Inherited metabolic disorders: prenatal diagnosis of lysosomal storage disorders

Abstract

Objective To offer accurate prenatal diagnosis of lysosomal storage disorders in early pregnancy.Method Prenatal enzymatic diagnoses of Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandoff, GM1, mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy and Batten diseases were made in uncultured chorionic villi samples by fluorometric/spectrophotometric methods.Results Of 331 prenatal enzymatic diagnosis, 207 fetuses (67%) were normal and 124 (37%) were affected. The interpretation of affected, normal and carrier fetuses was done using their respective reference ranges as well as % enzyme activity of normal mean. The prenatal molecular confirmation was feasible in 43 biochemically diagnosed fetuses. Of the 207 normal reported fetuses, post natal enzymatic confirmation was done in 23 babies, clinical status of another 165 babies was assessed as unaffected via questionnaire on telephone and 19 were lost to follow-up. In affected pregnancies, 123 opted for termination of which 44 were confirmed enzymatically after abortion. A single false positive was determined to be a carrier by prenatal mutation analysis and carried to term. ConclusionWe recommend uncultured chorionic villi for reliable prenatal enzymatic diagnosis of various lysosomal storage disorders on account of the low rate of false positive (0.5%) and false negative (2.2%) results.

Prenatal enzymatic diagnosis of lysosomal storage diseases using cultured amniotic cells, uncultured chorionic villus samples, and fetal blood cells: Hacettepe experience

“…High rates of admittance to termination of pregnancy are consistent with the aims of prenatal diagnosis. Similar high rates were also reported by Verma et al in their study …”

“…These outcomes can be attributed to the fact that even 2% contamination by decidua results in normal enzyme activity and would be sufficient for misdiagnosis . In addition to maternal contamination, factors such as high borderline enzyme activity for carrier and affected fetuses may lead to false‐positive diagnosis in specific diseases such as Krabbe disease …”

Genetic causes of dilated cardiomyopathy

“…Robust evidence for pathogenicity is essential for prenatal diagnosis and at the moment relatively few genetic diseases are available for prenatal genetic analysis. Examples include dystrophinopathies,63 Barth syndrome64 and Danon disease65 (see online supplementary table S3 for other examples) 66. In CMPs caused by mutations of mtDNA such as MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, see online supplementary table S2.…”

A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

“…The yield of CMA for cases of NIHF, however, has not specifically been investigated but may be in the range of 6% to 14% based on cohort studies of all anomalies . Also unclear is how much CMA adds to the diagnostic yield of karyotype for NIHF cases beyond detection of aneuploidy .…”

“…Enzyme assays and other biochemical tests to assess for LSDs are also available, although limitations include availability on a commercial basis for prenatal samples, standardized protocols for analysis, handling of isoenzymes, and prenatal reference ranges for interpretation . A systematic review of NIHF publications from 1979 to 2014 found that LSDs were reported to underlie NIHF in 5.2% cases, but that when a comprehensive work up was completed for this category of disorders, 29.6% of idiopathic cases were attributable to a LSD .…”