Although the combined frequency of lysosomal storage disorders (LSDs) is about 1 in 5000 live births, lysosomal dysfunction may be involved in the etiology of several more-common diseases. For example, an important genetic risk factor for developing Parkinson disease is the carrier state for Gaucher disease, and virtually all Gaucher disease patients develop Parkinson disease. Niemann Pick C is another LSD connected to the risk for Alzheimer disease. Such interconnectedness stems from the multifunctionality of the lysosome. For example, lysosomes play critical roles in (i) autophagy, resulting from fusion with the autophagosome; (ii) immunity, as they fuse with phagosomes; and (iii) membrane repair, through fusion with the plasma membrane.
LSDs are typically fatal, with many displaying profound neurologic impairment that begins in childhood. Studies show that several neurodegenerative LSDs also are associated with a dysregulation of the immune system. For example, immunosuppression occurs in Gaucher disease and mucopolysaccharidoses VII, whereas in Niemann Pick disease-type-C1, hyperactivation of the immune system is seen. The mechanistic basis of linkage to immunologic changes remains to be deciphered.
Despite this complexity, certain features are common to most diseases in this group:
Patient population consisting of infants and young children
Storage of insoluble intermediates in the mononuclear phagocyte system, giving rise to hepatosplenomegaly
Frequent CNS involvement with associated neuronal damage
Cellular dysfunction caused not only by storage of undigested material, but also by a cascade of secondary events, for example, macrophage activation and release of cytokines
Most of these conditions are very rare, and their detailed description is better relegated to specialized texts and reviews. Only a few of the more common conditions are considered here.
Tay-SachsDisease(GM2Gangliosidosis:DeficiencyinHexosaminidaseβ Subunit)
Gangliosidoses are characterized by accumulation of gangliosides, principally in the brain, as a result of a deficiency of one of the lysosomal enzymes that catabolize these glycolipids. Depending on the ganglioside involved, these disorders are subclassified into GM1 and GM2 categories. Tay-Sachs disease, by far the most common of all gangliosidoses, is caused by loss-of-function mutations of the β subunit of the enzyme hexosaminidase A, which is necessary for the degradation of GM2. More than 100 mutations have been described; most disrupt protein folding or intracellular transport. Tay-Sachs disease, similar to other lipid storage disorders, is most common among http://ebooksmedicine.net
Ashkenazi Jews, among whom the frequency of heterozygous carriers is estimated to be 1 in 30. Heterozygote carriers can be detected by measuring the level of hexosaminidase in the serum or by DNA sequencing.
In the absence of hexosaminidase A, GM2 ganglioside accumulates in many tissues (e.g., heart, liver, spleen, nervous system), but the involvement of neurons in the central and autonomic nervous systems and retina dominates the clinical picture. The accumulation of GM2 occurs within neurons, axon cylinders of nerves, and glial cells throughout the CNS. Affected cells appear swollen and sometimes foamy (
Fig. 7.9A ). Electron microscopy shows whorled onionskin-like configurations within lysosomes composed of layers of membranes (
Fig. 7.9B ). These pathologic changes are found throughout the CNS (including the spinal cord), peripheral nerves, and autonomic nervous system. The retina usually is involved as well, where the pallor produced by swollen ganglion cells in the peripheral retina results in a contrasting “cherry red” spot in the relatively unaffected central macula.