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Owing to the role of pyruvate and the tricarboxylic acid (TCA) cycle in energy metabolism, as well as in gluconeogenesis, lipogenesis and amino acid synthesis, defects in pyruvate metabolism and in the TCA cycle almost invariably affect the central nervous system. The severity and the different clinical phenotypes vary widely among patients and are not always specific, with the range of manifestations extending from overwhelming neonatal lactic acidosis and early death to relatively normal adult life and variable effects on systemic functions. The same clinical manifestations may be caused by other defects of energy metabolism, especially defects of the respiratory chain (Chap. 15). Diagnosis depends primarily on biochemical analyses of metabolites in body fluids, followed by definitive enzymatic assays in cells or tissues, and DNA analysis. The deficiencies of (PC) and (PEPCK) constitute defects in gluconeogenesis, and therefore fasting results in hypoglycemia with worsening lactic acidosis. Deficiency of the (PDHC) impedes glucose oxidation and aerobic energy production, and ingestion of carbohydrate aggravates lactic acidosis. Treatment of disorders of pyruvate metabolism comprises avoidance of fasting (PC and PEPCK) or minimizing dietary carbohydrate intake (PDHC) and enhancing anaplerosis. In some cases, vitamin or drug therapy may be helpful. (E3) deficiency affects PDHC as well as KDHC and the branched-chain 2-ketoacid dehydrogenase (BCKD) complex (Chap. 19), with biochemical manifestations of all three disorders. The deficiencies of the TCA cycle enzymes, the (KDHC) and , interrupt the cycle, resulting in accumulation of the corresponding substrates. deficiency represents a unique disorder affecting both the TCA cycle and the respiratory chain. Recently, defects of and (▸ Chap. 29) have been identified. Treatment strategies for the TCA cycle defects are limited.

This chapter deals mainly with inborn errors of neurotransmitter metabolism. Defects of their receptors and transporters, and disorders involving pyridoxine (vitamin B) and its derivative, pyridoxal phosphate, a cofactor required for the synthesis of several neurotransmitters, are also discussed.

Two defects of GABA metabolism are known: the very rare, severe, and untreatable , and the much more frequent which, to some extent, responds to GABA transaminase inhibition. is a dominantly inherited defect of the α1 subunit of the glycine receptor which causes excessive startle responses, and is treatable with clo nazepam. Mutations in the γ-subunit of the GABA receptor are a cause of dominantly inherited epilepsy. Disorders of the metabolism of glycine are discusssed in ▸ Chap. 24.

Five disorders of monoamine metabolism are discussed: impairs synthesis of dihydroxyphenylalanine (L-dopa), and causes an extrapyramidal disorder which responds to the latter compound. The clinical hallmark of is severe orthostatic hypotension with sympathetic failure. The other disorders of monoamine metabolism involve both catecholamine and serotonin metabolism. is located upstream of these intermediates. Treatment of its deficiency is more difficult and less effective. , located downstream, mainly causes behavioral disturbances; no effective treatment is known. is a defect upstream of L-dopa and 5-hydroxytryptophan (5-HTP) and, therefore, can be effectively treated with these compounds.

, a rare form of early or late infantile seizures, has been recently found to be caused by mutations of antiquitin, an enzyme intervening in the degradation of lysine (Fig. 23.1). Recently also, defective conversion of pyridoxine to pyridoxal phosphate, due to pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency, has been identified as a cause of neonatal epilepsy.

Genetic defects have been described in four of the six steps of the γ-glutamyl cycle. is the most frequently recognized disorder and, in its severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria (pyroglutamic aciduria), central nervous system (CNS) damage and recurrent bacterial infections. γ- is also associated with hemolytic anemia, and some patients with this disorder show defects of neuromuscular function and generalized aminoaciduria. γ- has been found in patients with CNS involvement and glutathionuria. 5- is associated with 5-oxoprolinuria but without a clear association with other symptoms.

are probably the same disorder. It is uncertain whether there is a relationship between the biochemical abnormalities and clinical symptoms. causes skin lesions and recalcitrant ulceration (particularly on the lower legs) in addition to other features, such as impaired psychomotor development and recurrent infections. The severity of clinical expression is highly variable.

Sphingolipidoses are a subgroup of lysosomal storage disorders in which sphingolipids accumulate in one or several organs as the result of a primary deficiency in enzymes or activator proteins involved in their degradative pathway. Traditionally, this subgroup also includes Niemann-Pick disease type C, characterized by impaired cellular trafficking of several lipids. With the exception of Fabry disease, which is X-linked recessive, sphingolipidoses have an autosomal recessive inheritance. The clinical presentation and course of the classical forms of the various diseases are often characteristic. With the help of relevant procedures (imaging, neurophysiology, ophthalmologic examination?, careful examination of the patient and perusal of the disease history (especially age and type of first symptom) should lead to a provisional diagnosis and oriented biochemical tests. Late-onset forms are often more difficult to recognize, and foetal presentations have also been overlooked in the past. No overall screening procedure is yet available to date. In most sphingolipidoses, the diagnosis is made by demonstration of the enzymatic defect, generally expressed in most cells, organs or even serum (leukocytes represent the most widely used enzyme source). In specific diseases, more complex biochemical tests or/and a molecular genetics assessment may be necessary. The past 15 years have seen the era of specific therapies for non-neuronopathic Gaucher disease and Fabry disease. But in spite of active research on animal models, knowledge on pathophysiology and progress toward therapy of the neurological forms in human patients remain to date limited.

