Homocystinuria is a rare, genetically determined metabolic disease in which the metabolism of the amino acid methionine is abnormal. What are the causes and symptoms of homocystinuria? Is it possible to treat it?
Homocystinuriais a genetic disease that is inherited autosomal recessively and is most often caused by a mutation in the CBS gene, and less frequently by mutations in the MTHFR, MTR, MTRR, and MMADHC genes.
This mutation occurs with a frequency of 1: 160,000 births. The disease affects men and women equally. Most often it occurs in Ireland, Germany, Norway, Qatar.
Homocystinuria is the presence of a deficiency of cystathionine beta-synthase (mutation in the CBS gene, approx. 160 different mutations have been registered) in the liver or a disturbance in the conversion of homocysteine to methionine (mutations in the above-mentioned genes), which results in an increase in the level of homocysteine in the blood and in urine and an increase in methionine levels. Cystathionine is an enzyme that takes part in the reaction that converts homocysteine into cysteine, with the participation of pyridoxine (vitamin B6).
The accumulation of homocysteine in the blood is toxic to humans. The epithelium is damaged, causing abnormalities in the connective tissue, bone tissue, the central nervous system and the tissues of the eyes.
In addition, there are coagulation disorders, blood clots in the vessels appear, often leading to pulmonary embolism, heart attacks, strokes, etc.
People with homocystinuria tend to be deficient in folic acid and vitamin B 12.
Homocystinuria: symptoms
Children with homocystinuria, despite the normal phenotype at birth, show features of delayed development: they gain little weight, show growth deficiency in relation to their peers, as the disease progresses. The disease is variable, with one person being mild and the other difficult.
Ocular symptoms may occur:
- myopia
- lens subluxation
- cataract
- optic nerve atrophy
- glaucoma
- retinal detachment
- trembling irises
Skeletal symptoms are manifested by posture defects and abnormalities in the structure of the chest (funnel-shaped, convex chest), the presence of osteoporosis, which increases the risk of fracturespathological.
Developing elongated limbs, slender, "spider-shaped" fingers, hollow foot, high, "gothic" palate, stiff joints with a tendency to contractions. Patients tend to be slender, lean.
There is often a progressive mental disability and even the presence of a mental illness. The level of intelligence and learning ability varies individually depending on the severity of the disease.
There may be personality and mood disorders as well as epilepsy.
Some patients develop hernias, especially inguinal and umbilical, fatty liver, low levels of clotting factors, unpleasant smell of urine, endocrine disorders, light, thin skin prone to discoloration, facial changes in the form of a rash or suddenly appearing flushing, cyanosis, anemia, pancreatitis.
The cause of death is usually thromboembolic complications resulting from the above-described changes in the coagulation system (usually in the 3rd decade of life)
There are two groups of patients with homocystinuria:
- patients responding to pyridoxine treatment - with a milder course; the disease most likely results from a trace activity of the CbS enzyme
- not responding to pyridoxine treatment - more severe
Homocystinuria: diagnosis
The homocystinuria diagnosis includes:
- a detailed interview (child's symptoms, family history)
- physical examination of the child (characteristics of homocystinuria)
- blood tests that analyze the level of amino acids in the blood and urine, including total homocysteine and methionine; testing the activity of cystathionine synthetase in selected cells and tissues as well as screening for CBS mutations. Cysteine levels are usually lowered
In Poland, according to the current Newborn Screening Program, screening for homocystinuria is performed.
- the family of a person with homocystinuria should be offered genetic counseling
- Differential diagnosis should be performed, which should include other causes of the above-mentioned malformations. Lens dislocation also occurs in other diseases, such as Marfan syndrome, Weill-Marchesani syndrome, hyperlysinemia, and sulfocysteinuria. Marfan syndrome should always be considered in the differential diagnosis of homocystinuria as it is most phenotypically similar
Homocystinuria: treatment
After the diagnosis of the disease in the newborn, early therapy should be implemented to maintain intellectual capacity and prevent disordersdevelopment in a child. At a later age, treatment is based on the prevention of thromboembolism and complications on the organ side.
In the group of patients who respond well to treatment with vitamin B6, therapeutic doses are administered along with vitamin B12 and folic acid.
In the second group, not responding to treatment with pyridoxine, a diet with restriction of animal protein and methionine, at the same time supplementing cysteine. This treatment regimen is supplemented with therapeutic doses of pyridoxine with vitamin B12 and folic acid. Additionally, betaine anhydrous (Cystadane) is implemented, which can lower homocysteine levels.
Treatment is aimed at correcting biochemical abnormalities, in particular maintaining plasma homocysteine levels - below 11 µmol / L, preferably below 5 µmol / L. This is possible if treatment is started early, which is achieved through neonatal screening.
Defects resulting from the course of homocystinuria should be treated properly, within the appropriate speci alties.
In the case of surgical treatment, the much greater risk of thromboembolic complications after anesthesia and surgeries in patients with homocystinuria should be taken into account.
The thromboembolic risk is high if the plasma homocysteine level exceeds 50 μmol / L - then anesthesia is contraindicated.
Before the planned surgery, the level of homocysteine and coagulation factor VII in the plasma should be checked, and a low-protein, low-methionine diet should be implemented due to thromboembolic complications. Anticoagulation therapy should be considered after surgery. As the risk of thrombosis increases in pregnant women suffering from homocystinuria, especially in the postpartum period, prophylactic anticoagulation is recommended in the third trimester and in the postpartum period.
Low molecular weight heparin is usually administered intravenously during the last two weeks of pregnancy and the first six weeks after birth. Consideration should also be given to giving low doses of aspirin during pregnancy.
Maternal homocystinuria, does not adversely affect the child's development and does not require closer monitoring of plasma homocysteine levels during pregnancy