Novel CTSA Variant Identified in a Thai Family With Late-Infantile Galactosialidosis

Area of Science:

• Genetics
• Biochemistry
• Immunology

Background:

• Galactosialidosis (GS) is a rare lysosomal storage disease (LSD) caused by defects in the protective protein/cathepsin A (PPCA) gene (CTSA).
• Late-infantile GS typically presents with developmental delay, visceromegaly, coarse facies, and cherry-red macula.
• This study focuses on a Thai-Lahu family with late-infantile GS exhibiting unusual T-cell defects.

Purpose of the Study:

• To report novel cases of late-infantile Galactosialidosis presenting with T-cell defects.
• To identify the genetic basis of GS in the affected Thai-Lahu family.
• To investigate the functional impact of the identified genetic variant on PPCA.

Main Methods:

• Clinical evaluation of affected individuals, including assessment of T-cell function.
• Lysosomal enzyme assays to measure PPCA activity.
• Genetic analysis including exome sequencing and identification of CTSA variants.
• In vitro functional analysis of the identified CTSA variant.

Main Results:

• Affected individuals presented with recurrent infections due to T-cell defects, alongside typical GS features.
• Lysosomal enzyme assays revealed undetectable PPCA activity.
• A novel homozygous missense CTSA variant (c.1307A>G; p.Gln436Arg) was identified in affected individuals.
• In vitro studies suggested the variant impairs PPCA dimerization and function, leading to reduced activity.

Conclusions:

• These cases represent the first reported instances of Galactosialidosis associated with T-cell defects.
• The novel CTSA variant contributes to reduced PPCA activity and the observed clinical phenotype.
• This study expands the known clinical and genotypic spectrum of Galactosialidosis.