Metabolic biomarkers of autism
Inventors
Cezar, Gabriela Gebrin • Smith, Alan M.
Assignees
Wisconsin Alumni Research Foundation • Stemina Biomarker Discovery Inc
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Publication Number
US-10330688-B2
Publication Date
2019-06-25
Expiration Date
Abstract
This invention provides methods and biomarkers for diagnosing autism by identifying cellular metabolites differentially produced in autistic patient samples versus non-autistic controls. Methods for identifying a unique profile of metabolites present or secreted in brain tissue, cerebrospinal fluid, plasma, or biofluids of autistic samples are described herein. The individual metabolites or a pattern of secreted metabolites provides metabolic signatures of autism, which can be used to provide a diagnosis thereof.
Core Innovation
The invention relates to diagnosing autism or autism spectrum disorder by detecting levels of a plurality of metabolites in a biosample from an individual suspected of having autism. It focuses on identifying metabolite differences between autistic patient samples and non-autistic controls using metabolomics to produce a metabolite biochemical fingerprint or biomarker profile.
The core workflow uses liquid chromatography electrospray-ionization time of flight mass spectrometry (LC-ESI-TOF-MS), with optionally described HILIC and C18 chromatography, to detect and profile small-molecule metabolites having a molecular weight range of about 10 to 1500 Da. The approach reports metabolite feature differences that are statistically significant and includes both annotated confirmed alterations and non-annotated candidate metabolites.
The document highlights specific altered metabolites reported for autistic samples, including L-cystathionine, 2-aminooctanoic acid, and N-acetylaspartylglutamic acid (NAAG), together with pathway mapping and discussion of metabolic pathways such as glutamate, cysteine, methionine, tryptophan, and GABA. It emphasizes applicability to brain tissue and biofluids, including cerebrospinal fluid, blood or plasma, and urine, to support improved non-invasive biomarker diagnostics relative to invasive tissue approaches.
Claims Coverage
The independent claim coverage includes 2 independent methods. Both claims share the same core inventive concept: detecting levels of a plurality of named metabolites from a biosample of an individual suspected of having autism using liquid chromatography electrospray-ionization time of flight mass spectrometry, with biosamples restricted to at least one of blood, cerebrospinal fluid, or urine; one independent claim additionally constrains the molecular weight range of the metabolites.
Autism metabolite detection by LC-ESI-TOF-MS in blood, cerebrospinal fluid, or urine
A method of detecting levels of a plurality of metabolites in a biosample from an individual suspected of having autism, by detecting levels of the plurality of metabolites using liquid chromatography electrospray-ionization time of flight mass spectrometry, where the metabolites comprise N-acetylaspartylglutamic acid, 2-aminooctanoic acid, 5-hydroxylysine, vinylacetylglycine, proline betaine, 3′-sialyllactosamine, dipalmitoyl-phosphatidylcholine, or SAICAR, and wherein the biosample is at least one of blood, cerebrospinal fluid, or urine.
Molecular-weight constrained autism metabolite detection by LC-ESI-TOF-MS
A method of detecting levels of a plurality of metabolites in a biosample by assaying a biosample isolated from a human patient suspected of having autism for levels of a plurality of metabolites having a molecular weight of from about 10 Daltons to about 1500 Daltons, and detecting levels of the plurality of metabolites in the biosample by liquid chromatography electrospray-ionization time of flight mass spectrometry, where the metabolites are N-acetylaspartylglutamic acid, 2-aminooctanoic acid, 5-hydroxylysine, vinylacetylglycine, proline betaine, 3′-sialyllactosamine, dipalmitoyl-phosphatidylcholine, or SAICAR, and wherein the biosample is at least one of blood, cerebrospinal fluid, or urine.
Across both independent claims, the key inventive features are a metabolite panel from the named metabolites detected by LC-ESI-TOF-MS in autism-suspected individuals using biosamples selected from blood, cerebrospinal fluid, or urine; the second independent claim additionally limits the assayed metabolites to a 10 to 1500 Da molecular-weight range.
Stated Advantages
Improved, non-invasive biofluid biomarker diagnostics relative to invasive tissue approaches.
Documented Applications
Diagnosing autism or autism spectrum disorder by metabolomics-based detection of metabolite biochemical fingerprints or biomarker profiles in biosamples from autistic patients and non-autistic controls.
Use of cerebrospinal fluid, blood or plasma, and urine as biofluid biosamples for the metabolite biomarker approach.
Use of brain tissue as part of the described metabolite profiling context.
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