Hyperhomocysteinemia: Clinical Insights

Abstract

ABSTRACT: Homocysteine (Hcy) is a sulfhydryl-containing amino acid, and intermediate metabolite formed in metabolising methionine (Met) to cysteine (Cys); defective Met metabolism can increase Hcy. The effect of hyperhomocysteinemia (HHcy) on human health, is well described and associated with multiple clinical conditions. HHcy is considered to be an independent risk factor for common cardiovascular and central nervous disorders, where its role in folate metabolism and choline catabolism is fundamental in many metabolic pathways. HHcy induces inflammatory responses via increasing the pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines which lead to Hcy-induced cell apoptosis. Conflicting evidence indicates that the development of the homocysteine-associated cerebrovascular disease may be prevented by the maintenance of normal Hcy levels. In this review, we discuss common conditions associated with HHcy and biochemical diagnostic workup that may help in reaching diagnosis at early stages. Furthermore, future systematic studies need to prove the exact pathophysiological mechanism of HHcy at the cellular level and the effect of Hcy lowering agents on disease courses.

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DOI: 10.1177/1179573520962230
Introduction
Homocysteine (Hcy) is a sulfhydryl-containing amino acid, a
homolog of cysteine with one additional methylene group.1,2
Hcy is not acquired through the diet, but is synthesized as an
intermediate metabolite from methionine (Met) metabolism. It
is converted to cysteine via the transsulfuration pathway or
resynthesized back to methionine via the re-methylation path-
way.3,4 In plasma, 99% of the Hcy is bound to proteins, including
cysteine, and cysteinylglycine via disulfide linkages, while only
1% is found in a free reduced form.5 For the estimation of the
Hcy level, plasma tissue homogenate samples are analyzed using
various methodologies such as immunoassay, capillary electro-
phoresis, enzymatic assay, liquid chromatography-mass spec-
trometry (LCMS) and high-pressure liquid chromatography
(HPLC).6 The normal Hcy levels is ranging between 5 and
15 μmol/L, while a mildly increased level is 15 to 30 μmol/L,
moderate from 30 to 100 μmol/L, and a value >100 μmol/L is
classified as severe hyperhomocysteinemia.7,8
The levels of Hcy can be increased through a defective
metabolism of Met, due to genetic defects of the transcription
of enzymes responsible for Hcy metabolism or deficiencies of
cofactors involved in these pathways such as vitamins B6, B12,
and folate.9 The effect of hyperhomocysteinemia (HHcy) on
human health was first described in the mid-20th century by
Kilmer S. McCully.10 Since then, many epidemiologic reports
indicated that HHcy is associated with multiple clinical condi-
tions, while controlled Hcy level in high risk group associated
with improved physical and mental health.11-14 It is considered
as an independent risk factor for cardiovascular disease, as well
as for stroke and myocardial infarction by the American Heart
Association.15,16 Although it is not directly involved in protein
synthesis, the exposure to a toxic effect of Hcy, induced cyto-
toxicity that lead to a reduction of cultured endothelial cells
viability through a direct and indirect effect on the pathway of
apoptosis.17,18
Studies have identified a strong association between HHcy
and induction of inflammatory determinants including the
expression of adhesion molecules, leukocyte adhesion, endothe-
lial dysfunction, oxidative stress, and reduced nitric oxide bio-
availability in both human and experimental models.19,20 In
HHcy state, NFκB, a transcription factor that regulates the
transcription of various genes involved in inflammatory and
immune responses is activated, additionally, marked increase in
pro-inflammatory cytokines and downregulation of anti-
inflammatory cytokines were observed.19
In HHcy patients, supporting evidence indicate that the
development of homocysteine-associated vascular disease may
be prevented by the maintenance of normal Hcy levels, with
conventional treatment of folate supplementation and vitamin
B6 and possibly vitamin B12.21 However, despite lowered Hcy
levels, the clinical picture of pathophysiological conditions
caused by an elevated Hcy level may not be reversible for cer-
tain conditions.22
Several studies were conducted to investigate the treatment
of HHcy in patients with a history of arteriosclerotic vascular
disease (ASVD).23,24 A large study was conducted with more
than a 1000 individuals with HHcy, to determine the effect of
supplementation with vitamins B12, B6, and folic acid for
6 weeks. The study reported that there was a proportional
reduction in the plasma Hcy level caused by the folic
Hyperhomocysteinemia: Clinical Insights
Fuad Al Mutairi1,2,3
1Medical Genetics Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi
Arabia. 2King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 3King
Abdullah International Medical Research Centre, Riyadh, Saudi Arabia.
