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Low serum sphingolipids in children with attention deficit-hyperactivity disorder.

Henríquez-Henríquez MP, Solari S, Quiroga T, Kim BI, Deckelbaum RJ, Worgall TS - Front Neurosci (2015)

Bottom Line: Groups were compared by parametrical statistics.Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20-30% relative reductions.Our results showed lower levels of all major serum sphingomyelins in ADHD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile Santiago, Chile.

ABSTRACT

Background: Attention deficit-hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric condition in childhood. ADHD is a multifactorial trait with a strong genetic component. One neurodevelopmental hypothesis is that ADHD is associated with a lag in brain maturation. Sphingolipids are essential for brain development and neuronal functioning, but their role in ADHD pathogenesis is unexplored. We hypothesized that serum sphingolipid levels distinguish ADHD patients from unaffected subjects.

Methods: We characterized serum sphingolipid profiles of ADHD patients and two control groups: non-affected relatives and non-affected subjects without a family history of ADHD. Sphingolipids were measured by LC-MS/MS in 77 participants (28 ADHD patients, 28 related controls, and 21 unrelated controls). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). Diagnostic criteria were assessed by two independent observers. Groups were compared by parametrical statistics.

Results: Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20-30% relative reductions. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity and 78% specificity.

Conclusions: Our results showed lower levels of all major serum sphingomyelins in ADHD. These findings may reflect brain maturation and affect neuro-functional pathways characteristic for ADHD.

No MeSH data available.


Related in: MedlinePlus

Sphingolipid metabolic pathways. Ceramide is central in sphingolipid metabolism, produced by de novo and recycling pathways. Serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting enzyme of de novo synthesis that generates ketosphinganine from serine and palmitoyl-CoA (bottom). Ketosphinganine is reduced to form sphinganine that is N-acylated by ceramide synthases with fatty acids of different chain lengths to form dihydroceramides. Dihydroceramides are desaturated by dihydroceramide desaturase (DES) to generate ceramides. Ceramides can be metabolized to sphingomyelin or glycosphingolipids. SPT generates deoxyceramides when utilizing alanine instead of serine. Notably, deoxyceramides only originate from de novo synthesis. The recycling pathway generates ceramides from sphingomyelin and other complex sphingolipids. Ceramidases degrade ceramides and release sphingoid bases, which are reutilized for complex sphingolipid biosynthesis or phosphorylated to sphingosine-1-phosphate. Boxed compounds indicate molecular species assayed in this study.
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Figure 1: Sphingolipid metabolic pathways. Ceramide is central in sphingolipid metabolism, produced by de novo and recycling pathways. Serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting enzyme of de novo synthesis that generates ketosphinganine from serine and palmitoyl-CoA (bottom). Ketosphinganine is reduced to form sphinganine that is N-acylated by ceramide synthases with fatty acids of different chain lengths to form dihydroceramides. Dihydroceramides are desaturated by dihydroceramide desaturase (DES) to generate ceramides. Ceramides can be metabolized to sphingomyelin or glycosphingolipids. SPT generates deoxyceramides when utilizing alanine instead of serine. Notably, deoxyceramides only originate from de novo synthesis. The recycling pathway generates ceramides from sphingomyelin and other complex sphingolipids. Ceramidases degrade ceramides and release sphingoid bases, which are reutilized for complex sphingolipid biosynthesis or phosphorylated to sphingosine-1-phosphate. Boxed compounds indicate molecular species assayed in this study.

Mentions: Sphingolipid profiles include the following molecular species: (1) sphinganine-1-phosphate and sphingosine-1-phosphate; (2) ceramides C16:0, C18:0, C20:0, C22:0, C24:0, and C24:1; dihydroceramides C18, C18:1, C24:0, and C24:1; deoxy-ceramide C16:0 and C24:1 and deoxy-dihydroceramides C16:0 and C24:1; (3) sphingomyelins (SM) SM C16:0, SM C18:0, SM C18:1, and SM C24:1. Their relative location in the sphingolipid metabolic pathway is summarized in Figure 1. Sphingolipid levels were quantified by high performance liquid chromatography-triple quadrupole-tandem mass spectrometry (HPLC-MS/MS) on an Agilent 1200 HPLC system, equipped with an Agilent C18 column as reported (Bui et al., 2012). Briefly, sphingolipids were extracted overnight in a 1:30 v/v solution of diethylamide 10%/dichloromethanol: methanol 1:1, at room temperature using sphingomyelin C12 (0.120 μM) as internal standard. HPLC conditions were: Mobile phase A was methanol/water/chloroform/formic acid (55:40:5:0.4 v/v); Mobile phase B was methanol/acetonitrile/chloroform/formic acid (48:48:4:0.4 v/v). The chromatography column was first pre-equilibrated for 6 s. After this period, the gradient gradually increased to 60% mobile phase B and 100% mobile phase B. 100% mobile phase B was held for 1.9 min. Flow rate was 0.6 ml/min. Injection into the HPLC-MS/MS system was set at 3 μl. All measurements were performed in triplicates.


