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Nature of the Genetic Difficulty
The National Institute of Neurological Disorders and Strokes (NINDS) says Lesch-Nyhan syndrome is a childhood genetic disorder in which there's a lack of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HHPRT). This enzyme is needed to break down uric acid in your body. Without it, uric acid builds up and your child develops such symptoms as gout (joint pain especially of the big toe), mild mental retardation, kidney stones and poor muscle control. Another interesting feature is that Lesch-Nyhan syndrome leads to self-mutilating behaviors. For example, your child may bite his lip or fingers on purpose. Also, your child may develop such nejjjblurological symptoms as repetitive movements of the extremities. Typically, mothers who carry this disease pass this on to their sons. This is referred to as an X-linked disorder.
Basis Facts of Disease
Overproduction of uric acid
One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant. Overproduction of uric acid may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder. Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness.
The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine. The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones or distinct large stones that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some victims suffer kidney damage due to such kidney stones. Stones may be the presenting feature of the disease, but can go undetected for months or even years.
Nervous system impairment
The periods before and surrounding birth are typically normal in individuals with LNS. The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals are late in sitting up, while most never crawl or walk. Lack of speech is also a very common trait associated with LNS.
Irritability is most often noticed along with the first signs of nervous system impairment. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia), writhing motions (choreoathetosis), and arching of the spine (opisthotonus). Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. As a result, most individuals are initially diagnosed as having cerebral palsy. The motor disability is so extensive that most individuals never walk, and are confined to a wheelchair for life.
Persons affected are cognitively impaired and have behavioral disturbances that emerge between two and three years of age. The uncontrollable self-injury associated with LNS also usually begins at three years of age. The self-injury begins with biting of the lips and tongue; as the disease progresses, affected individuals frequently develop finger biting and head banging. The self-injury can increase during times of stress. Self-mutilation is a distinguishing characteristic of the disease and is apparent in 85% of affected males.
The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms because of the behavioral disturbances and motor deficits associated with the syndrome. In many ways, the behaviors may be seen as a psychological extension of the compulsion to cause self-injury: Rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed, provoking anger from caregivers when affection is desired, and so on.
Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and involuntary swearing, or coprolalia. The development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life.
LNS in females
While carrier females are generally an asymptomatic condition, they do experience an increase in uric acid excretion, and some may develop symptoms of hyperuricemia, and suffer from gout in their later years. Testing in this context has no clinical consequence, but it may reveal the possibility of transmitting the trait to male children. Women may also require testing if a male child develops LNS. In this instance, a negative test means the son's disease is the result of a new mutation, and the risk in siblings is not increased.
Females who carry one copy of the defective gene are carriers with a 50% chance of passing the disease on to their sons. In order for a female to be affected, she would need to have two copies of the mutated gene, one of which would be inherited from her father. Males affected with LNS do not usually have children due to the debilitating effects of the disease. It is possible for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HPRT gene. Under these circumstances, a girl could be born with LNS, and though there are a few reports of this happening, it is very rare. The overwhelming majority of patients with LNS are male.
The prognosis for individuals with severe LNS is poor. Death is usually due to renal failure or complications from hypotonia, in the first or second decade of life.
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