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.

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Clinical characteristics of patients are not always related to specific syndromes. Array-comparative genomic hybridization (aCGH) is used to detect submicroscopic copy number variants within the genome not visible by conventional karyotyping. The clinical application of aCGH has helped the genetic diagnosis of patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, with or without multiple congenital anomalies. Since 2008, we have implemented aCGH with the 244K and 4 × 180K Agilent platform on 334 patients with various degrees of developmental delay/intellectual disability, seizures, autism spectrum disorders, multiple congenital anomalies and normal previous conventional karyotype. Many of the patients had also received a variety of other genetic tests (Fragile X syndrome, Rett syndrome, single FISH tests or metabolic screens), which were normal. Clinically significant submicroscopic imbalances with aCGH were detected in 84 (∼25.15%) patients. aCGH is proving to be a powerful tool for the identification of novel chromosomal syndromes, thus allowing accurate prognosis and phenotype-genotype correlations.