ABSTRACT: Homocysteine (Hcy) is a sulfhydryl-containing amino acid, and intermediate metabolite formed in metabolising methionine (Met)
to cysteine (Cys); defective Met metabolism can increase Hcy. The effect of hyperhomocysteinemia (HHcy) on human health, is well described
and associated with multiple clinical conditions. HHcy is considered to be an independent risk factor for common cardiovascular and central
nervous disorders, where its role in folate metabolism and choline catabolism is fundamental in many metabolic pathways. HHcy induces inflam-
matory responses via increasing the pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines which lead to Hcy-induced
cell apoptosis. Conflicting evidence indicates that the development of the homocysteine-associated cerebrovascular disease may be prevented
by the maintenance of normal Hcy levels. In this review, we discuss common conditions associated with HHcy and biochemical diagnostic
workup that may help in reaching diagnosis at early stages. Furthermore, future systematic studies need to prove the exact pathophysiological
mechanism of HHcy at the cellular level and the effect of Hcy lowering agents on disease courses.
KEYWORDS: Homocysteine, folate, cobalamin, vitamin B -12, methylenetetrahydrofolate reductase, homocystinurea
RECEIVED: June 23, 202 0. REVISED ARTICLE ACCEPTED: September 6, 20 20.
TYPE: Review
FUNDING: The author r eceived n o nanci al suppo rt for the r esearch , authors hip, and /or
publication of this article.
DECLARATION OF CONFLICTING INTERESTS: The author dec lared no po tential
conic ts of inter est with re spect to t he resear ch, autho rship, an d/or publ icatio n of this
article.
CORRESPONDING AUTHOR: Fuad Al Mutairi, Division of Genetics, Department of
Pediatri cs, Kin g Abdula ziz Medi cal City, Mi nistry o f Nationa l Guard- Health A ffairs
(MNGHA), P. O. Box 22490, Ma il Code 1490, R iyadh 11426, Saudi Ar abia.
Email: almutairifu@ngha.med.sa
962230CNS0010.1177/1179573520962230Journal of Central Nervous System DiseaseAl Mutairi
review-article2020

2 Journal of Central Nervous System Disease
acid treatment and that the level of the reduction was higher in
participants with pre-treated Hcy levels.25 The dosage required
for the treatment of HHcy may vary according to the underly-
ing condition, however, the minimum effective dose of folic
acid to obtain the maximal lowering of Hcy is 400 μg.26,27
Prolonged folic acid therapy is associated with decreased vita-
min B12 blood levels and worsening symptoms of B12 defi-
ciency, so a supplement vitamin B12 is usually taken in the
form of the cyanocobalamin.28 In a randomized controlled
trial, 104 patients were divided in 2 groups, the study group
received a combined nutraceutical containing 400 μg folate-
6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 μg vitamin
B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine once
daily for 2 months, and the control group received a supple-
ment of folic acid (5 mg/day). The results indicated that the
Hcy reduction was significantly higher in the treatment group
(P < .035).28 This may support the available evidences that
vitamin supplements significantly reduce the Hcy levels in a
sustained but suboptimal way, even if supraphysiological doses
are used.29,30 Recent study revealed the protective role of vita-
min E as antioxidant and melatonin may alleviate Hcy-induced
cell apoptosis, which may add insight into therapeutic
approaches to Hcy-induced damages in endothelial cells.31
The review will discuss Hcy and its biological functions in
the body, conditions that induce by or are related to HHcy, and
biochemical investigations that may ease the recognition of
suspected cases at early stage of disease course.
