General Discussion

 

Lesch-Nyhan syndrome is a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Purines are nitrogen-containing compounds found in many foods (e.g., organ meats, poultry, and legumes). In the absence of HPRT, the purines hypoxanthine and guanine are not built into nucleotides. Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys. Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic disorder that, with rare female exceptions, most often affects males. The symptoms of Lesch-Nyhan syndrome include impaired kidney function, acute gouty arthritis, and self-mutilating behaviors such as lip and finger biting and/or head banging. Additional symptoms include involuntary muscle movements, and neurological impairment.

Signs & Symptoms

 

The symptoms of Lesch-Nyhan syndrome may become apparent as early as six months of age. Earlier urate crystal formation, resulting from abnormally increased levels of uric acid in the urine, leads to the presence of orange colored deposits (“orange sand”) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, but it is seldom recognized diagnostically in early infancy.

 

Urate stones may develop in the kidneys of infants with Lesch-Nyhan syndrome as a result of excessive amounts of uric acid that are excreted as sodium urate.  These stones may cause blood to appear in the urine (hematuria) and increase the risk of urinary tract infections. Urate crystals may also be found in the joints, but in general, it is not until late teenagerhood or adulthood that untreated patients with Lesch-Nyhan syndrome experience recurring episodes of pain and swelling of the joints, just like those of adults with gout. These episodes may become progressively more frequent once they begin.

 

In older children with this disorder, deposits of sodium urate may collect in cartilaginous tissues in joints and in the ears; in the ears, they form visible “bulges” called tophi. This is the picture commonly known as gout.

 

Neurological symptoms associated with Lesch-Nyhan syndrome usually begin before the age of 12 months. These may include involuntary writhing movements of the arms and legs (dystonia) and purposeless repetitive movements (chorea) such as flexing of the fingers, raising and lowering of the shoulders, and/or facial grimacing. Infants who had previously been able to sit upright typically lose this ability. Initially, muscles may be soft (hypotonia) and lead to difficulty in holding the head in an upright position. Affected infants may fail to reach developmental milestones such as crawling, sitting or walking (developmental delay). Eventually, most children with Lesch-Nyhan syndrome experience abnormally increased muscle tone (hypertonia) and muscle rigidity (spasticity). Deep tendon reflexes are increased (hyperreflexia). Mental retardation may also occur and is typically moderate. However, accurate evaluation of intelligence may be difficult because of poorly articulated speech (dysarthria),and some patients have demonstrably normal cognitive function.

 

The most striking feature of Lesch-Nyhan syndrome, which has been observed in approximately 85 percent of cases, is self-mutilation. These behaviors most often begin between the ages of two and three years. However, they can also develop during the first year of life or much later during childhood. Self-injurious behavior may include repeated biting of the lips, fingers, and/or hands, and repetitive banging of the head against hard objects. Some children may scratch their face repeatedly. However, individuals with Lesch-Nyhan syndrome are not insensitive to pain. Additional behavioral abnormalities include aggressiveness, vomiting, and spitting. Self-mutilating behaviors regularly lead to loss of tissue.

 

Children with Lesch-Nyhan syndrome may have difficulty swallowing (dysphagia) and may be difficult to feed. Vomiting is common, and most affected children are underweight for their age. Additional symptoms may include irritability or screaming. Some children with Lesch-Nyhan syndrome may also develop a rare anemia known as megaloblastic anemia. (For more information on megaloblastic anemia, see the Related Disorders section of this report.)

 

Another symptom of Lesch-Nyhan syndrome may be a severe muscle spasm that causes the back to arch severely and the head and heels to bend backward (opisthotonos). Affected children may also experience hip dislocation, fractures, abnormal curvature of the spine (scoliosis) and/or permanent fixation of several joints in a flexed position (contractures).

 

Female carriers usually do not have symptoms of the disorder, but may develop gout later in life as a result of untreated excess uric acid in the blood (hyperuricemia).

 

Causes

 

Lesch-Nyhan syndrome is inherited as an X-linked genetic disease. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes, and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

 

Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

 

The only gene known to be associated with Lesch-Nyhan syndrome is located on the long arm of the X chromosome (Xq27) and called HPRT1. Abnormalities (mutations) in the HPRT1 gene result in the absence or deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) and the abnormal accumulation of uric acid in the blood.

 

Affected Populations

 

Lesch-Nyhan syndrome is a rare disorder that affects males. In extremely rare cases, females may be affected by the disorder. However, in most cases, females may be carriers of the disease gene, but do not exhibit any symptoms. According to one estimate, the disorder occurs at the rate of approximately one in 380,000 births in the United States.

 

Related Disorders

 

Symptoms of the following disorders can be similar to those of Lesch-Nyhan syndrome in the sense that self-injurious behavior may occur. Comparisons may be useful for a differential diagnosis:

 

Familial dysautonomia is a rare genetic disorder of the autonomic nervous system (ANS) that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. (For more information on this disorder, choose “dysautonomia, familial” as your search term in the Rare Disease Database.)

 

Cornelia de Lange syndrome is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth; characteristic abnormalities of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe mental retardation. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from case to case. (For more information on this disorder, choose “Cornelia de Lange” as your search term in the Rare Disease Database.)

 

Diagnosis

 

The diagnosis of Lesch-Nyhan syndrome may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized blood tests. Children with this disorder have abnormally high concentrations of uric acid in the blood. The absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) in cells from any tissue confirms the diagnosis. Molecular genetic testing for the HPRT1 gene is available to determine the specific disease-causing mutation.

 

Carrier testing for Lesch-Nyhan syndrome is possible using molecular genetic testing.

 

Prenatal diagnosis and preimplantation genetic diagnosis are possible if the disease-causing HPRT1 gene mutation has been identified in an affected family member. Prenatal diagnosis can also be done by enzyme analysis.

 

Standard Therapies

 

Treatment

 

The treatment of Lesch-Nyhan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.

 

The drug allopurinol is used to control the excessive amounts of uric acid associated with Lesch-Nyhan syndrome and control symptoms associated with excessive amounts of uric acid. However, this treatment has no effect on the neurological or behavioral symptoms associated with this disorder.

 

When kidney stones are present, they may be treated with extracorporeal shock wave lithotripsy (ESWL). During this procedure, the patient is immersed in water and high energy shock waves are directed to the body in the area of the kidney stone. The stone dissolves into small pieces, and these fragments are passed with the urine.

 

No sustained treatment or drug therapy has proven uniformly effective for the treatment of the neurological problems associated with Lesch-Nyhan syndrome. Baclofen or benzodiazepines have been used to treat spasticity. Diazepam may be useful.

 

Individuals with Lesch-Nyhan syndrome have been reported to benefit from behavior modification techniques designed to reduce self-mutilating behaviors, but real success is unusual. Children with Lesch-Nyhan syndrome usually require physical restraint at the hips, chest, and elbows so they do not injure themselves. Elbow restraints keep the hands free. Biting of fingers and/or lips, which can lead to permanent disfigurement, may be prevented by the use of a mouth guard (oral prosthetic) or the removal of the teeth. Many affected individuals request restraints themselves. With advancing age, some affected individuals’ self-mutilating behaviors may improve or cease.

 

In some cases, drugs have been used to treat behavioral abnormalities associated with Lesch-Nyhan syndrome. These include Depakote (sodium valproate), Gabapentin, baclofen, and carbamazepine. Benzodiazepines may be beneficial in treating anxiety symptoms sometimes associated with Lesch-Nyhan syndrome.

 

Genetic counseling will benefit families with children who have Lesch-Nyhan syndrome. Other treatment is symptomatic and supportive.

 

Resource : rarediseases.org