Abstract
Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.
Highlights
Hyperhomocysteinemia[1] can be caused by environmental or genetic factors, including inborn errors of metabolism (Table 1)
This paper reviews the clinical and biochemical findings and management of the three most frequent genetic causes of homocystinurias: cystathionine beta-synthase (CBS) deficiency or classical homocystinuria (HCU), methylmalonic aciduria with homocystinuria cblC type, and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. These three disorders all present with severe hyperhomocysteinemia, while Met levels are increased in HCU and decreased or normal in cblC and MTHFR deficiency, and methylmalonic acid (MMA) is increased only in cblC[9] (Table 1)
Homocystinurias are a group of inborn errors of sulfur amino acid metabolism
Summary
Hyperhomocysteinemia (tHcy >15 μM)[1] can be caused by environmental (such as nutritional deficiency of vitamins B12 or folate) or genetic factors, including inborn errors of metabolism (Table 1). Hcy is formed as a product of methyl-transfer reactions in methionine (Met) metabolism. In this process, Met is activated by ATP into S-adenosylmethionine (SAM), which is the universal methyl group donor, resulting in the formation of S-adenosylhomocysteine (SAH). This paper reviews the clinical and biochemical findings and management of the three most frequent genetic causes of homocystinurias: CBS deficiency or classical homocystinuria (HCU), methylmalonic aciduria with homocystinuria cblC type, and severe MTHFR deficiency These three disorders all present with severe hyperhomocysteinemia, while Met levels are increased in HCU and decreased or normal in cblC and MTHFR deficiency, and methylmalonic acid (MMA) is increased only in cblC[9] (Table 1).
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