Evidence for treatable inborn errors of metabolism cohort of 187 greek patients with autism spectrum (ASD)

Martha Spilioti, Athanasios E. Evangeliou, Despoina Tramma, Zoe Theodoridou, Spyridon Metaxas, Eleni Michailidi, Eleni Bonti, Helen Frysira, A. Haidopoulou, Despoina Asprangathou, Aggelos J. Tsalkidis, Panagiotis Kardaras, Ron A. Wevers, Cornelis Jakobs, K. Michael Gibson

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We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14years 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.

Original languageEnglish
Article number858
JournalFrontiers in Human Neuroscience
Issue numberDEC
Publication statusPublished - 24 Dec 2013


  • 3-hydroxyisovaleric acid
  • Autism
  • Biotin
  • Inborn errors of metabolism
  • Ketogenic diet
  • Lesch-nyhan disease
  • Phenylketonuria
  • Succinic semialdehyde dehydrogenase deficiency

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    Spilioti, M., Evangeliou, A. E., Tramma, D., Theodoridou, Z., Metaxas, S., Michailidi, E., Bonti, E., Frysira, H., Haidopoulou, A., Asprangathou, D., Tsalkidis, A. J., Kardaras, P., Wevers, R. A., Jakobs, C., & Michael Gibson, K. (2013). Evidence for treatable inborn errors of metabolism cohort of 187 greek patients with autism spectrum (ASD). Frontiers in Human Neuroscience, 7(DEC), [858]. https://doi.org/10.3389/fnhum.2013.00858