Biosynthesis and Metabolism of Homocysteine
Hcy is produced in all cells and biosynthesized from methio-
nine through multiple steps, initiated by the demethylation of
methionine (Met) as well as 3 subsequent steps.1,3 The first
step is the transfer of an adenosine group from ATP to methio-
nine by S-adenosyl methionine (SAM or AdoMet) synthetase
(also called methionine adenosyltransferase, MAT), resulting
in the formation of S-Adenosyl-L-methionine (AdoMet or
SAM)32-34 (Figure 1).
In the second step, the universal methyl donor, SAM,
donates a methyl group to acceptor molecules such as DNA,
RNA, proteins, and neurotransmitters.35 The resulting com-
pound S-adenosyl homocysteine (AdoHCys or SAH), lack-
ing the methyl group, can function as an inhibitor of most
methyltransferases and is subsequently cleaved via a revers-
ible reaction by S-adenosyl homocysteine hydrolase
(SAHH) to produce adenosine and L-homocysteine.4,36,37
Finally, the L-homocysteine can be metabolized by 2
Figure 1. The homocysteine metabolic cycle.
Abbreviations: ADK, adenosine kinase; AdoHCys or SAH, S-adenosyl homocysteine; AdoMet or SAM, adenosyl methionine; BHMT, betaine-homocysteine
methyltransferase; Cbl, cobalamin—vitamin B12; CBS, cystathionine beta-synthase; DMG, dimethylglycine; GNMT, glycine N-methyltransferase; Hcy, homocysteine; MAT,
methionine adenosyltransferase; 5-methyl-THF, 5-N-methyl tetrahydrofolate; 5,10-methylene-THF, 5,10-methylenetetrahydrofolate; MS, methionine synthase; MTHFR,
methylenetetrahydrofolate reductase; SAHH, S-adenosylhomocysteine hydrolase; SHMT, serine hydroxymethyltransferase.

Al Mutairi 3
reactions, transsulfuration or re-methylation, ultimately
producing L-methionine and L-cysteine, respectively.2,38
Remethylation
Remethylation involves recycling Hcy to methionine, by
using vitamin B12 as a cofactor. The methionine synthase
(MS) catalyzes the re-methylation reaction, restoring Met
by transferring the methyl group from 5-N-methyl tetrahy-
drofolate (5-methyl-THF) to Hcy.39-41 In this cycle, folate is
reduced to tetrahydrofolate, which is an important key
player in folate metabolism as a folate acceptor molecule,
which is then converted to 5,10-methylenetetrahydrofolate
(5,10-methylene-THF) by the pyridoxal phosphate (PLP)-
dependent serine hydroxymethyltransferase (SHMT).42
Methylenetetrahydrofolate reductase (MTHFR) reduces
5,10-methylene-THF to 5-methyl-THF.43
There is another pathway of remethylating Hcy that uses an
enzyme called betaine-homocysteine methyltransferase (BHMT).
The betaine pathway is restricted to the liver and kidney where
betaine can serve as methyl donor molecules. In this reaction, the
methyl group is transferred from betaine to Hcy to produce
methionine and dimethylglycine (DMG).41,44,45 Here choline
plays a significant role in Met regeneration, as it is oxidized to
betaine, which can be used in this conversion of Hcy.46,47
Transsulfuration
In the transsulfuration process, Hcy is irreversibly converted
to cysteine by cystathionine b-synthase (CBS), which is fol-
lowed by the catalysis done by cystathionine c-lyase (CTL).
