It is a rare inherited disorder caused by a dedeficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase ( HGPRT). This enzyme is responsible for recycling purines, a type of building block of DNA and RNA. When this enzyme is lacking, the breakdown of purines results in abnormally high levels of uric acid in all body fluids : both hyperuricemia and hyperuricosuria, which lead to problems such as severe gout and kidney problems, poor muscle control, and moderate mental retardation.These complications usually appear by the first year of life.
The main characteristic features of this syndrome is the self mutilating behaivours, characterized by lip and finger biting, that begin later. The neurological symptoms include facial grimacing, involuntary writing, and repetitive movements of the arms and legs as seen in the huntingtonââ‚¬â„¢s disease. The direct cause of the neurological symptoms are known. Some patients may develop megaloblastic anaemia due to the poor utilization of vitamin B12 due to the lack in the HGPRT gene.
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Treatment of the condition is limited. Allopurinol is useful to control the overproduction of uric acid and reduces the risk of nephrolithiasis and gouty arthritis. Few treatments have proven helpful for the neurologic or behaivoural difficulties. Spasticity is managed with a combination of baclofen and benzodiazepines, while the behaivoural abnormalities are best managed by a combination of behaivoural modification techniques and medications.
Most patients with the classic syndrome present at age 3-12 months with delayed motor development, most commonly hypotonia or failure to reach normal motor milestones. Between ages 6 and 18 months, abnormal involuntary movements indicative of extrapyramidal dysfunction become more prominent; some patients also develop corticospinal signs. Patients may often receive a diagnosis of cerebral palsy. After an initial period of progression that may last until 3-6 years of age, motor disability does not continue to progress.
A smaller number of patients presents with complications related to the overproduction of uric acid. Sometimes there is a history of "orange sand" in the diapers, which is caused by uric acid crystalluria and microhematuria. Other patients may present with renal failure or frank hematuria, resulting from nephrolithiasis. A few may present with gout.
Though self-injurious behavior is rarely the presenting feature of the illness, it eventually develops in nearly all cases. The emergence of the behavior often provides the essential clue to the diagnosis in a case with known developmental delay or hyperuricemia. Self-injury does not occur in the Lesch-Nyhan variants.
Signs and symptoms
LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behaivoural disturbances including self mutilation, and uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes sufferers to adopt a characteristic fencing stance due to the nature of the lesion. Virtually all patients are male; males suffer delayed growth and puberty, and most develop shrunken or testicular atrophy. Female carriers are at an increased risk for gouty arthritis.
Overproduction of uric acid
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.
At birth, 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.
Nervous system impairment
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.
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. 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.
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Self-mutilation is a distinguishing characteristic of the disease. 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.
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.
Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and involuntary swearing, or coprolalia.
LNS is due to mutations in the HPRT1 gene Since the HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease.The father of an affected male will not be the carrier of the mutant allele, and will not have the disease. An obligate carrier would be a woman who has an affected son and one other affected relative in the maternal line.
If a woman is the first in her family with an affected son, Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation. However, in this case Haldane's prediction is incorrect due to an increased risk of mutation arising from the father when compared to the mother.
The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female.
Males with LNS do not reproduce due to the characteristics of the disease. However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected.
HPRT normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools.In the absence of HPRT, these purine bases cannot be salvaged, and instead are degraded and excreted as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines is the basis for the overproduction of uric acid. The increased production of uric acid leads to hyperuricemia.
Since uric acid is near its physiological limit of solubility in the body, the persistent hyperuricemia increases the risk of uric acid crystal precipitation in the tissues to form tophi. Uric acid crystal deposition in the joints produces an inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urogenital system, increasing the risk of forming urate stones in the urinary collecting system. These stones may be passed as a sandy sludge or as larger particles that may obstruct urine flow and increase the risk for hematuria and urinary tract infections.
The pathogenesis of the neurological and behavioral features is incompletely understood. Neurochemical and neuroimaging studies have demonstrated significant abnormalities of dopamine neuron function in the basal ganglia that might account for the abnormal extrapyramidal neurological signs and many of the behavioral anomalies. Neuropathological studies suggest a neurodevelopmental defect, with no signs of a degenerative process. However, the mechanism by which HPRT deficiency influences the basal ganglia, and particularly the dopamine systems, remains unknown.
The gross overproduction of uric acid is often evident in routine blood and urine studies.
Uric acid levels in the blood typically are elevated, a helpful clue that can be obtained by routine clinical testing; Lesch-Nyhan syndrome have serum uric acid levels in the normal range. As a result, serum uric acid levels do not provide reliable diagnostic information.
Definitive diagnosis is obtained most often by measurement of HPRT enzyme activity in blood or tissue. Blood samples often are used, though intact fibroblasts or lymphocytes provide more precise information with prognostic implications.
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Diagnosis is confirmed by identifying a molecular genetic mutation in the HPRT gene. Molecular genetic diagnosis provides an ideal tool for carrier detection and prenatal screening of at-risk pregnancies.
Macrocytic anemia, sometimes profound, is relatively common. Vitamin B-12, folate, and iron results are typically normal.
The gross overproduction of uric acid must be controlled to prevent the development of urologic or articular complications. The goal is to maintain uric acid levels in the normal range. A common error is to attempt to suppress uric acid below normal levels, but this approach risks the development of oxypurine stones instead. The control of uric acid requires 2 important components.
Allopurinol, which inhibits the metabolism of hypoxanthine and xanthine to uric acid by the enzyme xanthine oxidase, is generally effective in limiting hyperuricemia and its consequences. The dose is titrated with the goal of bringing serum uric acid levels into the normal range.
Generous hydration at all times is essential. Hydration should be increased during periods of increased fluid loss, such as a febrile illness or recurrent emesis.
Despite the combined use of allopurinol and generous hydration, nephrolithiasis still may occur.
Several medications are available to mitigate the severity of the neurological features, though no agent has proved consistently efficacious in all cases. Benzodiazepines, such as diazepam or alprazolam, reduce severity and help attenuate anxiety that may indirectly exacerbate the extrapyramidal abnormalities. Antispasticity agents such as baclofen can also be helpful.
Management of the behavioral problems, and particularly the self-injurious behavior, can be very difficult. In general, behavioral problems are best managed with a combination of behavioral modification techniques and medication. Behavioral extinction methods with positive reinforcement are most beneficial; techniques involving negative reinforcement are not helpful and may even exacerbate the behavior problems. Adjunctive medications, sometimes useful for attenuating problem behaviors, include gabapentin and benzodiazepines. Neuroleptics are sometimes used when problems are particularly severe, although long-term use is discouraged due to side effects.