Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS

Silva, Margarida F. B.; Selhorst, J. J. M.; Overmars, H.; Gennip, Albert H.; Maya, Manuela T.; Wanders, Ronald J. A.; Almeida, Isabel Tavares de; Durán, Marinus

doi:10.1016/s0009-9120(01)00272-7

Cited by 30 publications

(22 citation statements)

References 18 publications

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“…Despite these biochemical abnormalities, defects in biotinidase, or holocarboxylase synthetase (Watanabe et al, 2005) could not be demonstrated in either sera or fibroblasts. Of interest, none of these 12 patients was undergoing valproate intervention, the latter a potential source of 3-OH-IVA elevation in urine (Silva et al, 2001). Despite an absence of confirmatory enzyme deficiencies in these 12 patients, we nonetheless opted to treat empirically with biotin for 3 weeks, 2 × 10 mg and then for 6 months at 2 × 5 mg, which led to a clear therapeutic benefit in 7/13 consisting of improvement in the Childhood Autism Rating Scale (CARS; Table 2).…”

Section: Resultsmentioning

confidence: 99%

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

Spilioti

Evangeliou²,

Tramma³

et al. 2013

Front. Hum. Neurosci.

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We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4–14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.

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Section: Resultsmentioning

confidence: 99%

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

Spilioti

Evangeliou²,

Tramma³

et al. 2013

Front. Hum. Neurosci.

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“…It has not been elucidated whether it occurs inside mitochondria, via CPT II. The carnitine conjugate of the dicarboxylic acid metabolite 2-npropylglutaric acid (propylglutarylcarnitine) has been reported by our group in the plasma of patients under VPA monotherapy (Silva et al 2001c). The specific enzyme mediating the reaction, possibly a dicarboxyl-CoA synthetase, and its subcellular localization have not been defined.…”

Section: Biotransformation Of Vpamentioning

confidence: 91%

“…The formation of valproylcarnitine seems to be of no quantitative importance in vivo (Silva et al 2001c) since its excretion accounts for less than 1% of the total acylcarnitine elimination in urine. In contrast, other acylcarnitines may be formed in higher amounts, including 3-hydroxyisovalerylcarnitine (C5OH) and 2-propylglutarylcarnitine as demonstrated in VPAtreated adults (Silva et al 2001c). This was confirmed by identification of an increase of C 5 OH-carnitine after VPA treatment in paediatric patients, in conjunction with a decrease of free carnitine (C 0 ) (Werner et al 2007).…”

Section: Carnitine Metabolismmentioning

confidence: 99%

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

Silva

Aires

Luis

et al. 2008

J of Inher Metab Disea

337

268

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Valproic acid (VPA; 2-n-propylpentanoic acid) is widely used as a major drug in the treatment of epilepsy and in the control of several types of seizures. Being a simple fatty acid, VPA is a substrate for the fatty acid beta-oxidation (FAO) pathway, which takes place primarily in mitochondria. The toxicity of valproate has long been considered to be due primarily to its interference with mitochondrial beta-oxidation. The metabolism of the drug, its effects on enzymes of FAO and their cofactors such as CoA and/or carnitine will be reviewed. The cumulative consequences of VPA therapy in inborn errors of metabolism (IEMs) and the importance of recognizing an underlying IEM in cases of VPA-induced steatosis and acute liver toxicity are two different concepts that will be emphasized.

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“…For metabolic defects that result in accumulation of acyl CoA esters, transesterification to acylcarnitines and elimination in urine is an important detoxification pathway. The analysis of l-carnitine and acylcarnitine profiles by flow injection analysis FIA-ESI-MS/MS has become very popular [42][43][44][45][46][47][48][49][50][51][52][53]. The technique utilises the selectivity of MS/MS to avoid the separation of carnitines prior to detection and quantitation [43].…”

Section: Carnitinesmentioning

confidence: 99%

“…Further advantages of this approach are improved sensitivity and the ability to automate much of the sample preparation. FIA-ESI-MS/ MS has been applied to the analysis of dried blood spots [44][45][46][47][48][49][50], plasma [48,[51][52][53], fibroblast cells [54][55][56], and urine [57]. Typically, the specimen is extracted with methanol, spiked with deuterated internal standards, evaporated, esterified to butyl esters, evaporated, reconstituted in the injection solvent, and infused into a tandem mass spectrometer.…”

Section: Carnitinesmentioning

confidence: 99%

A critical evaluation of high performance liquid chromatography‐electrospray ionisation‐mass spectrometry and capillary electrophoresis‐ electrospray‐mass spectrometry for the detection and determination of small molecules of significance in clinical and forensic science

Smyth¹,

Brooks

2004

Electrophoresis

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A critical review of applications for the period 2000-2003, taken from the Web of Knowledge database, of the techniques high performance liquid chromatography-electrospray ionisation-mass spectrometry (HPLC-ESI-MS) and capillary electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) to the detection and determination of small molecules of significance in clinical and forensic science is presented. The molecules of mass less than 500 Da are chosen according to selected structural classes in which they give ESI signals primarily as [M+H](+) ions although other ions such as [M-H](-), [M+Na](+) and [M+NH(4)](+) are also reported. The structural classes are drugs with amine-containing side chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines, carbohydrates, benzimidazoles, other heterocycles, sulphonylureas, anthracyclines, sulphonamides, penicillins, cephalosporins, tetracyclines, nitrocatechols, steroids, flavonoids, oxazaphosphorines, cannabinols, and miscellaneous molecules. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion-trap, triple quadrupole and time-of-flight mass spectrometers. The review then gives a critical evaluation of these recent HPLC-ESI-MS and CE-ESI-MS analytical methods for the detection and determination of small molecules of clinical and forensic significance. Analytical information on, for example, sample concentration techniques, HPLC and CE separation conditions, recoveries from biological media and limits of detection (LODs) are provided.

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Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS

Cited by 30 publications

References 18 publications

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

A critical evaluation of high performance liquid chromatography‐electrospray ionisation‐mass spectrometry and capillary electrophoresis‐ electrospray‐mass spectrometry for the detection and determination of small molecules of significance in clinical and forensic science

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