Approach

Currently, there is no curative treatment for Lesch-Nyhan disease (LND). Supportive treatment options depend on the phenotype, which includes overproduction of uric acid and its complications, as well as varying degrees of extrapyramidal and pyramidal signs, behavioral abnormalities including self-injurious behavior, and miscellaneous aspects such as macrocytic anemia.

Hyperuricemia

All patients have hyperuricemia. Allopurinol inhibits the conversion of xanthine and hypoxanthine to uric acid, and so reduces the risk of hyperuricemia-associated urologic and articular complications by effectively reducing serum acid levels.[37][38] Doses are titrated to maintain uric acid levels in the high-normal range and must be adjusted for renal insufficiency. In addition, generous hydration at all times is essential to wash out the oxypurines hypoxanthine and xanthine, and the allopurinol metabolite oxypurinol, which may also cause (radiolucent) renal stones.[39][40]

Renal stones

Renal stones, identified by renal colic, urinary obstruction, or routine ultrasound follow-up, require appropriate treatment in order to prevent long-term renal complications.[40][41] Kidney stones in allopurinol-treated LND patients may contain uric acid, the oxypurines xanthine and hypoxanthine, or the allopurinol metabolite oxypurinol.[39] These stones are radiolucent, so renal ultrasound is the preferred modality for diagnosis.[40] Small urate stones can usually be managed by increasing fluid intake and by urine alkalinization, with potassium citrate being the preferred agent. Large stones and oxypurine stones may require lithotripsy or surgery, although the latter are more difficult to eliminate.[39][41]

Dystonia, chorea and ballismus

Extrapyramidal features in LND are mostly resistant to currently available therapies.

Various drug therapies have been tried. Dopaminergic drugs such as levodopa have inconsistent effects on the motor disorder and have been reported to worsen the condition.[21][26][42] Early treatment with levodopa/carbidopa (i.e., starting <1 year after the onset of symptoms) has been reported to improve the movement disorder in one patient but confirmative studies are warranted.[43] Symptomatic treatment of severe dystonia (e.g., to improve hand function or prevent contractures) can be performed by botulinum toxin injections in selected muscles. Choreiform and ballistic movements do not consistently improve with a dopamine receptor antagonist (e.g., fluphenazine, pimozide) or drugs that deplete dopamine stores (tetrabenazine).[26][42][44][45] Detailed reports on the use of trihexyphenidyl in LND are lacking.

Physical therapy is generally useful to prevent contractures and preserve overall physical condition.

Pyramidal signs

Muscle relaxants such as baclofen and dantrolene can be used to manage spasticity.[3]

Alternatively, benzodiazepines (e.g., diazepam) may be used. Benzodiazepines have the added advantage of reducing anxiety, which is known to exacerbate the extrapyramidal and behavioral features.

Often, a muscle relaxant and a benzodiazepine are used concurrently.

In addition, physical therapy may prevent contractures and preserve overall condition.

Behavioral abnormalities

No pharmacologic treatment has consistently demonstrated effectiveness in managing the behavioral disturbances in LND, including medications that influence dopamine and serotonin metabolism.[26][44][45][46] No pharmacologic treatment has been reported as consistently reducing self-injurious behavior.[3] A positive effect of S-adenosylmethionine on behavior has not been established, as results are inconsistent.[47] Behavioral abnormalities do not respond consistently to formal psychological treatment either.[3] Negative reinforcement usually increases unwanted behaviors, including self-injury.[48][49]

The most effective method of dealing with difficult behaviors is to acknowledge the fact that they are beyond the patient's control, engage the patient in an active environment, provide positive reinforcement for desired behaviors, and actively ignore undesirable behaviors. For many patients, it is of utmost importance that they feel understood.

Most LND patients need some form of physical restraint, such as arm splints, limb straps, or protective gloves.[3][50][51] For biting, teeth extraction may be needed when conservative measures fail.[52] Hard objects that can be reached, including wheelchairs, need soft padding.[53]

During inpatient admissions, limited to those that are absolutely necessary, restraints should be applied at all times to prevent self-injury, including during sleep. This disease is exempted from the regulations of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) against continuous and long-term restraints.

Macrocytic anemia

Macrocytic anemia may be found in LND patients.[26][54] The cause is uncertain, as serum vitamin B12, folate, iron, and thyroid function tests are typically normal, and supplements are usually not effective.[3]

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