinuria are unremarkable. Typically, the homocysteine level in the blood is significantly elevated. This damages the blood vessels, which in the long term can lead to vascular calcification (atherosclerosis) and associated embolisms and thromboses. As a result, the life expectancy of those affected is significantly limited. The most striking symptom of the metabolic disorder in childhood is a prolapse of the eye lens. This is often accompanied by myopia. The earlier the first signs of the disease appear, the higher the risk of psychomotor retardation (mental retardation), which is irreversible. In most affected individuals, osteoporosis already exists in childhood. As a result, the spine flattens and gradually deforms. The high homocysteine level often results in tall stature and symptoms that may resemble Marfan syndrome on the surface. These include, for example, the presence of a chicken and funnel chest, a displaced eye lens (lens luxation or lens ectopy), glaucoma, retinal detachment, and spider fingeriness (arachnodactyly).
Diagnosis and course
Various laboratory analyses are used to diagnose homocystinuria. If an increased homocystin concentration and/or decreased methionine concentration (types II and III) is detected during a urinalysis (eg, cyanide-nitroprusside test), this may indicate homocystinuria. Blood analysis can be used to determine the concentration of homocysteine in the serum and to diagnose hyperhomocysteinemia associated with homocystinuria.The diagnosis is confirmed by culturing cells from a connective or liver tissue sample, which allows direct detection of the underlying genetic defect. The course of homocystinuria can vary from person to person in terms of symptoms and sequelae. However, with early diagnosis and early initiation of therapy, homocystinuria usually has a favorable course as well as a good prognosis.
Complications
Homocystinuria primarily causes severe psychological symptoms that can have an extremely negative impact on the patient’s life and daily routine. In most cases, a severe personality disorder occurs, which is accompanied by behavioral disorders. Especially in children, these disorders can lead to severe complications. As a rule, the patient is affected by social exclusion and withdraws more and more from life. Not infrequently, depressive moods occur as a result. Furthermore, there are complaints of the eyes, so that, for example, glaucoma or myopia can develop. Likewise, various diseases of the vessels occur much earlier and can thus lead to restrictions in movement. The treatment itself does not usually lead to any particular complications and is carried out with the help of medication. A positive course of the disease occurs relatively quickly. Even after treatment, in most cases there are no further complaints. Life expectancy is not reduced with early treatment. Psychological complaints can be treated supportively by a psychologist.
When should you see a doctor?
If symptoms such as behavioral problems, thrombosis, or developmental delays occur, a visit to the doctor is definitely needed. Similarly, signs of osteoporosis or arteriosclerosis should be clarified at an early stage. A doctor must determine the cause of the symptoms and, if necessary, initiate treatment. For this reason, the symptoms mentioned should be clarified quickly. Persons with a genetic defect are particularly susceptible to the development of homocystinuria. Affected individuals should consult closely with their family physician and inform him or her of any unusual symptoms. Basically, complaints that persist for more than a few days or increase in intensity over a longer period of time must be clarified. The characteristic signs of homocystinuria normally develop insidiously and are often only recognized when irreversible disease has already set in. This makes it all the more important to recognize the early symptoms and have them treated. People who notice physical or mental changes in themselves or others that may be related to metabolic disorders should talk to their family doctor as soon as possible. Other contacts include specialists in internal medicine or a specialty clinic for hereditary diseases.
Treatment and therapy
Therapy for homocystinuria depends on the underlying disease type or enzyme defect and is aimed at reducing and eliminating the elevated concentration of toxic homocysteine. Thus, type I of homocystinuria is treated with pyridoxine (vitamin B6) if there is residual activity of the defective enzyme. The substance increases the enzyme activity and lowers the homocysteine concentration in the blood. About 50 percent of those affected by this type respond very well to oral therapy with high doses of vitamin B6. In addition, a low-methionine and cystine-rich diet is recommended to support therapy. If there is residual enzyme activity in types II and III of homocystinuria, in which methionine synthesis from homocysteine is impaired, an attempt is made to limit the impairment with cobalamin preparations (vitamin B12). In both forms of homocystinuria, a diet rich in methionine is indicated. In addition, folic acid, which also has a positive effect on the activity of the defective 5,10-methylenetetrahydrofolate reductase, as well as methionine and betaine are used therapeutically in type II. Supportive anticoagulant drugs (acetylsalicylic acid) are used to prevent vascular diseases such as thrombosis and embolism.