Low serum sphingolipids in children with attention deficit-hyperactivity disorder.

Henríquez-Henríquez MP, Solari S, Quiroga T, Kim BI, Deckelbaum RJ, Worgall TS - Front Neurosci (2015)

Sphingolipid metabolic pathways. Ceramide is central in sphingolipid metabolism, produced by de novo and recycling pathways. Serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting enzyme of de novo synthesis that generates ketosphinganine from serine and palmitoyl-CoA (bottom). Ketosphinganine is reduced to form sphinganine that is N-acylated by ceramide synthases with fatty acids of different chain lengths to form dihydroceramides. Dihydroceramides are desaturated by dihydroceramide desaturase (DES) to generate ceramides. Ceramides can be metabolized to sphingomyelin or glycosphingolipids. SPT generates deoxyceramides when utilizing alanine instead of serine. Notably, deoxyceramides only originate from de novo synthesis. The recycling pathway generates ceramides from sphingomyelin and other complex sphingolipids. Ceramidases degrade ceramides and release sphingoid bases, which are reutilized for complex sphingolipid biosynthesis or phosphorylated to sphingosine-1-phosphate. Boxed compounds indicate molecular species assayed in this study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548182&req=5

Figure 1: Sphingolipid metabolic pathways. Ceramide is central in sphingolipid metabolism, produced by de novo and recycling pathways. Serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting enzyme of de novo synthesis that generates ketosphinganine from serine and palmitoyl-CoA (bottom). Ketosphinganine is reduced to form sphinganine that is N-acylated by ceramide synthases with fatty acids of different chain lengths to form dihydroceramides. Dihydroceramides are desaturated by dihydroceramide desaturase (DES) to generate ceramides. Ceramides can be metabolized to sphingomyelin or glycosphingolipids. SPT generates deoxyceramides when utilizing alanine instead of serine. Notably, deoxyceramides only originate from de novo synthesis. The recycling pathway generates ceramides from sphingomyelin and other complex sphingolipids. Ceramidases degrade ceramides and release sphingoid bases, which are reutilized for complex sphingolipid biosynthesis or phosphorylated to sphingosine-1-phosphate. Boxed compounds indicate molecular species assayed in this study.
Mentions: Sphingolipid profiles include the following molecular species: (1) sphinganine-1-phosphate and sphingosine-1-phosphate; (2) ceramides C16:0, C18:0, C20:0, C22:0, C24:0, and C24:1; dihydroceramides C18, C18:1, C24:0, and C24:1; deoxy-ceramide C16:0 and C24:1 and deoxy-dihydroceramides C16:0 and C24:1; (3) sphingomyelins (SM) SM C16:0, SM C18:0, SM C18:1, and SM C24:1. Their relative location in the sphingolipid metabolic pathway is summarized in Figure 1. Sphingolipid levels were quantified by high performance liquid chromatography-triple quadrupole-tandem mass spectrometry (HPLC-MS/MS) on an Agilent 1200 HPLC system, equipped with an Agilent C18 column as reported (Bui et al., 2012). Briefly, sphingolipids were extracted overnight in a 1:30 v/v solution of diethylamide 10%/dichloromethanol: methanol 1:1, at room temperature using sphingomyelin C12 (0.120 μM) as internal standard. HPLC conditions were: Mobile phase A was methanol/water/chloroform/formic acid (55:40:5:0.4 v/v); Mobile phase B was methanol/acetonitrile/chloroform/formic acid (48:48:4:0.4 v/v). The chromatography column was first pre-equilibrated for 6 s. After this period, the gradient gradually increased to 60% mobile phase B and 100% mobile phase B. 100% mobile phase B was held for 1.9 min. Flow rate was 0.6 ml/min. Injection into the HPLC-MS/MS system was set at 3 μl. All measurements were performed in triplicates.

Bottom Line: Groups were compared by parametrical statistics.Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20-30% relative reductions.Our results showed lower levels of all major serum sphingomyelins in ADHD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile Santiago, Chile.

ABSTRACT

Background: Attention deficit-hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric condition in childhood. ADHD is a multifactorial trait with a strong genetic component. One neurodevelopmental hypothesis is that ADHD is associated with a lag in brain maturation. Sphingolipids are essential for brain development and neuronal functioning, but their role in ADHD pathogenesis is unexplored. We hypothesized that serum sphingolipid levels distinguish ADHD patients from unaffected subjects.

Methods: We characterized serum sphingolipid profiles of ADHD patients and two control groups: non-affected relatives and non-affected subjects without a family history of ADHD. Sphingolipids were measured by LC-MS/MS in 77 participants (28 ADHD patients, 28 related controls, and 21 unrelated controls). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). Diagnostic criteria were assessed by two independent observers. Groups were compared by parametrical statistics.

Results: Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20-30% relative reductions. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity and 78% specificity.

Conclusions: Our results showed lower levels of all major serum sphingomyelins in ADHD. These findings may reflect brain maturation and affect neuro-functional pathways characteristic for ADHD.

No MeSH data available.


Related in: MedlinePlus