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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.
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Lysosomal Storage
Diseases Containing Lipid
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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.
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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).
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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. ...