Exploring Molecular and Phenotypic Characteristics of Arg234Gly and Asp312Asn Variants.

Introduction: Mucopolysaccharidosis type IIIB is an autosomal recessive lysosomal disorder caused by variants in the α-n-acetylglucosaminidase () gene. It is a progressive neurodegenerative disorder with no treatment. Previous enzyme therapies have been unsuccessful. It is important to understand the mechanism of the disease to be able to find new treatments.

Methods: We did whole-exome sequencing and standard Sanger sequencing on 7 cases of four consanguineous families diagnosed with autism spectrum disorder.

Results: We identified two recurrent damaging biallelic Asp312Asn and p.Arg234Gly variants in the gene. Structure modeling of these variants suggested that each variant affects the stability of the enzyme and results in a loss of activity. All affected individuals' enzymatic assay in leukocytes clearly showed that α-n-acetylglucosaminidase was completely inactive. Our patients underwent magnetic resonance imaging (MRI), revealing normal findings in two of them despite progressive clinical neurodegenerative symptoms. To our knowledge, these cases represent the second and third instances of normal MRI findings documented in the literature.