scholarly journals Pharmacological Restoration of Visual Function in a Zebrafish Model of von-Hippel Lindau Disease

2018 ◽  
Author(s):  
Rebecca Ward ◽  
Kayleigh Slater ◽  
Zaheer Ali ◽  
Alison L Reynolds ◽  
Lasse D Jensen ◽  
...  
Keyword(s):  
Visual Function ◽  
Vision Loss ◽  
Kinase Inhibitor ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Zebrafish Model ◽  
Von Hippel Lindau ◽  
Organ Systems ◽  
Vhl Disease

AbstractVon Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterized by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality ofVhl-/-micein uterorestricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in thevhlgene represent a viable, alterative vertebrate model to investigate associated ocularloss-of-functionphenotypes. Previous studies reported neovascularization of the brain, eye and trunk together with odema in thevhl-/-zebrafish eye. In this study, we demonstratevhl-/-zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in thevhl-/-eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed invhl-/-zebrafish. We conclude that the zebrafishvhlgene contributes to the endogenous molecular barrier that prevents development of intraretinal vasculature and that sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal and choroidal vessels invhl-/-zebrafish.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

Surgical management of spinal cord hemangioblastomas in patients with von Hippel—Lindau disease

2003 ◽  
Vol 98 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Russell R. Lonser ◽  
Robert J. Weil ◽  
John E. Wanebo ◽  
Hetty L. Devroom ◽  
Edward H. Oldfield
Keyword(s):  
Spinal Cord ◽  
Surgical Management ◽  
Postoperative Outcome ◽  
Tumor Location ◽  
Neurological Dysfunction ◽  
Autosomal Dominant Disorder ◽  
Content Type ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
Fine Print

Object. Von Hippel—Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients. Methods. Forty-four consecutive patients with VHL disease (26 men and 18 women) who underwent 55 operations with resection of 86 spinal cord hemangioblastomas (mean age at surgery 34 years; range 20–58 years) at the National Institutes of Health were included in this study (mean clinical follow up 44 months). Patient examination, review of hospital charts, operative findings, and magnetic resonance imaging studies were used to analyze surgical management and its outcome. To evaluate the clinical course, clinical grades were assigned to patients before and after surgery. Preoperative neurological status, tumor size, and tumor location were predictive of postoperative outcome. Patients with no or minimal preoperative neurological dysfunction, with lesions smaller than 500 mm3, and with dorsal lesions were more likely to have no or minimal neurological impairment. Syrinx resolution was the result of tumor removal and was not influenced by whether the syrinx cavity was entered. Conclusions. Spinal cord hemangioblastomas can be safely removed in the majority of patients with VHL disease. Generally in these patients, hemangioblastomas of the spinal cord should be removed when they produce symptoms or signs.

Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex

2019 ◽  
Vol 20 (1) ◽  
pp. 217-240 ◽  
Author(s):  
Catherine L. Salussolia ◽  
Katarzyna Klonowska ◽  
David J. Kwiatkowski ◽  
Mustafa Sahin
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Phenotypic Variability ◽  
Mtor Inhibitors ◽  
Multiple Organ ◽  
Great Promise ◽  
Optimal Timing ◽  
Autosomal Dominant Disorder ◽  
Organ Systems ◽  
Neuropsychiatric Manifestations

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.

scholarly journals Lactulose to the Rescue: A Case of Toxic Hepatic Encephalopathy Caused by Portosystemic Shunting and Epistaxis in a Patient with Hereditary Hemorrhagic Telangiectasia

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Ruchit N. Shah ◽  
Michael Makar ◽  
Nasir Akhtar ◽  
Erin Forster
Keyword(s):  
Hepatic Encephalopathy ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Rare Case ◽  
Autosomal Dominant ◽  
Rare Complication ◽  
Multiple Organ ◽  
Autosomal Dominant Disorder ◽  
Life Saving ◽  
Organ Systems ◽  
Portosystemic Shunting

Hereditary hemorrhagic telangiectasia (HHT) is an uncommon autosomal dominant disorder characterized by telangiectasias and arteriovenous malformations. Multiple organ systems are involved including the skin, lungs, gastrointestinal tract, and brain. Hepatic encephalopathy is an extremely rare complication of HHT and early diagnosis and treatment can be life-saving. We present a rare case of hepatic encephalopathy caused by HHT-induced portosystemic shunting treated with lactulose.

Endocrine Manifestations of von Hippel–Lindau Disease

2015 ◽  
Vol 139 (2) ◽  
pp. 263-268 ◽  
Author(s):  
Clarissa Cassol ◽  
Ozgur Mete
Keyword(s):  
Neuroendocrine Tumors ◽  
Autosomal Dominant ◽  
Suppressor Gene ◽  
Autosomal Dominant Disorder ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Sporadic Cases ◽  
Vhl Disease

von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

scholarly journals Is there a role for biomarkers in surveillance of pancreatic neuroendocrine neoplasms in Von Hippel-Lindau’s disease?

