The pale tremor (plt) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor, hypopigmentation, spongiform degeneration of the brain and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. In humans, the missense mutation FIG4I41T combined with a FIG4 null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show that Fig4 null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller caliber axons lack myelin sheaths entirely, while many large and intermediate caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In the Fig4 null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution but the number of myelinating OLs is greatly compromised. The total number of axons in the Fig4 null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression of Fig4, demonstrating a non-cell-autonomous function of Fig4 in OL maturation and myelin development. In transgenic mice with global over-expression of the human pathogenic FIG4 variant I41T there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4I41T mutant protein.

The P300 complex was derived from the electroencephalogram (EEG) as subjects mentally counted infrequent large checkerboard visual stimuli, presented randomly among frequent small checkerboard stimuli. Use of low contrast (10%) stimuli and four midline scalp electrodes, facilitated separation of cognitive and sensory components and enabled the P300 complex to be resolved into three distinct components--N200, P3a, and P3b. In 20 healthy adult subjects normative data were established and the P3a and P3b components were shown to depend on cognitive function. In 19 age-matched cirrhotic patients without overt hepatic encephalopathy (HE) the EEG and visual evoked potentials (VEPs) were normal, but latencies of P3a and/or P3b were prolonged in 9. Prolonged latencies were not associated with an abnormal number connection test. Ten additional age-matched cirrhotic patients without overt HE, who were alcohol, drug, and caffeine free, were randomized to receive flumazenil (1 mg) and placebo intravenously, double-blind. After flumazenil or placebo, latencies of P3a and P3b and psychometric test results did not change significantly. These findings suggest that in cirrhotic patients without overt HE (i) impaired cognitive sensory function may occur in the absence of abnormalities of a standard psychometric test, the EEG, or VEPs, and (ii) increased latencies of P3a and P3b may constitute a component of subclinical HE, which is not mediated by increased brain levels of central benzodiazepine receptor agonist ligands.

A 46-year-old man underwent subtotal resection of a 2.8 Â 2.7cm left temporoparietal glioblastoma (Fig. 1A-B). Levetiracetam 500 mg BID was started prophylactically for seizures. He was dis-

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