Lesch-Nyhan disease is an X-linked recessive disease involving abnormal purine metabolism. The disorder is due to complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme necessary for the recycling of free purine bases and reconversion into their nucleotide forms, after nucleotides are metabolized during DNA or RNA synthesis or after serving as coenzymes.^ Specifically, if HPRT is deficient, hypoxanthine, a free purine base, cannot be reconverted back to inosine 5 - monophosphate (IMP), from which adenosine 5 -monophosphate (AMP) and guanosine 5
-monophosphate (GMP) are synthesized by separate pathways. There is an acceleration of the de novo purine biosynthesis pathway, so hypoxanthine is converted, by xanthine oxidase, to uric acid, resulting in hyperuricemia. However, the hyperuricemia does not explain the neurological symptoms, the pathophysiology of which is essentially unknown. Based on animal models, speculation is that self-injurious behavior may be related to supersensitivity of the D subclass of dopamine receptors. Autopsies have revealed no specific cerebral gross anatomical or histopathological findings.
Incidence is rare, perhaps 1 in 380,000 births. The disorder occurs in many racial groups equally and is not more frequent in consanguineous populations. Patients are normal at birth, but by 6 months, developmental delay is evident. Axial hypotonia but appendicular spasticity and choreoathetoid movements appear in late infancy, and "cerebral palsy" is usually diagnosed at this time. The diagnosis is usually suspected in the toddler and early childhood years, when various kinds of compulsive self-mutilation, usually biting of lips, cheeks, or fingers, occur. Dysarthria makes communication difficult, and excitation may stimulate opisthotonus or torsion dystonia. Compulsive aggression can be directed toward anyone near the patient, including family members, and includes hitting as well as abusive language. Associated disorders are various hematological disorders, growth retardation, renal stones, and gouty arthritis if patients survive to adulthood.
Before the self-mutilating symptoms, other causes of nonprogressive or progressive extrapyramidal "cerebral palsy" should be considered, such as kernicterus, glutaricaciduria type 1, biopterin-dependent phenylketonuria, or biotinidase deficiency. Although some severely mentally retarded children of any etiology have self-abusive behaviors, such as head-banging, the relentlessness and compulsiveness of the self-injurious behavior in Lesch-Nyhan disease is extreme and unique.
The main clinical sign is self-injurious behavior resulting in tissue loss. Enzyme activity of HPRT can be assayed by radiochemical methods from dried blood spots, cultured skin fibroblasts, and hair follicle cells in probands and suspected female carriers. Biochemical analysis must be confirmed by molecular genetic analysis, particularly for female carriers. The entire HPRT locus has been sequenced, and the mutations in Lesch-Nyhan disease are extremely heterogeneous. The majority are detected by polymerase chain reaction-based techniques, usually amplification of genomic DNA and direct sequencing. In a small percentage, Southern blot analysis using HPRT complementary DNA as a probe is necessary to detect translocations or duplications.
Allopurinol, a xanthine oxidase inhibitor, decreases blood uric acid effectively but has no effect on the neurological symptoms. The following have been ineffective: folate, glutamine, magnesium, chlorpromazine, L-tryptophan, and clomipramine. Treatment with L-5-hydroxytryptophan plus carbidopa has been temporarily beneficial, but self-injurious behaviors re-emerge after discontinuing treatment or tolerance develops. Behavior modification-extinction, reinforcement of alternative behavior, or aversion therapy--shows inconsistent results. Physical restraints to prevent tissue injury are the most effective and include upper extremity splints to keep the arms straight, tying legs to wheelchairs so they cannot be brought up to the mouth, and dental guards to avoid teeth extraction as an extreme preventive measure.
Most patients are mentally retarded and do not stand or walk. Death frequently occurs during childhood. A patient with Lesch-Nyhan disease should be an ideal candidate for gene replacement therapy. The problem is to transfect an appropriate vector that would target brain cells, because neurological signs would not likely be affected by simple transplantation of infected cultured bone marrow cells into receptive hosts. Prenatal diagnosis using mutation detection and linkage analysis can detect 100 percent of affected males and excludes women who are suspected carriers if that family's HPRT mutation is known.
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