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Childhood Neurometabolic Disorders
19 January 2016
19 January 2016
13 May 2016 (online)
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, approximately 1,000 inborn errors of metabolism are estimated to have been identified to date.
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.
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.
The aim of this special issue entitled “Childhood neurometabolic disorders” is to analyze the most 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. Malignant forms of HPA are also described in a review article written by Mascaro et al. Those conditions are associated with 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, and VI) and, although it seems to be effective on reducing organomegaly, its efficacy in those cases with CNS involvement is not yet clear. Neurological features of Fabry disease are generally secondary to progressive accumulation of globotriaosylceramide (Gb3) within lysosomes in a variety of cell types including capillary endothelial and nerve cells. Acroparesthesias, headache, vertigo/dizziness, transient ischemic attacks, and ischemic stroke are some of neurological signs related to Fabry disease that are described in the review article “Neurological findings in Fabry disease” by Nicoletti et al, where the authors also describe the evolution of its clinical pictures after the advent of ERT.
The next article in this special issue describes a case series of patients with ceroid lipofuscinosis type 10, all belonging to one family, and summarizes the latest studies on this rare metabolic disease. Underlining the importance of a correct genetic counseling is one of the “take-home messages” presented in the article written by Grisolia et al.
The last article describes the evolution history of what is now considered the most important tool for the early detection of many congenital genetic and metabolic disorders: the newborn metabolic screening program. The aim of this program is to reach the earliest possible recognition and management of affected newborns to prevent the morbidity, mortality, and disabilities associated with an inherited metabolic disorder.
According to the increasing interest on inherited metabolic diseases worldwide, proved by the promotion of extended newborn screening programs in many parts of the world, I hope that this special issue could be helpful for pediatricians to recognize neurological aspects of some of the most frequent inherited metabolic diseases to improve their diagnostic and therapeutic skills in this interesting field.
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