History
Most patients with classic Lesch-Nyhan disease present at age 3-12 months with delayed motor development, most commonly hypotonia or failure to reach normal motor milestones. Between ages 6 and 18 months, abnormal involuntary movements indicative of extrapyramidal dysfunction become more prominent; some patients also develop corticospinal signs. Patients may often receive a diagnosis of cerebral palsy. After an initial period of progression that may last until age 3-6 years, motor disability does not continue to progress. [2]
A smaller number of patients present with complications related to the overproduction of uric acid. Sometimes there is a history of "orange sand" in the diapers, which is caused by uric acid crystalluria and microhematuria. Other patients may present with renal failure or frank hematuria, resulting from nephrolithiasis. A few patients may present with gout.
Though self-injurious behavior is rarely the presenting feature of the illness, it eventually develops in all cases. The emergence of the behavior often provides the essential clue to the diagnosis in a case with known developmental delay or hyperuricemia. Self-injury does not occur in the Lesch-Nyhan variants. These patients present with signs of motor delay or consequences of overproduction of uric acid. [3]
Physical Examination
The most salient feature of the general physical examination in classic cases of Lesch-Nyhan disease is growth retardation. Somatic growth is affected more than head circumference; bone age is affected only slightly. Testicular atrophy is common. Puberty is often delayed or absent. There may be evidence of tissue disfigurement, such as scarring of the lips or hands.
Neurologically, cognitive function is impaired, with average intelligence quotient (IQ) values of approximately 60. Basic sensory functions are intact, though motor function is severely compromised. All patients exhibit severe generalized dystonia. Some also exhibit other features, including choreoathetosis, opisthotonic spasms, and ballismus. Approximately 25% also display hyperreflexia and ankle clonus. The severity of the neurologic dysfunction precludes normal ambulation, and all patients are wheelchair bound.
Behavioral problems are also prominent. Frequent attempts toward self-injury may be evident (see the images below). Partial amputations of the fingers, lips, tongue, or oral mucosa, resulting from self-biting, are common. Serious injuries or scarring from repetitive self-abrasion or hitting also may result. In addition to self-injurious behavior, many patients display compulsive behaviors that often are interpreted as signs of aggression. These include hitting, spitting, coprolalia, copropraxia, and manipulative behavior.
The distal portions of several fingers are shortened by prior uncontrolled self-biting.
-
Purine metabolic pathways.
-
A small portion of the lower lip has been disfigured by persistent self-biting.
-
The distal portions of several fingers are shortened by prior uncontrolled self-biting.
-
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).
