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.