Childhood Neurometabolic Disorders

Abstract

Although individual inborn errors of metabolism are relatively rare conditions, as a group they reach a cumulative incidence varying between 1 in 1,500 and 1 in 5,000 live births. From the initial discoveries in this field, summarized by Garrod in his book Inborn Errors of Metabolism some 80 years ago,1 approximately 1,000 inborn errors of metabolism are estimated to have been identified to date.2 Considerable efforts were made through years to understand the pathophysiological aspects of metabolic diseases: from biochemical progress in the 1960s when the identification of metabolic products in urine, blood, or neural tissues became possible and allowed the identification of the enzymes responsible for metabolic alterations, to the genetic approach in the 1980s when the identification of genetic mutations permitted to uncover the genetic defects responsible for neurological diseases, to today’s proteomics and metabolomics techniques.3 Inherited disorders of metabolism encompass a narrow spectrum of conditions that have been biochemically defined. Broad categories include disorders of carbohydrate metabolism, disorders of amino acid metabolism, organic acidemias, lysosomal storage diseases, disorders of fatty acid metabolism, and mitochondrial disorders. Most of these conditions are associated with neurologic sequelae.4 The aim of this special issue entitled “Childhood neurometabolic disorders” is to analyze themost recent studies that have been conducted on the most frequent inherited metabolic diseases with neurological involvement. First, we present overview of the metabolic disorders devoting a particular attention to the involvement of the nervous system, especially in those neurological alterations that may exhibit an acute neonatal onset. At this age, neurological alterations such as coma, hypotonia, and seizures could be secondary not only to metabolic imbalances directly involving the central nervous system (CNS) but also to critical clinical conditions caused by metabolic intoxication and organ failures. Thereafter, we analyze hyperphenylalaninemia (HPA), one of the metabolic diseases with a natural history that was changed thanks to the introduction of neonatal screening programs. Early recognition of elevated blood concentrations of phenylalanine (Phe) permitted to start therapy early in the neonatal period and to prevent the development of neurological impairment in affected babies. The first used therapeutic approach was the administration of a diet poor in Phe that resulted in effective maintenance of low blood Phe concentrations. This approach continues to be used to treat HPA patients, although it is associated with compliance problems because of its dietary restriction. In addition to diet, an increasing number of different therapies are now available or are under study. One of the most important alternatives is the treatment of these patients with a BH4 analogue, which is used in classical HPA, in those patients whose enzymatic activity increases in response to BH4, and even more in malignant forms of HPA secondary to BH4 recycling defect.5 Malignant forms of HPA are also described in a review article written byMascaro et al. Those conditions are associatedwith a serious neurological impairment, mainly secondary to a defective synthesis of neurotransmitters. Cobalamin C deficiency, one of the most frequent metabolic diseases in southern Europe, is described in an article written by Ceravolo et al that particularly focuses on its neurological symptoms. Thereafter, a review article written by Sestito addresses the lysosomal storage disorders (LSDs). The author draws the chronological events from the observation of this clinical condition to the discovery of the first therapeutic approach consisting of an enzyme replacement therapy (ERT). This therapeutic option rapidly changed the natural history of LSDs. The author focuses on three LSDs characterized by varying degrees of neurological involvement: Gaucher disease, mucopolysaccharidosis (MPS), and Fabry disease. In Gaucher disease, a continuum of clinical forms can be observed from those without neurological involvement (Gaucher disease type 1) to those with varying degrees of neurological impairment (Gaucher disease type 2 and 3). MPSs are a group of diseases characterized by defects in the metabolism of heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate. Facial dysmorphisms, bone deformity, and organomegaly as well as a severe developmental delay and brain involvement are the most important clinical features of MPSs. Administration of ERT is suitable only for some forms of MPSs (MPS I, II, IV,