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Canavan disease

Marisa I Mendes, Desirée Ec Smith, Ana Pop, Pascal Lennertz, Matilde R Fernandez Ojeda, Warsha A Kanhai, Silvy J M van Dooren, Yair Anikster, Ivo Barić, Carolien Boelen, Jaime Campistol, Lonneke de Boer, Ariana Kariminejad, Hulya Kayserili, Agathe Roubertie, Krijn T Verbruggen, Christine Vianey-Saban, Monique Williams, Gajja S Salomons
We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase - the hydrolysis of N-acetyl-L-aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC-MS/MS...
January 19, 2017: Human Mutation
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
: Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-l-aspartate (NAA) to acetate and l-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Bharani Thangavelu, Vinay Mutthamsetty, Qinzhe Wang, Ronald E Viola
Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-l-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-associated enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examined (Wang et al...
December 8, 2016: Bioorganic & Medicinal Chemistry
Steven T Merrill, Gary R Nelson, Nicola Longo, Joshua L Bonkowsky
BACKGROUND: Canavan disease is a devastating autosomal recessive leukodystrophy leading to spongiform degeneration of the white matter. There is no cure or treatment for Canavan disease, and disease progression is poorly understood. RESULTS: We report a new presentation of a patient found to have Canavan disease; brain magnetic resonance imaging (MRI) revealed white matter cytotoxic edema, indicative of an acute active destructive process. We performed a comprehensive review of published cases of Canavan disease reporting brain MRI findings, and found that cytotoxic brain edema is frequently reported in early Canavan disease...
December 7, 2016: Orphanet Journal of Rare Diseases
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-L-aspartate (NAA) to acetate and L-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Trishul Siddharthan, Tracy Rabin, Maureen E Canavan, Faith Nassali, Phillip Kirchhoff, Robert Kalyesubula, Steven Coca, Asghar Rastegar, Felix Knauf
BACKGROUND: The majority of non-communicable disease related deaths occur in low- and middle-income countries. Patient-centered care is an essential component of chronic disease management in high income settings. OBJECTIVE: To examine feasibility of implementation of a validated patient-centered education tool among patients with heart failure in Uganda. DESIGN: Mixed-methods, prospective cohort. SETTINGS: A private and public cardiology clinic in Mulago National Referral and Teaching Hospital, Kampala, Uganda...
2016: PloS One
Mahesh H Hampe, Shrimant N Panaskar, Ashwini A Yadav, Pramod W Ingale
OBJECTIVE: The present study highlights the feasibility of gas chromatography/mass spectrometry (GC/MS)-based analysis for simultaneous detection of >200 marker metabolites in urine found in characteristic pattern in inborn errors of metabolism (IEM) in India. DESIGN AND METHODS: During this retrospective study conducted from July 2013 to January 2016, we collected urine specimens on filter papers from Indian children across the country along with relevant demographic and clinical data...
October 23, 2016: Clinical Biochemistry
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...
December 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...
November 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...
March 26, 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
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