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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Clinical features: This is a severe degenerative neurologic disease caused by a variant in the gene for aspartoacylase. The phenotype is variable, but presentation typically occurs in the first few months of life with delayed motor milestones. Thereafter, they may demonstrate macrocephaly, hypotonia, and intellectual disability. Life expectancy is variable.
Organic acid disorders and disorders of fatty acid oxidation
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Canavan leukodystrophy is a rare progressive neurological disorder that is caused by a defect in the ASPA gene. This defect leads to a deficiency of the enzyme aspartoacylase, which is responsible for the breakdown of N-acetylaspartic acid, a chemical that is essential for the correct functioning of the brain. The aspartoacylase deiciency leads to deterioration of the central nervous system (the brain and spinal cord), which is the main characteristic of the disorder. Canavan leukodystrophy has a higher prevalence in families of Eastern European Jewish ancestry.
Regeneration: Nanomaterials for Tissue Regeneration
Published in Harry F. Tibbals, Medical Nanotechnology and Nanomedicine, 2017
At the CNS Gene Therapy Center of Thomas Jefferson University in Philadelphia, researchers are working toward the goal of developing safe and effective in vivo gene therapy for the treatment of Canavan disease and other neurological disorders. Canavan disease is a leukodystrophy caused by a deficiency in the enzyme aspartoacylase that breaks down aspartic acid. The CNS Gene Therapy Center has developed gene therapy based on nonvi-ral plasmids in a lipid-entrapped, polycation-condensed delivery system for gene transfer into the central nervous system. This is an effective system that avoids the proliferative and immunological problems associated with virus and cell-based gene therapies. Toxicity and gene expression were tested in human cell cultures, showing effective transfer of genes for aspartoacylase and high levels of activity for the enzyme. The gene transfer system was then tested in rodents and primates before initial clinical tests on two children, with no significant adverse effects. The biochemical, radiological, and clinical changes in human patients are being assessed. If successful, this trial would have implications for Canavan disease, for which there is currently no treatment, and for other types of leukodystrophy [145].
Sialylated milk oligosaccharides alter neurotransmitters and brain metabolites in piglets: an In vivo magnetic resonance spectroscopic (MRS) study
Published in Nutritional Neuroscience, 2021
Hong Xin Wang, Yue Chen, Ziaul Haque, Michael de Veer, Gary Egan, Bing Wang
A positive correlation of brain NAA and total NAA, and total white matter volume was observed at TE 270 ms (Figure 5). These correlations were much stronger in both treatment groups compared with the control group (Figure 5A–B,P < .01). NAA is in a key MRS marker for neuronal cell integrity, neuronal health, viability and number [30]. It facilitates energy metabolism in neuronal mitochondria, and serves as a source of acetate for fatty acid and steroid synthesis in oligodendrocytes in the nervous system [31]. During early postnatal CNS development, the NAA-degrading enzyme aspartoacylase, is increased along with increased NAA production in neurons [30], while NAAG modulates glutamate release and may have a role in neuroprotection and synaptic plasticity [32]. The stronger correlation of NAA and total brain NAA with brain white matter volume in the two treatment groups compared with the control group piglets implies that SMOS supplementation might improve neuronal health and optimize neurodevelopment in early postnatal life. To our knowledge, these findings have not been previously reported.
Severe retinal degeneration in a patient with Canavan disease
Published in Ophthalmic Genetics, 2021
Matthew D. Benson, David J.A. Plemel, Paul R. Freund, James R. Lewis, Jörn Oliver Sass, Luzy Bähr, Corinne Gemperle-Britschgi, Patrick Ferreira, Ian M. MacDonald
Mutations in the gene ASPA are responsible for all cases of Canavan disease. This gene encodes aspartoacylase (aminoacylase-2), an enzyme that hydrolyses N-acetylaspartic acid (NAA) to aspartate and acetate in oligodendrocytes, for instance(4). Loss-of-function mutations in ASPA lead to reduced aspartoacylase activity with subsequent accumulation of NAA. Although the precise mechanism of disease in unclear, elevated levels of NAA are associated with aberrant myelination and spongy degeneration in the central nervous system(5). Both elevated levels of urinary or brain NAA and diffuse, subcortical, white matter changes seen with brain imaging support a diagnosis of Canavan disease(5).
Exploring the metabolomic profile of cerebellum after exposure to acute stress
Published in Stress, 2021
Aikaterini Iliou, Angeliki-Maria Vlaikou, Markus Nussbaumer, Dimitra Benaki, Emmanuel Mikros, Evangelos Gikas, Michaela D. Filiou
We have previously used metabolomic approaches to study neuropsychiatric phenotypes (Filiou et al., 2011, 2014, 2021; Papadopoulou et al., 2019; Zhang et al., 2011) and pertinent treatment responses (Kao et al., 2016; Nussbaumer et al., 2016; Park et al., 2016, 2017; Weckmann et al., 2017, 2019). Metabolomics has been also implemented to study stress effects in the brain, indicating alterations in lipids, amino acids, neurotransmitters and energy-related metabolites (Akimoto et al., 2019; Bassett et al., 2019; Dulka et al., 2017). Here, we report metabolic alterations in the cerebellum of mice after exposure to acute stress and we correlate metabolite levels with behavioral parameters. The most significantly altered metabolic pathway in our analysis was aspartate metabolism, which is implicated in neurotransmission. NAA is synthesized in neurons from aspartic acid and acetyl-coenzyme A, through acetylation by L-aspartate N-acetyltransferase. NAA is degraded by aspartoacylase (ASPA) which cleaves the acetate moiety of NAA to be used in lipid and myelin synthesis in oligodendrocytes responsible for the myelination of the neuronal axons. NAA turnover has been linked to behavioral deficits and neurodegenerative disorders. Region-specific myelin differences have been associated with resilience versus susceptibility upon chronic social defeat stress in mice (Bonnefil et al., 2019). Deletion of an aspartate N-acetyltransferase encoding gene induced behavioral deficits in rodents, including reduced social interaction and altered immobility time in the FST (Toriumi et al., 2015). Decreased NAA levels have been also reported in patients diagnosed with bipolar disorder, Alzheimer’s disease and stroke, pointing toward NAA as a marker of brain health (Deicken et al., 2003; Saunders, 2000; Valenzuela & Sachdev, 2001).