LeschNyhan Syndrome

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Lesch-Nyhan Syndrome

• Daniela Cosentino
• Mei Shi

2
Introduction

• Rare X-chromosome-linked disorder 1/400,000 live
  births
• First characterized by Michael Lesch William
  Nyhan in 1964
• Cause mutation in HPRT gene on X-chromosome
  HPRT deficiency
• HPRT recycles purines deficiency purine ?
  uric acid build-up

http//embryology.med.unsw.edu.au/Defect/ images/l
esch-nyhan_syndrome.jpg
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Signs Symptoms

• Hyperuricemia
• Urate crystal formation
• Kidney stones
• Impaired kidney function ? renal failure
• Gout-like arthritis
• Tophi
• Neurological disabilities
• Grimacing expression
• Spasticity
• Choreathetosis (involuntary/repetitive movement)
• Decreased muscle tone

http//www.moondragon.org/images2/gout.jpg
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Signs Symptoms

• Behavioural Abnormalities
• Impaired cognitive function
• Self-mutilation
• Aggression/Impulsion

http//www.emedicine.com/neuro/images/Large/681Mis
singFingers.gif
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Biochemistry of LNS

• Purines can be synthesized
• in 2 ways
• De novo from scratch
• Salvage pathway recycle
• Hypoxanthine-guanine phosphoribosyltransferase
  (HPRT) is responsible for catalyzing the
  formation of GMP and AMP (purine nucleotides)
• The nucleotides that are formed act in a negative
  feedback loop inhibiting the de novo process

http//www.emedicine.com/neuro/images/683PATHWAYS.
GIF
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Biochemistry of LNS

• In a patient with LNS, functional HPRT are absent
• Impaired salvage pathway means that all purine
  synthesis must occur via de novo pathway
• De novo synthesis becomes uncontrolled and purine
  production goes into overdrive

http//web.virginia.edu/Heidi/chapter27/chp27.htm
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Biochemistry of LNS

• When the excess purine nucleotides are
  catabolized, very high levels of uric acid
  accumulate in the blood (hyperuricemia)
• This catabolic pathway involves the activity of
  xanthine oxidase
• At high concentrations, above the limit of
  solubility, urate crystals form

http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridstry
er.figgrp.3527
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Treatment

• Symptomatic
• Three categories
• Hyperuricemia
• Neurological
• Behaviourial

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Treatment

• Hyperuricemia
• Allopurinol
• Xanthine oxidase inhibiter
• 1. Structural analogue of hypoxanthine and
  xanthine
• 2. Higher affinity for xanthane oxidase

http//www.nature.com/leu/journal/v17/n12/fig_tab/
2403156f11.html
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Treatment

• Neurological
• No standard treatment
• Anticonvulsants, sedatives, skeletal muscle
  relaxants
• carbidopa/levodopa, diazepam, phenobarbital,
  haloperidol
• Spasticity can be treated via baclofen
  benzodiazepines
• Behavioural abnormalities
• Restraints
• Teeth extraction
• Behavioural modification
• therapy
• behaviours wane when
• patient reaches 10-12 years of age

http//www.lndinfo.org/LNDPatients/Equipment/sleep
ing.JPG
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Application to Pharmacy Practice

• Pharmacists role
• Be sympathetic
• Monitor for early signs of self-injury
• Educate the caregiver
• Promote continuity of care

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Summary

• What is LNS?
• X-linked disorder resulting in absence of
  functional enzyme HPRT
• Signs Symptoms
• Hyperuricemia which can lead to gout, kidney
  stones, tophi
• Neurological disabilities such as spasticity,
  hyperreflexia
• Behavioural abnormalities including impaired
  cognitive abilities, self-mutilation, aggression
• Biochemistry
• Purines are synthesized via two pathways de novo
  salvage
• HPRT, which is absent in LNS patients, is the key
  enzyme in salvaging and recycling old purines
  from DNA and RNA degradation
• Nucleotides made by the salvage pathway provide
  feedback inhibition to the de novo pathway to
  conserve energy
• Without HPRT, the salvage pathways is impaired
  and de novo synthesis goes into overdrive due to
  lack of negative inhibition
• Excess amounts of purines are broken down into
  uric acid, by means of the enzyme xanthine
  oxidase, leading to hyperuricemia
• Treatment (symptomatic, not curative)
• To treat hyperuricemia, allopurinol (xanthine
  oxidase inhibitor) is given to inhibit the
  production of uric acid
• Neurological symptoms may be reduced with
  sedatives, muscle relaxants, anticonvulsants
• Behavioural abnormalities may be controlled by
  means of teeth extraction, physical restraints
• Application to Pharmacy Practice
• Pharmacists must be sympathetic, monitor for
  self-injury, educate the caregiver, promote
  continuity of care

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References

• Anderson, L. (2008). Understanding the Nature of
  Behaviour. In Lesch-Nyhan Disease Registry.
  Retrieved January 26, 2008 from
  http//www.lndinfo.org/Basics/behaviour.html
• Angstadt, C. (1997, December 4). Salvage of
  Bases. In Purine and Pyrimidine Metabolism.
  Retrieved January 18, 2008, from
  http//library.med.utah.edu/NetBiochem/pupyr/pp.ht
  mPu20Catab
• Berg, J., et al. (2006). Biochemistry, 6th
  Edition. New York W.H. Freeman Co.
• Canadian Pharmacists Association. (2008).
  Compendium of Pharmaceuticals and Specialties,
  online version (e-CPS). Retrieved January 24,
  2008, from
  https//www-e-therapeutics-c
  a.myaccess.library.utoronto.ca/
• Jinnah, H. (2007). Lesch-Nyhan Syndrome.
  Retrieved January 21, 2008 from
  http//www.emedicine.com/NEURO/topic630.htm
• Lyons, R. (2006, December 15). Purine
  Nucleotides Biosynthesis, Degradation and
  Salvage. In Nucleotide Metabolism. Retrieved
  January 18, 2008, from http//seqcore.brcf.med.umi
  ch.edu/mcb500/nucsyl/nucmetab.html
• National Institute of Neurological Disorders and
  Stroke. (2007). NINDS Lesch-Nyhan Syndrome
  Information Page. Retrieved January 21, 2008 from
  http//www.ninds.nih.gov/disorders/lesch_nyhan/les
  ch_nyhan.htm
• Nyhan, W., et al. (2007, November 27).
  Lesch-Nyhan Syndrome. Retrieved January 26, 2008
  from http//www.genetests.org/query?dzlns