Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment

PLoS One. 2021 Oct 6;16(10):e0258202. doi: 10.1371/journal.pone.0258202.

PMID: 34614013

Rahma Mkaouar, Zied Riahi, Cherine Charfeddine

Highlights: This article presents the clinical and genetic study of six patients from two Tunisian families with alpha-mannosidosis.

Abstract

Background: A lack of lysosomal alpha-mannosidase, which is produced by the MAN2B1 gene, results in the ultra-rare storage disorder known as alpha-mannosidosis (AM). Mental retardation, recurrent infections, hearing loss, dysmorphic traits, and motor dysfunctions are some of the clinical signs of AM. In Tunisia, AM has never been reported.

Objective and results: Here, the findings are provided from a clinical and genetic analysis of six AM patients from two Tunisian families. An enzymatic activity assay supported the AM diagnosis. Sanger sequencing of the mutational hotspots for the first family's members and ES analysis for the second family members were used to undertake genetic investigations. The MAN2B1 gene in the first family contained a frameshift duplication known as p.(Ser802GlnfsTer129). In the second family, ES analysis revealed that four affected family members had the missense mutation p.(Arg229Trp) in the MAN2B1 gene. The p.(Ser802GlnfsTer129) mutation results in a premature termination codon that could cause the NMD system to start degrading RNA. The severe phenotype shown in the index case may be explained by a decrease in MAN2B1 synthesis levels. The research indicates that the p.(Arg229Trp) missense variant, which is correlated with a moderate clinical sub-type, has no effect on MAN2B1 maturation and transportation. Exome analysis made it possible to identify two plausible pathogenic variants in the GHR and SLC19A3 genes that may be linked to cognitive decline, which helped to explain the intra-familial heterogeneity of cognitive impairment.

Conclusion: The current study highlights the underdiagnosis of AM in the area, which prevents patients from receiving adequate treatment. It is true that early diagnosis is essential for halting disease development and recommending enzyme replacement therapy.

Keywords: alpha-mannosidosis, MAN2B1 gene, cognitive impairment