Both enzymes need the cofactor pyridoxal-50-phosphate
(vitamin B6) to function.48 Serine can be enzymatically
added to homocysteine by CBS and vitamin B6, to form cys-
tathionine, which can be cleaved by CTL to form cysteine.49
Once cysteine is formed, it can be used in protein synthesis
and glutathione (GSH) production and cannot be converted
to back to Hcy.50
Causes of Hyperhomocysteinemia
Enzyme defects associated with Hcy metabolism are consid-
ered the most prevalent cause of HHcy. The enzyme defects
has been researched, especially the polymorphisms of the main
enzymes involved in Hcy metabolism such as Cystathionine
b-synthase (CBS) deficiency, Methylenetetrahydrofolate
reductase (MTHFR) deficiency, Methionine synthase defi-
ciency, and Methionine adenosyltransferase deficiency
(Table 1).37,51,52 In addition to genetic causes, many other fac-
tors related to age, lifestyle such as cigarette smoking, alcohol
consumption and nutritional deficiencies in folic acid, vitamin
B6, vitamin B12, and betaine are as responsible for HHcy.53-56
In this review, we will discuss the main enzymatic defects in
this pathway.
Cystathionine beta-synthase (CBS) deficiency or
classical homocystinuria
Classical homocystinuria (HCU) (OMIM 236200), is an auto-
somal recessive disease caused by biallelic pathogenic variations
in the CBS gene.57 Deficiency of the CBS enzyme causes ele-
vated tissue and plasma levels of Hcy and its precursor, methio-
nine.58 Typically, patients can manifest a wide range of
symptoms with variable severity involving the ocular, skeletal,
vascular, and central nervous systems.59,60
The prevalence of CBS deficiency has been reported as
1:200 000 to 1:335 000 and >200 pathogenic variants have
Table 1. Causes of hyperhomocysteinemia.
Severe >100 μmol/L
Cystathionine synthase (CBS) deciency
Untreated methylenetetrahydrofolate reductase (MTHFR)
deciency
Moderate 60 to 100 μmol/L
Methylenetetrahydrofolate reductase (MTHFR) deciency
Methionine synthase (MS) deciency
Moderate 30 to 60 μmol/L
Intracellular cobalamin metabolism, for example, cblC, cblD,
cblE, cblF, and cblG
Methionine adenosyltransferase I/III deciency
Glycine N-methyltransferase (GNMT) deciency
S-adenosylhomocysteine hydrolase (SAHH) deciency
Adenosine kinase (ADK) deciency
Sever nutritional inadequacy, for example, folate and vitamin B12
Compound heterozygosity of MTHFR
Mild 16 to 30 μmol/L
Impaired folate or vitamin B12 absorption
Mild to moderate nutritional inadequacy, for example, folate and
vitamin B12
Vegetarian diet (low vitamin B12 intake)
Chronic renal failure
Hypothyroidism
Anemia
Malignant tumors
Certain drugs affecting Hcy metabolism: cholestyramine,
metformin, methotrexate, nicotinic acid (niacin), bric acid
derivatives, and oral contraceptive pills (OCPs)
Advanced age
Lifestyle conditions such as excessive coffee or alcohol
consumption, cigarette smoking

4 Journal of Central Nervous System Disease
been described in the CBS gene, however, mutations such as
p.Ile278Thr, p.Thr191Met, p.Gly307Ser, and p.Trp323Ter are
the most prevalent mutations and represent half of all HCU
alleles.61-63 Considering the significant effect of genetic poly-
morphisms on the increase of the HCys level, current studies
are investigating the correlation between the polymorphisms
and stroke events, however, the results are still conflicting.56 Not
all polymorphisms in CBS have an effect on enzyme activity,
however a T833C polymorphism in CBS, caused mild HHcy in
different ethnic groups.64-66 Current treatment options for CBS
are very limited and often inefficient, partially due to low patient
compliance with a very strict dietary regimen.67 However recent
studies shows the efficacy of some novel therapies including
enzyme replacement and gene therapy approaches.68
Methylenetetrahydrofolate reductase (MTHFR)
