WO2011010104A1 - Procédés - Google Patents

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Publication number
WO2011010104A1
WO2011010104A1 PCT/GB2010/001395 GB2010001395W WO2011010104A1 WO 2011010104 A1 WO2011010104 A1 WO 2011010104A1 GB 2010001395 W GB2010001395 W GB 2010001395W WO 2011010104 A1 WO2011010104 A1 WO 2011010104A1
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individual
metabolite
methyl
assessing
mammalian
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PCT/GB2010/001395
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English (en)
Inventor
Jeremy Kirk Nicholson
Ivan Kok Seng Yap
Elaine Holmes
John Christopher Lindon
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Imperial Innovations Limited
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Publication of WO2011010104A1 publication Critical patent/WO2011010104A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry

Definitions

  • the present invention relates to methods and uses for determining whether an individual has or has an increased risk of developing an autism spectrum disorder
  • Autism spectrum disorder consists of a continuum or spectrum of complex neurodevelopmental disorders with a serious lifelong impact on individuals from all ethnic and socioeconomic backgrounds (Minschew, 2007 The Summer Institute of Neurodevelopmental Disorders UC Davis M I N D Institute, Sacramento, California, August 2-3, Pessah, 2006 Understanding immunological and neurobiology susceptibilities contributing to autism risk UC Davis MIND Institute Conference, Sacramento, California, November 2-3, Grandjean & Landigan, 2006 www thelancet com Published online November 8, 2006 DOI 10 1016/S0140-6736 (06) 69665-7, London & Etzel, 2000 Environmental Health Perspectives Supplements 108) Both genetic and environmental factors appear to contribute to the development of ASD (Herbert, 2006 Clinical implications of environmental toxicology for children's neurodevelopment in autism UC Davis MIND Institute Conference, Sacramento, California, November 2-3, Hertz-Pi
  • a first aspect of the invention provides a method for determining whether an individual has, or has an increased risk of developing, autism spectrum disorder (ASD), the method comprising assessing any one or more of a mammalian-microbial co- metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4- pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), in a sample taken from an individual, wherein the method does not comprise assessing only hippurate and/or 4-hydroxyhippurate, and wherein the method does not comprise assessing ⁇ /-methyl-2-pyridone-5-carboxamide alone.
  • ASD autism spectrum disorder
  • the invention provides a method for determining whether an individual has, or has an increased risk of developing, autism spectrum disorder (ASD), the method comprising assessing any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), in a sample taken from an individual, wherein the method does not comprise assessing any of: only hippurate; only 4-hydroxyhippurate; only ⁇ /-methyl-2-pyridone-5-carboxamide; only the combination of hippurate and 4-hydroxyhippurate; only the combination of hippurate and ⁇ /-methyl-2-pyridone-5-car
  • any metabolite produced by gut bacteria and co-metabolised by a mammalian host may be a mammalian-microbial co-metabolite.
  • Clostridia produce para-cresol, which is co-metabolised in a mammal to para-cresol sulfate.
  • the mammalian-microbial co- metabolite may be any metabolite produced by Clostridia, which metabolite has been co- metabolised by a mammalian host.
  • Phase 1 metabolism adds extra functionality (eg additional OH groups) and Phase 2 metabolism forms chemically bonded conjugates to these functional groups, which may increase water solubility or aid excretion.
  • the mammalian-microbial co-metabolite may be any metabolite produced by gut bacteria that has undergone Phase 1 and 2 metabolism.
  • the mammalian-microbial co- metabolite may be a cresol metabolite including any metabolite that is the product of cresol being metabolised in a mammalian host (eg by Phase 1 and/or Phase 2 metabolism) such as p-tolyl sulfate, 4-methylenecyclohexa-2,5-dienone, A- hydroxybenzoate, hippurate and 4-hydroxyhippurate.
  • a mammalian host eg by Phase 1 and/or Phase 2 metabolism
  • Phase 1 and/or Phase 2 metabolism such as p-tolyl sulfate, 4-methylenecyclohexa-2,5-dienone, A- hydroxybenzoate, hippurate and 4-hydroxyhippurate.
