Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

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.

Genes Responsible for H2S Production and Metabolism Are Involved in Learning and Memory in Drosophila melanogaster

“…Previous numerous experiments demonstrated a strong protective role of exogenous H 2 S treatment in various pathologies, including neurodegenerative diseases and aging [ 65 , 66 ]. In addition, human mutations of CBS genes result in homocystinuria accompanied by strong cognitive impairments and many other abnormalities [ 16 , 18 , 19 ]. These data led us to hypothesize that the obtained deletions of CBS and CSE genes in Drosophila may be a perfect tool to reveal the role of individual H 2 S-producing genes in learning and memory processes.…”

“…Second, the application of various H 2 S donors often exhibited a strong neuroprotective effect, and such treatment may ameliorate memory impairment and restore cognitive functions in various model studies and the case of several human neurodegenerative diseases [ 11 , 12 , 13 , 14 ]. Finally, numerous missing mutations that disrupt the structure of CBS in humans result in classical homocystinuria due to cystathionine β-synthase ( CBS ) deficiency [ 15 , 16 ]. Individuals with homocystinuria, the most frequent disorder of sulfur metabolism, have many developmental and cognitive difficulties, with a significant number of cases having a learning disability, atherosclerosis, or thromboembolic disease [ 15 , 17 ].…”

Long-term Outcome of a Patient With Transcobalamin Deficiency Caused by the Homozygous c.1115_1116delCA Mutation in TCN2 Gene: a Case Report

“…In this form there is a combined de ciency of synthesis of both methylcobalamin (methionine synthase coenzyme) and adenosyl cobalamin (methylmalonyl-CoA mutase coenzyme), with the consequent possibility of homocystinuria and methylmalonic aciduria. A massive homocystinuria with methylmalonic aciduria is characteristic of the combined de cits of the common intracellular metabolism of the B 12 (5). Isolated de ciencies of the speci c metabolic pathways of adenosylcobalamin and methylcobalamin lead, respectively, to methylmalonic aciduria and homocystinuria.…”

Long-term Outcome of a Patient With Transcobalamin Deficiency Caused by Tcn2 Mutation: A Case Report

“…In this form there is a combined de ciency of synthesis of both methylcobalamin (methionine synthase coenzyme) and adenosyl cobalamin (methylmalonyl-CoAmutase coenzyme), with the consequent possibility of homocystinuria and methylmalonic aciduria. A massive homocystinuria with methylmalonicaciduria is characteristic of the combined de cits of the common intracellular metabolism of the B 12 (5).…”