Canavan disease

Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder...

Two 9-week-old female littermate German Shepherd puppies showed severe high-frequency low-amplitude trembling that worsened with movement. The white matter (WM) of the central nervous system (CNS) showed bilateral diffuse severe spongiosis in the cerebellum, brainstem, spinal cord, and the neuropil of the oculomotor and red nuclei. The cortical corona radiata was less severely affected. Rare necrotic or apoptotic glia-like cells also were identified in the WM. Luxol fast blue staining disclosed severe diffuse myelin loss in the entire CNS; peripheral nerves were spared...

Canavan disease (CD) is a fatal hereditary neurological disorder caused by a mutation in the aspartoacylase (ASPA) gene and characterized by neurological signs and vacuolation in the central nervous system (CNS). The mutation inhibits the hydrolysis of N-acetyl-aspartate (NAA) resulting in accumulation of NAA in the CNS. A new Aspa-knockout rat was generated by transcription activator-like effector nuclease (TALEN) technology. Herein we describe the pathological and morphometrical findings in the brain and spinal cords of Aspa-knockout rats...

Pulmonary balloon valvuloplasty (PBV) is the treatment of choice for subjects with isolated pulmonary valve stenosis (IPS). The purpose of this study was to define fetal echocardiographic features associated with an inpatient PBV prior to newborn hospital discharge and characterize resource utilization of IPS fetuses among participating centers. Six center, retrospective case series of singleton fetuses identified between 2010 and 2020 with IPS. Third-trimester echocardiogram data was compared with postnatal data, included pulmonary valve Doppler velocities, pulmonary valve insufficiency and ductus arteriosus flow direction...

Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools. In this review, we talk about these MRI study findings for each leukodystrophy, associated genetics, blood work that can help in differentiation, emerging diagnostics, and a follow-up imaging strategy...

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OBJECTIVE: To analyze the clinical phenotype and genetic characteristics for a child with Canavan disease. METHODS: A child who was admitted to the Children's Hospital Affiliated to Shandong University on April 9, 2021 for inability to uphold his head for 2 months and increased muscle tone for one week was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored compound heterozygous variants of the ASPA gene, including a paternally derived c...

Canavan disease (CD, OMIM# 271900) is an autosomal recessive neurodegenerative disorder caused by homozygous or compound heterozygous mutations in ASPA gene, which result in catalytic deficiency of the aspartoacylase enzyme and the accumulation of N-acetylaspartic acid (NAA). Clinical presentation varies according to the age of disease onset. Here, we generated a human induced pluripotent stem cell line (hiPSCs) SDQLCHi064-A from a 5-month old boy with CD carrying two novel frame shift mutations c.556_559dupGTTC (p...

Canavan disease is a leukodystrophy caused by ASPA mutations that diminish oligodendroglial aspartoacylase activity, and is characterized by markedly elevated brain concentrations of the aspartoacylase substrate N-acetyl-l-aspartate (NAA) and by astroglial and intramyelinic vacuolation. Astroglia express NaDC3 (encoded by SLC13A3), a sodium-coupled transporter for NAA and other dicarboxylates. Astroglial conditional Slc13a3 deletion in aspartoacylase-deficient Canavan disease model mice ("CD mice") reversed brain NAA elevation and improved motor function...

AIMS: To evaluate changes in glycated haemoglobin (HbA1 c) and sensor-based glycaemic metrics after glucose sensor commencement in adults with T1D. METHODS: We performed a retrospective observational single-centre study on HbA1 c, and sensor-based glycaemic data following the initiation of continuous glucose monitoring (CGM) in adults with T1D (n = 209). RESULTS: We observed an overall improvement in HbA1 c from 66 (59-78) mmol/mol [8...

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia...

INTRODUCTION: Hafnia alvei is a Gram-negative, facultative anaerobic bacillus that is most often found as an enteric commensal. It is seldom considered to be pathogenic in immunocompetent individuals. CASE REPORT: We describe a case of a 23-year-old, previously healthy male, who presented to the emergency department with a two-day history of hemoptysis, mild dyspnea, pleuritic chest pain, fevers, and chills. Bloods revealed leukocytosis and elevated C-reactive protein...

N-acetyl-L-aspartic acid (NAA) is a prominent amino acid derivative primarily associated with vertebrate brain metabolism. This review delineates the critical role of NAA across various cell types and its significance in pathophysiological contexts, including Canavan disease and cancer metabolism. Although traditionally linked with myelination and aspartoacylase-driven carbon donation, its significance as a carbon source for myelination remains debated. Evidence suggests that intact NAA might substantially impact cellular signaling, particularly processes such as histone acetylation...

Canavan disease (CD) is a leukodystrophy caused by mutations in the N-acetylaspartate (NAA) hydrolase aspartoacylase (ASPA). Inability to degrade NAA and its accumulation in the brain results in spongiform myelin degeneration. NAA is mainly synthesized by neurons, where it is also a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). Hydrolysis of this peptide by glutamate carboxypeptidases is an additional source of extracellular NAA besides the instant neuronal release of NAA. This study examines to what extent NAA released from NAAG contributes to NAA accumulation and pathogenesis in the brain of Aspanur7/nur7 mutant mice, an established model of CD...

BACKGROUND: Patients with esophageal cancer often receive care in a collaborative (multi-institutional) treatment model as opposed to a single institutional model. The effect of a collaborative model on the quality of trimodality therapy and survival is unknown. METHODS: The National Cancer Database (NCDB) was used to identify patients receiving neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy for esophageal cancer between 2012-2017. Patients who received neoadjuvant therapy and surgery at a single institution were compared to those that received collaborative treatment across multiple institutions...

Myelin defects cause a collection of myelin disorders in the brain. The lack of human models has limited us from better understanding pathological mechanisms of myelin diseases. While human induced pluripotent stem cell (hiPSC)-derived spheroids or organoids have been used to study brain development and disorders, it has been difficult to recapitulate mature myelination in these structures. Here, we have developed a method to generate three-dimensional (3D) myelin spheroids from hiPSCs in a robust and reproducible manner...

BACKGROUND: Advanced vessel sealing electrosurgical systems have been widely adopted for grasping, cutting, and sealing vessels. Data remain sparse with regard to its use in thoracic procedures. Thus, a prospective case series, utilizing the ENSEAL X1 Curved Jaw Tissue Sealer (X1CJ) and its companion energy source, the Generator 11 (GEN11), in thoracic procedures was performed in a Japanese cohort. METHODS: Subjects were recruited at two Japanese surgical sites...

BACKGROUND: In some cases of right-sided lung cancer, tumor extension, bronchial involvement, or pulmonary artery infiltration may necessitate bilobectomy. Although the middle lobe is believed to represent a fraction of total lung function, the morbidity and mortality associated with bilobectomy is not well described. METHODS: We retrospectively identified patients in The Society of Thoracic Surgeons Database who underwent lobectomy, bilobectomy, or pneumonectomy for lung cancer from 2009 to 2017...

Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance...

BACKGROUND: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up. SUMMARY: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team...