@article{3159703,
    title = "Evidence for treatable inborn errors of metabolism in a cohort of 187
Greek patients with autism spectrum disorder (ASD)",
    author = "Spilioti, Martha and Evangeliou, Athanasios E. and Tramma, Despoina and and Theodoridou, Zoe and Metaxas, Spyridon and Michailidi, Eleni and Bonti, and Eleni and Frysira, Helen and Haidopoulou, A. and Asprangathou, Despoina and and Tsalkidis, Aggelos J. and Kardaras, Panagiotis and Wevers, Ron A. and and Jakobs, Cornelis and Gibson, K. Michael",
    journal = "Frontiers in Human Neuroscience",
    year = "2013",
    volume = "7",
    publisher = "Frontiers Research Foundation",
    doi = "10.3389/fnhum.2013.00858",
    keywords = "autism; inborn errors of metabolism; biotin; ketogenic diet;
3-hydroxyisovaleric acid; Lesch-Nyhan disease; succinic semialdehyde
dehydrogenase deficiency; phenylketonuria",
    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."
}