  • DMA dimethylamine
  • PAG phenylacetylglutamine
  • PCS para-cresol sulfate
  • a 'vitamin B metabolite' we include any B vitamin (eg vitamin B3) and its associated metabolites (eg any metabolite on the same metabolic pathway).
  • a vitamin B metabolite may be a metabolite within 8, 7, 6, 5, 4, 3, 2 or 1 reaction steps of the B vitamin.
  • Particular examples of vitamin B3 metabolites include ⁇ /-methyl-4-pyridone-3- carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), all of which the inventors have found to be perturbed in autistic children relative to normal children.
  • ⁇ /-methyl-4-pyridone-3- carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND) are assessed.
  • a mammalian-microbial co-metabolite alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide
  • A/-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND) may be assessed. Further, and as mentioned above, more than one mammalian-microbial co- metabolite and/or more than one vitamin B metabolite may be assessed.
  • DMA dimethylamine
  • PAG phenylacetylglutamine
  • PCS para-cresol sulfate
  • alanine glycine
  • creatinine creatinine
  • glutamate taurine
  • formate formate
  • inosine succinate
  • DMA dimethylamine
  • PAG phenylacetylglutamine
  • PCS para-cresol sulfate
  • alanine glycine
  • creatinine creatinine
  • glutamate taurine
  • formate formate
  • inosine succinate
  • acetate an ⁇ /
  • the assessing comprises comparing the amount of any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxarnide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), in the sample to the amount of the respective any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide (4PY),
  • any suitable method may be used to assess a given metabolite in a sample taken from an individual, and it is appreciated that more than one method may be employed.
  • the metabolite may be assessed using NMR spectroscopy and/or mass spectrometry (eg by multiple ion monitoring).
  • the sample may be fractionated prior to analysis, for example by liquid chromatography.
  • 1 H NMR to assess urinary metabolites is described in Example 1 , and the measurement of metabolites using NMR or mass spectrometry is discussed in US patent no. 7,373,256 and in WO 03/107270.
  • the metabolite may be assessed by making use of a binding partner that binds selectively to the metabolite, or by making use of an enzyme linked assay (eg enzyme linked immunosorbent assay, (ELISA) or an assay in which the metabolite is converted (either directly or indirectly) into a molecule which can readily be detected) that can be used to quantify the metabolite.
  • the sample taken from the individual may be any suitable sample.
  • the sample may be any of urine, blood, blood plasma, blood serum, saliva, sweat, tears, breath or breath condensate.
  • the sample is a urine sample.
  • the individual may be a human or mammalian individual, such as a horse, dog, pig, cow, sheep, rat, mouse, guinea pig or primate.
  • the individual is a human individual.
  • the individual is a pre-pubescent individual.
  • a pre-pubescent individual we include the meaning of a neonate up to the age at which the brain is fully developed.
  • the human individual may be aged 18 years or less, 17 years or less, 16 years or less, 15 years or less, 14 years or less, 13 years or less, 12 years or less, 11 years or less, 10 years or less, 9 years or less, 8 years or less, 7 years or less, 6 years or less, 5 years or less, 4 years or less, 3 years or less, 2 years or less or 1 year or less.
  • a second aspect of the invention provides a use of a means for assessing any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), in a sample taken from an individual in determining whether an individual has, or has an increased risk of developing, ASD, wherein the use does not comprise the use of means for assessing only hippurate and/or 4-hydroxyhippurate, and wherein the use does not comprise the use of means for assessing ⁇ /-methyl-2-pyridone-5-carboxamide alone.
  • a mammalian-microbial co-metabolite such as ⁇
  • the invention provides a use of a means for assessing any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND) 1 in a sample taken from an individual in determining whether an individual has, or has an increased risk of developing, ASD, wherein the use does not comprise the use of means for assessing any of: only hippurate; only 4- hydroxyhippurate; only ⁇ /-methyl-2-pyridone-5-carboxamide; only the combination of hippurate and 4-hydroxyhippurate; only the combination of hippurate and ⁇ /-methyl-2- pyridone
  • any suitable means may be used to assess one or more given metabolites in a sample taken from an individual.
