bubble_chart Overview

Homocystinuria is a hereditary disease caused by enzyme deficiency in the methionine metabolic pathway. The main clinical manifestations include multiple thromboembolism, intellectual disability, lens dislocation, and arachnodactyly. Cases have been reported domestically.

bubble_chart Etiology

This disease is an autosomal recessive genetic disorder, with the gene located on the long arm of chromosome 21 (21qzz). There are at least three different types of generation and transformation defects: ① Cystathionine synthase deficiency type (referred to as the "synthase type"), caused by a blockage in the metabolic pathway converting homocysteine to cystathionine. This type is the most common. Vitamin B₆ is a coenzyme of cystathionine synthase, so high-dose B₆ is effective in some cases. ② Methyltetrahydrofolate-homocysteine methyltransferase deficiency type (referred to as the "methyltransferase type"), resulting from a disruption in the metabolic pathway converting homocysteine to methionine. This metabolic process is catalyzed by two methyltransferases, and vitamin B₁₂ serves as their coenzyme. ③ 5,5-N-Methylenetetrahydrofolate reductase deficiency type (referred to as the "reductase type"). Normally, this reductase provides a methyl group to homocysteine for its conversion to methionine. When this enzyme is deficient, insufficient methylation of homocysteine leads to its accumulation in the body along with homocysteine.

bubble_chart Pathological Changes

The pathology of "synthase type" primarily manifests in various blood vessels, where the membrane within the vessels of various organs, including brain tissue, exhibits thickening and fibrosis, potentially leading to thrombosis. The main stirred pulse may show narrowing or dilation. Multiple infarct foci are present in the brain. This condition is often accompanied by lens dislocation and skeletal deformities. These pathological changes may result from excessive homocysteine activating coagulation factors and inhibiting collagen formation, leading to abnormal connective tissue.

bubble_chart Clinical Manifestations

Typical symptoms are seen in cases of cystathionine synthase deficiency. The child appears normal at birth, with symptoms appearing between 5 to 9 months. The main symptoms include skeletal abnormalities, lens dislocation, thrombosis, intellectual developmental delay, seizures, etc.

Skeletal deformities include slender limbs and digits (arachnodactyly), which can be easily mistaken for Marfan syndrome. X-ray examinations may reveal osteoporosis, biconcave vertebral bodies, and scoliosis. Ocular symptoms often involve lens dislocation, mostly occurring between 3 to 10 years of age, frequently accompanied by glaucoma and retinal detachment. Thrombosis can occur in any organ, with about 50% of cases experiencing one or more thromboembolic episodes. Intracranial vessels, coronary arteries, renal arteries, pulmonary vessels, and cutaneous vessels may all develop thrombosis, leading to corresponding symptoms. Neurological symptoms are quite pronounced, including intellectual disability and seizure episodes. Multiple cerebrovascular accidents may result in hemiplegia or pseudobulbar palsy, and psychiatric symptoms may also occur. Other symptoms may include facial flushing, marbled skin, thin skin, sparse and brittle hair, reduced prothrombin levels, and myopathy.

The "methyltransferase deficiency type" of this disease presents milder symptoms, such as skeletal deformities, delayed physical and intellectual development, but rarely involves lens dislocation or thrombosis. This type may also coexist with methylmalonic aciduria.

The "reductase deficiency type" of this disease primarily manifests with neurological symptoms, such as seizures, intellectual disability, schizophrenia-like symptoms, and myopathy. There are no bone deformities, lens dislocation, or vascular symptoms.

bubble_chart Diagnosis

Based on clinical manifestations and laboratory tests. ①Measurement of urinary homocysteine can be performed using a screening method, namely the nitroprusside test: Add 1 ml of urine to a 5% sodium cyanide aqueous solution, let it stand for 5 minutes, then add one drop of a 5% nitroprusside aqueous solution. A red or purple-red color indicates a positive result, suggesting excessive sulfur-containing amino acids in the urine. ②Definitive diagnosis relies on enzyme activity measurement, which can be performed using skin fibroblasts to determine enzyme activity. This method can also detect heterozygotes. ③Prenatal diagnosis can be achieved by measuring the enzyme activity of amniotic fluid cells.

This disease needs to be differentiated from Marfan syndrome. The common features of both include ectopia lentis, arachnodactyly, and cardiovascular symptoms. However, their inheritance patterns and disease progression differ. This disease is recessive, while Marfan syndrome is autosomal dominant. The slender fingers and toes in Marfan syndrome are evident from birth, whereas homocystinuria appears normal at birth, with disproportionate skeletal growth and limb elongation developing over several years. Additionally, homocystinuria presents with thromboembolic symptoms, osteoporosis, and biconcave vertebral deformities. More importantly, Marfan syndrome does not exhibit the metabolic abnormalities of generation and transformation seen in this disease.

bubble_chart Treatment Measures

For the "synthase type" of this disease, methionine intake should be restricted or protein intake should be limited. For the "methyltransferase type" and "reductase type," methionine intake should not be restricted. All types of this disease can be treated with high-dose vitamin therapy. Initially, vitamin B₆

at 100–500 mg/day can be used for several weeks. If effective, the dose can be gradually reduced and then maintained at the lowest effective dose (approximately 25 mg/day). For patients who do not respond to B₆, folic acid at 10–20 mg/day and vitamin B{|104|}6{|105|} at 0.5–1.0 mg/day can be added. Combination therapy with high doses may be considered as appropriate. For patients who show no response to high-dose vitamin therapy at all, methionine intake should be restricted, cysteine supplementation should be provided, and betaine should be added.