Rickets and Vitamin D Deficiency

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Rickets and Vitamin D Deficiency

• Sterling Udom
• and
• Carolyn Wise

2
Learning Objectives

• 1. Differentiate between the two types of Rickets
• 2. Know the reaction for P450 monooxygenase.
• 3. Discuss the mechanism by which vitamin D is
  synthesized.
• 4. Identify key enzyme in the absorption of
  vitamin D.

3
Vitamin D

• Like Vitamins A, E, and K, it is fat soluble
• Produced through sun exposure or diet
• Regulates calcium and phosphate absorption and
  affects the immune system.
• http//en.wikipedia.org/wiki/Vitamin_D

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Forms of Vitamin Dhttp//en.wikipedia.org/wiki/V
itamin_D
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Vitamin D Biochemistry Review

• Vitamin D can be obtained from 7-dihydrocholestero
  l, the last intermediate in cholesterol
  biosynthesis from lanosterol
• The key reaction converting vitamin D3 to its
  most potent form, 1,25(OH)2 (calcitriol), is
  performed in the kidney by P450 1-OHase

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Synthesis/Activation of Vitamin D3
7
UV activation of Previtamin D3
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P450 1-hydroxylase Enzyme
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P450 enzymes

• Superfamily of hemoproteins found in all domains
  of life.
• HGP identified 57 humans genes that code P450
  enzymes.
• Monooxygenase reaction is the most common among
  these enzymes
• RH O2 2H 2e- ? ROH H2O
• Reactions are performed in mitochondria
• and endoplasmic reticulum of humans.
• 1-hydroxylase is activated by
• PTH.

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Vitamin D Dependent Rickets

• Results from a defect in P450 1-hydroxylase
  enzyme leading to the synthesis of 1,25(OH)2D.
• Can be treated with vitamin D therapy.

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Vitamin D Resistant Rickets

• Genetic resistance to vitamin D.
• In 1978, M.H. Brooks and colleagues described a
  patient with osteomalacia hypophosphatemia, and
  secondary hyperparathyroidism.
• The patient had elevtated serum levels of
  1,25(OH)2D.
• Resistance to Vitamin D in Type II rickets is
  hereditary and has been designated hereditary
  hypocalcemic vitamin D-resistant rickets (HVDRR).

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Clinical Features of Rickets

• Defective intestinal calcium absorption leads to
  impaired mineralization of newly forming bone and
  cartilage.
• Patients suffer from bone pain, alopecia totalis,
  hypotonia, and occasionally convulsions from
  hypocalcemia.
• Hypocalcemia also leads to secondary
  hyperparathyroidism elevating PTH levels.

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Clinical Features of Resistant Rickets

• 25(OH)D levels are normal
• 1,25(OH)2D levels are elevated.
• Patients are resistant to supraphysiological
  doses of all forms of vitamin D therapy.

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Genetics of Resistant Rickets

• Type II rickets follows an autosomal recessive
  pattern of inheritance.
• parents who are heterozygous for the genetic
  trait show a normal phenotype.
• In many, if not all cases, parental relatedness
  is associated with the disease.
• Males and females are affected equally and often
  a family has several affected children.

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Normal Action

• Lipophilic Calcitriol binds to VDR.
  Conformational change opens surfaces on the
  molecule.
• Upon activation by vitamin D, VDR forms a
  heterodimer with with the retenoid-X receptor.

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Vitamin D Receptor

• Is a member of the nuclear receptor family of
• transcription factors.
• nuclear receptor proteins responsible for
• sensing the presence of steroid and thyroid
• hormone, and other molecules.
• transcription factor protein that binds to DNA
• sequence and activates or represses the
• recruitment of RNA polymerase.
• VDR contains a cysteine rich N-terminal
• DNA binding domain and a C-terminal hormone
• Binding domain.

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Normal Action

• 3. DNA binding occurs via two zinc finger modules
  of the DNA binding domain
• 4. Once bound to DNA, coactivators are recruited
• 5. Resulting VDR-RXR-coactivator complex
  interacts with transcription apparatus. Gene
  transcription and translation begins.

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Coactivator Recruitment
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VDR mutation

• 2 classes
• Normal calcitriol binding to VDR
• Receptor positive or Ligand Binding Positive
• Defect in DBD of VDR
• Decreased or absent calcitriol binding to VDR
• Receptor negative or Ligand Binding Negative
• Defect in LBD of VDR

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Calcium

• Signal Transduction Pathways
• Acts as second messenger
• Neurotransmitter Release from Neurons
• Cofactor for many enzymes
• Parathyroid hormone regulates reabsorption of
  calcium

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What is Rickets?

