Journal of Inherited Metabolic Disease

, Volume 28, Issue 1, pp 1-12

First online:

Preimplantation diagnosis of a lysosomal storage disorder by in situ enzymatic activity: ‘Proof of principle’ in acid sphingomyelinase-deficient mice

  • A. ButlerAffiliated withDepartment of Human Genetics, Mount Sinai School of Medicine
  • , S. C. HendersonAffiliated withBrookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine
  • , R. E. GordonAffiliated withDepartment of Pathology, Mount Sinai School of Medicine
  • , A. DaganAffiliated withDepartment of Biochemistry, Hebrew University - Hadassah School of Medicine
  • , S. GattAffiliated withDepartment of Biochemistry, Hebrew University - Hadassah School of Medicine
  • , E. H. SchuchmanAffiliated withDepartment of Human Genetics, Mount Sinai School of MedicineCarl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine Email author 

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Genetic diagnosis of preimplantation embryos (PGD) can substantially reduce the chance that at-risk couples have children afflicted with inherited diseases. However, PGD requires DNA,which is usually obtained from single cells following embryo biopsy. In addition, PGD requires that the genetic defect(s) causing the disorder be known. We have therefore developed an alternative to PGD, which we term preimplantation enzymatic diagnosis (PED). PED has several advantages over PGD, including the facts that it does not require embryo biopsy and that the gene defect(s) causing the disorder need not be known. We have demonstrated ‘proof of principle’ for this approach using embryos obtained from a mouse model (ASMKO mice) of acid sphingomyelinase (ASM)-deficient Niemann-Pick disease, an inherited lysosomal storage disorder. For this technique, fluorescently (BODIPY)-conjugated sphingomyelin was used to detect ASM activity in situ. Wild-type, preimplantation embryos degraded the substrate following a short ‘pulse-chase’ period, resulting in markedly reduced fluorescence compared to ASMKO embryos, which retained the fluorescent substrate. Thus, the two embryo types could be easily distinguished by fluorescent microscopy. The fluorescent sphingomyelin was not toxic to the embryos, and the entire procedure could be accomplished within 48 h without embryo biopsy. We suggest that PED may be useful for the preimplantation diagnosis of lysosomal storage disorders, and perhaps other enzymatic defects where similar in situ assay methods are available.