Elevated CSF
            <i>N</i>
            -acetylaspartylglutamate in patients with free sialic acid storage diseases

Mochel, Fanny; Engelke, Udo F. H.; Barritault, Julie; Yang, Bing-Zhi; McNeill, Nathan; Thompson, Jack; Vanderver, Adeline; Wolf, Nicole I.; Willemsen, M.A.A.P.; Verheijen, Frans W.; François, Sabine; Wevers, Ron A.; Schiffmann, Raphael

doi:10.1212/wnl.0b013e3181cbcdc4

Cited by 21 publications

(19 citation statements)

References 10 publications

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“…It was almost undetectable in the neocortex and the cerebellar cortex, but reached high expression levels in different nuclei of the midbrain and brain stem, as well as deep cerebellar nuclei and the spinal cord. Thus, NAAGS-II is expressed in those areas with high NAAG concentrations (1,18,20,35). NAAGS-I may be responsible for the overall basal NAAG synthesis, whereas NAAGS-II evolved to ensure high NAAG levels in the caudal brain regions and spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated NAAG concentrations have been found in the cerebrospinal fluid of Pelizaeus-Merzbacher disease patients (39,40), and the Pelizaeus-Merzbacher disease-like disease caused by mutations in the connexin 47 gene (41), sialic acid storage diseases (35), and a leukodystrophy with an unknown genetic cause (22). Slightly elevated NAAG levels in cerebrospinal fluid also occur in Canavan disease (39,40), which is caused by deficiency in the NAA degrading enzyme aspartoacylase (25).…”

Section: Discussionmentioning

confidence: 99%

“…Slightly elevated NAAG levels in cerebrospinal fluid also occur in Canavan disease (39,40), which is caused by deficiency in the NAA degrading enzyme aspartoacylase (25). However, a number of unrelated leukodystrophies do not show changes in NAAG concentrations (35,39). The metabolic changes responsible for these disease-specific elevated NAAG concentrations are currently not known, but mutations in the GCP-II gene appear not to be responsible (22).…”

Section: Discussionmentioning

confidence: 99%

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N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

Lodder-Gadaczek¹,

Becker²,

Gieselmann

et al. 2011

Journal of Biological Chemistry

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N-Acetylaspartylglutamate (NAAG) is found at high concentrations in the vertebrate nervous system. NAAG is an agonist at group II metabotropic glutamate receptors. In addition to its role as a neuropeptide, a number of functions have been proposed for NAAG, including a role as a non-excitotoxic transport form of glutamate and a molecular water pump. We recently identified a NAAG synthetase (now renamed NAAG synthetase I, NAAGS-I), encoded by the ribosomal modification protein rimK-like family member B (Rimklb) gene, as a member of the ATP-grasp protein family. We show here that a structurally related protein, encoded by the ribosomal modification protein rimK-like family member A (Rimkla) gene, is another NAAG synthetase (NAAGS-II), which in addition, synthesizes the N-acetylated tripeptide N-acetylaspartylglutamylglutamate (NAAG 2 ). In contrast, NAAG 2 synthetase activity was undetectable in cells expressing NAAGS-I. Furthermore, we demonstrate by mass spectrometry the presence of NAAG 2 in murine brain tissue and sciatic nerves. The highest concentrations of both, NAAG 2 and NAAG, were found in sciatic nerves, spinal cord, and the brain stem, in accordance with the expression level of NAAGS-II. To our knowledge the presence of NAAG 2 in the vertebrate nervous system has not been described before. The physiological role of NAAG 2 , e.g. whether it acts as a neurotransmitter, remains to be determined. N-Acetylaspartylglutamate (NAAG)3 is an abundant peptide in the vertebrate nervous system, found at high micromolar to low millimolar concentrations (1-3). A number of studies demonstrated that NAAG acts as a specific agonist at the group II metabotropic mGluR3 glutamate receptors (4 -6). Agonistic and antagonistic effects of NAAG at N-methyl-D-asparatate receptors have been described (5, 7, 8), but could not be confirmed in later studies (9). Several reports indicate a neuroprotective role of NAAG (10 -12), and in line with this, inhibitors of the NAAG hydrolyzing glutamate carboxypeptidase (GCP)-II have a significant neuroprotective effect in different model systems (13). Increasing NAAG concentrations by GCP-II inhibition appear to reduce glutamate release through activation of presynaptic mGluR3 receptors (for review, see Ref. 13).NAAG may also be involved in neuron-glia signaling (14), although its specific role is not fully understood. Theoretically, synthesis of NAAG could also be an efficient way to transfer large amounts of glutamate from neurons to the extracellular fluid, avoiding the excitotoxic effect of free glutamate (15). A possible role of NAAG as a molecular water pump has also been suggested (16).NAAG is synthesized independently of ribosome from N-acetylaspartate (NAA) and glutamate by NAAG synthetases. Although neurons are the major source of NAAG, it is also present in cultured oligodendrocytes and activated microglia (17). In the mammalian nervous system, the highest NAAG levels have been found in the brain stem, spinal cord, and peripheral nerves (1, 18 -21). NAAG is released from synaptic ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

Lodder-Gadaczek¹,

Becker²,

Gieselmann

et al. 2011

Journal of Biological Chemistry

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“…An increase of NAAG was also observed in the CSF of one patient with Canavan disease [3], one PMLD patient harboring a homozygous deletion in the GJC2 gene [4] and two patients with a severe hypomyelination pattern of unknown cause [5]. In addition, we recently reported that CSF NAAG was increased in 6 patients with sialic acid storage disease (SASD) associated with mutations[6]. …”

Section: Introductionmentioning

confidence: 99%

Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases

Mochel

Boildieu

Barritault

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Background In order to identify biomarkers useful for the diagnosis of genetic white matter disorders we compared the metabolic profile of patients with leukodystrophies with a hypomyelinating or a non-hypomyelinating MRI pattern. Methods We used a non-a priori method of in vitro 1H-NMR spectroscopy on CSF samples of 74 patients with leukodystrophies. Results We found an elevation of CSF N-acetylaspartylglutamate (NAAG) in patients with Pelizaeus-Merzbacher disease (PMD) – PLP1 gene –, Pelizaeus-Merzbacher-like disease – GJC2 gene – and Canavan disease – ASPA gene. In the PMD group, NAAG was significantly elevated in the CSF of all patients with PLP1 duplication (19/19) but was strictly normal in 6 out of 7 patients with PLP1 point mutations. Additionally, we previously reported increased CSF NAAG in patients with SLC17A5 mutations. Conclusions Elevated CSF NAAG is a biomarker that suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Our findings also point to unique pathological functions of the overexpressed PLP in PMD patients with duplication of this gene.

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“…SLC17A5-related conditions include infantile sialic acid storage disease (ISSD; OMIM #269920, a lethal multisystem disorder), Salla disease (OMIM #604369, a slowly progressive, predominantly neurological condition), and intermediate phenotypes (Aula et al 2000;Verheijen et al 1999). Recently, SLC17A5 mutations have also been identified in children and adults with cerebral palsy-like chronic encephalopathy; thus, the recognized spectrum of clinical phenotypes continues to expand (Debray et al 2011;Mochel et al 2009Mochel et al , 2010. ISSD is situated at the opposite (severe) end of the SLC17A5 disease spectrum; cardinal features include profound developmental delay, failure to thrive, hepatosplenomegaly, coarse facies, hypopigmentation, and (typically) death in infancy (Lemyre et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation

et al. 2013

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Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434: c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.

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Elevated CSF N -acetylaspartylglutamate in patients with free sialic acid storage diseases

Cited by 21 publications

References 10 publications

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases

Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation

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