title: Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD).
abstract: 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.
authors.affiliation: First Department of Neurology, AHEPA Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Martha
authors.initials: M
authors.lastname: Spilioti
authors.affiliation: Fourth Department of Pediatrics, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Athanasios E
authors.initials: AE
authors.lastname: Evangeliou
authors.affiliation: Fourth Department of Pediatrics, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Despoina
authors.initials: D
authors.lastname: Tramma
authors.affiliation: Department of Special Educational Needs, St. Luke's Hospital Thessaloniki, Greece.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Theodoridou
authors.affiliation: Second ENT Department, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Metaxas
authors.affiliation: Department of Pediatrics, Medical School, University of Crete Heraklion, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Michailidi
authors.affiliation: Department of Pediatrics, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Bonti
authors.affiliation: Department of Pediatrics, Athens University Medical School, Agia Sophia Children's Hospital Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Frysira
authors.affiliation: Fourth Department of Pediatrics, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Haidopoulou
authors.affiliation: Fourth Department of Pediatrics, Papageorgiou Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Despoina
authors.initials: D
authors.lastname: Asprangathou
authors.affiliation: Department of Pediatrics, Medical School, University of Thrace Alexandroupolis, Greece.
authors.forename: Aggelos J
authors.initials: AJ
authors.lastname: Tsalkidis
authors.affiliation: Third Department of Pediatrics, Hippokration Hospital, Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kardaras
authors.affiliation: Laboratory of Genetic, Endocrine and Metabolic Diseases, Department of Laboratory Medicine, RUNMC Nijmegen, Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Amsterdam, Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.affiliation: Section of Clinical Pharmacology, College of Pharmacy, Washington State University Spokane, WA, USA.
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
keywords: 3-hydroxyisovaleric acid; Lesch-Nyhan disease; autism; biotin; inborn errors of metabolism; ketogenic diet; phenylketonuria; succinic semialdehyde dehydrogenase deficiency