Lesch-Nyhan syndrome

From Iusmgenetics

Contents 1 Lesch-Nyhan syndrome 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.4.1 Facts of HPRT Defect 1.4.2 Consequence of Uric Acid Overproduction 1.5 Pathogenesis 1.5.1 LNS Variants 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Lesch-Nyhan syndrome

General background information

• Disorder of purine metabolism
• Deficiency of the activity of the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT).
• Approximately 1 in 380,000 individuals
• Occurs with a similar frequency in all populations
• Nearly all cases are in males. Only rarely has it been reported in females

Mode of inheritance

• X-linked recessive

Single important gene

• HPRT: hypoxanthine-guanine phosphoribosyltransferase
  • An important enzyme in the purine salvage pathway

Etiology

• HPRT normally serves to convert hypoxanthine and guanine to IMP and GMP, respectively.
• Xanthine oxidase (XO) converts hypoxanthine and guanine to xanthine and then to uric acid.
  • It is this pathway that handles the hypoxanthine and guanine that can't be converted to IMP and GMP.

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Facts of HPRT Defect

• HPRT expressed in all cells of the body and brain.
• Emerging evidence suggests that LNS result from dyfunction of the striatum.
• Neurochemical surveys demonstrated a 60-80% loss of dopamine in all striatal subregions.
• Loss of striatal dopamine fibers in affected individuals in vivo.

Consequence of Uric Acid Overproduction

• Leads to the development of uric acid crystals or stones in the kidneys, ureters, or bladder.
  • May be secreted from urine as a grainy orange substance or as hard-to-pass stones (per wikipedia).
• Crystals deposited in joints later in the disease may produce gout-like arthritis.
• Possible cause of neurotoxicity?
  • But no sufficient research has been done to support this hypothesis.
• Uric acid crystals in urine.
• Soft tissue swelling in the olecranon bursa (white arrow) erosions (blue arrows).

Pathogenesis

• Present normal at birth and first few months

LNS Variants

• Because there is phenotypic variation, we have other names for instances of LNS that do not present with all the classic phenotypes.
• Patients who also have neurological problems, but no behavioral symptoms and self-injury, have 'HPRT-related hyperuricemia with neurological dysfunction' (HRND).
• The condition with only problems due to too much uric acid is called 'HPRT-related hyperuricemia' (HRH).
• Classic Lesch-Nyhan Disease (LND)

Phenotypic information

• Red-orange "sand" in diapers
• Hyperuricemia (elevated uric acid in the blood)
• Very irritable
• Poor head support, hypotonicity
  • Tone increases above normal later
• Impaired motor and physical development
• Self-mutilation: biting lips / fingers / arms / tongue, limb extension at doorway, head snapping, head banging, feet under wheelchair, fingers in wheelchair, eye poking

• Neurologic dysfunction
  • hypotonia and delayed motor skills
  • severe action dystonia
  • spasticity
• Cognitive and behavioral disturbances
  • cognitively impaired
  • self-injurious behavior
• Overproduction of uric acid; caused by purine metabolism problems.
• Gouty arthritis
• Growth and puberty are delayed

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• Classic Lesch-Nyhan disease has very low HPRT activity
• Neurologic variant has higher HPRT activity.
  • Includes self-injurious behavior with stressors like pain, kidney stones, or hospitalization.
  • Environmental or other factors likely influence the phenotype.
• Hyperuricemic variant has the highest HPRT activity

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Diagnosis

• Looks much like cerebral palsy until the child develops hyperuricemia or self mutilation.

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  • Note: to see this and some other images on this page, one must have access to the journal Nature. For IUPUI students, simply signing into the VPN and refreshing the page should be sufficient.
• http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=1811
• The neurologic picture closely resembles athetoidcerebral palsy.
• Most affected children are initially diagnosed as having cerebral palsy.

• Manifest the characteristic neurologic, cognitive, and behavioral disturbances.
• A urinary urate-to-creatinine ratio greater than 2.0.
  • Often uric acid crystals are observed in the diaper.
• Serum uric acid concentration > 8 mg/dL.
• (HPRT) enzyme activity less than 1.5% of normal in cells from any tissue (diagnostic).
• Sequence analysis of HPRT1.

• HPRT enzyme activity.
  • HPRT enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) establishes the diagnosis of Lesch-Nyhan syndrome. The assay that is simplest and most readily available is performed on erythrocytes in anticoagulant or on dried blood spots on filter paper.

• Sequence analysis and mutation scanning.
  • Using these two methods, mutations in the HPRT1 gene are detected in the majority of males who display the full Lesch-Nyhan syndrome phenotype.
• Deletion / duplication analysis.
  • 21-24% of mutations in HPRT1 are large deletions that cannot be detected in females by sequence analysis; other test methods to detect exonic or whole gene deletions are required.

Treatment

• Allopurinol inhibits XO (xanthine oxidase) and is used to treat hyperuricemia.
  • Allopurinol keeps XO from converting hypoxanthine and guanine to uric acid.

• Uric acid overproduction
  • Allopurinol
  • Hydration (this can help with hydrolysis of uric acid)
• Motor disability
  • Assistive devices (to keep patients from hurting themselves)
  • Benzodiazepines
  • Baclofen
• Aberrant behaviors
  • Assistive devices
  • Behavior modification
  • Pharmacotherapy

Recent research

5 important facts

1. LNS is single gene disorder
2. LNS is caused by mutation of HPRT gene
3. LNS demonstrated deficiency of the activity of HPRT
4. HPRT enzyme activity and sequencing are diagnostic
5. HPRT deficiency influences the developmental programs that regulate their neurochemicalphenotype

Not to be confused with

Questions and answers

1. Are the over production of urine uric acid and serum uric acid are diagnostic to LNS?
2. What is the most accurate dianostic test for LNS?