Makindo Medical Notes

Related Subjects: |Hyperuricaemia |Acute and Chronic Gout |Allopurinol |Rasburicase |Lesch-Nyhan syndrome |Autosomal Dominant |Autosomal Recessive |X Linked Recessive

Lesch-Nyhan Syndrome (LNS) is a rare inherited disorder of purine metabolism due to the deficiency of an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HPRT). This enzyme deficiency leads to the overproduction of uric acid, a waste product normally excreted in urine, causing a range of serious health problems, including severe neurological symptoms and self-injurious behaviours.

About

• Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT): A critical enzyme in purine metabolism.
• Inheritance: X-linked recessive, affecting nearly all males.
• Results in severe metabolic, neurological, and behavioral symptoms.

Aetiology

• HGPRT Deficiency: Leads to impaired conversion of:
  • Hypoxanthine to inosine monophosphate (IMP)
  • Guanine to guanosine monophosphate (GMP)
• This failure results in the overproduction and accumulation of uric acid.

Pathophysiology

• Purinergic Metabolism Disruption: The lack of HGPRT enzyme activity results in excessive purine turnover and uric acid production.
• Neurological Impact: The exact mechanism is unclear but thought to involve dysfunction in dopamine pathways in the basal ganglia, contributing to the severe motor dysfunction and self-injurious behavior seen in LNS.
• Accumulation of Uric Acid: Leads to gout, urate crystals, and renal complications such as kidney stones.

Clinical Features

• Neurological Symptoms: Severe psychomotor retardation, spasticity, dystonia, and involuntary movements.
• Behavioral Symptoms: Self-injurious behaviors, such as biting lips, fingers, and other body parts.
• Uric Acid Overproduction: Causes orange-colored crystals in the diapers of infants due to high uric acid excretion.
• Renal Complications: Gout, tophi formation, and urate nephropathy leading to kidney stones.
• Other Symptoms: Intellectual disability, seizures, and sensorineural hearing loss.

Complications

• Gout and Tophi: Due to persistently high uric acid levels, leading to painful joint inflammation.
• Kidney Stones: Caused by uric acid crystallization in the urinary tract, leading to pain and potential kidney damage.
• Progressive Neurological Decline: Increasing severity of movement disorders and muscle stiffness over time.
• Reduced Life Expectancy: Due to complications such as renal failure and infections; many patients rarely live beyond 40 years.

Investigations

• Blood and Urine Tests: Elevated uric acid levels confirm overproduction.
• Enzyme Assay: Measures the activity of the HPRT enzyme in blood or tissue samples, confirming enzyme deficiency.
• Genetic Testing: Identifies mutations in the HPRT1 gene, confirming diagnosis and allowing carrier testing for female relatives.
• Imaging: Ultrasound or CT scans to identify kidney stones and assess renal damage.

Management

• Hydration and Nutrition: Ensure adequate fluid intake to prevent kidney stones and maintain proper nutrition.
• Allopurinol: Reduces uric acid production to prevent gout and kidney stone formation. Similar medications like febuxostat may also be considered.
• Muscle Relaxants: Baclofen or benzodiazepines to manage spasticity and muscle rigidity.
• Behavioral Management: Use of protective devices like mouth guards or arm restraints to prevent self-injury when necessary.
• Pain Management: For joint pain due to gout or discomfort from muscle spasms.
• Supportive Therapies: Physical and occupational therapy to maintain mobility and improve quality of life.
• Monitoring: Regular follow-up to monitor uric acid levels, kidney function, and neurological progression.
• Genetic Counseling: Important for families to understand inheritance patterns and the risk of recurrence in future pregnancies.

Prognosis

• Most patients have a significantly reduced life expectancy due to complications from kidney damage, infections, and progressive neurological decline.
• Early diagnosis and aggressive management of symptoms can improve quality of life but cannot fully prevent the progression of neurological symptoms.

References

• Lesch-Nyhan Syndrome Overview - NCBI
• Lesch-Nyhan Syndrome - NORD