  • the means may be a NMR spectrometer or a mass spectrometer arranged to detect one or more given metabolites in a sample.
  • Example 1 describes the use of an NMR spectrometer to detect and quantify urinary metabolites in a sample.
  • a mass spectrometer may be used in multiple ion monitoring mode, such that only certain ion fragments are entered into the instrument and detected by the mass spectrometer.
  • the mass spectrometer can be programmed to detect only those ion fragments derived from that particular metabolite. It is appreciated that to confirm NMR and mass spectrometry assignments, spectra may also be compared to known reference standards of the particular metabolites in question.
  • Other means of assessing one or more given metabolites in a sample taken from an individual include an enzyme linked assay (eg ELISA or an assay in which the metabolite is converted (either directly or indirectly) into a molecule which can be readily detected) or an agent that binds to a metabolite.
  • the metabolite may be a substrate in an enzymatic reaction, such that an enzyme linked assay can be used to quantify the metabolite.
  • Enzyme linked assays are standard practice in the art and typically involve colorimetric, fluorescent, or chemiluminescent detection.
  • An agent that binds to a metabolite may be used to assess the metabolite by measuring the binding between the agent and the metabolite. Conveniently, the agent is detectably labelled so that the presence of the metabolite can readily be detected. Examples of labels include peptide labels, chemical labels, fluorescent labels or radio labels.
  • a mammalian-microbial co-metabolite alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein,
  • a third aspect of the invention provides a method for classifying an individual as being one who has, or has an increased risk of developing, a pathological condition, the method comprising assessing a mammalian-microbial co-metabolite in a sample taken from the individual, wherein when assessing para cresol sulphate (PCS) alone the individual is not classified according to whether or not the individual has multiple sclerosis, wherein when assessing only hippurate and/or 4-hydroxyh ⁇ ppurate the individual is not classified according to whether or not the individual has ASD, and wherein when assessing ⁇ /-methyl-2-py ⁇ done-5-carboxam ⁇ de alone, the individual is not classified according to whether or not the individual has ASD
  • PCS para cresol sulphate
  • the invention provides a method for classifying an individual as being one who has, or has an increased risk of developing, a pathological condition, the method comprising assessing a mammalian-microbial co-metabolite in a sample taken from the individual, wherein when assessing para cresol sulphate (PCS) alone the individual is not classified according to whether or not the individual has multiple sclerosis, and
  • PCS para cresol sulphate
  • the individual when assessing any of only hippurate, only 4-hydroxyh ⁇ ppurate, only N- methyl-2-pyr ⁇ done-5-carboxam ⁇ de, only the combination of hippurate and 4- hydroxyhippurate, only the combination of hippurate and ⁇ /-methyl-2-pyr ⁇ done-5- carboxamide, only the combination of 4-hydroxyh ⁇ ppurate and ⁇ /-methyl-2-pyr ⁇ done-5- carboxamide, or only the combination of hippurate, 4-hydroxyh ⁇ ppurate and ⁇ /-methyl-2- pyr ⁇ done-5-carboxam ⁇ de, the individual is not classified according to whether or not the individual has ASD
  • the individual is classified as one who has, or has an increased risk of developing, ASD
  • the individual may also be classified as one who has, or has an increased risk of developing, any of the following pathological conditions motor neuron disease, cirrhosis of the liver and migraine headaches, which are conditions related to sulfate deficiencies, Parkinson's disease, a neurological condition such as Schiz
  • the amount of a mammalian-microbial co-metabolite in the sample taken from the individual may be compared to the amount of a mammalian-microbial co-metabolite in a standard sample obtained from one or more individuals who are known to have, or have a known risk of developing, ASD.
  • any pathological condition for which assessing a mammalian-microbial co-metabolite is predictive may be characterised by assessing a mammalian-microbial co-metabolite. Methods for identifying such pathological conditions are standard practice in the art and are described in, for example, US 7,373,256 and WO 03/107270.
