Lesch-Nyhan disease in Pediatric Age

Introduction to Lesch-Nyhan Disease

Lesch-Nyhan disease (LND) is a rare X-linked recessive disorder of purine metabolism, characterized by overproduction of uric acid, neurological dysfunction, and behavioral abnormalities including self-mutilation.

Epidemiology

Incidence: Approximately 1 in 380,000 live births
Predominantly affects males due to X-linked inheritance
Female carriers are usually asymptomatic

Genetics

Caused by mutations in the HPRT1 gene on the X chromosome
HPRT1 encodes hypoxanthine-guanine phosphoribosyltransferase (HPRT)
Over 300 different mutations have been identified

Historical Context

First described in 1964 by medical student Michael Lesch and his mentor, Dr. William Nyhan, at Johns Hopkins Hospital.

Pathophysiology of Lesch-Nyhan Disease

1. HPRT Deficiency

HPRT is crucial for purine salvage pathway
Deficiency leads to accumulation of hypoxanthine and guanine
Results in increased de novo purine synthesis

2. Uric Acid Overproduction

Excess purines are converted to uric acid
Leads to hyperuricemia and uric acid crystal formation
Results in gout-like symptoms and nephropathy

3. Neurological Dysfunction

Exact mechanism not fully understood
Hypotheses include:
- Altered neurotransmitter function (particularly dopamine)
- Impaired neuronal development
- Oxidative stress in the brain

4. Biochemical Alterations

Decreased levels of guanine-based purines (GTP, GDP, GMP)
Alterations in neurotransmitter systems:
- Reduced dopamine levels in the basal ganglia
- Changes in serotonin metabolism

5. Genotype-Phenotype Correlation

Severity of symptoms correlates with degree of enzyme deficiency
Complete HPRT deficiency leads to classic LND
Partial deficiency results in milder phenotypes (Kelley-Seegmiller syndrome)

Clinical Manifestations of Lesch-Nyhan Disease

1. Neurological Symptoms

Developmental delay and intellectual disability
Dystonia (often mistaken for cerebral palsy initially)
Chorea and athetosis
Spasticity
Hyperreflexia
Dysarthria

2. Behavioral Abnormalities

Self-mutilation (hallmark feature)
- Lip and finger biting
- Head banging
- Often requires physical restraints or dental extractions
Aggression towards others
Impulsivity and attention deficits

3. Uric Acid-Related Symptoms

Gout-like arthropathy
Nephrolithiasis
Tophi (urate crystal deposits in soft tissues)
Nephropathy

4. Other Manifestations

Growth retardation
Testicular atrophy
Anemia (may be megaloblastic)

5. Timeline of Symptom Onset

Birth to 3 months: Often asymptomatic
3-6 months: Developmental delay becomes apparent
6-12 months: Extrapyramidal symptoms emerge
2-3 years: Self-mutilating behaviors typically begin

6. Variant Forms

Kelley-Seegmiller syndrome (partial HPRT deficiency)
- Hyperuricemia and gout
- Milder or absent neurological symptoms
HPRT-related hyperuricemia
- Hyperuricemia only
- No neurological or behavioral symptoms

Diagnosis of Lesch-Nyhan Disease

1. Clinical Diagnosis

Based on characteristic clinical features:
- Neurological dysfunction
- Self-mutilating behavior
- Hyperuricemia
Family history consistent with X-linked inheritance

2. Biochemical Testing

Serum uric acid levels (typically >10 mg/dL)
Urine uric acid-to-creatinine ratio
HPRT enzyme activity in erythrocytes or fibroblasts
- <1.5% of normal in classic LND
- 1.5-20% in variant forms

3. Genetic Testing

Sequencing of HPRT1 gene
Deletion/duplication analysis if sequencing is negative

4. Prenatal Diagnosis

Amniotic fluid or chorionic villus sampling for:
- HPRT enzyme activity
- HPRT1 gene analysis

5. Neuroimaging

MRI: May show basal ganglia abnormalities
PET: Reduced dopamine transporters in basal ganglia

6. Differential Diagnosis

Cerebral palsy
Familial hyperuricemia
Other causes of intellectual disability with self-injurious behavior
Juvenile gout

Management of Lesch-Nyhan Disease

1. Uric Acid Management

Allopurinol: Xanthine oxidase inhibitor
- Reduces uric acid production
- Typically 300-600 mg/day in divided doses
Hydration and alkalinization of urine
Dietary purine restriction

2. Neurological Symptom Management

Physical therapy for motor dysfunction
Medications for dystonia and spasticity:
- Baclofen
- Benzodiazepines
- Botulinum toxin injections
Deep brain stimulation in select cases

3. Behavioral Management

Physical restraints (as a last resort)
Protective devices (e.g., elbow splints, mouthguards)
Dental interventions (e.g., extractions, lip guards)
Behavioral therapy
Medications for aggression and impulsivity:
- Gabapentin
- Carbamazepine
- Selective serotonin reuptake inhibitors (SSRIs)

4. Supportive Care

Nutritional support
Occupational therapy
Speech therapy
Special education services

