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Canavan disease

Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
October 4, 2016: Neurobiology of Disease
Hibret Tilahun, Binyam Fekadu, Habtamu Abdisa, Maureen Canavan, Erika Linnander, Elizabeth H Bradley, Peter Berman
Ethiopia implemented an innovative community-based health program, called the health extension program, to enhance access to basic health promotion, disease prevention and selected curative services by establishing health posts in every village, also called kebeles, with average of 5000 people, staffed with two health extension workers (HEWs). This time and motion study was done to estimate the amount of time that HEWs spend on various work duties and to explore differences in urban compared with rural settings and among regions...
September 21, 2016: Health Policy and Planning
Osama K Zaki, Navaneethakrishnan Krishnamoorthy, Heba S El Abd, Soumaya A Harche, Reem A Mattar, Rana S Al Disi, Mariam Y Nofal, Rajaa El Bekay, Khalid A Ahmed, C George Priya Doss, Hatem Zayed
Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme, which catalyzes the hydrolysis of N-acetyl-L-aspartate (NAA) into aspartate and acetate. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on two Egyptian patients diagnosed with CD, the first patient harbors five missense mutations (c...
August 17, 2016: Metabolic Brain Disease
Matthew Maddocks, Samantha S C Kon, Jane L Canavan, Sarah E Jones, Claire M Nolan, Alex Labey, Michael I Polkey, William D-C Man
BACKGROUND: Frailty is an important clinical syndrome that is consistently associated with adverse outcomes in older people. The relevance of frailty to chronic respiratory disease and its management is unknown. OBJECTIVES: To determine the prevalence of frailty among patients with stable COPD and examine whether frailty affects completion and outcomes of pulmonary rehabilitation. METHODS: 816 outpatients with COPD (mean (SD) age 70 (10) years, FEV1% predicted 48...
June 12, 2016: Thorax
Sarah Jolly, Alexander Fudge, Nigel Pringle, William D Richardson, Huiliang Li
Detection of gene expression in different types of brain cells e.g., neurons, astrocytes, oligodendrocytes, oligodendrocyte precursors and microglia, can be hampered by the lack of specific primary or secondary antibodies for immunostaining. Here we describe a protocol to detect the expression of three different genes in the same brain section using double fluorescence in situ hybridization with two gene-specific probes followed by immunostaining with an antibody of high specificity directed against the protein encoded by a third gene...
2016: Journal of Visualized Experiments: JoVE
Seemin Seher Ahmed, Stefan A Schattgen, Ashley E Frakes, Elif M Sikoglu, Qin Su, Jia Li, Thomas G Hampton, Andrew R Denninger, Daniel A Kirschner, Brian Kaspar, Reuben Matalon, Guangping Gao
Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice...
June 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Claire M Nolan, Louise Longworth, Joanne Lord, Jane L Canavan, Sarah E Jones, Samantha S C Kon, William D-C Man
BACKGROUND: The EQ-5D, a generic health status questionnaire that is widely used in health economic evaluation, was recently expanded to the EQ-5D-5L to address criticisms of unresponsiveness and ceiling effect. AIMS: To describe the validity, responsiveness and minimum important difference of the EQ-5D-5L in COPD. METHODS: Study 1: The validity of the EQ-5D-5L utility index and visual analogue scale (EQ-VAS) was compared with four established disease-specific health status questionnaires and other measures of disease severity in 616 stable outpatients with COPD...
June 2016: Thorax
Vykuntaraju K Gowda, Maya D Bhat, Varun M Srinivasan, Chandrajit Prasad, Asha Benakappa, Mohammed Faruq
BACKGROUND: Canavan disease is an autosomal recessive disorder with spongy degeneration of white matter of the brain. It presents with developmental delay, visual problems and macrocephaly. PATIENT DESCRIPTION: We report a ten-month old boy with Canavan disease who presented with global developmental delay, seizures, abnormal eye movements and microcephaly. RESULTS: MRI brain revealed diffuse involvement of the supra tentorial white matter, globus pallidi, thalami, dentate nuclei and brainstem with sparing of the corpus callosum...
September 2016: Brain & Development
Andrew Smyth, Matthew Griffin, Salim Yusuf, Johannes F E Mann, Donal Reddan, Michelle Canavan, John Newell, Martin O'Donnell
BACKGROUND: Chronic kidney disease (CKD) is prevalent and associated with significant morbidity and mortality. Dietary modification may be an approach to reducing CKD. DESIGN: In this prospective cohort study, we evaluated the association between diet quality, sodium and potassium intakes, and major renal outcomes. A total of 544,635 community-dwelling adults, aged 51 to 70 years, living in 6 states and 2 urban areas in the United States, from the National Institutes of Health-American Association of Retired Persons Diet and Health Study...
September 2016: Journal of Renal Nutrition
R T Grimes, K Bennett, R Canavan, L Tilson, M C Henman
AIMS: To measure the costs associated with the use of antidiabetic agents, monitoring materials and cardiovascular disease (CVD) agents in the management of newly treated type 2 diabetes, and to investigate the factors associated with these costs. METHODS: A population-based retrospective cohort study was conducted using the Irish national pharmacy claims database. Newly treated patients were identified for 2012 and followed for one year post treatment initiation...
