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Overview of Lysosomal Storage Disorders

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects or deficiencies of lysosomal enzymes (or other lysosomal components) can result in accumulation of undegraded metabolites. Because there are numerous specific deficiencies, storage diseases are usually grouped biochemically by the accumulated metabolite. Subgroups include

The most important are the mucopolysaccharidoses and sphingolipidoses. Type 2 glycogenosis is a lysosomal storage disorder, but most glycogenoses are not.

Because reticuloendothelial cells (eg, in the spleen) are rich in lysosomes, reticuloendothelial tissues are involved in a number of lysosomal storage disorders, but, generally, tissues richest in the substrate are most affected. Thus the brain, which is rich in gangliosides, is particularly affected by gangliosidoses, whereas mucopolysaccharidoses affect many tissues because mucopolysaccharides are present throughout the body.

Mucopolysaccharidoses (MPS)

MPS are inherited deficiencies of enzymes involved in glycosaminoglycan breakdown. Glycosaminoglycans (previously termed mucopolysaccharides) are polysaccharides abundant on cell surfaces and in extracellular matrix and structures. Enzyme deficiencies that prevent glycosaminoglycan breakdown cause accumulation of glycosaminoglycan fragments in lysosomes and cause extensive bone, soft tissue, and central nervous system changes. Inheritance is usually autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more (except for MPS type II).

Age at presentation, clinical manifestations, and severity vary by type (see table Mucopolysaccharidosis (MPS) Mucopolysaccharidosis (MPS) Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects... read more ). Common manifestations include coarse facial features, neurodevelopmental delays and regression, joint contractures, organomegaly, stiff hair, progressive respiratory insufficiency (caused by airway obstruction and sleep apnea), cardiac valvular disease, skeletal changes, and cervical vertebral subluxation.

Diagnosis of mucopolysaccharidoses is suggested by history, physical examination, bone abnormalities (eg, dysostosis multiplex) found during skeletal survey, and elevated total and fractionated urinary glycosaminoglycans. Diagnosis is confirmed by DNA analysis and/or enzyme analysis of cultured fibroblasts (prenatal) or peripheral white blood cells (postnatal). (Also see testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .) Additional testing is required to monitor organ-specific changes (eg, echocardiography for valvular disease, audiometry for hearing changes).

Treatment of mucopolysaccharidosis type I is enzyme replacement with laronidase, which effectively halts progression and reverses all non-central nervous system complications of the disease. Hematopoietic stem cell (HSC) transplantation has also been used. The combination of enzyme replacement and HSC transplantation is under study. For patients with MPS type IV-A (Morquio A syndrome), enzyme replacement with elosulfase alfa may improve functional status, including mobility.

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Sphingolipidoses

Sphingolipids are normal lipid components of cell membranes; they accumulate in lysosomes and cause extensive neuronal, bone, and other changes when enzyme deficiencies prevent their breakdown. Although incidence is low, carrier rate of some forms is high.

Others sphingolipidoses include

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Mucolipidoses and other lysosomal disorders

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