Specific Neurological Phenotypes in Autism Spectrum Disorders Are Associated with Sex Representation

Abstract

Autism spectrum disorder (ASD) is a heritable disorder occurring predominantly in males. The aim of this study was to compare sex differences in the prevalence of specific neurological phenotypes commonly described in ASD. The study included 663 participants, aged 18 months to 15 years, diagnosed with ASD. Neurological and behavioral assessments were performed using standardized tests, and obtaining medical, developmental, and familial histories from the parents. Phenotypes under investigation were macro- and microcephaly, developmental regression, minor neurological and musculoskeletal deficits (MNMD), and seizures. Male : female ratio in the ASD group was 6.7:1. No sex differences in autism severity, cognitive ability, and adaptive functioning were noted. Mean head circumference percentile for males (50.1 ± 25.6) was significantly larger than females (43.4 ± 30.2). Micro- and macrocephaly were more frequent in ASD than expected (5.9%; 18.1%, respectively). Microcephaly in females (15.1%) was significantly more prevalent than in males (4.5%). The prevalence of macrocephaly in both sexes did not differ significantly. Regression was noted in 30.2% of the females with ASD, significantly higher than in males (18.9%). MNMD was documented in 73.8% of the females, significantly higher than in males (57.1%). M:F ratio decreased in a group with two or more phenotypes (3.6:1), while male predominance was more significant in the group without phenotypes (13.6:1). Neurological phenotypes associated with ASD are more prevalent in females than in males, resulting in more complex clinical and neurological manifestations in females. Therefore, involvement of different etiologies is suggested in ASD in females.

Early Generalized Overgrowth in Autism Spectrum Disorder: Prevalence Rates, Gender Effects, and Clinical Outcomes

“…Although gender effects on the prevalence of macrocephaly or megalencephaly have been more frequently investigated, the results also remain inconclusive. Macrocephaly rates have been reported to be higher in boys than in girls with ASD 23 or comparable between the two sexes 22, 24–26 . Evidence for enlargement in total brain volume (TBV) in young females with ASD is also mixed, with some reporting presence of TBV enlargement 15, 27, 28 and others reporting none 9 .…”

A Review of the Differences in Developmental, Psychiatric, and Medical Endophenotypes Between Males and Females with Autism Spectrum Disorder

“…Previous research suggests that sex could represent a naturally occurring subgroup that differentiates ASD symptoms (Ben-Itzchak et al, 2013; Hartley and Sikora, 2009; Holtmann et al, 2007; Lai et al, 2013; Carter et al, 2007; Mandy et al, 2012; Kirkovski et al, 2013). Endophenotypes may also represent subgroups that differentiate ASD symptoms and lend clues to causes of the disorder.…”

Structural MRI biomarkers of shared pathogenesis in autism spectrum disorder and epilepsy

“…In sum, findings from head circumference studies are variable but generally support macrocephaly and microcephaly as biomarkers that are potentially predictive of divergent clinical phenotypes. For example, microcephaly is more frequently found in children with other medical disorders [108] and in females [109]; while accelerated head growth and the presence of macrocephaly by 4-6 months of age are predictive of higher risk of developmental regression in boys [110].…”