title: Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.
abstract: Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital-frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC+4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87%; 54/62), plasma taurine (69%; 46/67) and reduction of plasma cystine (72%; 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC ≥2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hobert
authors.affiliation: Center for Autism, Pediatrics Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Embacher
authors.affiliation: 1] Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.affiliation: 1] Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Center for Autism, Pediatrics Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Frazier
authors.affiliation: 1] Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [3] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA [4] CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000652:urine; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000097:blood / Q000235:genetics* / Q000652:urine; D002675:Child, Preschool; D003553:Cystine / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000097:blood / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013654:Taurine / Q000097:blood; D055815:Young Adult
chemical_list: D013654:Taurine; D001224:Aspartic Acid; D003553:Cystine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human