Lesch-Nyhan Syndrome

Introduction

Lesch-Nyhan syndrome (LNS) is a rare, inherited X-linked genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT),an enzyme of purine salvage pathway. The enzyme is responsible for recycling purines by converting guanine and hypoxanthine into guanosine monophosphate and inosine monophosphate, respectively. Lack of the enzyme causes an increase in guanine and hypoxanthine, which eventually gets converted into uric acid, Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys.

LNS is inherited as an X-linked recessive genetic disorder that mostly affects males, with rare female exceptions. Lesch-Nyhan syndrome was first described in 1964 by Lesch and Nyhan, when two brothers originally diagnosed with cerebral palsy were later recognized as living with a previously undescribed inherited metabolic disease because of the familial occurrence and unusual clinical features.

Causes

Lesch-Nyhan syndrome is an X-linked recessive disorder resulting from mutation of the HPRT1 gene, located at a q26-27 position on the long arm of the X chromosome. Though only a single gene is associated with this syndrome, over 600 mutations have been identified, each leading to varying levels of severity of clinical presentations making HPRT enzyme deficiency a spectrum rather than a single disease. Males who receive the defective X chromosome from the carrier mothers manifest the disease. Females are mostly carriers but may develop the disease if the healthy X chromosome undergoes lionization, and the defective X chromosome is expressed phenotypically.

Signs and Symptoms

The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to symptoms such as:

• Severe gout
• Poor muscle control
• Moderate developmental disabilities, which appear in the first year of life.

• Banging the head or limbs.
• Biting lips, fingers and cheeks.
• Poking the eyes.

Other common symptoms include muscle control problems such as:

• Constant repetitive movement of the arms or legs (ballismus).
• Difficulty crawling, walking or feeding with hands.
• Difficulty swallowing (dysphagia).
• Exaggerated reflexes (hyperreflexia).
• Arched back due to muscle spasms (opisthotonos).
• Involuntary movements (dystonia) or facial expressions.
• Involuntary twitching, wiggling or writhing (choreoathetosis).
• Jerking movements (chorea).
• Muscles that stiffen or tighten, preventing movement (spasticity).
• Slurred or slow speech (dysarthria).

That increase in uric acids causes them to appear normal when they are born, but by about the third month they are unable to lift their heads or sit up. They display hypotonia, a lack of muscle tone, and many also suffer from dystonia, a lack of motor control. Clinically, LNS is characterized by mental retardation, choreoathetosis(Involuntary writhing), spastic cerebral palsy, and aggressive self-mutilating behavior.

Other neurological sign and symptoms in people with LNS includes the following:

• Facial grimacing
• Repetitive movements of the arms and legs similar to Huntington's disease

The absence of HGPRT enzyme is the cause of hyperuricemia in LNS patients. As a result, orange deposits also known as "orange sand" can sometimes be seen the diapers of infants as the first manifestation of LNS which when present can contribute to the early diagnosis and management before the progression of manifestations.

Epidemiology

The prevalence of Lesch-Nyhan syndrome that has been estimated is between 1:235,000 and 1:380,000.Although it is an X-linked genetic disorder manifesting mostly in males, a few females with Lesch Nyhan syndrome have been reported and studies show that it occurs in relatively equal frequencies in all populations.

Diagnosis

• Diagnosis of LNS is based mainly on history, clinical examination and blood analysis. Genetic analysis to detect the mutated gene is confirmatory.
• The definitive diagnosis of LNS is either enzymatic assay or molecular testing. Enzymatic diagnosis is an estimate of HPRT enzyme activity in erythrocyte lysate. Other cells like lymphocytes, cultured fibroblasts can also be used.
• Complete blood count(CBC) can also be used to check for megaloblastic anemia and An electroencephalogram (EEG) to rule out seizures as the cause for inattention may be considered.
• Increased serum uric acid (>8 mg/dl) and increased urine uric acid (urinary uric acid: creatinine ratio of ≥3-4: 1) is suggestive but is neither sensitive nor specific to the diagnosis.
• Prenatal testing can be done using either chorionic villus sampling or amniocentesis in male infants with a family history of Lesch-Nyhan syndrome.

Complications

• Nephrolithiasis(Kidney and bladder stones)
• Gout
• Kidney failure
• Megaloblastic anemia due to a lack of vitamin B12.
• Repeated vomiting.
• Learning issues

Differential diagnosis

Many conditions have symptoms that resemble Lesch-Nyhan syndrome. For example, autism spectrum disorder and cerebral palsy both have similarities to LNS. Getting an accurate diagnosis is important, so your child can receive the appropriate care for their needs.

Other conditions similar to Lesch-Nyhan syndrome include:

• Fragile X syndrome.
• Huntington's disease.
• Rett syndrome.
• Tourette syndrome.

Physiotherapy management

The physiotherapy management for patients with LNS includes the following:

Prognosis

The outlook for children with Lesch-Nyhan syndrome is generally poor. They usually cannot walk and require a wheelchair. Most have short lifespans, rarely living more than 20 years due to disease complications. A care team can help you and your child manage symptoms so your child can be as comfortable and active as possible.