Chapter 574

Lysosomal storage disorders (LSDs) comprise a group of approximately 30 relatively rare inherited diseases that are characterized by defective functioning of one or several lysosomal enzymes. As a result of the enzyme deficiency, a storage material (glycogen, glycoproteins, shingolipids, cholesterol) accumulates in various organs, including central nervous system (CNS), liver, spleen, and kidneys. While most individual LSDs are quite rare, as a group their incidence is estimated to be between 1:5000 to 1:10,000. The prevalence of some of LSDs is higher in certain populations. LSDs are classified based on the type of the enzymatic defect or type of stored substrate product. Clinical symptoms (both somatic and neurological manifestations) tend to progress as the substrate accumulates over time. Several LSDs with CNS involvement are discussed below. These disorders are further discussed in Chapters 160 and 161. Diagnosis is usually made by enzyme assay or mutation analysis. Hematopoietic stem cell transplant (HSCT) has been used for the treatment of several LSDs over the past three decades. Enzyme replacement therapy (ERT) became available for the treatment of few LSDs in the past 15 years. New therapies have emerged in most recent years; small molecule drugs (chaperones) can reduce substrate production (substrate reduction therapy) or increase residual enzyme activity (enzyme enhancing therapy). Gene therapy may become available for the treatment of some LSDs in the future and is under investigation.

### Lysosomal Storage Diseases Containing Lipid

#### GM1 Gangliosidosis

GM1 gangliosidosis is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, GM1 ganglioside β-galactosidase, a lysosomal enzyme requiring a complex of sphingolipid activator protein (saposin B), protective protein, and neuraminidase enzyme in order to function properly. β-galactosidase deficiency results in accumulation of GM1 ganglioside within the brain and storage of galactose-containing glycoproteins and keratan sulfate within various body organs.

Deficiency of β-galactosidase is expressed clinically as 2 different diseases: GM1 gangliosidosis and Morquio B disease. GM1 gangliosidosis is characterized by a neurodegenerative process with associated visceral involvement. Generalized bone disease without CNS involvement is the hallmark of Morquio B disease. Molecular analysis has confirmed allelic mutations of the same gene in these diseases mapped to chromosome 3 (3p21.33).

The clinical phenotype of GM1 gangliosidosis can be divided into 3 forms: type I (infantile), type II (juvenile), and type III (adult). Type I, or infantile, form presents at birth or during early infancy with characteristic facial appearance of depressed nasal bridge, frontal bossing, epicanthal folds, puffy eyelids, gingival hypertrophy, enlarged tongue, low-set ears, and small jaw. Peripheral and facial edema may be seen. Other features include skeletal dysplasia, manifesting as thoracolumbar kyphoscoliosis and hepatosplenomegaly. Psychomotor delay and hypotonia are apparent early; later neurologic signs include seizures and irritability. Vision is poor; a cherry-red macula develops after several months in at least 50% of children. Bronchopneumonia or cardiac failure often causes death within first few years. MRI may ...

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