Follow-Up of a Child with Hypoacetylaspartia

Boltshauser, Eugen; Schmitt, Beatriz Dittrich; Wevers, Ron A.; Engelke, Udo F. H.; Burlina, A.B.

doi:10.1055/s-2004-821036

Cited by 33 publications

(17 citation statements)

References 22 publications

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“…The disorder has been reported in two unrelated girls and is characterized by severe hypomyelination, absence of psychomotor development, and a near complete lack of myelination in cerebral MRI scans. In another remarkable case, a child with reduced myelination, psychomotor retardation, secondary microcephaly and seizures was reported to have brain NAA levels too low to detect by MRS, possibly due to a genetic mutation in the gene for the NAA synthetic enzyme Asp-NAT (Boltshauser et al, 2004;Burlina et al, 2006b). In this single known case of hypoacetylaspartia, NAA and NAAG were also undetectable in the patient's cerebrospinal fluid by capillary electrophoresis.…”

Section: Other Genetic Disruptions In Myelinogenesismentioning

confidence: 84%

“…It is synthesized enzymatically from NAA and glutamate (Arun et al, 2006;Boltshauser et al, 2004;Cangro et al, 1987;Gehl et al, 2004) and is localized in specific types of neurons throughout the CNS (Anderson et al, 1987;Moffett et al, 1993;Moffett and Namboodiri, 1995;Tieman et al, 1991;Tieman and Tieman, 1996). NAAG is released from synapses in a calcium dependent manner (Williamson et al, 1991), and acts through presynaptic metabotropic glutamate receptors to modulate the release of classical neurotransmitters (Xi et al, 2002;Zhao et al, 2001).…”

Section: Naa and Naag Biosynthesismentioning

confidence: 99%

“…If redundant metabolic and transport pathways do not exist, mutations in genes for all of these proteins could theoretically lead to various leukodystrophies (Boltshauser et al, 2004).…”

Section: Other Genetic Disruptions In Myelinogenesismentioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,208

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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Section: Other Genetic Disruptions In Myelinogenesismentioning

confidence: 84%

Section: Naa and Naag Biosynthesismentioning

confidence: 99%

See 1 more Smart Citation

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,208

1,126

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“…Finally, it should be noted that a recent report has described a young child with severe CNS developmental abnormalities who lacks the NAA signal in magnetic resonance spectrograms (40), most likely as a consequence of a mutation in the gene for Asp-NAT, the NAA synthetic enzyme. The pathophysiology is not identical to that of CD but involves severe developmental CNS anomalies, including hypomyelination, secondary microcephaly, and severe psychomotor dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

Madhavarao

Arun

Moffett

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

170

153

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Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC 3.5.1.15). ASPA acts to hydrolyze N-acetylaspartate (NAA) into L-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper CNS development is unclear. We hypothesize that one function of ASPA is to provide acetate for the increased lipid synthesis that occurs during postnatal CNS myelination. The gene encoding ASPA has been inactivated in the mouse model of CD, and here we show significant decreases in the synthesis of six classes of myelinassociated lipids, as well as reduced acetate levels, in the brains of these mice at the time of peak postnatal CNS myelination. Analysis of the lipid content of white matter from a human CD patient showed decreased cerebroside and sulfatide relative to normal white matter. These results demonstrate that myelin lipid synthesis is significantly compromised in CD and provide direct evidence that defective myelin synthesis, resulting from a deficiency of NAAderived acetate, is involved in the pathogenesis of CD.acetyl CoA ͉ leukodystrophy ͉ oligodendrocytes ͉ aspartoacylase N -acetylaspartate (NAA) attains one of the highest concentrations of any molecule in the human CNS (1), yet the functions it serves remain controversial. NAA is synthesized from L-aspartate and acetyl CoA in neuronal mitochondria by the enzyme aspartate N-acetyltransferase (Asp-NAT) (EC 2.3.1.17) (2, 3). NAA is found predominantly in neurons, (4) but the catabolic enzyme aspartoacylase (ASPA) is present primarily in oligodendrocytes in the CNS (5). The high concentration of NAA in the CNS and its characteristic peak in water-suppressed proton magnetic resonance spectroscopy (MRS) permits noninvasive determinations of NAA concentrations in the human brain. MRS determinations of NAA levels are commonly used for evaluating the integrity of neurons in a number of neurological disorders, and this method has emerged as a preferred technique for following the clinical course of several CNS pathologies (6-8). MRS studies operate on the assumptions that NAA is synthesized by and accumulated in neurons and that the steady-state NAA levels in the brain can be interpreted as indicating overall neuronal health or integrity (9, 10).Canavan's disease (CD) is a fatal, hereditary leukodystrophy that compromises normal CNS development and is caused by mutations in the gene for the enzyme ASPA (11, 12). ASPA currently is thought to function exclusively to hydrolyze NAA, a neuron-specific amino acid derivative, into L-aspartate and free acetate. However, ASPA is strongly expressed in other tissues, such as kidney, even though the only known substrate, NAA, is present predominantly in the nervous system (13). Despite the established connection between mutations in the gene for ASPA in CD and the lost capacity to deacetylate NAA, the specific connection between ASPA deficiency and the failure of proper CNS development is unclear (14). Furt...

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“…The lack of ASPA activity appears to be responsible for CD, and in this early-onset syndrome, there is a global buildup of NAA, NAAG, and water in brain that is associated with severe osmotic consequences including megalocephaly and spongiform degeneration in white matter as well as with profound cognitive and motor failures. The second inborn error in NAA and NAAG metabolism is a singular known case where there is a lack of NAA and NAAG in brain (hypoacetylaspartia; Martin et al, 2001; Boltshauser et al, 2004). In this case, the neuronal NAA synthase that joins AcCoA with Asp is inactive (Wiame et al, 2010), resulting in the inability of neurons to synthesize NAA, and therefore in the absence of both NAA and its adduct NAAG in brain.…”

Section: Discussionmentioning

confidence: 99%

The Vertebrate Brain, Evidence of Its Modular Organization and Operating System: Insights into the Brain's Basic Units of Structure, Function, and Operation and How They Influence Neuronal Signaling and Behavior

Baslow

2011

Front. Behav. Neurosci.

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The human brain is a complex organ made up of neurons and several other cell types, and whose role is processing information for use in eliciting behaviors. However, the composition of its repeating cellular units for both structure and function are unresolved. Based on recent descriptions of the brain's physiological “operating system”, a function of the tri-cellular metabolism of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) for supply of energy, and on the nature of “neuronal words and languages” for intercellular communication, insights into the brain's modular structural and functional units have been gained. In this article, it is proposed that the basic structural unit in brain is defined by its physiological operating system, and that it consists of a single neuron, and one or more astrocytes, oligodendrocytes, and vascular system endothelial cells. It is also proposed that the basic functional unit in the brain is defined by how neurons communicate, and consists of two neurons and their interconnecting dendritic–synaptic–dendritic field. Since a functional unit is composed of two neurons, it requires two structural units to form a functional unit. Thus, the brain can be envisioned as being made up of the three-dimensional stacking and intertwining of myriad structural units which results not only in its gross structure, but also in producing a uniform distribution of binary functional units. Since the physiological NAA–NAAG operating system for supply of energy is repeated in every structural unit, it is positioned to control global brain function.

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Follow-Up of a Child with Hypoacetylaspartia

Cited by 33 publications

References 22 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

The Vertebrate Brain, Evidence of Its Modular Organization and Operating System: Insights into the Brain's Basic Units of Structure, Function, and Operation and How They Influence Neuronal Signaling and Behavior

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