The
enzyme hypoxanthine-guanine phosphoribosyltransferase (
HPRT) catalyzes the reutilization of
hypoxanthine and
guanine to the
purine nucleotides IMP and GMP, respectively.
HPRT deficiency is an X-linked disorder characterized by
uric acid overproduction and variable neurologic impairment. The complete deficiency of
HPRT is diagnostic of
Lesch-Nyhan syndrome manifested by choreoathetosis, spasticity,
mental retardation, and self-injurious behavior. In some
HPRT-deficient patients the
enzyme defect appeared to be "partial" and the
neurologic symptoms mild to severe (
Kelley-Seegmiller syndrome). This has prompted the classification of
HPRT deficiency in 2 distinct groups:
Lesch-Nyhan syndrome and
Kelley-Seegmiller syndrome, which has created much
confusion. A spectrum of clinical consequences of
HPRT deficiency has been recognized in small series of patients, but the complete spectrum of the
neurologic disorder has not been described in a single series of patients examined by the same observers. We analyzed our experience with 22 patients belonging to 18 different families with
HPRT deficiency diagnosed at "La Paz" University Hospital in Madrid over the past 16 years. The clinical spectrum of these
HPRT-deficient Spanish patients was similar to the different phenotypes occasionally reported in the literature, in some cases diagnosed as Lesch-Nyhan "variants." The clinical, biochemical, enzymatic, and molecular genetic studies on these 22 patients allowed us to delineate a new classification of
HPRT deficiency. Based on the
neurologic symptoms, dependency for personal care,
HPRT activity in hemolysate and in intact erythrocytes, and predicted
protein size, patients were classified into 4 groups: Group 1 (2 patients), normal development with no
neurologic symptoms,
HPRT activity was detectable in hemolysates and in intact erythrocytes, and the mutation did not affect the predicted
protein size. Group 2 (3 patients) mild
neurologic symptoms that did not prevent independent lives,
HPRT activity was detectable in intact erythrocytes, and the
protein size was normal. Group 3 (2 patients), severe neurologic impairment that precluded an independent life, no residual
HPRT activity, and normal
protein size. Group 4 (15 patients), clinical characteristics of
Lesch-Nyhan syndrome (some may not show self-injurious behavior), no residual
HPRT activity, and in most (7 of 8 patients in whom the mutation could be detected) the mutation affected the predicted
protein size. This classification of
HPRT deficiency into 4 groups may be more useful in terms of accuracy, reproducibility, assessment for treatment trials and prognosis. The study of this Spanish series allows us to conclude that
HPRT deficiency may be manifested by a wide spectrum of
neurologic symptoms; the overall severity of the disease is associated with mutations permitting some degree of residual
enzyme activity; and mutation analysis provides a valuable tool for prognosis, carrier identification, and prenatal diagnosis.