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Genetics of Lysosomal Storage Diseases

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P771

2026-08-13

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Lysosomal genes are regarded as “housekeeping,” that is, they are expressed in the majority of cell types and are essential for cellular function, such that complete absence of most of the enzymes is incompatible with life; Fabry disease is an important exception. All LSDs are inherited in an autosomal recessive fashion except for Fabry, MPS II and Danon, which are X-linked. One lysosomal gene, SMPD1 encoding acid sphingomyelinase (ASM), is known to be “paternally imprinted” (i.e., preferentially expressed from the maternal chromosome). Diverse mutations underly individual LSDs, and the majority of these are unique (“private”) to individual pedigrees. Broad genotype-phenotype relationships have been established. GD is a good example—major organizational disruptions of the gene are associated with a more severe phenotype.

In general, heterozygous “carriers” of single mutations in a lysosomal gene do not develop clinical symptoms of the disorder, except in the X-linked disorders. For example, in Fabry disease X-inactivation patterns can lead to clusters of cells without enzyme activity, and heterozygous females often develop disease-related pathology primarily as a result of unbalanced X chromosome inactivation. Heterozygous carriers of glucocerebrosidase gene (GBA1) mutations have a much increased risk of developing Parkinson dis ease (PD).

Some LSD-specific populations have recurrent mutations caused by founder effects and/or consanguinity. This facilitates the use of DNA-based screening methods for their detection. This has been translated into clinical use in the Ashkenazi Jewish population and has led to the establishment of a DNA-based “Jewish Genetic Disease” screening panel. Evolving cost-effective, high-throughput sequencing methods are likely to open other populations and disorders to these screening approaches. However, DNA-based methods will generate large numbers of GVUS (genetic variants of uncertain significance) and should not be used to predict clinical outcomes in patients unless the biochemical consequences of the mutations are fully established. An example of a mutation which was formerly a GVUS, but has recently been demonstrated to undoubtedly be associated with late-onset hypertophic cardiomyopathy in Fabry disease, is c.472 G>A; however, detailed studies have shown that although this variant is a necessary requirement for Fabry cardiomyopathy in affected individuals, it is not sufficient and other disease mechanisms are important for disease manifestations to develop.