  • the individual may be classified as having any one or more particular pathological conditions.
  • a fourth aspect of the invention provides a use of a means for assessing a mammalian- microbial co-metabolite in a sample taken from an individual, in classifying an individual as being one who has, or has an increased risk of developing, a pathological condition, wherein when assessing para cresol sulphate (PCS) alone the individual is not classified according to whether or not the individual has multiple sclerosis, wherein when assessing only hippurate and/or 4-hydroxyhippurate the individual is not classified according to whether or not the individual has ASD, and wherein when assessing N- methyl-2-pyridone-5-carboxamide alone, the individual is not classified according to whether or not the individual has ASD.
  • PCS para cresol sulphate
  • the invention provides a use of a means for assessing a mammalian-microbial co- metabolite in a sample taken from an individual, in classifying an individual as being one who has, or has an increased risk of developing, a pathological condition,
  • hippurate when assessing any of only hippurate; only 4-hydroxyhippurate; only N- methyl-2-pyridone-5-carboxamide; only the combination of hippurate and 4- hydroxyhippurate; only the combination of hippurate and ⁇ /-methyl-2-pyridone-5- carboxamide; only the combination of 4-hydroxyhippurate and ⁇ /-methyl-2-pyridone-5- carboxamide; or only the combination of hippurate, 4-hydroxyhippurate and ⁇ /-methyl-2- pyridone-5-carboxamide, the individual is not classified according to whether or not the individual has ASD.
  • Preferences for classifying the individual are as described above with respect to the third aspect of the invention.
  • the invention in addition to assessing any one or more of a mammalian- microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4- pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND) in a sample taken from the individual, the invention may comprise assessing at least one further biological parameter.
  • the at least one further biological parameter may be assessed either in the same sample or in a different sample taken from the individual.
  • the at least one further biological parameter may be any of the sequence of a particular region of a chromosome, the status of a specific protein or the status of a particular metabolite or a combination thereof. Additionally or alternatively, the at least one further biological parameter may be a phenotypic trait of an individual such as behaviour.
  • the at least one further biological parameter comprises the status of a gene that encodes factors related to sulfation or sulfation deficiency.
  • Analysis of the status of said gene factor applies to any attributes inherent in a gene, for instance its nucleotide sequence, chromosomal position, or copy number. Variations of these factors may expose differences from a sequence normal to a population, specifically a single nucleotide polymorphism (SNPs), multiple site polymorphisms or other mutations, differences in normal gene copy number (copy number variations, CNVs), and variance in epigenetic regulation, including factors regulating expression such as DNA methylation.
  • SNPs single nucleotide polymorphism
  • CNVs copy number variations
  • epigenetic regulation including factors regulating expression such as DNA methylation.
  • the analysis of the gene measures an SNP that relates to a defect in the gene-encoded factor.
  • said at least one further biological parameter to be assessed is a sulfate transporter.
  • Sulfate transporters are critical to regulation of free sulfate available to cells. Defects in said sulfate transporters are correlated with decreased salvage of dietary or systemic sulfate necessary for detoxification and other processes.
  • the sulfate transporters measured in this invention may be any of the group comprising the renal transporters NaS1, sat-1, or CFEX, the intestinal transporters NaS1 , Diastrophic Dysplasia Sulfate Transporter (DTDST), or Down Regulated in Adenoma transporter (DRA), and the mucosal sodium sulfate symporter.
  • the at least one further biological parameter is a polymorphism that confers hyper-activity to a competing sulfotransferase or glutathione transferase (by competing transferase it is meant a transferase enzyme that conducts sulfation reactions on metabolites or xenobiotics other than the phenolic compounds of interest of this invention).
  • competing transferase it is meant a transferase enzyme that conducts sulfation reactions on metabolites or xenobiotics other than the phenolic compounds of interest of this invention.
  • competing sulfotransferases are those for androsterones (SULT2A1), estrogens (SULT1 E1), dopaminergics (SULT1A3), cholesterol (SULT2B1), and tyrosyl protein sulfotransferases (TS-PSTs), among others.
