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

Rahma Mkaouar,Amel Tounsi,Imen Chelly,Ichraf Kraoua,Christine Petit,Sami Bouchoucha,Ahlem Ben Hmid,Fabrice Giraudet,Olfa Messaoud,Hela Boudabbous,Hamza Dallali,Zied Riahi,Nadia Zitouna,Crystel Bonnet,Meriem Hechmi,Sonia Abdelhak,Soumeya Bekri,Ridha Mrad,Lotfi Zekri,S Maâlej ,J Marrakchi ,Chérine Charfeddine ,G Besbes ,Néji Tebib ,Rym Kéfi ,Imen Youssef ,Médiha Trabelsi

doi:10.1371/journal.pone.0258202

Abstract

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Highlights

Alpha-Mannosidosis (AM; OMIM #248500) is an ultra-rare autosomal recessive storage disorder induced by the deficiency of lysosomal Alpha-Mannosidase (LAMAN, EC 3.3. 1.24) [1]
This family originates from a city located in North-Eastern Tunisia
The first individual diagnosed with AM is the index case’s sister (Individual TNDF617-2, Fig 1) in 2003 at the National Institute of Neurology Mongi BEN HMIDA in Tunis

Summary

Introduction

Alpha-Mannosidosis (AM; OMIM #248500) is an ultra-rare autosomal recessive storage disorder induced by the deficiency of lysosomal Alpha-Mannosidase (LAMAN, EC 3.3. 1.24) [1]. AM is characterized by a progressive disease course and has been classified into three clinical sub-types based on disease severity and age at onset. Type 1 is the mildest form with slow progression of mental retardation, no skeletal abnormalities, and is usually diagnosed during or after adolescence (>10 years old). Type 2 form is relatively moderate; it begins before the age of 10 and is distinguished by skeletal abnormalities, slow progression of ID, and the possibility of developing ataxia by the age of 20–30 years. Type III is the most severe form of the disease diagnosed in the neonatal period with rapid progression followed by death due to alteration of the central nervous system [4,5]

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