There are 6 metabolic diseases in this group.
1) Homocystinuria
2) Cystinuria
3) Cystathionemia
4) Cystinosis
5) Hypermethioninemia
6) Sulfite oxidase (molybdenum cofactor deficiency) deficiency
Homocystinuria
Homocystinuria Type-1 (Classical homocystinuria)
• Cystathionine (3-synthase is deficient. It is autosomal recessive. It is the most common disease of methionine metabolism.
• The cofactor of cystathione synthase is pyridoxine (B6). Since 40% of the patients respond to high-dose B6 treatment, the clinical findings of this group are milder than those who do not respond to B6.
• Homocysteine cannot be converted to cystathionine. Homocystin deposition disrupts the cross-linking process of collagen. It is a metabolic disease that mimics collagen tissue diseases.
• Babies are normal at birth. Symptoms begin between the ages of 3-10.
Eye Findings
• Ocular lens subluxation (first finding)
• Glaucoma
• Cataract
• Myopia, astigmatism
• Spontaneous retinal detachment
CNS Findings
• Mental retardation
• Psychological disorders
Skeletal anomalies
• Similar to Marfan syndrome in late childhood. Long extremities, thin and long body structure, arachnodactyly develops. Scoliosis, pectus excavatum/ carinatum, pes cavus, genu valgum, high palate and crowded teeth are common findings.
Vascular Anomalies
• Vascular intima are defective and platelets adhere easily to the vascular endothelium. Venous thrombosis is the most common cause of death in these patients.
• The risk of thromboembolism increases after surgical interventions.
Diagnosis
• Diagnosis is made when homocystin and methionine levels are high and cystine levels are low in body fluids.
• Observing the cyclamen color in the urine with the Na-nitroprusside test is helpful in the diagnosis.
• It can be diagnosed by enzyme deficiency in liver or cultured fibroblasts or by analysis of ONA.
Treatment:
• High-dose vitamin B6 (200-1000 mg/day) provides rapid improvement in vitamin-responsive cases.
• Folate replacement first, followed by methionine-restricted-cysteine-rich diet and betaine treatment is recommended for patients with poor B6 response.
• Heterozygous carriers are asymptomatic. However, the incidence of thromboembolism and coronary disease in these individuals is higher than in the normal population.
Homocystinuria Type-2
• Homocystinuria (associated with B12) due to defects in methyl cobalamin formation or methionine synthase deficiency
• They present with vomiting, hypotonia, lethargy, convulsions and developmental delay in the neonatal period.
• Having megaloblastic anemia is from homocystinuria type III; The fact that methionine levels are not high is the feature that distinguishes them from type I.
Treatment: High-dose vitamin B12
Homocystinuria Type-3
• Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency (folate-related)
• Apnea, convulsion, microcephaly, ataxia, psychiatric findings, thromboembolism are seen. Use of the anesthetic nitrous oxide (which inhibits methionine synthase) may cause neurological deterioration and death in these patients.
Treatment: Folic acid, methionine, B6, B12, betaine are used.
Cystinuria
• There is a defect in absorption of dibasic amino acids from the small intestine and renal tubular transport.
• It is autosomal recessive.
• Since the transport of cystine and 3 dibasic aa (ornithine, lysine, arginine) is impaired, their urinary excretion has increased.
• The formation of hexagonal cystine stones is the greatest risk, since cystine is excreted in the urine and especially has low urinary solubility.
• Although lysine passes into the urine in larger amounts, it does not form stones due to its high solubility.
Diagnosis: Cystine excretion above 250 mg/gr creatinine in the urine is diagnostic.
Treatment: Drinking plenty of fluids, alkalizing the urine, D-penicillamine, 2-mercaptopropioni glycine and captopril reduce stone formation.
Cystinosis
• It is a lysosomal storage disease that develops due to the lack of carrier protein in cystine transport through lysosomal membranes.
• OR passes.
• Cystine crystals are stored in the reticuloendothelial system ( bone marrow and lymph nodes) and parenchymatous organs. Accumulation in the thyroid causes the development of hypothyroidism.
• Fanconi syndrome (fastest damage occurs in the renal tubules), growth retardation and hypophosphatamic rickets are seen. Progressive kidney changes cause kidney failure (cystinosis is the most common cause of Fanconi syndrome). They are lost from kidney failure.
• Hypothyroidism may develop as a result of accumulation in the thyroid gland.
• Cystine crystals also accumulate in the cornea and conjunctiva, there is photophobia in the early period. Patients are light colored, yellow, pale in appearance.
• Diagnosis is made by demonstrating cystine deposition in bone marrow, lymph node biopsy, leukocytes and fibroblast cultures.
• There is no specific treatment for the disease. High doses of vitamin D can prevent the symptoms of rickets. Cysteamine prevents intracellular cystine accumulation. Cysteamine eye drops completely clear the cystine crystals in the cornea.
Sulfite Oxidase Deficiencies (Molybdenum Kof Actor Deficiency)
• Molybdenum is the cofactor of sulfide oxidase. It is also a cofactor of the xanthine oxidase enzyme, which oxidizes xanthine and hypoxanthine to uric acid.
• In this disease, hypotonia, resistant-pyridoxine-dependent convulsions (tonic, clonic or myoclonic) and microcephaly are seen starting from the neonatal period.
• Lens dislocation is detected in living patients from the first months of life.
• Serum and urine uric acid and sulfate levels are low.
• Most die in the first 2 years.
• There is no cure. High dose B6 is given for convulsions.