  • Specific glutathione-s-transferases (GSTs) for polymorphism analysis include GST P
  • the at least one further biological parameter to be assessed is an enzyme involved in the generation of sulfur-containing compounds that can be used as substrates for Phase Il detoxification reactions.
  • Said enzymes include cysteine dioxygenase, cystathione B-synthase, methionine synthetase, and Organic Anion Transporter B (OATPB).
  • the at least one further biological parameter to be assessed is a sulfur-containing metabolite or metabolite ratio indicative of a subject's sulfation capacity.
  • Said metabolites and metabolite ratios may comprise sulfate, sulfite, thiosulfate, thiocyanate, transulfurated androgens, plasma glutathione (GSH)/ glutathione disulfide (GSSG) ratio, cysteine, taurine, sulfate, free sulfate, GSSG, or paracetamol sulfate/paracetamol glucuronide ratio.
  • the at least one further biological parameter may be known to be discriminatory for a particular pathological condition (eg ASD), such that it would be beneficial to assess at least said one further biological parameter in addition to any one or more of a mammalian-microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4-pyridone-3-carboxamide (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND).
  • a mammalian-microbial co-metabolite alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /
  • the at least one further biological parameter may be a further marker for ASD such as a diagnostic biomarker of ASD or any characteristic trait of an individual with ASD.
  • the at least one further biological parameter to be assessed is a gene known in the art to be associated with ASD such as a neuronal cell adhesion/synapse formation marker (PCDH10, CDH10, CDH9, NRXN1 , CNTN4), a copy number variation on NLGN1 , ASTN2, a factor in the ubiquitin pathway displaying copy number variations (for example, UB3A, PARK2, RFWD2, FBXO40), dopamine B- hydroxylase, or MET kinase.
  • PCDH10, CDH10, CDH9, NRXN1 , CNTN4 a gene known in the art to be associated with ASD
  • PCDH10, CDH10, CDH9, NRXN1 , CNTN4 a gene known in the art to be associated with ASD
  • the at least one further biological parameter may include genes correlated to pathologies associated with autism spectrum disorders, such as Rett syndrome (genes MECP2 and CDKL5), Angelman syndrome (genes SLC9A6 and UBE3A), and Fragile X (gene FMR4).
  • the at least one further biological parameter to be assessed is at least one further metabolite that is assessed in the same or a different sample.
  • Samples containing said at least one further biological parameter may be collected in blood (blood, cells, plasma or serum), tissue homogenates, fecal samples, urine samples, hair samples, interstitial fluid, cerebrospinal fluid, synovial fluid, or saliva samples that allow for the preservation of genetic information.
  • the preservation of these samples is conducted by common methods in the art, including the use of gentle homogenization and collection, and frozen storage until use.
  • the detection and measurement of genetic information is accomplished by any of the techniques common in the art, including RNA or DNA microarrays, fluorescence hybridizations such as fluorescence in situ hybridization (FISH), or genomic sequencing techniques.
  • FISH fluorescence in situ hybridization
  • the at least one further biological parameter to be assessed may be a further mammalian-microbial co-metabolite or a further mammalian metabolite
  • the method may comprise assessing more than one mammalian-microbial co-metabolite or mammalian metabolite in a sample taken from the individual Assessing more than one mammalian-microbial co-metabolite or mammalian metabolite may provide for more powerful discriminatory models for classifying individuals, than when only one such metabolite is assessed.
