Late onset neurological symptoms involving the motor system have been reported in adult patients with early treated phenylketonuria (Thompson et al 1990, Lancet). Impairment of fine motor skills is known to be a valid indicator of mild forms of brain damage in children. We investigated 20 children (10 f, 10 m, age 13.1 (12-14)) with early treated PKU still under diet and 20 controls, matched for age, sex and social status of the family. We employed a test battery (Motorische Leistungsserie, Schoppe), which requires different dimensions of fine motor abilities. The subtests are (1) steadiness (keeping a stable position), (2) line following (slow directed movements), (3) metal sticks (pegboard with long or short sticks), (4) aiming (fast aiming movements), (5) tapping, (6) pursuit rotor (visual-motor integration). We found significantly impaired fine motor skills in PKU patients compared to controls in all tested variables. The results for dominant and nondominant hand were comparable. Performance in subtests 1 and 2 (measuring stillness of hand, esp. tremor) was significantly correlated to the actual blood level of phenylalanine (796 (67 -1489) uMol/l phenylalanine; test 1: PCC 0.48, p<0.05; test 2: PCC 0.61, p<0.005). The assessment of fine motor skills with automatic registration techniques seems to be an appropriate approach to detect mild forms of dysfunction in the motor system. By longitudinal examinations it will be possible to decide wether impaired fine motor skills in PKU are markers of a mild, but stable impairment of brain function (as for example a subnormal IQ) or an early indicator of a further deteriorating neurological syndrome. (Grant by DFG 196/3-1 and German Fed Dept. of Research and Technology FK7 706568/0).