• Edward Mellenby discovered Vitamin D and its role
  in rickets in 1919.
• Affects children
• Caused by bodys inability to absorb calcium and
  phosphate.
• http//www.cdriindia.org/Site/images/musium/d1.jpg
  

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Osteomalacia

• Milder, Adult form of rickets
• Caused by defective bone mineralization
• Most symptoms overlap with osteoporosis

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https//cornellbiochem.wikispaces.com/Rickets
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Types of Rickets

• Vitamin D Dependent
• Vitamin D Resistant
• Both genetic defects
• Caused by problems processing Vitamin D
• Often results in kidney disorder

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Vitamin D Dependent (Type I)

• Caused by a defect of 1(OHase)
• Most commonly seen in breastfed babies
• Treated by adding 1,25(OH)2 D3 (which is the
  active hormone form).

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Vitamin D Resistant (Type II)

• X-linked forms of rickets
• Caused by vitamin D receptor mutations
• Supplementing Vitamin D is ineffective
• Defect in renal tubular resorption of phosphate

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http//edrv.endojournals.org/cgi/content/abstract/
20/2/15
28
Ricketshttp//www.thachers.org/images/RicketsXR1.
GIFhttp//img262.imageshack.us/img262/8168/ricket
swo9.jpghttp//dwb.unl.edu/teacher/nsf/c10/c10lin
ks/georgia.ncl.ac.uk/VitaminD/vitaminD.html
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Diagnosishttps//cornellbiochem.wikispaces.com/Ri
ckets

• Blood Test
• Bone Biopsy
• X-Ray
• Alopecia

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Treatmenthttp//images.google.com/images?hlencl
ientsafarirlsenum1sa1qxrayofnormalknee
btnGSearchImagesaqfoqhttp//depts.washingto
n.edu/bonebio/ASBMRed/diseases/rickets/knee.jpg

• Type I can be treated by Vitamin D (from sunlight
  or diet)
• Bone deformities will correct themselves
• Type II is not treatable

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Sources of Vitamin Dhttp//www.health-fitness.com
.au/images/vitamin-d-food-sources.jpg
32
http//www.ehponline.org/members/2007/9937/fig1.jp
g

• 40 of the US Population is vitamin-D deficient
• 42 of African American Women (childbearing age)
  are vitamin-D deficient
• 48 of girls (9-11 years old) are vitamin-D
  deficient.
• Up to 60 of all hospital patients are vitamin-D
  deficient.
• 76 of pregnant mothers are severely vitamin-D
  deficient, causing widespread vitamin-D
  deficiencies in their unborn children.
• Up to 80 of nursing home patients are vitamin-D
  deficient

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Case Studyhttp//gait.aidi.udel.edu/educate/ricke
t.htm

• Child diagnosed at 2 1/2
• Started walking at 27 months
• With treatment her legs unbowed by age 4.

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Sources

• "Biochemistry and Physiology of Vitamin D." About
  Vitamin D. 19 June 1999. University of
  California, Riverside. 19 Apr. 2009
  lthttp//vitamind.ucr.edu/biochem.htmlgt.
• "Classifications and Types of Rickets
  Nutritional Versus Genetic - Associated Content."
  Associated Content - associatedcontent.com. 09
  Sept. 2007. 19 Apr. 2009 lthttp//www.associatedcon
  tent.com/article/409798/classifications_and_types_
  of_rickets.html?cat25gt.
• "Causes of rickets." Bone, joint, and muscle
  disorders - arthritis, osteoporosis, gout,
  muscular dystrophy. 18 July 2005. 19 Apr. 2009
  lthttp//bone-muscle.health-cares.net/rickets-cause
  s.phpgt.
• "Cytochrome P450 Homepage." Cytochrome P450
  Homepage Default. 01 Sept. 1999. University of
  Tennessee. 19 Apr. 2009 lthttp//drnelson.utmem.edu
  /CytochromeP450.htmlgt.
• The Endocrine Society 20 (1999) 156-88.
  Endocrine Reviews. Apr. 1999. Endocrine Society.
  19 Apr. 2009 lthttp//edrv.endojournals.org/cgi/rep
  rint/20/2/156gt.
• International Union of Pure and Applied
  Chemistry. "cytochrome P450". Compendium of
  Chemical Terminology Internet edition. Danielson
  P (2002). "The cytochrome P450 superfamily
  biochemistry, evolution and drug metabolism in
  humans". Curr Drug Metab 3 (6) 56197.
  doi10.2174/1389200023337054. PMID 12369887.
• "Vitamin D (Cholecalciferol, Calcitriol)."
  Arbl.cvmbs.colostate.edu. 16 Oct. 2007. Colorado
  State University. 19 Apr. 2009 lthttp//www.vivo.co
  lostate.edu/hbooks/pathphys/endocrine/otherendo/vi
  tamind.htmlgt.
• "Vitamin D Processing and Familial Rickets." D.
  W. Brooks Site. 15 Aug. 2000. University of
  Newcastle. 19 Apr. 2009 lthttp//dwb.unl.edu/teache
  r/nsf/c10/c10links/georgia.ncl.ac.uk/VitaminD/vita
  minD.htmlgt.

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QuizGood Luck!

• What are the two types of rickets?
• Write the general reaction for P450 monooxygenase
  enzyme.