March 2016: Diabetes Research and Clinical Practice
Navaneethakrishnan Krishnamoorthy, Hatem Zayed
Aspartoacylase (ASPA) is an abundant enzyme in the brain, which catalyzes the conversion of N-acetylaspartate into acetate and aspartate, deficiency in its activity leads to degeneration of the white matter of the brain and is a recognized cause of Canavan disease (CD), which affect children. Although genotype-phenotype correlation have been reported for Canavan disease patients, this relationships is still not straightforward. In this communication, we use molecular modeling to address the structural consequences resulting from the missense variant p...
June 2016: Metabolic Brain Disease
Mahesh Kamate, Vinayak Kabate, Mukul Malhotra
No abstract text is available yet for this article.
March 2016: Pediatric Neurology
Mahmoudreza Ashrafi, Alireza Tavasoli, Pegah Katibeh, Omid Aryani, Mohammad Vafaee-Shahi
Objective Canavan disease (CD) is a type of vacuolating leukodystrophy with autosomal recessive inheritance. Aspartoacylase deficiency results in decrease of myelin biosynthesis, dysmyelination and brain edema. Although CD is a very common in Ashkenazi Jews patients, several cases have been reported from non-Jewish population. This report is based on a homozygous C.202G>A mutation in the ASPA gene identified from an Iranian patient. To our knowledge, this type of mutation has not been reported in non-Jewish population in the literature...
2015: Iranian Journal of Child Neurology
Theresa N Canavan, Craig A Elmets, Wendy L Cantrell, John M Evans, Boni E Elewski
Our ability to successfully treat patients with moderate to severe psoriasis has improved significantly over the last several years with the development of more targeted therapies. IL-17A, a member of the IL-17 family of interleukins, is involved in regulating the innate and adaptive immune systems and has been identified as a key cytokine involved in the pathogenesis of psoriasis and psoriatic arthritis. In this review, we summarize our understanding of IL-17 and its role in psoriasis and psoriatic arthritis, as well as key findings from clinical trials using anti-IL-17 medications for the treatment of the aforementioned diseases...
February 2016: American Journal of Clinical Dermatology
Osama K Zaki, Heba S El Abd, Shaimaa A Mohamed, Hatem Zayed
Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme that catalyzes the deacetylation of NAA. It is a severe progressive leukodystrophy characterized by spongiform degeneration of the white matter of the brain. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on a 2 year-old Egyptian child with severe CD who harbors a novel homozygous missense variant (c...
June 2016: Metabolic Brain Disease
Dominic J Gessler, Guangping Gao
Metabolic disorders comprise a large group of heterogeneous diseases ranging from very prevalent diseases such as diabetes mellitus to rare genetic disorders like Canavan Disease. Whether either of these diseases is amendable by gene therapy depends to a large degree on the knowledge of their pathomechanism, availability of the therapeutic gene, vector selection, and availability of suitable animal models. In this book chapter, we review three metabolic disorders of the central nervous system (CNS; Canavan Disease, Niemann-Pick disease and Phenylketonuria) to give examples for primary and secondary metabolic disorders of the brain and the attempts that have been made to use adeno-associated virus (AAV) based gene therapy for treatment...
2016: Methods in Molecular Biology
Catherine Sarret, Odile Boespflug-Tanguy, Diana Rodriguez
Canavan disease (CD) is a rare metabolic disorder caused by aspartoacylase (ASPA) deficiency. It leads to severe neurological degeneration with spongiform brain degeneration. Accumulation of N-acetylaspartate (NAA) in brain and urine is specific to the disease and guides diagnosis. Magnetic resonance imaging (MRI) usually shows diffuse white matter abnormalities with involvement of the basal ganglia. Mild forms of the disease with a more favorable clinical course and radiological involvement of the basal ganglia without white matter abnormalities have also been reported...
April 2016: Metabolic Brain Disease
Qinzhe Wang, Mojun Zhao, Gwenn G Parungao, Ronald E Viola
Canavan disease (CD) is a neurological disorder caused by an interruption in the metabolism of N-acetylaspartate (NAA). Numerous mutations have been found in the enzyme that hydrolyzes NAA, and the catalytic activity of aspartoacylase is significantly impaired in CD patients. Recent studies have also supported an important role in CD for the enzyme that catalyzes the synthesis of NAA in the brain. However, previous attempts to study this enzyme had not succeeded in obtaining a soluble, stable and active form of this membrane-associated protein...
March 2016: Protein Expression and Purification
Helena Maier, Lihua Wang-Eckhardt, Dieter Hartmann, Volkmar Gieselmann, Matthias Eckhardt
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood...
October 28, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Stefan A Hoyng, Fred de Winter, Martijn R Tannemaat, Bas Blits, Martijn J A Malessy, Joost Verhaagen
Clinical phase I/II studies have demonstrated the safety of gene therapy for a variety of central nervous system disorders, including Canavan's, Parkinson's (PD) and Alzheimer's disease (AD), retinal diseases and pain. The majority of gene therapy studies in the CNS have used adeno-associated viral vectors (AAV) and the first AAV-based therapeutic, a vector encoding lipoprotein lipase, is now marketed in Europe under the name Glybera. These remarkable advances may become relevant to translational research on gene therapy to promote peripheral nervous system (PNS) repair...
2015: Frontiers in Molecular Neuroscience
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