The Natural Course of Bosch-Boonstra-Schaaf Optic Atrophy Syndrome

Area of Science:

• Genetics and rare diseases
• Neurodevelopmental disorders
• Ophthalmology

Background:

• Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare neurodevelopmental disorder linked to pathogenic variants in the NR2F1 gene.
• The syndrome presents with diverse symptoms including intellectual disability, developmental delay, and visual impairment.
• Limited information exists on the natural progression of BBSOAS.

Purpose of the Study:

• To comprehensively assess the phenotype and symptom progression in individuals with BBSOAS.
• To investigate genotype-phenotype correlations within the NR2F1 gene.
• To provide insights into the natural course of BBSOAS.

Main Methods:

• A questionnaire was developed and distributed to collect data on phenotype and symptom development from 47 individuals with BBSOAS.
• Medical documents and photographs were also collected to supplement questionnaire data.
• Genotype-phenotype correlations were analyzed by comparing clinical features of individuals with variants in the DNA-binding domain (DBD) versus other gene regions.

Main Results:

• Common symptoms include developmental delay, hypotonia, optic atrophy, nystagmus, strabismus, autistic features, and thin corpus callosum.
• Individuals with NR2F1 variants in the DNA-binding domain (DBD) exhibited a higher prevalence of severe features like infantile spasms and nonverbality.
• Age at diagnosis differed significantly between genotypic groups, with DBD variants associated with earlier diagnosis.
• Overall, symptom improvement was reported more frequently than worsening.

Conclusions:

• The study confirms characteristic clinical features of BBSOAS and highlights the association between NR2F1 DNA-binding domain variants and a more severe phenotype.
• Evidence suggests that BBSOAS symptoms may improve over time rather than progress, contrary to typical neurodegenerative disease patterns.
• Further prospective longitudinal studies are necessary to definitively understand the disease's progression.