  • Methods for generating models to classify individuals based on multiple variables that may be used in the context of the present invention include those described in US patent no 7,373,256 and WO 03/107270
  • any one or more of a mammalian-microbial co- metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl-4- pyr ⁇ done-3-carboxam ⁇ de (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), may comprise assessing the ratio of any one or more of a mammalian- microbial co-metabolite, alanine, glycine, creatinine, glutamate, taurine, formate, inosine, succinate, acetate, an ⁇ /-acetyl glycoprotein, or a vitamin B metabolite such as ⁇ /-methyl- 4-pyr ⁇ done-3-carboxam ⁇ de (4PY), ⁇ /-
  • a mammalian-microbial co-metabolite such as ⁇ /-methyl-4-py ⁇ done-3-carboxam ⁇ de (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND), as a ratio with at least one other metabolite, for example to account for bulk mass differences between samples
  • a mammalian-microbial co-metabolite such as ⁇ /-methyl-4-py ⁇ done-3-carboxam ⁇ de (4PY), ⁇ /-methyl nicotinic acid (NMNA) or ⁇ /-methyl nicotinamide (NMND)
  • 4PY ⁇ /-methyl-4-py ⁇ done-3-carboxam ⁇ de
  • NMNA ⁇ /-methyl nicotinic acid
  • NMND ⁇ /-methyl nicotinamide
  • the at least one further biological parameter to be assessed is at least one protein assessed in the same or different sample.
  • interleukin-13 or cysteine deoxygenase may be assessed in a sample taken from the individual.
  • the data produced from carrying out the methods of the invention may conveniently be recorded on a data carrier.
  • the invention includes a method of recording data on whether an individual has, or has an increased risk of developing, autism spectrum disorder (ASD) by using any of the methods of the first aspect of the invention and recording the results on a data carrier.
  • ASD autism spectrum disorder
  • the invention includes a method of recording data on whether an individual is one who has, or has an increased risk of developing, a pathological condition by using any of the methods of the third aspect of the invention and recording the results on a data carrier.
  • the data are recorded in an electronic form and the data carrier may be a computer, a disk drive, a memory stick, a CD or DVD or floppy disk or the like.
  • Information recorded on the data carrier may include the name, date of birth, age, sex, height and body mass index of the individual or individuals.
  • FIG. 1 (A) PCA scores plot of the first 2 components from the normalized UV-scaled NMR data and (B) the corresponding PLS-DA cross-validated scores plot for all three group. PLS-DA cross-validated scores plot of pairwise comparison between (C) controls versus siblings and (D) controls versus autistics.
  • Example 1 Urinary metabolic phenotvpes of autistic and non-autistic siblings and age-matched normal children Summary
  • Autism is an early-onset developmental disorder with severe life long impact on behavior and social functioning.
  • Clear metabolic phenotype metalabotype differences were observed between autistic and controls, which were associated with perturbation in urinary mammalian-microbial co-metabolites including dimethylamine, hippurate and phenyacetylglutamine (PAG).
  • ASD Autism spectrum disorders
  • ASD Autism spectrum disorders
  • ASD typically develop during the first 3 years of life and are characterized by a myriad of deficits in language/communication skills, and socially detached as well as repetitive and stereotypic behaviours.
  • the etiopathology of ASD is multi-factorial and has been linked to genetic abnormalities such as fragile X syndrome, inborn errors of metabolism but there are many possible, but largely ill-defined, triggers including infectious agents and environmental toxins.
  • Various abnormalities in immunological function and gastrointestinal disturbances are also involved in ASD though their etiological significance is unknown.
  • Clostridia can produce powerful neurotoxins, and these have been implicated in ASDs with certain Clostridial species being found to be specific to autistic individuals (not present in normal children).
  • Clostridial species are found to be specific to autistic individuals (not present in normal children).
  • the faecal flora of ASD individuals have been found to contain higher numbers of Clostridium histolyticum group of bacteria as compared to healthy children and their non-autistic siblings were found to have intermediate levels of the same group of bacteria indicating the importance of gastrointestinal microbiota compositions in ASD.
  • Individuals with ASD has also been shown to have abnormal sulfur metabolism.
  • Waring et al showed that individuals with autism have lower levels of plasma sulfate but higher levels of urinary sulfate as compared to normal individuals, indicating that autistic individuals suffer from a deficiency in detoxification involving sulfation as evidenced by their inability to sulfate paracetamol[11].
  • Metabonomic technologies offer the possibility of measuring the metabolic end points (metabolic profiles) that are determined by host genetic and environmental factors, and enable possible identification of metabolites that could be indicative of ASD.
