Lhermitte–Duclos disease caused by a novel germline PTEN mutation R173P in a patient presenting with psychosis

Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.
Neuropathology and Applied Neurobiology (Impact Factor: 3.93). 09/2009; 36(1):86-9. DOI: 10.1111/j.1365-2990.2009.01041.x
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    ABSTRACT: PTEN's nodal role in a significant number of different metabolic pathways was revealed both by direct analysis, but also through the study of the pathologic features present in its absence. Majority of times the experiments are performed in vitro and are subjected to technical imperfections. For the PTEN mutations that result in loss of function, a specific clinical entity entitled PTEN Hamartoma Tumor Syndrome (PHTS) was described allowing in vivo study. One of the main characteristics of PHTS is the presence of vascular anomalies requiring acute and chronic medical management. In this chapter we will focus on describing the role of PTEN in vascular organization via clinical studies on pediatric patients with PHTS. We will start by a review of PTEN's activity in angiogenesis control proven as the PTEN mutation allows uninhibited angiogenesis stimulation by Akt/mTOR pathway. To integrate basic science findings into clinical picture, the characteristics of PTEN Hamartoma Tumor Syndrome with emphasis on the radiologic and histological description of typical vascular anomalies prevalent in PHTS will follow. We will analyze the current trends in therapeutic management including interventional radiology procedures and medical therapies. Data supporting the rationale of administration of oral rapamycin will be presented as the medication restores the lost inhibitory control of PTEN over mTOR and significantly improves acute symptomatology, decreases vascularity in the irregular vascular network and presumably prevents more vascular anomalies development with chronic use. Understanding the mechanism of action of PTEN can be done through one of the rare translational models where a real-life knock-off of a specific gene (as it happens in PHTS patients) dramatically influences the structure of the whole mTOR pathway, explaining the clinical findings that a directed therapy (already available) is restoring, at least partially, to the normal pattern.
    No preview · Article · Jan 2013
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    ABSTRACT: Lhermitte-Duclos Disease (LDD), a neurological manifestation of Cowden syndrome (CS), is a rare and benign cerebellar disorder, featured by dysplastic cerebellar ganglion cells which replace granular and Purkinje cells. PTEN is confirmed as the susceptibility gene for CS which represents the most complex features and is not easily recognizable. We reported two index patients with LDD diagnosed either in an isolated form or coexist with CS. These two patients displayed progressive though comparable phenotypes and were found to carry an identical PTEN c.950_953delTACT mutation in either germline or somatic sources of DNA, respectively. Negative or moderate expression levels of PTEN were validated by immunohistochemistry in corresponding patients' affected tissues. This study has revealed a novel pathogenicity locus to LDD/CS as a candidate for early molecular diagnosis. In addition, the differential PTEN mutation status with corresponding LDD phenotypes suggests a potential correlation between germline or somatic mutation and coexisting LDD/CS or isolated LDD, respectively. Furthermore, our data could lend some reference to the underlying molecular mechanism of LDD pathogenesis in the future.
    Full-text · Article · Sep 2013 · Clinical Genetics
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    ABSTRACT: Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP 3 ), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. This review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration.
    Full-text · Article · Sep 2015