Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

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Recent research has shown that TNF‐á affects insulin signaling by up‐regulating ganglioside‐GM3 production in adipocytes; however little is known about these effects in skeletal muscle. Caveolae are specialized plasma membrane microdomains thought to serve as signaling platforms for several receptors including the insulin receptor (IR) and glucose transporters (Glut‐1, ‐4), via interaction with caveolin proteins (Cav‐1, ‐3). We hypothesized that exposure of C2C12 cells to TNFá will result in deregulation of the insulin signaling cascade and alteration of the pattern of IR and Glut‐4 localization to the plasma membrane by promoting a shift from the caveolae to other membrane domains enriched in ganglioside‐GM3 expression. Here, C2C12 myocytes were differentiated into skeletal myotubes and treated with TNF‐á, insulin, and a TNF‐á antagonist. Treated cells were subjected to Western blot analysis with antibodies against IR, phosphorylated IR, Akt, GM3‐synthase, Glut‐4, Cav‐1, Cav‐3, and actin (loading control). Western blot demonstrated higher levels of AKT, and GM3‐S after treatment with TNF‐á. Immunofuorescence analysis demonstrated a disruption of the colocalization of IR and Glut‐4 to caveolae domains in cells treated with TNF‐á, which was reversed by treatment with the antagonist. These results identify TNF‐á and gangliosides as potential therapeutic targets during insulin resistance.