TY  - CHAP
M1  - Book, Section
TI  - Hypophosphatasia
A1  - Whyte, Michael P.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.242
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Hypophosphatasia  (McKusick  146300,  241500,  241510)  is  a  metabolic  bone  disease  that  establishes  a  critical  (but  as  yet  undefined)  role  for  alkaline  phosphatase  (ALP)  in  skeletal  mineralization  in  humans.  Subnormal  activity  of  ALP  in  serum  (hypophosphatasemia)  is  the  biochemical  hallmark  and  reflects  a  generalized  deficiency  of  activity  of  the  tissue-nonspecific  -liver/bone/kidney-  ALP  isoenzyme  (TNSALP).  Catalysis  by  the  tissue-specific  ALP  isoenzymes—intestinal,  placental,  and  germ-cell  (placental-like)  ALP—is  not  diminished.TNSALP  is  a  zinc  metalloglycoprotein  that  is  catalytically  active  as  a  multimer  of  identical  subunits.  The  bone  and  liver  isoforms  differ  by  post-translational  modification.  TNSALP  is  attached  to  the  extracellular  surface  of  plasma  membranes  by  glycosylphosphatidylinositol  linkage.  The  TNSALP  gene  is  greater  than  50  kb  and  localized  on  chromosome  1p36.1-34  (McKusick  171760).  The  tissue-specific  ALP  isoenzymes,  perhaps  including  a  fetal  form  of  intestinal  ALP,  are  encoded  by  a  family  of  smaller  genes  on  chromosome  2q34-37  (McKusick  171740,  171750,  171800,  171810).Hypophosphatasia  causes  defective  skeletal  mineralization  that  manifests  clinically  as  rickets  in  infants  and  children  and  as  osteomalacia  in  adults.  Expressivity  is  remarkably  variable.  Stillbirth  can  follow  in  utero  disease  in  the  perinatal  (“lethal”)  form,  which  is  apparent  in  newborns  and  is  associated  with  the  most  severe  skeletal  hypomineralization  and  deformity.  The  infantile  form  presents  as  a  developmental  disorder  by  age  6  months.  It  can  result  in  craniosynostosis  and  nephrocalcinosis  from  hypercalcemia  and  hypercalciuria  and  is  often  fatal.  Premature  loss  of  deciduous  teeth,  rickets,  and  myopathy  are  the  cardinal  clinical  features  of  childhood  hypophosphatasia.  Adult  hypophosphatasia  typically  causes  recurrent  metatarsal  stress  fractures  and  pseudofractures  in  long  bones  and  occasionally  produces  arthritis  from  calcium  pyrophosphate  dihydrate  (CPPD)  and  calcium  phosphate  crystal  deposition.  Odontohypophosphatasia  refers  to  mildly  affected  individuals  who  have  dental  but  no  skeletal  manifestations.  Pseudohypophosphatasia  is  an  extremely  rare  severe  variant  in  which  serum  ALP  activity  is  normal  in  clinical  laboratory  assays.Three  phosphocompounds  (phosphoethanolamine  [PEA],  inorganic  pyrophosphate  [PPi],  and  pyridoxal  5′-phosphate  [PLP])  accumulate  endogenously  in  hypophosphatasia  and  are  inferred  to  be  natural  substrates  for  TNSALP.  PLP,  a  cofactor  form  of  vitamin  B6,  collects  extracellularly,  but  a  variety  of  evidence  shows  that  levels  of  PLP  within  cells  are  normal.  This  observation  explains  the  usual  absence  of  symptoms  of  deficiency  or  toxicity  of  vitamin  B6  in  patients  and  indicates  that  TNSALP  functions  as  an  ectoenzyme.  Extracellular  accumulation  of  PPi,  which  at  low  concentrations  promotes  calcium  phosphate  deposition  but  at  high  concentrations  acts  as  an  inhibitor  of  hydroxyapatite  crystal  growth,  seems  to  account  for  the  associated  CPPD  deposition,  and  perhaps  calcific  periarthritis,  and  the  defective  mineralization  of  bones  and  teeth.Perinatal  and  infantile  hypophosphatasia  are  transmitted  as  autosomal  recessive  traits  and  can  be  due  to  homozygosity  or  compound  heterozygosity  for  a  considerable  number  and  variety  of  mutations  in  the  TNSALP  gene.  Defective  regulation  of  TNSALP  gene  expression  or  TNSALP  biosynthesis  may  explain  especially  rare  cases.  Patients  with  childhood,  adult,  or  odonto  forms  of  hypophosphatasia  can  also  be  compound  heterozygotes  for  TNSALP  gene  mutations.  In  some  kindreds,  however,  mild  forms  of  hypophosphatasia  manifest  with  autosomal  dominant  inheritance.  The  TNSALP  gene  knock-out  mouse  is  an  excellent  model  for  infantile  hypophosphatasia,  but  prominently  features  lethal  seizures  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.242
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181475686
ER  -