Approach Considerations
In Lesch-Nyhan disease, 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: (1) inhibiting the metabolism of hypoxanthine and xanthine to uric acid with allopurinol and (2) generous hydration. 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.
In patients with Lesch-Nyhan disease, hospital admissions should be limited to those absolutely necessary for medical interventions, because moving these patients into an unfamiliar environment will exacerbate behavioral problems such as self-injury.
Protective devices such as straps or splints should be applied at all times to prevent self-injury; this includes nighttime sleeping periods and also during transfer for any tests. These devices should be viewed as protective devices (rather than restraints) that are permitted in hospitals for patients with developmental disorders. Most patients and families will request them and may become upset if they are removed.
Pharmacologic Therapy
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. Febuxostat is a newer option for patients who cannot tolerate allopurinol.
Despite the combined use of allopurinol and generous hydration, nephrolithiasis still may occur. Several medications are available to mitigate the severity of the neurologic 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 behavioral problems
Management of the behavioral problems, 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 because of side effects.
Dental, Orthopedic, and Other Interventions
The metabolic defect does not preclude safe application of standard anesthetic or surgical procedures when indicated. Dental work is perhaps the most commonly required surgical intervention in Lesch-Nyhan disease. Dental extraction may be the only procedure for preventing serious tissue injury if self-injurious biting cannot be controlled with behavioral and/or medical therapy.
Orthopedic intervention is often required for management of the consequences of the neurologic disorder. Procedures may be required for release of contractures, reduction of subluxed joints, or stabilization of spinal deformity.
Nephrolithiasis may require surgical intervention for extraction of stones or relief from urogenital obstruction.
Some studies have provided a promising suggestion that deep brain stimulation surgery may be useful for controlling both dystonia and self-injury. [14] The procedure is considered experimental, and further studies are needed before the procedure can be broadly recommended, because the brain targets seem to differ from those used for other disorders.
Consultations
Genetic counseling is essential for informing the family of the risk of additional children with the disorder.
Consultations with neurologists and physiatrists may be necessary for management of associated motor disorders, and consultations with psychiatrists or psychologists are nearly universally required for management of behavioral disorders associated with Lesch-Nyhan disease.
An orthopedist may be required for joint complications, as well as a urologist for management of kidney stones.
Diet and Activity
Most patients can be on a normal diet. Dysphagia may be a significant problem, particularly with aging. Some patients respond to changes in the consistency of the diet, while others may require gastrostomy.
Despite their profound motor handicap, most patients with Lesch-Nyhan disease prefer to remain actively engaged in their environments.
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Purine metabolic pathways.
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A small portion of the lower lip has been disfigured by persistent self-biting.
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The distal portions of several fingers are shortened by prior uncontrolled self-biting.
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The HPRT gene has 9 exons, with the coding region depicted as light gray boxes. Genetic mutations in Lesch-Nyhan disease and its variants are heterogenous and include point mutations leading to amino acid substitution (yellow circles), point mutations leading to premature stop (red squares), insertions (blue triangles), deletions (white lines), and other more complex changes (not shown).