Although the outcome for many inborn errors remains poor there have been very encouraging developments in recent years particularly the use of ERT in lysosomal disorders. However formidable obstacles remain particularly for those disorders where there is significant in utero damage or where the CNS is primarily affected.

The liver glycogen storage disorders (GSDs) comprise GSD I, the hepatic presentations of GSD III, GSD IV, GSD VI, the liver forms of GSD IX, and GSD 0. GSD I, III, VI, and IX present similarly with hypoglycemia, marked hepatomegaly, and growth retardation. GSD I is the most severe affecting both glycogen breakdown and gluconeogenesis. In GSD Ib there is additionally a disorder of neutrophil function. Most patients with GSD III have a syndrome that includes hepatopathy, myopathy, and often cardiomyo pathy. GSD VI and GSD IX are the least severe: there is only a mild tendency to fasting hypoglycemia, liver size normalises with age, and patients reach normal adult height. GSD IV manifests in most patients in infancy or childhood as hepatic failure with cirrhosis leading to end-stage liver disease. GSD 0 presents in infancy or early childhood with fasting hypoglycemia and ketosis and, in contrast, with postprandial hyperglycemia and hyperlactatemia. Treatment is primarily dietary and aims to prevent hypoglycemia and suppress secondary metabolic decompensation. This usually requires frequent feeds by day, and in GSD I and in some patients with GSD III, continuous nocturnal gastric feeding.

The muscle glycogenoses fall into two clinical groups. The first comprises GSD V, GSD VII, the muscle forms of GSD IX (VIII according to McKusick), phosphoglycerate kinase deficiency (IX according to McKusick), GSD X, GSD XI, GSD XII and GSD XIII, and is characterised by exercise intolerance with exercise-induced myalgia and cramps, which are often followed by rhabdomyolysis and myoglobinuria; all symptoms are reversible with rest. Disorders in the second group, consisting of the myopathic form of GSD III, and rare neuromuscular forms of GSD IV, manifest as sub-acute or chronic myopathies, with weakness of trunk, limb, and respiratory muscles. Involvement of other organs (erythrocytes, central or peripheral nervous system, heart, liver) is possible, as most of these enzymes defects are not confined to skeletal muscle.

Generalized glycogenoses comprise GSD II, caused by the deficiency of a lysosomal enzyme, and Danon disease due to the deficiency of a lysosomal membrane protein. Recent work on myoclonus epilepsy with Lafora bodies (Lafora disease) suggests that this is a glycogenosis, probably due to abnormal glycogen synthesis. GSD II can be treated by enzyme replacement therapy, but there is no specific treatment for Danon and Lafora disease.

Three inborn errors of galactose metabolism are known. The most important is classic galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency. A complete or near-complete deficiency is life threatening with multiorgan involvement and long-term complications []. Partial deficiency is usually, but not always, benign. Uridine diphosphate galactose 4-epimerase (GALE) deficiency exists in at least two forms. The very rare profound deficiency clinically resembles classical galactosemia. The more frequent partial deficiency is usually benign. Galactokinase (GALK) deficiency is extremely rare and the most insidious, since it results in the formation of nuclear cataracts without provoking symptoms of intolerance. The Fanconi- Bickel syndrome (Chap. 11) is a congenital disorder of galactose transport due to GLUT2 deficiency leading to hypergalactosemia. Other secondary causes of impaired liver handling of galactose in the neonatal period are congenital portosystemic shunting and multiple hepatic arteriovenous malformations.

Three inborn errors in the pentose phosphate pathway are known. In , there is a defect in the first, irreversible step of the pathway. As a consequence NADPH production is decreased, making erythrocytes vulnerable to oxidative stress. Drug-and fava bean-induced haemolytic anaemia is the main presenting symptom of this defect. As this is a haematological disorder it is not discussed further.

has been described in one patient who suffered from a progressive leucoencephalopathy and developmental delay.

has been diagnosed in three unrelated families. All patients presented in the newborn period with liver problems. One of the patients died soon after birth from liver failure and cardiomyopathy, whereas another patient is now 15 years old and suffers from liver cirrhosis. Her neurological and intellectual development has been normal.

, due to a defect in the enzyme xylitol dehydrogenase, affects the related glucuronic acid pathway. