Early onset alpha‐mannosidosis with slow progression in three Hispanic males

Abstract

Alpha-mannosidosis (AMS) is an autosomal recessive lysosomal storage disorder which results from a deficiency of lysosomal alpha-mannosidosis activity and displays a wide range of clinical phenotypes. Patients have traditionally been divided into type I, a more severe form that presents in infancy, and type II, a milder form that typically presents in later childhood. We describe three Hispanic males who presented in infancy with relatively mild forms of AMS. They were aged between 6 and 24 years at their last assessment. Homozygous mutations in the MAN2B1 gene were found in all three patients, one of which is a newly reported mutation. Two of the patients were brothers who were homozygous for the same MAN2B1 mutation. Despite being homozygous for the same mutation, the older brother had more severe developmental delay, hearing loss, and growth retardation. This report illustrates the difficulty in determining a strict genotypephenotype correlation in AMS, and supports screening for oligosaccharides in children with neurodevelopmental delay with mild phenotypic signs and symptoms.Alpha-mannosidosis (AMS) is an autosomal recessive lysosomal storage disorder caused by lysosomal alpha-mannosidosis deficiency. 1 AMS is encoded by the MAN2B1 gene. 2 Characteristic clinical features of AMS include mental retardation,* coarse facial features, ataxia, hearing loss, dysostosis multiplex, and recurrent infections.Patients with AMS are often classified into one of two groups depending on the age at onset of the disorder and the severity of disease progression. The more severe form of AMS is designated type I or the infantile phenotype. 3,4 This type is characterized by hepato-splenomegaly, severe dysostosis multiplex, hypotonia, rapidly progressive cognitive deterioration, and death, often occurring between 3 and 12 years of age. [3][4][5] The milder form of AMS is termed type II or the juvenile-adult phenotype. 3,4 Type II AMS is characterized by normal early development, mental retardation during childhood, and survival well into adulthood. 4,5 Although patients have typically been placed into one of these two types of AMS, the clinical findings in patients may actually represent more of a continuum. 3 We describe three new cases of AMS in two families from Honduras. The patients showed variable clinical expression that correlates more readily with a continuum of clinical features. All three patients were found to have rare mutations in the MAN2B1 gene but no clear-cut genotype-phenotype correlation. Case reportsThe following patients were seen in Honduras (by KRH). The

A multi-species comparative structural bioinformatics analysis of inherited mutations in α-D-Mannosidase reveals strong genotype-phenotype correlation

“…Our comprehensive analysis, taking into account all non-splicing mutations (see Additional file 1: table S1) known to cause α-mannosidosis, reveals a strict genotype-phenotype correlation, contrary to the reports of Malm and Nilssen [2] and Lyons et al [8]. This disease can be comparatively well studied as it occurs in different species, providing us with an evolutionary basis for the conserved regions of the protein sequence, as well as active site conservation, where mutations could result in disastrous consequences.…”

“…From OMIM (Online Mendelian Inheritance in Man) [6], OMIA (Online Mendelian Inheritance in Animals) [7] and published literature [8], a list of inherited mutations for α-mannosidosis has been identified. Various mutations like missense, nonsense, insertions, deletions and also some splicing mutations have been described in the four species to date.…”

Identification of 83 novel alpha-mannosidosis-associated sequence variants: Functional analysis of MAN2B1 missense mutations

“…Disease‐causing sequence variants have been identified in all animal models Berg et al, 1997, 2002; Tollersrud et al, 1997, and we have previously been involved in the identification of 29 disease‐causing variants in 44 unrelated alpha‐mannosidosis patients Berg et al, 1999; Broomfield et al, 2010; Castelnovo et al, 2007; Frostad Riise et al, 1999; Lyons et al, 2007; Magner et al, 2008; Nilssen et al, 1997; Ölmez et al, 2003; Urushihara et al, 2004. Most of these variants were private, but one missense mutation (c.2248C>T, p.Arg750Trp) was present in 18 patients from eight different countries Berg et al, 1999; Magner et al, 2008.…”

Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients

“…Lyons et al 4 reported three Hispanic males with alpha-mannosidosis that, despite early clinical signs, showed relatively benign long-term outcomes. Normal development leading to an independent life seems to be achieved only occasionally.…”