Clinical picture
Children with Lesch-Nyhan disease have a characteristic collection of problems. These problems are usually grouped into three main areas. The first of the problems involves overproduction of uric acid, leading to kidney stones and gout. More information on this problem can be found in the sections below.
The second problem involves developmental delay with subsequent neuromotor disability. The third problem area involves difficult behaviors. These problems are also described in more detail below.
Not everyone gets all of these problems. For example, the most mildly affected boys only have problems related to uric acid, but they lack neurological or behavioral problems. Others have problems related to uric acid and some neurological difficulties, but no behavioral problems. Those who lack problems in all three areas are known as Lesch-Nyhan variants.
Developmental delay
Normal babies learn how to do many new things as they grow up. They usually learn how to sit without help around 6 months of age, and they begin learn how to walk and talk around 1 year of age. Developmental delay is diagnosed when babies do not learn new things, or they learn them late.
There are many different causes for developmental delay. Lesch-Nyhan disease is one of them. Because there are so many different causes for developmental delay, a thorough evaluation by a pediatrician or pediatric neurologist is usually required. Lesch-Nyhan disease is only suspected when developmental delay is combined with evidence for overproduction of uric acid or self-injurious behaviour.
Crystals and stones
Children with Lesch-Nyhan disease make too much uric acid. When too much uric acid is made, it begins to stick together in clumps known as crystals. See the figure how they look under miscroscope. With the naked eye, pure uric acid crystals often look like yellow grains of sand. They may be as small as a poppy seed or as big as a lemon.
These crystals and stones like to form in three main areas of the body. The first area is the joints between bones, especially those of the toes or fingers. When this happens, the crystals cause irritation of the joints, a problem known as gout. Gout can be seen as a finger or toe that becomes swollen, red, and painful.
The second area that crystals and stones form is just under the skin in cool parts of the body. When they form here, they can be seen through the skin as tophi.
The last area crystals and stones form is in the kidneys. These are the most dangerous stones. Sometimes a stone will pass out of the kidney to show up in the urine, where it can actually be seen. Sometimes a stone will get stuck on its way to the bladder. This often causes pain in the belly, back, or upper leg. A trapped stone can also block the flow of urine. If a large stone gets stuck in the kidney or on its way to the bladder, it can prevent the kidney from doing its job and cause kidney failure.
Neuromotor disability
Individuals with classic Lesch-Nyhan disease have neuromotor disability, difficulty controlling their muscles. Their muscles seem stiff, particularly when they try to use them. This problem is known as dystonia, and all have it. These problems are severe enough that they often prevent walking or using hands for feeding.
Some with Lesch-Nyhan disease also have spasticity. This is also a form of muscle stiffness, and it can be difficult to distinguish it from dystonia. A few also have choreoathetosis or ballismus, motor disorders characterized by wiggling, writhing and flinging movements.
Behavioral problems
Patients with Lesch-Nyhan disease almost always have behavior problems. Some of these troublesome behaviors include attempting to hit others, spitting on others, or using foul language. However, the Lesch-Nyhan variants do not have behavior problems.
These behaviors may look like acts of aggression towards others, but they are not. People with Lesch-Nyhan disease are not aggressive. Many admit that they are impulsive and cannot control these acts, and they are often apologetic after they do something bad. Despite their remorse about these bad behaviors, the impulses are often irresistible, and they can't control all of them.
Learning disabilities
Early studies of cognitive function suggested that all people with Lesch-Nyhan disease had severe mental retardation. As a result, many pediatrics books and doctors say that individuals Lesch-Nyhan disease are severely retarded. This is not true. Recent studies have suggested much less severe cognitive disability. IQ testing reveals a wide range in scores with some falling in the normal range. The IQ scores usually fall between 60-70, which is classified as mild or moderate cognitive impairment.
More importantly, recent studies have addressed different cognitive domains, such as memory or language skills, to determine the reason IQ scores are low. As a group, individuals with Lesch-Nyhan disease have relatively good memories and language. But their attention spans are terrible, and they have difficulty with complex planning and predicting the consequences of future events. These limitations make it hard for them to get through the usual lengthy cognitive testing sessions, and to learn in normal school environments. IQ scores and school performance improve if educational opportunities and tests are tailored to their weaknesses.
Self-injurious behavior
Boys with Lesch-Nyhan disease can also have other disagreeable behaviors, such as hitting others, spitting on people, or using foul language. The Lesch-Nyhan variants do not have self-injurious behavior, and most do not exhibit the other difficult behaviors.
Other issues
Several other problems may also occur in Lesch-Nyhan disease. One of these is recurrent vomiting. This is sometimes severe enough to impair nutrition and growth. If it is severe, a feeding tube may have to be inserted into the stomach.
Another problem is anemia with very large red cells in the blood. This problem is usually caused by dietary deficiency of vitamin B12 or folic acid, and sometimes by other problems. However, patients with Lesch-Nyhan disease do not usually have such deficiencies, and supplements do not correct the anemia. Fortunately, it does not usually cause significant disability, so it does not need to be treated.
Variants
The clinical picture of the classic form of Lesch-Nyhan disease usually includes three things: uric acid crystals or stones, neurological disability, and difficult behaviors. But not all patients have all three problems. Some are spared the behavioral problems and self-injury. Others have only uric acid problems. These individuals with less severe problems are called the Lesch-Nyhan variants (LNV), to distinguish them from the more severely affected patients.
The condition with only problems due to too much uric acid is called 'HPRT-related hyperuricemia' (HRH). Patients who also have neurological problems, but no behavioral symptoms and self-injury, have 'HPRT-related hyperuricemia with neurological dysfunction' (HRND). See this figure for a schematic representation of the clincial spectrum of these conditions.
The reasons that some patients are less severely affected are an important area of current research. They may hold clues for how to spare others from getting all three of the problems.