Stable isotope dilution analysis of<i>N</i>‐acetylaspartic acid in CSF, blood, urine and amniotic fluid: Accurate postnatal diagnosis and the potential for prenatal diagnosis of canavan disease

Jakobs, Cornelis; Brink, H.J. ten; Langelaar, Stephan; Zee, Tom; Stellaard, Frans; Maçek, Milan; Srsnová, K; Srsen, S; Kleijer, Wim J.

doi:10.1007/bf01799929

Cited by 52 publications

(49 citation statements)

References 13 publications

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“…The high concentrations necessitated diluting the urine more than 100-fold on some occasions to bring the concentration within the range of linearity of the assay. The overall reference range for all age groups obtained by LC-MS/MS of 0-39 mmol/mol creatinine was in excellent agreement with those generated by GC-MS and reported by Jakobs et al (1991) of 6.6-35.4 mmol/mol creatinine and by Kelley and Stamas (1992) of 12.7 ± 7.8 mmol/mol creatinine.…”

Section: Resultssupporting

confidence: 75%

“…NAA is a polar dicarboxylic acid with low extraction efficiency in common organic solvents. Stable isotope dilution gas chromatography mass spectrometry (GC-MS) methods for NAA involving liquid-liquid extraction or solid-phase extraction followed by derivatization and using a variety of ionization techniques are used for the prenatal and postnatal diagnosis of CD (Jakobs et al, 1991;Kelly and Stamas 1992;Leis et al, 1992;Inoue and Kuhara 2004;Liu et al, 2004). Methods based on GC-MS are highly sensitive and selective but are tedious due to laborious sample preparation and lengthy chromatographic turnaround time.…”

Section: Introductionmentioning

confidence: 99%

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Stable isotope dilution analysis of N‐acetylaspartic acid in urine by liquid chromatography electrospray ionization tandem mass spectrometry

Al-Dirbashi

Rashed

Al-Mokhadab

et al. 2007

Biomedical Chromatography

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N-acetylaspartic acid (NAA) is a specific urinary marker for Canavan disease, an autosomal recessive leukodystrophy. We developed a 'dilute and shoot' stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method for determination of NAA in urine. Deuterated internal standard d(3)-NAA was added to untreated urine and the mixture was injected into the LC-MS/MS system operated in the negative ion mode. Chromatography was carried out on a C(8) minibore column using 50% acetonitrile solution containing 0.05% formic acid at a flow rate of 0.25 mL/min. The retention time was 1.6 min and the turnaround time was 2.2 min. NAA and d(3)-NAA were analyzed in multiple reaction monitoring mode. Calibrators and quality control samples were prepared in pooled control urine. The assay was linear up to 2000 micromol/L with limit of quantification at 1 micromol/L (S/N = 12). Interassay and intraassay coefficients of variation were less than 7% and recovery at three different concentrations was 98.9-102.5%. The LC-MS/MS method for NAA as described involves no extraction and no derivatization, showed no interference and gave excellent recovery with low variability and short analytical time. The method was successfully applied for the retrospective analysis of urine from 21 Canavan disease cases.

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Section: Resultssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Stable isotope dilution analysis of N‐acetylaspartic acid in urine by liquid chromatography electrospray ionization tandem mass spectrometry

Al-Dirbashi

Rashed

Al-Mokhadab

et al. 2007

Biomedical Chromatography

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“…Clinically, CD is characterized by megalocephaly, hypotonia of neck muscles that results in poor head control, muscle rigidity, developmental delay of motor and verbal skills, visual impairment, and feeding difficulties (20)(21)(22)(23)(24). Lack of ASPA activity leads to a dramatic increase of NAA concentration in the brain, spinal fluid, blood, and urine (19,25). Measurement of elevated NAA levels in urine is used to confirm the diagnosis of CD (24).…”

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confidence: 99%

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

Bitto

Bingman

Wesenberg

et al. 2007

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

120

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Aspartoacylase catalyzes hydrolysis of N-acetyl-L-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8-and 1.8-Å resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10 -13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded ␤-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N-and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypetides in the active site. The structures revealed that residues 158 -164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.N-acetyl-L-aspartate ͉ x-ray structure ͉ zinc-dependent hydrolase

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“…Normal concentrations of N-acetylated amino acids in CSF from patients with ACY1 deficiency make us question the role of the enzyme in brain tissue. In ACY2 deficiency (Canavan disease), NAA does accumulate in CSF (380 mmol/l; reference value < 2 mmol/l (17,20)). The relation between the molecular defect and the neurological signs and symptoms is obvious in Canavan disease.…”

Section: Discussionmentioning

confidence: 99%

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

et al. 2008

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Aminoacylase 1 deficiency is a novel inborn error of metabolism. The clinical significance of the deficiency is under discussion, as well as the possible consequences of the defect for brain metabolism and function. This study includes the five originally published cases as well as three novel ones. NMR spectroscopy of urine, serum and cerebrospinal fluid has been used to study these patients. A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients. The concentration of most of the accumulating metabolites is typically 100-500 micromol/mmol creatinine. Two additional minor N-acetylated metabolites remain unidentified. The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient. Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids.

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Stable isotope dilution analysis ofN‐acetylaspartic acid in CSF, blood, urine and amniotic fluid: Accurate postnatal diagnosis and the potential for prenatal diagnosis of canavan disease

Cited by 52 publications

References 13 publications

Stable isotope dilution analysis of N‐acetylaspartic acid in urine by liquid chromatography electrospray ionization tandem mass spectrometry

Stable isotope dilution analysis of N‐acetylaspartic acid in urine by liquid chromatography electrospray ionization tandem mass spectrometry

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

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