Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases

Joanna Jakóbkiewicz-Banecka,Bogdan Banecki,Magdalena Gabig-Cimińska,Zyta Banecka-Majkutewicz,Alicja Węgrzyn,Grzegorz Węgrzyn

doi:10.1007/s11011-013-9455-6

Abstract

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70 %) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.

Highlights

There are several thousand inherited diseases identified to date (Korf and Rehm 2013), among which many affect brain functions
Genotype-phenotype correlations in LSDs are clear for some types of mutations, when null mutations occur in both alleles of the affected gene
Phenotypes of patients bearing mutations resulting in residual activities of affected enzymes depend on other factors, various stresses caused by different agents

Summary

Introduction

There are several thousand inherited diseases identified to date (Korf and Rehm 2013), among which many affect brain functions. It is not a surprise that many articles were published in which authors tried to understand genotype-phenotype correlations in different inherited metabolic diseases, including LSDs. contrary to an early assumption that knowing mutation(s) in the affected gene one should be able to predict patient’s phenotype (highlighted and discussed by Silverman and Mahadevan 2005), after years of studies, it appears that such a scenario is possible only in some cases, and often the clinical phenotype is weakly related to the particular mutation (reviewed by Lippi and Favaloro 2009).

Results

Conclusion