Methylenetetrahydrofolate reductase (MTHFR) deficiency
(OMIM 236250), an autosomal-recessive inheritance disease, is
caused by a mutation in the MTHFR gene which encode
MTHFR, a key enzyme of folate metabolism in the process of
one-carbon metabolism.69 Polymorphisms of MTHFR would
cause impaired methylation as well as a deficiency of folate, and
a wide range of diseases including cardiovascular, tumors, neuro-
logic, and psychiatric disorders.70,71 One of the most studied
polymorphisms in MTHFR is C677T.72-74 This polymorphism
is responsible for an increase of Hcy concentration and folate
deficiency compared to a normal genotype individual.75 It is esti-
mated that 10% of the global population is homozygous (TT
genotype), which may vary in different populations reaching
25%.42 The treatment in MTHFR is symptomatic including the
treatment of associated neurological symptoms.76 Vitamin sup-
plementation should be considered in these patients including
vitamin B12, folic acid, vitamin B6, betaine, and methionine.77
Methionine synthase
Methionine synthase promotes the methyl group transfer from
methylated folate to homocysteine to yield methionine, and
Cbl act as a cofactor in this catalytic reaction. This enzyme is
encoded by the MTR gene. Mutations in this gene are the
underlying cause of methylcobalamin deficiency cblG-type.78,79
In patients with a methionine synthase deficiency (CbIG),
complementation studies on cultured fibroblasts indicated a
cblG defect.80 This deficiency is rarely reported in literature,
and the patients do not have specific neurological symptoms
for example, blindness or leukoencephalopathy associated with
normal vitamin B12 and folate, hyperhomocysteinemia with
hypomethioninemia in the absence of methylmalonic acid.74
Acquired and inherited disorders of cobalamin
Cobalamin (Cbl-Vitamin B12) is an essential cofactor for MS
in the folate cycle to ultimately produce the 5-Methyl THF
which provides a methyl group to convert homocysteine to
methionine.69,81 Inborn errors of cobalamin metabolism can
affect its absorption (intrinsic factor deficiency, Imerslund-
Gräsbeck syndrome), transportation (transcobalamin
deficiency), as well as genetic defects of the intracellular cobal-
amin metabolism such as CblC, CblD, CblE, CblF, and
CblG.82-84 Megaloblastic anemia, pancytopenia and failure to
thrive are the main manifestation of Cbl deficiency. However,
if the diagnosis is delayed, it may be accompanied by irreversi-
ble neurological deficits.83 Cbl deficiency rarely requires instant
therapy, however, treatment should be started timeously to pre-
vent severe neurologic symptoms (eg, seizures, gait distur-
bances, mental changes and extensive sensory defects) due to
the risk of irreversibility.85
Methylation disorders
Inherited methylation disorders are a group of disorders affecting
the transmethylation processes in the metabolic pathway between
methionine and Homocysteine, including methionine adenosyl-
transferase I/III, glycine N-methyltransferase, Sadenosylhomo-
cysteine hydrolase and adenosine kinase deficiencies.86 Although
isolated hypermethioninemia is the biochemical hallmark of this
group of disorders, mild to moderate HHcy can be present in all
patients.87 Three of these directly affect the reactions in the
methionine pathway. The first is the conversion of methionine to
AdoMet, catalyzed by methionine adenosyltransferase. The sec-
ond enzyme is glycine N-methyltransferase (GNMT), which
transfers a methyl group to glycine producing sarcosine. The third
enzyme, S-adenosylhomocysteine hydrolase (SAHH), is a homo-
tetrameric enzyme, which converts S adenosylhomocysteine to
homocysteine and adenosine.88-90 In methylation disorders, a low
methionine diet can be beneficial in patients with MAT I/III defi-
ciency, and to a lesser extend in SAHH and AKD.
