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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.
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
Of the 47 annotated metabolites, 19 exhibited significant alterations between stressed and control mice as shown by univariate analysis employing the least overlapped peak, using the binned, normalized NMR data. These include metabolites related to neurotransmission, energy, purine/pyrimidine and amino acid metabolism (Figure 3). Regarding purine/pyrimidine metabolism, stressed mice exhibit lower levels of adenosine (Padj = 0.01), adenosine diphosphate (ADP) (Padj = 0.01), AMP (Padj<0.001), IMP (Padj = 0.02) and uridine monophosphate (UMP) (Padj = 0.02), whereas inosine (Padj = 0.01), hypoxanthine (Padj = 0.005) and uridine diphosphates (UDPs) (Padj = 0.03) levels were higher compared to control mice. Neurotransmission alterations in the cerebellum of stressed mice were evidenced by increased levels of gamma-aminobutyric acid (GABA) (Padj = 0.002) and ethanolamine (Padj = 0.003) as well as decreased levels of NAA (Padj = 0.02). The ratio of N-acetylaspartyl-glutamic acid (NAAG) to N-acetylaspartic acid was also significantly increased (Padj = 0.004). Amino acids showing statistically significant altered levels after stress exposure included arginine (Padj = 0.03), aspartic acid (Padj = 0.001), phenylalanine (Padj = 0.02) (increased in stressed versus control mice) and glutamine (Padj = 0.008) (decreased in stressed versus control mice), all of which are involved in neurotransmission, either as neurotransmitter precursors or as neurotransmitters. Αcetic acid (Padj = 0.001) and lactic acid (Padj = 0.01) levels were increased in stressed mice, whereas acetone (Padj<0.001) and formic acid (Padj = 0.04) levels were decreased. Detailed statistics of the metabolomic data are provided in Supplementary Table S4, while the boxplots of the non-significant metabolites are shown in Supplementary Figure S5.