RT Book, Section
A1 Weisfeld-Adams, James
A1 Kirmse, Brian
A2 Murray, Michael F.
A2 Babyatsky, Mark W.
A2 Giovanni, Monica A.
A2 Alkuraya, Fowzan S.
A2 Stewart, Douglas R.
SR Print(0)
ID 1102703192
T1 Hyperhomocysteinemia
T2 Clinical Genomics: Practical Applications in Adult Patient Care
YR 2014
FD 2014
PB McGraw-Hill Education
PP New York, NY
SN 9780071622448
LK accessmedicine.mhmedical.com/content.aspx?aid=1102703192
RD 2024/04/19
AB Disease  summary:Homocysteine  (Hcy)  is  a  sulfur-containing  amino  acid  whose  metabolism  stands  at  an  intersection  of  two  biochemical  pathways.  A  remethylation  pathway  converts  Hcy  to  methionine,  and  requires  the  presence  of  folate  and  vitamin  B12,  while  a  trans-sulfuration  pathway  converts  Hcy  to  cystathionine  and  cysteine  in  a  reaction  requiring  vitamin  B6.Important  monogenic  forms  of  hyperhomocysteinemia  (HHcy)  include  the  following:Cystathionine  beta-synthase  (CBS)  deficiency,  also  known  as  classic  homocystinuria,  is  associated  with  a  skeletal  and  ocular  phenotype  similar  to  Marfan  syndrome,  as  well  as  variable  developmental  delay  and  a  strong  predisposition  to  thromboembolism;  around  50%  of  cases  respond  to  supplementation  with  vitamin  B6.Disorders  of  B12  metabolism:  several  disorders  of  intermediary  cobalamin  metabolism  (CblC,  CblD,  CblE,  CblF,  and  CblG  diseases)  as  well  as  transcobalamin  deficiency  can  cause  moderate-to-severe  HHcy;  treatment  is  centered  around  daily  hydroxocobalamin.Mutations  and  common  polymorphisms  of  methylenetetrahydrofolate  reductase  (MTHFR)  cause  HHcy  of  variable  severity  in  both  the  homo-  and  heterozygous  states.Multifactorial  HHcy  is  also  associated  with  a  range  of  common  adult  diseases  including  thrombophilia,  coronary  artery  disease,  stroke,  neuropsychiatric  disease,  and  osteoporosis.Hereditary  basis:CBS  deficiency,  most  cobalamin  disorders  and  MTHFR  deficiency  follow  autosomal  recessive  inheritance.  Milder  forms  of  HHcy  follow  complex  or  multifactorial  patterns  of  inheritance.Twin  studies:In  a  large  Danish  twin  study,  the  impact  of  the  MTHFR  locus  was  estimated  to  explain  53%  of  the  total  phenotypic  variation  in  Hcy  concentrations  in  persons  18  to  39  years  old,  and  24%  in  persons  40  to  65  years  old,  that  is,  almost  all  additive  genetic  variance.  Hcy  concentrations  have  a  high  heritability  that  decreases  with  age.Genome-wide  association  studies  (GWAS):Significant  genome-wide  associations  have  been  found  between  total  homocysteine  (tHcy)  and  single-nucleotide  polymorphisms  (SNPs)  located  near  GPR51  (9q22)  and  MTHFR  (1p36).  A  GWAS  looking  at  the  coronary  artery  disease  phenotype  noted  an  association  with  MTHFD1L,  which  is  important  in  methionine-homocysteine  metabolism.Pharmacogenomics:Common  MTHFR  polymorphisms  (677C>T  and  1298A>C)  confer  increased  sensitivity  to  fluoropyrimidines  (eg,  5-FU)  and  antifolates  (eg,  methotrexate).