S-adenosylmethionine supplementation may specifically be useful
in patients with MAT I/III deficiency.86
Conditions Associated With Hyperhomocysteine
Hcy function in folate metabolism and choline catabolism is
fundamental for the synthesis of different sulfur-containing
amino acids and methylated compounds which are important
for may cellular pathways.42,91 Numerous studies demonstrated
that the disruption of the Hcy metabolism which lead to HHcy
by common MTHFR gene polymorphism, increases the risk
for several complex disorders and it plays an important role in
the pathogenicity of such disorders, including the cardiovascu-
lar system for example, congestive heart disease and arthroscle-
rosis.92-94 In the central nervous system, the disorders include
cognitive impairment, Parkinson’s disease, Alzheimer’s disease
(AD), multiple sclerosis and epilepsy.95 In addition, an elevated
Hcy was linked to osteoporosis, chronic renal failure, hypothy-
roidism, insulin resistant diabetes, polycystic ovarian syndrome,
and gastrointestinal disorders.96-100 Although the molecular
mechanism in this role has not been fully defined, age related

Al Mutairi 5
disorders such as acoustic dysfunction, and age related macular
degeneration has been reported.101-104
Stroke and cardiovascular diseases
Literature support the theory of a correlation between HHcy
and the risk for peripheral vascular diseases, including stroke,
venous thromboembolism and cardiovascular disease, for
example congestive cardiomyopathy, myocardial infarction and
coronary artery disease.105 A potential mechanism is the
thrombotic activity of Hcy and its direct effect of endothelial
dysfunction, where the Hcy acts as an inhibitor of endothelial
nitric oxide synthase (eNOS), which will cause reduced bioa-
vailability of NO, through the inhibitory effect of asymmetric
dimethylarginine (ADMA).106 Findings from a clinical study
investigating patients with heart failure, support through pre-
clinical evidence that the myocardium is especially vulnerable
to damage by HHcy, which is associated with the production of
reactive oxygen species and cause the progression of cardiovas-
cular disease and left ventricle remodeling.107,108
Cognitive impairment, Alzheimer’s disease,
Parkinson’s disease and epilepsy
Several case control studies confirmed a positive correlation
between HHcy as a neurotoxic condition and both vascular
dementia and AD. However, it remains unclear whether an
elevated blood homocysteine level is a direct risk factor for AD
or possibly, poor vitamin nutrition in the elderly.101 The mech-
anism through which high levels of Hcy cause AD is still being
investigated, however, in an experimental study, HHcy resulted
in increased gene expression of proinflammatory markers such
as IL1b and TNFa in microglia and an increased expression of
kinases in neuronal cells.109 Studies have also shown an increase
in neurodegeneration due to homocysteine-related oxidative
stress, causing an increase in the production of superoxide and
other reactive oxygen species, and apoptosis.110 Another pro-
posed mechanism for Hcy neurodegeneration involves its role
as an agonist for AMPA (both metabotropic and ionotropic)
and NMDA receptors. All those changes in vascular smooth
muscle cells, provide further neurotoxic peculiarity to HHcy as
a risk factor for neurodegenerative diseases.111 Recently, an
experimental model, linked the HHcy to increased oxidative
stress, upregulated expression of proteins that promote blood
coagulation, exacerbated blood-brain barrier dysfunction and
promoted the infiltration of inflammatory cells into the cortex
in traumatic brain injury (TBI).112
Gastrointestinal disorders
There is growing evidence that HHcy is associated with inflam-
matory bowel disease (IBD) and many autoimmune dis-
eases.113,114 In a meta-analysis of 28 studies, the Hcy levels were
significantly higher in IBD patients, compared to the controls.115
The pathophysiological mechanisms leading to vascular damage
in hyperhomocysteinemia are multifactorial, and still poorly
understood. Studies have also shown that the colonic mucosa of
patients with IBD has a higher level of Homocysteine and it has
been hypothesized that the lamina propria mononuclear cells
(LPMC) play an important role in homocysteine production.116
Chronic renal diseases
Hcy has been documented in patients with chronic renal fail-
ure (CRF), on dialysis or after a kidney transplant, at higher
concentrations than in individuals without kidney disease.117 A
study was conducted with 89 renal failure patients on dialysis,
