Neuropathological Findings of a Patient With Pyruvate Dehydrogenase-e1-alpha Deficiency Presenting As a Cerebral Lactic-acidosis

Neuropathological findings are reported of a 6-month-old female child with a ''cerebral'' lactic acidosis. A mutation in the pyruvate dehydrogenase (PDH) E1alpha gene was found. Gross examination of the brain revealed a severe thinning of the cerebral parenchyma marked hydrocephalus sparing the aqueduct and fourth ventricle, agenesis of the corpus callosum and heterotopic noduli of gray matter in subependymal regions. Microscopical examination showed heterotopic inferior olives, absent pyramids and focal neuroglial overgrowth into meninges. In addition some heterotopia of Purkinje cells and dysplasia of the dentate nuclei were observed. There was a marked vascular proliferation with many thin-walled, congestive vessels in the cerebral and cerebellar white matter. and to a lesser extent in the striatum. To our knowledge these cerebellar and vascular abnormalities have not been reported before in patients with ''cerebral'' lactic acidosis.The combination of these neuropathological findings might be characteristic for PDH deficiency and more specifically for its E1alpha subtype. Neuropathological examination could lead to the retrospective diagnosis of PDH E1alpha deficiency in those cases where biochemical investigations were not or incompletely performed. This may have potential implications for genetic counseling

Pyruvate-dehydrogenase Deficiency - Clinical and Biochemical-diagnosis

A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathologic, and molecular genetic data. She was dysmorphic, with a high forehead, low-set ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus callosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH E1-alpha gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH E1-alpha gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF

Anterior fontanelle pressure monitoring for the evaluation of asymptomatic infants with increased head growth rate

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Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.

Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2)(*-)-dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473) and Thr(308) as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr(156/139), close to their active site Asp(166/149), in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein nitration as a major mechanism in the regulation of Ang II and insulin signaling pathways and more particularly as a key regulator of protein kinase activity.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe