Etiologic Investigation of 654 patients with Autism Spectrum Disorder (ASD): the experience at Hospital Pediátrico de Coimbra in Portugal

Background: ASD may be a neurodevelopmental syndrome with many different causes leading to the same final common pathway, a hypothesis supported by the multiple rare medical conditions associated with the disorder.

Objectives: This study assessed the diagnostic yield for autism in a large sample of children observed over several years at HPC.

Methods: Assessment of ASD entailed extensive interaction with patients in a clinical setting, the majority of whom return frequently for follow up. ASD was diagnosed using the ADI-R and CARS. A comprehensive clinical history was collected, including the pre and perinatal periods. Laboratorial assessment included testing for chromosomal abnormalities (karyotyping, 15q11-13 FISH analysis), neurocutaneous syndromes, endocrine, metabolic and genetic disorders.

Results: Of the 654 ASD patients who participated in the study (518 males, mean age 12.6±4.8), 17% were non-idiopathic. 4% presented chromosomal abnormalities: five patients on ch15q11-13, two on chromosome9, one each on chromosomes 1, 3, 5, 6, 7, 8; trisomy 21 was present in eleven ASD children. Nineteen cases had a genetic syndrome of unknown origin (2.9%). FMR1 mutations were found in seventeen cases (2.6%) and Rett Syndrome was confirmed by molecular analysis in two cases; one additional MECP2 non-synonymous variant was found in a male patient. NLGN4 sequence analysis in 148 cases detected two non-synonymous changes. Lactate levels were increased in 21% of the patients; mitochondrial disease was confirmed in 8 cases and probable in 3 cases out of 20 fully tested. Six patients presented a neurocutaneous syndrome, five had abnormalities in brain development. Fourteen patients had documented pre or peri-natal incidents, five post natal infections, one hypothyroidism and one brain tumour.

Conclusions: This study illustrates the etiological diversity associated with autism in an important percentage of cases, and supports the need of screening for specific medical disorders with implications in recurrence risk and medical support.