to determine the frequency of the MTHFR gene mutation or
polymorphism and hyperhomocysteinemia. The study con-
firmed the high prevalence of hyperhomocysteinemia in
patients on dialysis, diagnosed in 76 patients (85.39%), as well
as the high incidence of the C677T and A1298C mutation, in
42 (47.19%) and 29 (32.58%) patients, respectively.118
A Clinical Approach for Hyperhomocysteinemia
It must be noted that HHCY, the biochemical hallmark of a
large group of diseases that characterized by variable presenta-
tion affecting many organs, however, the predominant associated
features are hematological and unexplained neurological signs
and symptoms.22 Predominantly, HHcy is associated with vita-
min B12 deficiency, where the measurements of metabolites,
such as methylmalonic acid (MMA) and Hcy, are more sensitive
in the diagnosis than the measurement of serum B12 levels
alone, with 98.4% with elevated serum MMA levels, and 95.9%
with elevated serum homocysteine levels in B12 deficiency
cases.119-121 The differing treatments for each genetic cause of
HHcy necessitate identifying a specific underlying causes, in
order to provide paradigmatic treatment. In suspected cases, a
careful clinical evaluation that using a variety of metabolites
including, total Hcy, PAA, Vitamin B6, Vitamin B12 levels, and
serum and urine levels of MMA rather than just Hcy will help
elucidate the cause of HHcy, should facilitate their exclusion
(Figure 2). The level of elevation and Hcy and the status of asso-
ciated metabolites will help in narrowing the diagnosis.
Combined sever HHcy with high methionine in PAA frequently
seen in CBS deficiency (classical homocystinuria), while in
methylation disorders (MAT I/III, GNMT, ADK, and SAHH),
HHcy is moderately elevated. In case if HHcy associated with
low methionine, MTHFR and MS should be considered. The
elevation of MMA is also important if associated with HHcy
because it is indicate inherited cobalamin disorders or vitamin
B12. After accurate interpretation of these metabolites the diag-
nosis can be confirmed by investigations at the levels of metabo-
lites, enzymatic studies and/or molecular genetic analysis.86,122
In several countries, C3-propionylcarnitine and methionine
is used as markers in newborn screening programs in asympto-
matic newborns, where C3-propionylcarnitine is used as a

6 Journal of Central Nervous System Disease
marker to detect patients with vitamin B12 deficiency, intracel-
lular Cbl disorders, while elevated methionine used for CBS
deficiency and methylation defects, such as MAT I/III and
GNMT.90 After making a diagnosis and initiating a treatment
plan, follow-up is important to determine the patient’s response
to therapy. In mild vitamin B12 deficiency, depending on the
underlying cause, frequent measurements of serum vitamin
B12, Hcy, and MAA levels is recommended for monitoring of
therapy.123-126
Conclusion
Hcy is now considered as a risk marker for cardiovascular and
cerebrovascular disease in addition to other modified and non-
modified individual factors. Simultaneous measurement of vita-
min B12, Hcy, MMA, and PAA is accepted as a sensitive method
of screening for several conditions associated with HHcy.
HHcy-induced inflammation could play a role in blood brain
barrier (BBB) dysfunction and the pathogenesis. Thus, the elim-
ination of excess homocysteine could be a potential therapeutic
intervention therefor may be value in preventative supplementa-
tion, especially folic acid, vitamin B12 and betaine, if the foods
indicated are not being consumed in sufficient quantities.
Authors’ contributions
FAM prepared and summarized the literature, designed the
figures and tables and wrote the manuscript.
Availability of data and materials
All data generated or analyzed during this study are included
in this published article, any additional data/files may be
obtained from the corresponding author.
ORCID iD
Fuad Al Mutairi https://orcid.org/0000-0002-7780-8863
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Figure 2. Algorithm for diagnosis of hyperhomocysteinemia.
Abbreviations: ADK, adenosine kinase; AdoHCys or SAH, S-adenosyl homocysteine; AdoMet or SAM, adenosyl methionine; Cbl, cobalamin—vitamin B12; CBS,
cystathionine beta-synthase; GNMT, glycine N-methyltransferase; Hcy, homocysteine; HHcy, hyperhomocysteinemia; MAT, methionine adenosyltransferase; MS,
methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAHH, S-adenosylhomocysteine hydrolase.

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