Outlook and prognosis
With early diagnosis and intensive therapy, the prognosis of homocystinuria is usually favorable. Although the disease is not curable because it is a genetic defect.However, within the framework of therapy, the permanent reduction of the concentration of homocysteine and methionine is possible, which significantly reduces the likelihood of developmental disorders and complications. The degree of expression of homocystinuria can be varied. There are forms of the disease that are initially inconspicuous and also have a mild course. However, there is also a greater risk of developing arteriosclerosis, thromboses, embolisms, heart attacks and strokes at the age of 20 or 30. However, if the homocysteine concentration is already very high in infancy, there is a great risk of physical and mental developmental disorders in the child without intensive treatment. Mental retardation may already become apparent in the first two years of life. Often, affected children also suffer from osteoporosis. In up to 70 percent of untreated children, eye problems develop, which finds its clearest expression in a prolapse of the eye lens. Further consequences for the eyes can include glaucoma, extreme myopia, retinal detachment and blindness. In addition, if severe forms of the disease are treated too late or not at all, thrombosis and embolism develop in 30 percent of all patients under the age of 20.
Prevention
Because homocystinuria is a genetic disease, it cannot be prevented. However, early initiation of therapy can prevent or limit the sequelae of homocystinuria. In addition, those affected can have their unborn child tested for homocystinuria as part of prenatal diagnostics (amniocentesis). Siblings of affected individuals are also advised to be tested for homocystinuria.
Follow-up
Depending on the type of enzyme defect that is causative for the metabolic disorder, a whole range of measures are useful and necessary as part of the follow-up of homocystinuria. In the case of homohystinuria type I, the patient must follow a vitamin-rich diet to accompany the medical administration of vitamin B6. Vitamin B6 increases the activity of the defective enzyme and consequently leads to a lower concentration of homocysteine in the blood. The diet must be followed permanently to maintain this effect. The same applies to the consumption of foods rich in cystine and low in methionine. In homocystinuria type II, the diet must also continue in order to achieve long-term effects. In addition, regular progress monitoring applies during follow-up. The physician must check the activity of the affected enzymes and adjust the therapy if necessary. Since homocystinuria is generally not a serious disease, medical checks at intervals of three to six months are sufficient. In the case of severe disorders, a specialist should be consulted monthly after completion of the actual therapy. In addition, attention must be paid to unusual symptoms, as the metabolic disorder may cause other diseases in the long term that require treatment.
What you can do yourself
Depending on the type of enzyme defect underlying homocystinuria and the therapy used by the doctor, patients can do a few things themselves to alleviate their symptoms. First of all, a diet rich in cystine is important. The affected person should consume mainly rice, nuts, soybeans and oat products. The active ingredient is also found in watermelons, sunflower seeds and green tea. The doctor will also prescribe vitamin B12 supplements to limit the impairment. The affected person can support these measures by working with a nutritionist to create a diet plan rich in methionine and implementing it consistently. Foods with a high protein content such as eggs or meat should be avoided. Low-protein foods are allowed, including fruits, vegetables, and low-protein pasta, bread, or flour from specialty stores. This diet should also be supported with various B vitamins as well as folic acid. After the condition has resolved, the patient should have further check-ups. Homocystinuria is a lifelong disease that requires regular evaluation in a specialized treatment center. Through close monitoring, problems with the metabolism can be detected and treated at an early stage before complications arise.