5. Management of Complications

Nephrological care for renal complications
Orthopedic management for joint problems
Treatment of anemia if present

6. Experimental Therapies

Gene therapy (in research phase)
Enzyme replacement therapy (under investigation)
S-adenosylmethionine (SAMe) supplementation

7. Family Support

Genetic counseling
Psychosocial support for caregivers
Connection with patient support groups

Lesch-Nyhan Disease in Pediatric Age

What is Lesch-Nyhan disease?
Lesch-Nyhan disease is a rare genetic disorder characterized by overproduction of uric acid, neurological problems, and behavioral issues.
What causes Lesch-Nyhan disease?
Lesch-Nyhan disease is caused by mutations in the HPRT1 gene, which leads to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
What is the inheritance pattern of Lesch-Nyhan disease?
Lesch-Nyhan disease is inherited in an X-linked recessive manner.
Why is Lesch-Nyhan disease more common in males?
As an X-linked disorder, Lesch-Nyhan disease primarily affects males because they have only one X chromosome.
What is the role of the HGPRT enzyme in the body?
HGPRT is involved in the recycling of purines, which are building blocks of DNA and RNA.
How does HGPRT deficiency lead to uric acid overproduction?
HGPRT deficiency results in excessive breakdown of purines, leading to overproduction of uric acid.
What are the early signs of Lesch-Nyhan disease in infants?
Early signs include delayed motor development, hypotonia (low muscle tone), and orange crystals in the diaper.
At what age do symptoms of Lesch-Nyhan disease typically appear?
Symptoms typically appear in infancy or early childhood, usually within the first few months of life.
What neurological symptoms are associated with Lesch-Nyhan disease?
Neurological symptoms include dystonia, choreoathetosis, spasticity, and intellectual disability.
What is the most distinctive behavioral feature of Lesch-Nyhan disease?
The most distinctive behavioral feature is self-mutilating behavior, particularly biting of the lips and fingers.
How does Lesch-Nyhan disease affect cognitive development?
Lesch-Nyhan disease typically causes severe intellectual disability, though cognitive abilities can vary among affected individuals.
What renal complications can occur in Lesch-Nyhan disease?
Renal complications include kidney stones, renal colic, and potentially kidney failure due to uric acid accumulation.
How does Lesch-Nyhan disease affect the musculoskeletal system?
It can cause joint problems, including gouty arthritis, due to uric acid crystal deposition.
What is the prevalence of Lesch-Nyhan disease?
Lesch-Nyhan disease is rare, affecting approximately 1 in 380,000 live births.
How is Lesch-Nyhan disease diagnosed?
Diagnosis is based on clinical symptoms, elevated uric acid levels, and genetic testing for HPRT1 mutations.
Can Lesch-Nyhan disease be detected through newborn screening?
Currently, Lesch-Nyhan disease is not routinely included in newborn screening programs.
What is the primary treatment approach for Lesch-Nyhan disease?
Treatment is supportive and focuses on managing symptoms, including medications to reduce uric acid production and behavioral interventions.
What medications are commonly used to manage uric acid levels in Lesch-Nyhan disease?
Allopurinol is commonly used to reduce uric acid production in patients with Lesch-Nyhan disease.
How is self-injurious behavior managed in children with Lesch-Nyhan disease?
Management may include physical restraints, protective devices, behavioral therapy, and in some cases, medication.
What role does physical therapy play in managing Lesch-Nyhan disease?
Physical therapy is crucial in maintaining joint mobility, preventing contractures, and improving motor function.
How does Lesch-Nyhan disease affect life expectancy?
Life expectancy is reduced, with many patients surviving into their 20s or 30s with proper management.
Are there any experimental treatments being researched for Lesch-Nyhan disease?
Research is ongoing, including studies on gene therapy and enzyme replacement therapy, but no curative treatments are currently available.
How does Lesch-Nyhan disease affect speech and language development?
Many children with Lesch-Nyhan disease have impaired speech and language development due to neurological involvement.
What is the role of occupational therapy in managing Lesch-Nyhan disease?
Occupational therapy helps improve daily living skills and adapt the environment to the child's needs.
How does Lesch-Nyhan disease affect growth and development?
Children with Lesch-Nyhan disease often experience growth delays and developmental issues.
What is the importance of hydration in managing Lesch-Nyhan disease?
Adequate hydration is crucial to help prevent uric acid crystal formation and reduce the risk of kidney stones.
How does Lesch-Nyhan disease affect the cardiovascular system?
Cardiovascular complications can occur due to hypertension and vascular damage from long-term uric acid elevation.
What is the role of genetic counseling in families affected by Lesch-Nyhan disease?
Genetic counseling provides information about inheritance patterns, carrier testing, and options for future pregnancies.
How does Lesch-Nyhan disease differ from other uric acid disorders?
Lesch-Nyhan disease is distinguished by its severe neurological and behavioral symptoms, which are not typically seen in other uric acid disorders.
What prenatal testing options are available for Lesch-Nyhan disease?
Prenatal testing can be done through chorionic villus sampling or amniocentesis if the mother is a known carrier.