Antenatal manifestations of inborn errors of metabolism: biological diagnosis

Abstract

Inborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency. Cultured AF or fetal cells allow the measurement of enzyme activities for most IEMs, whole-cell assays, or metabolite measurements. The cultured cells or tissue samples taken after fetal death can be used for metabolic profiling, enzyme activities, and DNA extraction. Fetal blood can also be helpful. The identification of vacuolated cells orients toward an LSD, and plasma is useful for diagnosing peroxisomal disorders, FAODs, CSDs, some LSDs, and possibly CDGs and aminoacidopathies. We investigated AF of 1700 pregnancies after exclusion of frequent etiologies of nonimmune hydrops fetalis and identified 108 fetuses affected with LSDs (6.3 %), 29 of them with mucopolysaccharidosis type VII (MPS VII), and six with GSD IV (0.3 %). In the AF of 873 pregnancies, investigated because of intrauterine growth restriction and/or abnormal genitalia, we diagnosed 32 fetuses affected with Smith-Lemli-Opitz syndrome (3.7 %).

Development of a new tandem mass spectrometry method for urine and amniotic fluid screening of oligosaccharidoses

“…In utero presentations of LSDs have emphasized the need to screen these rare disorders in AF. Since 1990, OS screening in AF supernatant has been currently performed by TLC in our lab for this purpose . The MS/MS method presents a much higher sensitivity, thus allowing a much more reliable result than TLC.…”

“…Antenatal presentations with non‐immune hydrops fetalis (NIHF) or persistent ascites can occur in several oligosaccharidoses (sialidosis, galactosialidosis, GM1 gangliosidosis) but also in other LSDs (infantile sialic acid storage disease (ISSD), mucopolysaccharidosis (MPS) type VII and type IVA, Gaucher disease, acid lipase deficiency, Niemann‐Pick type A and Niemann‐Pick type C diseases) …”

“…TLC screening of β ‐mannosidosis is poorly reliable, even if changing the migration solvent can improve its detection . The same TLC technique can also be used for the screening of oligosaccharidoses in amniotic fluid (AF) supernatant, but OS concentration is lower …”

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

“…They are the most typical and historical group (such as sphingolipidoses, mucopolysaccharidoses or glycoproteinopathies) in which signs and symptoms primarily result from the abnormal accumulation of compound(s) proximal to the block and potentially reverse as soon as the accumulation is removed. In general, there is no antenatal manifestation although, in some severe forms, this is possible such as hydrops or malformations . Neurological presentations display progressive disorders with late‐onset neurodegeneration with or without obvious « storage » signs .…”

“…In general, there is no antenatal manifestation although, in some severe forms, this is possible such as hydrops or malformations. 45 Neurological presentations display progressive disorders with late-onset neurodegeneration with or without obvious « storage » signs. Diagnosis is mostly based on urine screening (mucopolysaccharides, oligosaccharides, sulfatides, sialic acid) and leukocytes enzyme analysis.…”