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  1. Inborn errors of metabolism (IEMs) are rare disorders, most of them only present after delivery.

  2. Several IEMs may affect the fetus, producing congenital malformations and/or brain insults.

  3. Prenatal diagnosis is usually possible following the birth of an affected child; in patients without a family history, even in the presence of severe malformations, a definitive diagnosis is usually only made after delivery.

  4. Biochemical tests and molecular studies are indicated in selected cases.


The in utero metabolic microenvironment during embryogenesis (fetal metabolome) profoundly influences the entire range of developmental processes underlying fetal organogenesis.

Inborn errors of metabolism (IEMs) are inherited disorders with mostly single gene defects resulting in the development of enzymatic blocks within biochemical pathways, often due to the deficiency of an enzyme or cofactor. There may be secondary accumulation or formation of toxic intermediaries, as well as deficiency of critical end products necessary for cell function. The resulting changes influence the internal and external cellular microenvironment, as well as cellular homeostatic mechanisms.1 The association of IEMs with developmental malformations has long been recognized (Figure 12–1). Following initial reports of association of callosal dysgenesis with IEMs,2 widespread developmental abnormalities in the morphogenesis of the brain have been described.3 A logical extension of these observed associations is the exploration of the possibilities of detection and diagnosis during the prenatal period. A majority of these conditions are usually diagnosed in postnatal life in the index case. During subsequent pregnancies, early detection and diagnosis carry the potential for early therapeutic interventions in the fetus or carefully considered decisions to terminate the pregnancy in the event of the diagnosis of an incurable disorder with no hope for a meaningful quality of life.

Figure 12–1.

Markers of IEM's on fetal ultrasonography.

A variety of interactions between the planes of genome–proteome and metabolome regulate developmental processes that ultimately influence the formation and maturation of all organ systems, including the fetal brain. In early fetal life, interference with formation of the telencephalic vesicles (holoprosencephaly), dysgenesis of the corpus callosum, absence of the septi pellucidi, cerebellar dysgenesis, and abnormalities in ventricular shape (colpocephaly and single ventricle) may be visualized through targeted neurosonography. As the brain grows in complexity, abnormalities may extend to involve the gray matter (atrophy of the cortical ribbon and basal ganglia), white matter (thinning out or loss of volume, demyelination, or dysmyelination of white matter), encephaloclastic lesions (porencephalic cysts), and neuronal migration defects (pachygyria) and can be identified with the aid of high-resolution fetal magnetic resonance imaging (MRI). Neuronal loss or cell death (neurotoxic or apoptotic) is followed by wallerian (secondary axonal) degeneration, leading to atrophy and volume loss in the gray and white matter. These changes result in ventriculomegaly and a prominence of ...

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