Introductory Remarks

LESCH-NYHAN SYNDROME is a rare inborn error of purine metabolism, first identified in 1964,  is characterized by absence or deficiency of HGPRT enzyme activity. HGPRT refers to hypoxanthine-guanine phosphoribosyltransferase. This congenital disorder is passed down from mothers to their male offspring and rarely affects female children.

Lesch-Nyhan syndrome is known to affect the behaviour and brain of a child, leading to uncontrollable self-mutilating behaviours such as biting lips and banging the head.

In this condition, uric acid which is a waste product of the body, accumulates in tissues. Chidren with this condition also suffer from gout, dystonia (poor muscle control), and mental disabilities.

Several treatment options are employed to manage symptoms and reduce complications. Lesch-Nyhan syndrome does not have a cure. Prognosis is also poor.

 

Other names

What are the synonymns for Lesch-Nyhan syndrome?

• Lesch-Nyhan syndrome has several other names such as:

1.  Juvenile gout.
2. Juvenile hyperuricemia syndrome.
3. Lesch-Nyhan disease (LND).
4.  X-linked hyperuricemia.
5. Total HGPRT deficiency.
6. Compete HGPRT deficiency.
7. Choreoathetosis self-mutilation syndrome.
8. Kelley-Seegmiller syndrome.

 

 Statistics & Facts

What are the facts and statistics that surround Lesch-Nyhan syndrome?

• Age of onset: Infancy.
• Prevalence: 1-9 per 1 million.
• Estimated prevalence at birth: 1 per 235, 000 to 1 per 380,000.
• Inheritance: X-linked recessive.
• It is an X-linked disorder that is manifested mostly in males. A few female individuals have been noted to have the syndrome.
• It results from HGPRT1 gene, which is located position q26-27 of the long arm of X chromosome.
• This condition is rare. It affects about 1 in 380,000 persons.

 

Risk Factors

What are the risk factors for Lesch-Nyhan syndrome?

•  Sex. It commonly affects males.
• Genetics. Inheritance of mutated HGPRT1 gene. Also, mutation of this gene suddenly in healthy individuals(who previously did not have the condition) can lead to development of Lesch-Nyhan syndrome.

 

Causes

What are the causes of Lesch-Nyhan syndrome?

• It is caused by a genetic alteration in HGPRT1 gene, which makes HGPRT enzyme. This enzyme is known to catalyze  chemical conversion of:

1.  Hypoxanthine to inositol mono-phosphate (IMP).
2.  Guanine to guanine mono-phosphate (GMP).

• These reactions occur through the purine salvage pathway.

 

• PRPP is used as a co-substrate, and therefore its deficiency leads to hypoxanthine and guanine accumulating by 2 ways:

1.  Reduced utilization for synthesis of purines.
2.  Increased availability of 5-phosphoribosyl-1-pyrophosphate (PRPP) for utility in IMP synthesis by the de novo pathway, which is then converted to hypoxanthine and then to uric acid.

• This leads to hyperuricemia.
• Uric acid in excess precipitates to form tophi and renal calculi in joints and kidneys.

 

 Types

What types of Lesch-Nyhan syndrome exist?

• Classic Lesch-Nyhan syndrome which is severe.
• HGPRT1-related neurologic function (HND) type.
• HGPRT1-related hyperuricemia which is the mildest form. It is also referred to as Kelley-Seegmiller syndrome.

 

 Signs & Symptoms

What are the clinical manifestations and indicators of Lesch-Nyhan syndrome?

•  These symptoms can be categorized under the following:

1. Injury to self and others.
2. Muscle and movement disorders.
3. Medical problems.
4. Learning difficulties.

 

Injury to oneself and others

• As the teeth start to grow in these children, compulsive self-injury behaviour can be noted and thi includes:

1. Poking the eyes.
2. Biting lips and fingers.
3. Banging the head.

 

Muscle and movement disorders

• These include:

1. Dysphagia (difficulty swallowing).
2. Hyperreflexia.
3. Chorea (jerky movements).
4. Dysarthria (slow speeches).
5. Spasticity (muscle tightening).
6. Difficult walking or feeding using hands.
7. Constant repetitive movement of the limbs.

 

Medical problems

• Accumulation of uric acid in the body can lead to :

1. Gout.
2. Renal stones and renal failure.
3. Bladder stones.
4. Megaloblastic anemia.

 

Learning difficulties

1. Poor memory.
2. Short span of attention.
3. Learning disabilities.

 

 Diagnostic Procedures & Tests

How is Lesch-Nyhan syndrome diagnosed?

• Physical exam.
• Symptoms which the child presents with.
• Family history.

 

Health-care providers ask further questions to check for;

• Developmental delays.
• Self-mutilation behavior.

 

• Urine or blood test to check for hyperuricemia.
• Genetic testing is the definitive method for confirming diagnosis of this condition.
• Enzyme analysis.

 

• Pre-natal testing includes:

1.  Amniocentesis.
2. Chorionic villus sampling.

 

 Treatment & Management

Does Lesch-Nyhan syndrome have a cure?

No. This condition does not yet have a definitive curative strategy.

 

• Being a condition with several symptoms, Lesch-Nyhan synrome requires a team of workers to handle.
• This team may be comprised of:

1. A nephrolohist.
2. A pediatrician.
3. A urologist.
4. A neurologist.
5. A physical therapist.
6. A social worker.
7. An occupational therapist.

 

• Treatment srategies are based on the symptoms which the child presents with and how severe they are.
• The following may be recommended:

1. Medications that treat hyperuricemia. Also, those which ease behavioral symptoms.
2. Use of a wheelchair to increase mobility.
3. Physical and occupational therapy.
4. Medical procedures such as laser lithotripsy. This is done to break up kidney stones.
5. Devices such as mouthguard to prevent biting of fingers.

 

Differential Diagnosis

• Conditions similar to Lesch-Nyhan syndrome are:

1.  Fragile X syndrome.
2. Autism spectrum disorder (ASD).
3. Cerebral palsy.
4. Rette syndrome.
5. Hereditary sensory neuropathy.
6. Glucose-6-phosphate dehydrogenase (G6PG) deficiency. This condition affects erythrocytes (red cells).
7. Tourette syndrome.
8. Phosphoribosyl pyrophosphate (PPRP) synthetase hyperactivity. This leads to overproduction pf uric acid.
9. Huntington’s disease.

 

 Complications

What are the complications of Lesch-Nyhan syndrome?

1. Renal failure.
2. Nephrolithiasis.
3. Megalobastic anemia (due to vitamin B12 deficiency).
4. Repeated vomiting.
5. Gout.

 

 Prevention Strategies

How can we prevent Lesch-Nyhan syndrome?

• Lesch-Nyhan syndrome happens when the fetus is developing in the uterus as a result of genetic alterations.
• Prenatal testing can be conducted to detect the genetic mutation responsible for the syndrome.