Premature Aging: An Examination of HutchinsonGilford Progeria Syndrome

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Premature Aging An Examination of
Hutchinson-Gilford Progeria Syndrome

• By Sarah Lake HNU 461
• April 3, 2009

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Outline

• What is Hutchinson-Gilford Progeria Syndrome?
• Clinical manifestations
• The genetic defect
• Possible causes of the aging phenotype
• Treatment options
• Nutrition therapy
• Conclusions/Questions

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Hutchinson-Gilford Progeria

• A rare dominant autosomal genetic disorder
• Incidence 1 in every 4-8 million births
• 40 known cases worldwide
• Affects children within the first decade of life
• Premature aging and growth deceleration
• Uniformly fatal at the average age of 12
• Due to cardiovascular complications

(Gordon et al., 2007)
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Clinical Manifestations

• Growth retardation
• Short stature
• Lack of subcutaneous fat
• Prominent scalp veins
• Hardening of skin
• Premature arteriosclerosis
• Osteoporosis

• Body hair loss
• Bone deformations
• Cranial facial disproportions
• Delayed tooth formation

(Capell et al., 2005) (Kieran, Gordan,
Klienman, 2007)
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Clinical Manifestations Cont'd...
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Clinical Manifestations Cont'd...
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The Genetic Defect

• Single-based substitution mutation
• LMNA gene, chromosome 1 (Codon 608 exon 11)
• Gene which encodes for Lamina proteins
• Lamina Filamentous mesh layer between cell
  membranes

(McClintock et al., 2007) (Capell et al.,
2005).
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The Genetic Defect Contd

Healthy Individuals
Hutchinson-Gilford Progeria Syndrome
LMNA GENEEncodes for PRELAMIN A
(Farnesylated) Detaches from membrane(Due to
cleavage of Farnesyl group) MATURE LAMIN PROTEIN
LMNA GENEEncodes for PRELAMIN
A(Farnesylated) Does not detach from
membrane(Due to retention of the Farnesyl
group) NO MATURE LAMINA PROTEINNew mutant
protein Deemed PROGERIN
(Kieran, Gordon Kleinman, 2007)
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The Genetic Defect Contd
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Aging Phenotype

• Theorized, but unknown
• Changes in protein properties
• Altering interactions with other proteins
• Damage to DNA
• Also linked to cardiovascular complications
• Mechanism(s) responsible in HGPS similar to that
  found in aging of healthy individuals

(Glynn Glover, 2005) (Capell, Collins
Nabel, 2007) (Scaffidi Misteli, 2006)
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Treatment Options

• Farnesyltransferase inhibitors
• First developed as a cancer drug
• Tested on mice with induced Progeria
• Increased survival by 6-8 weeks
• Improved body weight and growth curves
• Not used extensively in those with Progeria
• More research is needed, timing of administration
  may be altered

• (Yang, Quio, Fong Young, 2008)

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Nutrition Therapy

• Nutrition intervention is minimal
• Malnutrition not to blame for stunted growth
• Shown to meet energy requirements and normal
  measured serum pre-albumin/albumin levels
• Some research supporting high calorie intakes,
  paired with growth hormone therapy
• Reduced effect over time, little impact on CVD
• Normal diet recommended, unless deranged lipid
  profile

(Merideth et al. 2008) (Abdenur, Brown,
Friedman, Smith Lifshitz, 1997) (Brown, Gordon
Collins, 2006).
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Nutrition Therapy Cont'd

• Nutrition supplementation (boost, ensure etc..)
  helps to achieve caloric and micronutrient
  requirements

(Harten, Hardy Gordon, 2002)
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Conclusions

• Rare and devastating diagnosis
• Little research on impact of nutrition
  interventions
• Nutrition focus should be on quality of life
• Treatments may be key to prolonging life
• More research on normal aging

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Questions ?
References available upon request