  • These high throughput metabolic profiling methods using high resolution spectroscopic platforms (NMR and/or mass spectrometry (MS)) with subsequent multivariate statistical analyses is a well-established strategy for differential metabolic pathway profiling and disease diagnosis.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Urine samples were prepared by mixing 400 ⁇ l of urine with 220 ⁇ l of a phosphate buffer (90% D 2 O, 1 mM 3-trimethylsilyl-1-[2,2,3,3- 2 H4] propionate (TSP), and 3 mM sodium azide; pH 7.4) and left to stand for 10 min. The samples were centrifuged at 11000 g for 10 min and 600 ⁇ l of the supematants were then transferred into 5 mm (outer diameter) NMR tubes.
  • a phosphate buffer 90% D 2 O, 1 mM 3-trimethylsilyl-1-[2,2,3,3- 2 H4] propionate (TSP), and 3 mM sodium azide; pH 7.4
  • Spectra were obtained on a Bruker DRX600 spectrometer (Bruker Biospin; Rheinstetten, Germany) at 600.13 MHz (ambient probe temperature 27°C).
  • a standard 1 -dimensional (1 D) pulse sequence was used [recycle delay (RD)-90°-f 1 -90 o -f m -90°-acquire free induction decay (FID)].
  • the water signal was suppressed by irradiation during RD of 2 s, and mixing time (t m ) of 150 ms.
  • t ⁇ was set to 3 ⁇ s and the 90° pulse length was adjusted to ⁇ 10 ⁇ s.
  • 1 H NMR spectra of urine samples were manually phased and baseline corrected using XwinNMR 3.5 (Bruker Biospin; Rheinstetten, Germany). The 1 H NMR spectra were referenced to the TSP resonance at ⁇ 0.0. The spectra were digitized using a MATLAB (version 7, The Mathworks Inc.; Natwick, MA, USA) script developed in-house. The regions containing the water and urea resonances were removed from each spectrum to eliminate baseline effects of imperfect water saturation. For each spectrum, recursive peak alignment algorithm [23] was applied to minimize spectral peak shift due to residual pH differences within samples prior to normalization to the total sum of the residual spectrum and pattern recognition analyses.
  • Principal component analysis was applied to the unit variance (UV)-scaled spectral data to reveal intrinsic illness-related patterns within the data.
  • Projection to latent structure discriminant analysis (PLS-DA) with UV-scaled spectral data was also carried out in order to improve classification of the different groups of individuals as well as to identify changes in urinary metabolites that are unique to a particular group.
  • Permutation testing 200 permutations was performed on the PLS-DA models to ensure statistical model validity. Inter-individual variation can confound data interpretation, particularly in multivariate data of high dimensionality.
  • orthogonal-projection to latent structure discriminant analysis [24] was performed on UV-scaled spectral data in a MATLAB environment to optimally model class differences and to systematically identify metabolites contributing to the differences between autistic, siblings and control groups.
  • the O-PLS-DA method decomposes the variation in X (NMR data) into 3 parts; the first being the variation in X related to Y (the class variable), and the last 2 containing the specific systemic variation in X and residual, respectively.
  • the contribution of each metabolite to sample classification is interpreted using the O-PLS coefficients with back-scaling transformation.
  • the colors projected onto the spectrum indicate the correlation of the metabolites discriminating autistic and siblings from the corresponding controls. Red indicates a high correlation and blue denotes no correlation with sample class.
  • the direction and magnitude of the signals relate to the covariation of the metabolites with the classes in the model.
  • Typical urinary 600 MHz 1 H NMR median spectra of individuals from the 3 groups consist of a wide range of low-molecular-weight metabolites of diverse chemical classes (typically ⁇ 1 kDa) from both mammalian and associated gut-microbial metabolism.
  • the urinary NMR spectra are dominated by dietary and microbial-derived methylamines (dimethylamine (DMA), trimethylamine ⁇ /-oxide (TMAO)) and phenolics such as hippurate and phenylacetylglutamine (PAG) ( Figure 1).
