|Providing new hope to families facing the
debilitating aspects of lysosomal storage diseases.
|Lysosomal Storage Diseases
Lysosomal Storage Diseases (LSDs) are caused by inherited enzyme deficiencies and result in an
accumulation of substrate in the cellular lysosome organelles. The severity of these diseases
generally varies with the degree of protein deficiency. The most severe deficiencies cause death in
early childhood while milder deficiencies may not present clinically until adulthood. The type and
location of the cells affected and the rate of the substrate accumulation form the basis of the clinical
abnormalities and the timing of initial onset. These diverse clinical manifestations, the infrequent
occurrence of the individual diseases, and the variation in severity have made early diagnosis of these
diseases extremely difficult.
The overall incidence of diagnosed LSDs has been estimated to be approximately one per 7700 births
based on long-term studies conducted in Australia (Meikle 1999). This does not include the incidence
of neuronal ceroid lipofucinosis, Batten disease, which is now also designated as a lysosomal storage
disease. Measurement of the actual incidence has been difficult because of the lack of accurate
newborn screening and the delayed clinical manifestations of the disease in late-onset phenotypes.
An additional consideration is the large range of incidence rates between various ethnic groups with
some of these groups having an incident rate ten times greater than the worldwide average.
Of the more than 40 known lysosomal enzyme deficiencies (partial listing shown in figure 1) more than
60% have central nervous system (CNS) disease involvement (Liu et al., 2005, Meikle et al., 1999).
The inability of neuronal cells to regenerate makes LSDs with CNS involvement clinically significant and
makes early treatment essential. Many of the systemic aspects of some LSD disorders are today being
treated with clinically available, yet expensive, Enzyme Replacement Therapy (ERT). ERT requires
that a patient be infused with the deficient enzyme every one to two weeks. Since 1994, when the first
ERT was commercialized in the United States, this therapy has become the clinical "gold standard" and
has resulted in major clinical improvement in the systemic aspects of these diseases. Unfortunately,
this treatment does not cross the blood-brain barrier and is ineffective in treating the CNS aspects. It is
not surprising therefore that the initial efforts in developing ERT for LSDs by the biotherapeutic industry
has been for Gaucher Disease, MPS I, Fabry Disease, and Pompe, which in most cases do not have
CNS involvement. There is presently no proven clinical therapy available for the CNS aspects of any of
the LSDs, and the CNS involvement remains a devastating and often fatal aspect of these diseases.
Considering that most of the LSDs without CNS involvement have already been addressed with ERT,
additional advancements in treating LSDs will require that the neurological aspects of these diseases
Figure 1. The relative incidences of lysosomal storage diseases are shown based on diagnosed cases in the
Australian population. The relative incident rate is the number of patients diagnosed with one disease divided by the
total number of patients diagnosed with LSD. Those diseases having major CNS involvement are shown in red.
Categories with only low levels of CNS involvement or none are shown in blue. Categories with a mix of disease states
with CNS involvement are shown with diamond pattern. Incidence rates were calculated based on the incidence in
Australia (Meikle 1999).
Lysosomal storage diseases are generally classified by the type of macromolecule that accumulates in
the cells. There are six major classifications of LSDs including sphingolipidoses,
mucopolysaccharidoses, mucolipidoses, glycoproteinoses, glycogenoses, and neuronal ceroid
lipofuscinoses. Within sphingolipidoses, see figure 2, there exists a family of diseases caused by the
inability to adequately catabolize gangliosides, which are complex glycosphingolipid molecules. These
gangliosidosis diseases, including GM2 Gangliosidosis and the Tay-Sachs disease variant in particular,
have severe CNS involvement. A focus on the Tay-Sachs variant of GM2 Gangliosidosis will be used
as a specific example of the clinical nature and metabolic cause of these diseases.
Figure 2. Sphingolipidoses are group of diseases which are caused by an enzyme deficiency and result in the
lysosomal storage of lipids. These sphingolipids share a common sphingosine backbone. The disease name is
shown adjacent to limiting pathway. The deficient enzyme is shown in parentheses below the disease name.
Abbreviations used: Cer, ceramide; Glc, glucose; Gal, galactose; NANA, N-acetyl-neuraminic acid; GalNAc,
N-acetylgalacactosamine; GM, ganglioside molecule. (Drawing by J. Keimel, PowerPoint, based on Devlin 1992)
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