Abstract
Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic CBS mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. The early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the CBS gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region.
Highlights
Inborn errors of metabolism represent a large group of genetic disorders that result from an inherited deficiency or lack of proteins involved in metabolic pathways
This review aims to examine the mutations spectrum of the cystathionine beta-synthase (CBS) gene in homocystinuria patients with a greater emphasis on those reported in the Middle East and North Africa (MENA) region
Significant advances were made toward curing homocystinuria and protein misfolding, yet, there are no curative treatments for this disease
Summary
Inborn errors of metabolism represent a large group of genetic disorders that result from an inherited deficiency or lack of proteins involved in metabolic pathways. Classical homocystinuria (OMIM 236200) is an autosomal recessive disease and the most common form of homocystinuria worldwide It is an inborn error of metabolism with high clinical variability resulting in a metabolic disorder due to deficiency in cystathionine beta-synthase CBS enzyme activity (Figure 1). In Inplasma addition, thefrom raised levels could200 alter the CBS deficient patients [3] This build-up could lead to several complications such as nearsightedness signaling and cause endoplasmic reticulum stress with endothelial dysfunction [4,5]. The lack of CBS elevates the level of homocysteine and methionine and lowers the concentrations of cystathionine and cysteine in the plasma of homocystinuria patients. Classical homocystinuria, due to a deficiency in CBS activity, is the most common inborn error of sulfur amino acid metabolism. This review aims to examine the mutations spectrum of the CBS gene in homocystinuria patients with a greater emphasis on those reported in the Middle East and North Africa (MENA) region
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