  • mammalian metabolites such as citrate, succinate, creatinine, lactate, ⁇ -hydroxyisobutyrate and amino acids (alanine, glutamine and glycine) are also excreted.
  • urinary spectra were very similar with the autistic individuals showing subtle differences in urinary succinate, ⁇ /-methyl nicotinic acid (NMNA) and N-methyl nicotinamide (NMND) as compared to the controls ( Figure 1).
  • the NMR aromatic spectral region of both the ASDs and siblings are very similar to those of the controls. Metabolic differences within the cohort.
  • pattern recognition analyses were employed on the data set to extract useful metabolic information.
  • the corresponding coefficients plot indicated differences in the urinary metabolic profile between the two groups with the autistics showing higher levels of urinary acetate, DMA, ⁇ /-acetyl glycoproteins (NAG), glycine, succinate, alanine, taurine, formate, inosine, NMNA, NMND and ⁇ /-methyl-4-pyridone-3-carboxamide (4PY), whilst the healthy controls showing higher levels of urinary glutamate, hippurate and PAG.
  • NAG ⁇ /-acetyl glycoproteins
  • urinary ammo acids alanine and glycine were found to be elevated in autistic individuals as compared to the controls Several studies have shown that children with ASD often suffer from dysregulated amino acid metabolism [34,35] In addition, Rolf et al reported that platelet serotonin was significantly increased and amino acids aspartic acid, glutamine, glutamic acid and ⁇ -aminobuty ⁇ c acid were significantly decreased in autistic individuals as compared to the controls [36] This is in agreement with our current finding where urinary glutamate was found to be lower in autistic group.
  • NMNA nicotinic acid
  • NMND nicotinic acid
  • Nicotinamide is the amide derivative of nicotinic acid, which is involved in the tryptophan-NAD pathway that supplies pyridine nucleotides to the liver.
  • Nicotinamide is metabolized to NMND via nicotinamide N-methyltransferase and subsequently to 2PY and 4PY via the action of aldehyde oxidase.
  • both 4PY and NMNA has been suggested as potential markers of peroxisome proliferation.
  • the changes in urinary 4PY, NMNA and NMND observed in the current study suggested possible perturbation of nicotinic acid metabolism in autistic individuals.

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Abstract

L'invention porte sur un procédé de détermination du point de savoir si ou non un individu a, ou a un risque accru de développer, un trouble du spectre autistique, le procédé comprenant l'évaluation de l'un quelconque ou de plusieurs d'un co-métabolite microbien de mammifère, l'alanine, la glycine, la créatinine, le glutamate, la taurine, le formate, l'inosine, le succinage, l'acétate, une N-acétyl glycoprotéïne ou un métabolite de vitamine B tel que le N-méthyl-4-pyridone-3-carboxamide (4PY), l'acide N-méthyl nicotinique (NMNA) ou le N-méthyl nicotinamide (NMND), dans un échantillon prélevé d'un individu, le procédé ne comprenant pas l'évaluation de l'hippurate et/ou du 4-hydroxyhippurate seul, et le procédé ne comprenant pas l'évaluation du N-méthyl-2-pyridone-5-carboxamide seul. L'invention porte sur une utilisation d'un moyen d'évaluation de l'un quelconque ou de plusieurs d'un co-métabolite microbien de mammifère, l'alanine, la glycine, la créatinine, le glutamate, la taurine, le format, l'inosine, le succinate, l'acétate, une N-acétyl glycoprotéine ou un métabolite de vitamine B tel que le N- méthyl-4-pyridone-3-carboxamide (4PY), l'acide N-méthyl nicotinique (NMNA) ou le N-méthyl nicotinamine (NMND) dans un échantillon prélevé d'un individu, dans la détermination du point de savoir si ou non un individu a, ou a un risque accru de développer, un ASD, l'utilisation ne comprenant pas l'utilisation de moyens d'évaluation de l'hippurate et/ou du 4-hydroxyhippurate seul, et l'utilisation ne comprenant pas l'utilisation de moyens d'évaluation du N-méthyl-2-pyridone-5-carboxamide seul.
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