Quantitative measurements with localized <sup>1</sup>H MR spectroscopy in children with Canavan's disease

Wittsack, HJ; Kugel, Harald; Roth, Bernhard; Heindel, Walter

doi:10.1002/jmri.1880060609

Cited by 83 publications

(30 citation statements)

References 20 publications

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“…The MRS is requested from the patient because of the MRI findings that were consistent with the CD reported in the literature. Specific NAA pike in MRS was also detected in our patient which is specific for CD (Figure 3) (6).…”

Section: Discussionsupporting

confidence: 58%

Canavan disease: a rare form of leukodystrophy

Doğan¹,

Sigirci²

2017

J Turgut Ozal Med Cent

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Canavan disease (CD) is a rare autosomal recessive leukodystrophy characterized by spongy degeneration of the white matter of brain. It is characterized by accumulation of N-acetyl aspartic (NAA) acid in mitochondria which inhibits myelin synthesis. Axial hypotonia, ataxia, defects in cognitive functions, defective visual follow and sucking, irritability and macrocephaly are seen in the patients. Increased high NAA peaks are seen magnetic resonance spectroscopy (MRS). Here we report a case with defective head control and could not sit without support who had no other symptoms before. She had axial hypotonia and bilateral nystagmus on neurological examination. The diagnosis of CD is based on these clinical findings and radiologic evaluations.

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Section: Discussionsupporting

confidence: 58%

Canavan disease: a rare form of leukodystrophy

Doğan¹,

Sigirci²

2017

J Turgut Ozal Med Cent

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“…This finding may have clinical significance for CD patients, who are reported to have 10-to 100-fold higher excretion of NAA in the urine than normal (Kvittingen et al, 1986;Hagenfeldt et al, 1987;Matalon et al, 1988) and a 0-to 3-fold increase in NAA levels in the brain as compared with normal individuals (Wittsack et al, 1996). One hypothesis on the pathogenesis of CD is that the increased brain NAA concentrations result from a lack of catabolic activity and the excess NAA plays an etiological role in the disease, possibly due to brain edema (Baslow, 2003).…”

Section: Discussionmentioning

confidence: 70%

Progress toward Acetate Supplementation Therapy for Canavan Disease: Glyceryl Triacetate Administration Increases Acetate, but NotN-Acetylaspartate, Levels in Brain

Mathew¹,

Arun²,

Madhavarao³

et al. 2005

J Pharmacol Exp Ther

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Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into L-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose-and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20-to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD.

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“…NAA levels measured by MRS have been shown to be changed in a number of neurological disorders and conditions. Most of these studies have detected decreases in NAA concentrations in the affected brain areas, with the notable exception of Canavan disease which involves accumulation of NAA throughout the brain (Wittsack et al, 1996). In earlier studies, the decreases in NAA associated with various neuropathologies were interpreted to represent irreversible loss of neurons.…”

Section: Magnetic Resonance Spectroscopy and Imaging Of Naamentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

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1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Quantitative measurements with localized ¹H MR spectroscopy in children with Canavan's disease

Cited by 83 publications

References 20 publications

Canavan disease: a rare form of leukodystrophy

Canavan disease: a rare form of leukodystrophy

Progress toward Acetate Supplementation Therapy for Canavan Disease: Glyceryl Triacetate Administration Increases Acetate, but NotN-Acetylaspartate, Levels in Brain

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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Quantitative measurements with localized 1H MR spectroscopy in children with Canavan's disease

Cited by 83 publications

References 20 publications

Canavan disease: a rare form of leukodystrophy

Canavan disease: a rare form of leukodystrophy

Progress toward Acetate Supplementation Therapy for Canavan Disease: Glyceryl Triacetate Administration Increases Acetate, but NotN-Acetylaspartate, Levels in Brain

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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Quantitative measurements with localized ¹H MR spectroscopy in children with Canavan's disease