A deficiency of the enzyme hypoxanthine-guanine-phosphoribosyl transferase (HPRT) has been found in all typical cases of this disease. The HPRT gene lies on the X chromosome (Xq 26-q 27), and accurate diagnosis of affected males and carriers can be made by genetic analysis. As a result of this deficiency, hypoxanthine is either excreted or catabolized to xanthine and uric acid. The details of the biochemical abnormality responsible for CNS dysfunction are unclear.
In the differential diagnosis, one must consider nonspecific mental retardation or autism with hand biting and other self-mutilations, athetosis from birth trauma, and encephalopathies with chronic renal disease. Hyperuricemia has also been reported in a family with spinocerebellar ataxia and deafness and in another with autism and mental retardation, neither of them with the enzymatic defect of Lesch-Nyhan disease. As mentioned earlier, there are several other disorders of purine and pyrimidine metabolism, some of them with hyperuricemia, that present with a neurologic syndrome like that of Lesch-Nyhan.
Treatment This is with the xanthine oxidase inhibitor allopurinol, which blocks the last steps of uric acid synthesis, reduces the uric acid in Lesch-Nyhan disease, and prevents the uricosuric nephropathy, but it seems to have no effect on CNS symptoms. Guanosine 5-monophosphate and inosine 5-monophosphate, both of which are deficient in Lesch-Nyhan disease, have been replaced without benefit to the patient. Transitory success has also been achieved by the administration of 5-hydroxytryptophan in combination with l-dopa. Fluphenazine (Prolixin) is reported to have suppressed the self-mutilation after haloperidol (Haldol) had failed to do so. Behavior modification programs may be of some value. Symptomatic treatment is available for the dystonia.
Calcification of Vessels in Basal Ganglia and Cerebellum
Ferrugination and calcification of vessels in the basal ganglia occur to a slight degree in many elderly persons (and in other mammals) who are otherwise normal. The widespread use of CT and MRI has brought the condition to light with increasing frequency (Fig. 36-9). Usually the calcification may be dismissed as an aging phenomenon of no clinical significance. When it occurs early in life, or later in life with extrapyramidal symptoms, and is of such degree as to be visible in plain films of the skull, it must always be regarded as abnormal.
calcification) An adult case of this type was described by Fahr, so that his name is sometimes attached to this disorder. This is an idiopathic and sometimes familial form of calcification of the basal ganglia and cerebellum in which choreoathetosis and rigidity are prominent acquired features. The clinical state may also take the form of a parkinsonian syndrome or bilateral athetosis. In two of our patients there was unilateral choreoathetosis, which was replaced gradually by a parkinsonian syndrome, and in another of our sporadic cases, the initial abnormality was a unilateral dystonia responsive to l-dopa. Some patients have been developmentally delayed but most are intellectually normal. The serum calcium levels in the aforementioned diseases are usually normal and there is no explanation of the calcification. A mutation of SLC20A2, coding for a protein involved in phosphate transport, is responsible for half of instances and a smaller number are caused by mutations in the PDGFRB. Both are heritable in an autosomal dominant fashion. Other, less frequent mutations have been identified in small groups.