Ability to Form Words, Sentences Linked with Autism Spectrum Disorder Severity in Young Males with Fragile X

A greater ability to generate words, phrases and sentences correlates with lower autism spectrum disorder (ASD) symptom severity in adolescent and young adult males with fragile X syndrome (FXS), according to a study.

The research, “ASD Comorbidity in Fragile X Syndrome: Symptom Profile and Predictors of Symptom Severity in Adolescent and Young Adult Males,” appeared in the Journal of Autism and Developmental Disorders.

FXS, the most common genetic cause of autism, is characterized by low levels or absence of the FMRP protein. Males have more pronounced clinical manifestations than females.

Males with FXS may experience symptoms of ASD. Over 90% show behaviors typical of nonsyndromic — not linked to other neurological diseases or syndromes — ASD, such as repetitive speech, motor stereotypes — rhythmic movements such as hand flapping — and poor eye contact.

Children with FXS differ in their reactions to stranger approach and social demands, as well as their specific language abilities, depending on whether they have an ASD diagnosis. However, relying solely on an ASD diagnosis may mask relevant differences in symptom severity among FXS patients and between FXS and nonsyndromic ASD, researchers cautioned. This may have important implications for therapeutic approaches.

Research has shown that ASD symptoms appear in the first year of life of patients with FXS and remain stable during preschool years. A subsequent age-related aggravation is observed up to late childhood, but whether a continued worsening into adulthood occurs is unclear.

Individuals with FXS and ASD tend to have a lower IQ than those with FXS only. Also, nonverbal cognition is related to ASD symptom severity in children, but only to its social affective domain in early adolescence.

Boys with both FXS and ASD also have different levels of impairment in specific language dimensions than those with nonsyndromic ASD, which affects social interaction.

Regarding psychiatric conditions, a study that used parent reports revealed FXS patients had a higher rate of anxiety and manic/hyperactivity symptoms than those with nonsyndromic ASD. However, a previous study in adolescent and young adult males found no difference in anxiety, which scientists attributed to age-related differences or potential differences in measurement.

So far, the limited evidence on FMRP levels and ASD symptoms in FXS shows no correlation between the amount of this protein and ASD symptom severity or diagnosis. However, available studies did not assess the total amount of FMRP, but rather the proportion of sampled cells expressing FMRP, the authors noted.

Given the existing gaps in the literature, the team aimed to further describe ASD symptoms in adolescent and young adult males with FXS.

They also intended to evaluate the relative contributions of IQ, expressive syntax — the arrangement of words and phrases — psychiatric factors and FMRP protein levels to overall ASD symptom severity as well as to symptoms in social affective domains and restricted and repetitive behaviors (RRB).

A total of 44 patients ages 15-22 were included and tested at the University of California, Davis or University of South Carolina. Data were obtained at the patients’ first annual assessment, except for blood for genetic analysis, which was collected later.

Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), a measure to assess social affective and RRB symptoms, was given to patients according to their speech fluency level and age. A score of 1-10 was used to reflect overall ASD symptom severity.

Individual ADOS items were evaluated to analyze specific ASD symptoms. Also, each patient’s biological mother provided information on the participant’s developmental history and the presence of ASD symptoms at or near age 4 via the Autism Diagnostic Interview-Revised (ADI-R).

Nonverbal cognition and syntax were assessed using the Leiter international performance scale-revised (LeiterR) and the Syntax Construction subtest of the Comprehensive Assessment of Spoken Language (CASL), respectively. Each patient was asked to respond to a picture by imitating the examiner, completing a sentence, answering a question, formulating a sentence, and/or using a model sentence.

The 28-item Anxiety, Depression, and Mood Scale was used to screen psychiatric disorders. Mothers responded to this scale, which addresses five domains – manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and obsessive/compulsive behavior.

Thirty-three patients (33%) met the criteria for ASD, with the ADOS-2 score (5.57) reflecting mild ASD. Most participants on the intermediate verbal fluency level (module 2) — “phrase speech up to fluent speech” — showed at least some impairment of eye contact (86%), directed facial expressions (93%) and quality of social overtures (90%), all of which are social affective items.

A smaller percentage of participants with better verbal fluency (module 3) — “fluent speech, approximately equivalent to or higher than the expressive language skills of a typically developing 4-year-old” — showed impairment in these areas.

As for RRB items, nearly 80% of patients in module 2 revealed no impairment in repetitive interests/stereotyped behavior and about half in unusual sensory interests and hand/finger/complex mannerisms. A similar pattern was observed in module 3.

Overall, results from ADOS-2 largely matched those provided by caregivers in their autism diagnostic (ADI-R) interview.

The only variables that were independent predictors of the ADOS-2 score were syntax and whether FMR1 mutations had mosaicism, which refers to mutations in cells that are passed on only to its daughter cells. In particular, less severe ASD symptoms were observed in patients with better expressive syntax.

The same two variables were the greatest predictors of social affective severity score. In turn, RRB severity was best predicted by psychiatric factors and cognitive impairment.

“In conclusion, our findings are important in demonstrating the need to supplement studies using the categorical diagnosis of ASD in FXS with an understanding of individual symptoms and symptom domains and the underlying problems that they reflect,” researchers stated.