G C A T T A C G G C A T genes Review The Spectrum of Mutations of Homocystinuria in the MENA Region Duaa W. Al-Sadeq 1,2,* and Gheyath K. Nasrallah 1,3,* 1 Biomedical Research Center, Qatar University, P.O. Box 2713 Doha, Qatar 2 College of Medicine, Member of QU Health, Qatar University, P.O. Box 2713 Doha, Qatar 3 Department of Biomedical Science, College of Health Sciences, Qatar University, P.O. Box 2713 Doha, Qatar * Correspondence: [email protected] (G.K.N.); [email protected] (D.W.A-S.); Tel.: +974-4403-6623 (D.W.A-S.); +974-4403-4817 (G.K.N.); Fax: +974-4403-1351 (G.K.N.) Received: 20 February 2020; Accepted: 13 March 2020; Published: 20 March 2020 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. Keywords: homocystinuria; cystathionine β-synthase; mutations; MENA 1. Introduction 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. The majority are defects of single genes that code for enzymes, which catalyze essential biologically and biochemical reactions. Although each specific inborn error of metabolism is rare, taken together, they represent a significant source of congenital disabilities. For instance, it is estimated that a genetically caused inborn error of metabolism occurs in 1/2500 births [1]. A prototypical example of an inborn error of metabolism is homocystinuria due to CBS deficiency [2]. 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 (Figure1). Consequently, an impaired CBS activity leads to the elevation of both the Genes 2020, 11, 330; doi:10.3390/genes11030330 www.mdpi.com/journal/genes Genes 2020, 11, 330 2 of 17 Genes 2019, 10, x FOR PEER REVIEW 2 of 16 methionine and homocysteine levels in the blood and urine, leading to hyperhomocysteinemia, homocystinuria,enzyme activity hypermethioninaemia, (Figure 1). Consequently, and an hypocysteinaemia. impaired CBS activity In healthyleads to the adults, elevation the concentration of both the of totalmethionine homocysteine and homocysteine in plasma ranges levels fromin the 5 blood to 15 µandM; urine, however, leading it reaches to hyperhomocysteinemia, 200 µM in untreated CBS deficienthomocystinuria, patients hypermethioninaemia, [3]. This build-up could and leadhypocyst to severaleinaemia. complications In healthy adults, such the as nearsightednessconcentration and dislocatedof total homocysteine eye lenses. in In plasma addition, ranges the from raised 5 to homocysteine 15 µM; however, levels it reaches could 200 alter µM the in intracellularuntreated signalingCBS and deficient cause patients endoplasmic [3]. This reticulum build-up could stress lead with to several endothelial complications dysfunction such as [4 ,nearsightedness5]. Consequently, leadingand to thromboembolism,dislocated eye lenses. vascular, In addition, and the other raised diseases homocysteine [6]. Clinically, levels could CBS alter deficient the intracellular patients may signaling and cause endoplasmic reticulum stress with endothelial dysfunction [4,5]. Consequently, present with intellectual disability, a variety of psychiatric and behavioral disorders, skeletal and leading to thromboembolism, vascular, and other diseases [6]. Clinically, CBS deficient patients may ocular abnormalities, vaso-occlusive disease, as well as vascular system complications [7]. Affected present with intellectual disability, a variety of psychiatric and behavioral disorders, skeletal and babiesocular are healthy abnormalities, at birth, vaso-occlusive but may exhibit disease, a failureas well toas vascular thrive during system infancycomplications and developmental[7]. Affected delay duringbabies are the healthy first years at birth, of life.but may To date, exhibit there a failure is no to cure thrive for during homocystinuria infancy and anddevelopmental the available treatmentsdelay target during lowering the first theyears homocysteine of life. To date, level ther throughe is no betaine,cure for homocystinuria folic acid, and pyridoxineand the available (vitamin B6) supplements.treatments target The mainlowering aim the is tohomocysteine keep the plasma level through homocysteine betaine, asfolic close acid, to theand normalpyridoxine range as possible.(vitamin However, B6) supplements. a considerable The main fraction aim is to of keep aff ectedthe plasma patients homocysteine is nonresponsive as close toto the pyridoxine normal treatment.range In as addition, possible. a methionine-restrictedHowever, a considerable diet isfracti noton optimal, of affected and poorpatients compliance is nonresponsive leads to serious to complicationspyridoxine [8]. treatment. Therefore, In currentlyaddition, a the methionine-res therapeutictricted approach diet foris not homocystinuria optimal, and poor is shifted compliance toward leads to serious complications [8]. Therefore, currently the therapeutic approach for homocystinuria stabilizing and rescuing the protein’s native structural conformations through chemical chaperones is shifted toward stabilizing and rescuing the protein’s native structural conformations through and proteasomechemical chaperones inhibitors. and Furthermore, proteasome inhibitors. several studies Furthermore, are focusing several studies on other are approaches, focusing on other such as gene andapproaches, enzyme replacementsuch as gene and therapies enzyme that replacement will be explained therapies laterthat will in Section be explained6 (Current later in and Section potential 6 treatment(Current approaches). and potential treatment approaches). Figure 1. Homocysteine metabolism pathway. Methionine adenosyltransferase (MAT); Figure 1. Homocysteine metabolism pathway. Methionine adenosyltransferase (MAT); methyltransferase (MT); S-adenosylhomocysteinase hydrolase (SAHH); betaine-homocysteine methyltransferase (MT); S-adenosylhomocysteinase hydrolase (SAHH); betaine-homocysteine methyltransferasemethyltransferase (BHMT); (BHMT); pyridoxal-phosphate pyridoxal-phosphate (PLP); cystathionine(PLP); cystathionine gamma-lyase gamma-lyase (CGL); methionine(CGL); synthasemethionine (MS); serine-hydroxymethyltransferase synthase (MS); serine-hydroxymethyltransferase (SHMT); methyl-tetrahydrofolate-reductase (SHMT); methyl-tetrahydrofolate- (MTHFR), hydrogenreductase sulfide (MTHFR), (H2S). hydrogen sulfide (H2S). MethionineMethionine is an is essential an essential sulfur-containing sulfur-containing amino amino acid acid that that isis involved in in the the development development and and properproper mammalian mammalian growth. growth. Once Once the the dietary dietary proteins proteins are areingested ingested and methionine methionine enters enters thethe cells, cells, methioninemethionine adenosyltransferase adenosyltransferase (MAT) (MAT) will catalyzewill catalyze the condensationthe condensation of methionineof methionine with with ATP ATP and and form S-adenosylmethionineform S-adenosylmethionine (SAM), also (SAM), known also as AdoMet.known as SAMAdoMet. serves SAM as serves a crucial as methyla crucial donor methyl for donor various methyltransferase reactions, including hormones biosynthesis and generating S-adenosylhomocysteine (SAH). SAH is then reversibly hydrolyzed into adenosine and homocysteine through the action of Genes 2020, 11, 330 3 of 17 S-adenosylhomocysteinase hydrolase (SAHH). Homocysteine is a nonproteinogenic toxic intermediary amino acid residing at the intersections of several pathways. It can be remethylated through methionine