Pathogenesis

Pathogenesis refers to the study of how the defect in the hprt gene causes the problems that occur in Lesch-Nyhan disease. This research has provided some important answers, but there is still a lot to learn. This section describes the pathogensis of some of the main problems.

The research has already uncovered why patients with Lesch-Nyhan disease make so much uric acid. Much less is known about how errors in the hprt gene cause neurological and behavioral problems. We now know that most of the neurological and behavioral problems come from abnormal operations of a small area in the brain known as the basal ganglia. Exactly what is going on in this area, and what other brain regions might also be affected, is a very active area of current research. More information on this topic can be found in the Research section.

Uric acid

The loss of HPRT prevents the body from recycling purines, so the body has to make more purines 'from scratch' to keep up with its needs. Because the purines are not recycled, they get wasted. In the human body, most of the purine wastes are turned into uric acid. This leads to a process where the body keeps making more purines, which keep getting turned into uric acid. This vicious cycle explains why people with Lesch-Nyhan disease make too much uric acid.

Uric acid itself is not bad for the body. The kidneys concentrate most of it into the bladder so it can be eliminated in the urine. But when too much uric acid accumulates, it clumps together to form tiny crystals or stones. These crystals like to form in cool parts of the body, such as the skine or joints of the hands and feet.

The crystals also like to form in the kidneys and bladder, where they are especially concentrated. These stones are most dangerous, as described in the next section.

Kidney stones

Kidney stones are common in Lesch-Nyhan disease. The main ingredient is usually uric acid. The stones develop as the kidneys try to concentrate the uric acid into the bladder for elimination in the urine. If there is not enough fluid in the system to constantly flush the uric acid and small crystals (figure) out in the urine, the stones enlarge.

The stones are dangerous because they can clog up the kidney or get stuck in the ureter, the tube the kidneys use to eliminate urine. When they get stuck they can block the flow of urine. An important warning sign in this situation is pain. The pain is usually severe, and felt mostly in the flank near the kidney, down into the lower belly and upper thigh region. The pain can come and go, depending on the location and movements of the stone.

If the urine can not get out, the kidney will have no place to dump its urine, and it will stop working. If the kidney is left in this situation for a long time, it will slowly degenerate. Most people have two kidneys and one will continue to work if the other is blocked. But if both kidneys are blocked, renal failure develops. This is a life-threating emergency.

Fortunately, the development of uric acid stones can be prevented in most situations by proper treatment. Even if stones develop, they can be removed if they are found. For more information, go to the section on Treatment.

Neurobehavioral features

The processes by which the defect in the hprt gene leads to changes in the brain that cause the problems we see in people with Lesch-Nyhan disease are not well understood. Recent research has focussed on the operations of a region of the brain known as the "basal ganglia". This region is a network of connected structures located at the base of the cortex. The relevant structures include the caudate, putamen, accumbens, globus pallidus, substantia nigra, and parts of the thalamus. The major circuit of the basal ganglia (figure) has been linked to the control of movement, but several additional circuits have been linked to mental abilities and behavioral patterns.

Diseases of the basal ganglia often combine abnormalities of motor control, cognitive impairment, and behavioral change. Some common diseases of the basal ganglia include Huntington's disease, Parkinson disease, and Tourette syndrome. A growing body of evidence has suggested that many of the problems of Lesch-Nyhan disease also result from dysfunction of the basal ganglia. Their difficulties with motor control, dystonia and chorea, are typically associated with dysfunction of the motor circuit of the basal ganglia. Studies of other diseases and animals have linked the problem of self-injurious behavior to the basal ganglia as well. Their pattern of cognitive impairments may reflect dysfunction of the cognitive circuits of the basal ganglia, but may also reflect broad involvement of the cerebral cortex.

Standard brain scans (MRI and CT) of people with Lesch-Nyhan disease often appear normal, but close inspection may reveal shrinkage of two basal ganglia structures, the caudate and putamen. Also more sophisticated scans and biochemical studies have suggested abnormal basal ganglia function. In particular, shortage of dopamine seems to play an important role. Dopamine is a neurotransmittor, a brain chemical which is involved in signalling between brain cells.