Lesch-Nyhan Syndrome

Overview

Plain-Language Overview

Lesch-Nyhan syndrome is a rare genetic disorder that mainly affects boys. It causes problems with the body's ability to break down purines, which are substances found in many foods and cells. This leads to a buildup of uric acid in the blood, causing painful gout and kidney problems. Children with this condition often have delayed development and show unusual movements like muscle stiffness and jerking. A key feature is self-injurious behavior, such as biting their lips or fingers, which can be very distressing.

Clinical Definition

Lesch-Nyhan syndrome is an X-linked recessive metabolic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This enzyme deficiency impairs the purine salvage pathway, leading to excessive production and accumulation of uric acid. Clinically, it presents in infancy or early childhood with hyperuricemia, leading to gouty arthritis, nephrolithiasis, and renal failure. Neurologically, patients exhibit dystonia, choreoathetosis, and spasticity. A hallmark of the syndrome is self-mutilating behavior, including lip and finger biting. Intellectual disability and developmental delay are common. Diagnosis is confirmed by measuring HGPRT enzyme activity or identifying mutations in the HPRT1 gene. Management is supportive, focusing on controlling uric acid levels and addressing neurological symptoms. The syndrome is fatal if untreated, with most patients surviving into adolescence or early adulthood.

Inciting Event

There is no specific inciting event; the condition is caused by a genetic mutation present from birth.

Latency Period

none

Diagnostic Delay

Delayed diagnosis may occur due to the rarity of the disease and initial attribution of symptoms to more common neurological disorders.

Clinical Presentation

Signs & Symptoms

Self-mutilation including biting of lips and fingers.
Severe intellectual disability and developmental delay.
Hyperuricemia leading to gout and nephrolithiasis.
Spasticity, dystonia, and choreoathetosis.
Delayed motor development and hypotonia.

History of Present Illness

Infants present with developmental delay, hypotonia, and dystonia.
Self-mutilating behaviors such as lip and finger biting typically develop by 2 to 3 years of age.
Symptoms of gout and kidney stones may appear due to hyperuricemia.

Past Medical History

No specific past medical history is typical before symptom onset as the disorder is congenital.

Family History

Often a history of affected male relatives with similar neurological and behavioral symptoms.
Carrier females may be asymptomatic but can pass the mutation to offspring.

Physical Exam Findings

Presence of self-mutilating behaviors such as lip and finger biting.
Generalized hypotonia and delayed motor milestones.
Dystonia and choreoathetosis observed during movement.
Signs of gouty tophi may be present in older patients.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Lesch-Nyhan syndrome requires demonstration of markedly reduced or absent HGPRT enzyme activity in erythrocytes or fibroblasts, combined with clinical features including hyperuricemia, characteristic neurological symptoms such as dystonia and choreoathetosis, and self-injurious behavior. Genetic testing confirming mutations in the HPRT1 gene supports the diagnosis. Elevated serum and urine uric acid levels and typical radiographic findings of gouty arthritis may assist but are not definitive alone.

Pathophysiology

Key Mechanisms

Lesch-Nyhan syndrome results from a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), leading to impaired purine salvage.
The enzyme deficiency causes an accumulation of uric acid, resulting in hyperuricemia and related complications.
Neurological symptoms arise due to dysfunction in the basal ganglia, affecting motor control and behavior.

Involvement	Details
Organs	Kidneys are affected by uric acid nephropathy and stone formation.
Organs	Brain involvement causes neurological symptoms including dystonia, choreoathetosis, and cognitive impairment.
Tissues	Brain tissue, especially the basal ganglia, is affected leading to movement disorders and behavioral abnormalities.
Tissues	Renal tissue is involved due to uric acid crystal deposition causing nephropathy.
Cells	Erythrocytes are used in diagnostic assays to measure hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme activity.
Cells	Neurons are affected by HGPRT deficiency leading to neurological symptoms such as dystonia and self-injurious behavior.
Chemical Mediators	Uric acid accumulates due to HGPRT deficiency causing gout and kidney stones.
Chemical Mediators	Dopamine levels are decreased in the basal ganglia contributing to neurological and behavioral symptoms.

Treatment

Pharmacological Treatments

Allopurinol
- Mechanism: Inhibits xanthine oxidase to reduce uric acid production
- Side effects: rash, gastrointestinal upset, hypersensitivity reactions
Benzodiazepines
- Mechanism: Enhance GABAergic neurotransmission to reduce self-injurious behavior
- Side effects: sedation, dependence, respiratory depression
Neuroleptics
- Mechanism: Dopamine receptor antagonism to manage behavioral symptoms
- Side effects: extrapyramidal symptoms, sedation, metabolic syndrome

Non-pharmacological Treatments

Physical restraints can be used to prevent self-mutilation in affected patients.
Behavioral therapy aims to reduce self-injurious behaviors through structured interventions.
Dental extraction may be performed to prevent oral self-harm.

Prevention

Pharmacological Prevention

Allopurinol to reduce uric acid production and prevent gout.
Febuxostat as an alternative xanthine oxidase inhibitor.
Benzodiazepines or other agents to manage dystonia and spasticity.

Non-pharmacological Prevention

Use of protective devices to prevent self-injury.
Behavioral therapy to reduce self-mutilating behaviors.
Regular monitoring of renal function and uric acid levels.
Physical therapy to improve motor function and reduce spasticity.

Outcome & Complications

Complications

Severe infections from self-inflicted wounds.
Renal failure due to chronic urate nephropathy.
Severe disability from neurological impairment.

Short-term Sequelae	Long-term Sequelae
Wound infections from self-mutilation. Acute gout attacks causing joint pain and inflammation.	Chronic kidney disease from urate nephropathy. Permanent neurological disability including dystonia and cognitive impairment. Joint destruction from recurrent gouty arthritis.

Differential Diagnoses

Lesch-Nyhan Syndrome versus Klinefelter Syndrome

Lesch-Nyhan Syndrome	Klinefelter Syndrome
Marked hyperuricemia due to hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency.	Presence of gynecomastia and small, firm testes with elevated gonadotropins.
Characteristic self-mutilating behavior and dystonia starting in infancy.	Normal uric acid levels without evidence of self-mutilation or neurological symptoms.
Normal male karyotype 46,XY without chromosomal abnormalities.	Karyotype showing 47,XXY chromosomal pattern.

Lesch-Nyhan Syndrome versus Rett Syndrome

Lesch-Nyhan Syndrome	Rett Syndrome
X-linked recessive disorder affecting males with HGPRT deficiency.	Primarily affects females with normal early development followed by loss of purposeful hand skills and stereotypic hand-wringing.
Marked hyperuricemia and compulsive self-injurious behavior.	No significant hyperuricemia or self-mutilation behaviors.
No loss of purposeful hand skills or stereotypic hand movements.	Mutation in MECP2 gene with characteristic EEG abnormalities.

Lesch-Nyhan Syndrome versus Wilson Disease

Lesch-Nyhan Syndrome	Wilson Disease
Elevated uric acid levels due to defective purine salvage pathway.	Presence of Kayser-Fleischer rings and low serum ceruloplasmin.
Severe self-mutilation and choreoathetosis beginning in infancy.	Hepatic dysfunction with elevated liver enzymes and possible cirrhosis.
Normal serum ceruloplasmin and absence of Kayser-Fleischer rings.	Neurological symptoms include tremor, dysarthria, and psychiatric disturbances without self-injury.