2021 ◽  
Author(s):  
Myrthe R Naber ◽  
Saya Ahmad ◽  
Annemarie A Verrijn Stuart ◽  
Rachel H Giles ◽  
Gerlof D Valk ◽  
...  
Keyword(s):  
Early Detection ◽  
Unmet Need ◽  
Neuroendocrine Neoplasms ◽  
Surveillance Program ◽  
Autosomal Dominant Disorder ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Von Hippel Lindau ◽  
Vhl Disease

Abstract Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess what their clinical relevance in diagnosing panNENs in VHL patients is. We searched the databases of Pubmed/Medline, Embase and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.

scholarly journals DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

2020 ◽  
pp. jmedgenet-2019-106805
Author(s):  
Jonathan Marquez ◽  
Nina Mann ◽  
Kathya Arana ◽  
Engin Deniz ◽  
Weizhen Ji ◽  
...  
Keyword(s):  
Kidney Tissue ◽  
Multiple Organ ◽  
Cystic Kidney ◽  
Loss Of Function ◽  
Craniofacial Malformations ◽  
Cystic Kidneys ◽  
Organ Systems ◽  
Discs Large ◽  
Frog Model ◽  
Shed Light

BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

scholarly journals Temporal Arteritis and Vision Loss in Microscopic Polyangiitis: A Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Alexander G. Goglia ◽  
Michael Makar ◽  
Craig Vanuitert ◽  
Vadim Finkelstein
Keyword(s):  
Vision Loss ◽  
Temporal Arteritis ◽  
Microscopic Polyangiitis ◽  
Systemic Vasculitis ◽  
Temporal Artery ◽  
Multiple Organ ◽  
The Body ◽  
Temporal Artery Biopsy ◽  
Rare Finding ◽  
Organ Systems

Microscopic polyangiitis (MPA) is an idiopathic autoimmune disease characterized by systemic vasculitis. While the lungs and kidneys are the major organs affected by MPA, it is known to involve multiple organ systems throughout the body. Temporal artery involvement is a very rare finding in MPA. This report presents a patient whose initial presentation was consistent with giant cell arteritis but was ultimately found to have microscopic polyangiitis. It highlights the importance of considering alternative types of vasculitis in the differential diagnosis for patients with atypical temporal artery biopsy findings.

scholarly journals Vascular Injury Changes Topology of Vessel Network to Adapt to Partition of Blood Flow for New Arteriovenous Specification

2020 ◽  
Author(s):  
Kyung In Baek ◽  
Shyr-Shea Chang ◽  
Chih-Chiang Chang ◽  
Mehrdad Roustei ◽  
Yichen Ding ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell Proliferation ◽  
Loss Of Function ◽  
Vascular Networks ◽  
Loop Formation ◽  
Zebrafish Model ◽  
Cardinal Vein ◽  
Segmental Artery ◽  
Vascular Regeneration ◽  
Organ Systems

AbstractWithin vascular networks, wall shear stress (WSS) modulates endothelial cell proliferation and arteriovenous specification. Mechano-responsive signaling pathways enable vessels within a connected network to structurally adapt to properly partition blood flow between different parts of organ systems. Here, we study vascular regeneration in a zebrafish model system, performing tail amputation of the Dorsal Aorta (DA)-Posterior Cardinal Vein (PCV) embryonic circulatory loop (ECL) at 3 days post fertilization (dpf). Following severing the ECL, the topology of the micro-circular network is reorganized to engender local increase in blood flow and peak WSS in the closest Segmental Artery (SeA) to the amputation site. Remodeling of this artery increases its radius, and blood flow. These hemodynamic WSS cues activate post-angiogenic Notch-ephrinb2 signaling to guide network reconnection and restore microcirculation. Gain- and loss-of-function analyses of Notch and ephrinb2 pathways, manipulations of WSS by modulating myocardial contractility and blood viscosity directly implicate that hemodynamically activated post-angiogenic Notch-ephrinb2 signaling guides network reconnection and restore microcirculation. Taken together, amputation of the DA-PCV loop induces changes in microvascular topology to partition blood flow and increase WSS-mediated Notch-ephrinb2 pathway, driving the new DLAV-PCV loop formation for restoring local microcirculation.

scholarly journals Primary Clear Cell Microcystic Adenoma of the Sinonasal Cavity: Pathological or Fortuitous Association?

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Rosalin Cooper ◽  
Hannah Markham ◽  
Jeffery Theaker ◽  
Adrian Bateman ◽  
David Bunyan ◽  
...  
Keyword(s):  
Clear Cell ◽  
Surgical Excision ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Cell Renal Cell Carcinoma ◽  
Inherited Cancer ◽  
Von Hippel Lindau ◽  
Microcystic Adenoma ◽  
Vhl Disease ◽  
Inherited Cancer Syndrome

Primary clear cell microcystic adenoma of the sinonasal cavity is rare. It has previously been described only as a VHL-associated tumour. Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome characterised by an elevated risk of neoplasia including clear cell renal cell carcinoma (ccRCC), haemangioblastoma, and phaeochromocytoma. We describe the second reported case of a primary clear cell microcystic adenoma of the sinonasal cavity. The 39-year-old patient with VHL syndrome had previously undergone resection and ablation of ccRCC. He presented with epistaxis. Imaging demonstrated a mass in the ethmoid sinus. Initial clinical suspicion was of metastatic ccRCC. However, tumour morphology and immunoprofile were distinct from the previous ccRCC and supported a diagnosis of primary microcystic adenoma. Analysis of DNA extracted from sinonasal tumour tissue did not show loss of the wild-type allele at the VHL locus. Although this did not support tumour association with VHL disease, it was not possible to look for a loss-of-function mutation. The association of primary microcystic adenoma of the sinonasal cavity with VHL disease remains speculative. These lesions are benign but are likely to require regular surveillance. Such tumours may require repeated surgical excision.

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