Neuroimaging in Inborn Errors of Metabolism

Abstract

Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders, classically caused by enzyme deficiency. They are associated with different pathogenic mechanisms from enzyme substract accumulation or product deficiency to formation of an abnormal, toxic molecule. Occasionally, the deficient protein has non-enzymatic functions such as membrane transport or others, making the boundaries of IEM difficult to establish. IEM are individually rare (orphan diseases) but relatively numerous as a group, since more than 500 different entities have been identified (Scriver et al., 2001). Overall, their incidence is estimated to be 1:1,500 (Raghuveer et al., 2006). The age of onset varies. Signs and symptoms of IEM present a considerable overlap among the diverse IEM and many other diseases, not allowing the differential diagnosis on a clinical basis. There is no correlation between genotype and phenotype, in general. Most symptoms are apparent at or soon after birth, but clinical onset may occur prenatally or at any age, including adulthood. Multisystem involvement is frequent, with the presence of nervous system manifestations in most patients, either at disease onset or during the evolution. IEM are most probably underdiagnosed. In spite of all contributions from varied fields of medical science, etiological diagnosis is not achieved in a significant percentage of suspected patients. Despite being frequently difficult, diagnosis may be done selectively based on clinical features or pre-symptomatically by neonatal screening and achieved by biochemical, enzymatic and/or genetic studies. The diagnosis of IEM is challenging due to their rarity and clinical heterogeneity. To address these diagnostic problems, several schemes based on clinical, biochemical, neuroradiological, morphologic, enzymatic and genetic criteria have been proposed. Neuroimaging techniques are essential for assessing brain structures, namely white matter and/or gray matter involvement (Barkovich, 2007). They are undoubtedly useful in neurologically affected patients’ diagnosis and follow-up. Neuroradiological features of many IEM overlap and are stage-dependent. Patients occasionally show distinctive patterns of central nervous system involvement in magnetic resonance imaging (MRI). These patterns may characterise some disorders, especially during the early stages, or they can show guiding characteristics, or reveal non-specific changes. In later phases, the MRI findings are similar for most IEM with neurological involvement, often presenting diffuse loss of brain tissue and increased water in the remaining tissue. For this reason, it is