MUTATIONS AND PHENOTYPE IN ISOLATED GLYCEROL KINASE-DEFICIENCY

We demonstrate that isolated glycerol kinase (GK) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated G K deficiency can be silent. Patient 2 had GK deficiency and a severe p henotype involving psychomotor retardation and growth delay, bone dysp lasia, and seizures, similar to the severe phenotype of one of the fir st described cases of GK deficiency. His younger brother, patient 3, a lso had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors i n causation of the severe phenotype of patient 2. Patient 4 had both G K deficiency with mental retardation and a GK missense mutation (D440V ). Possible explanations for the phenotypic variation of these four pa tients include ascertainment bias; metabolic or environmental stress a s a precipitating factor in revealing GK-related changes, as has previ ously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK de ficiency on normal development.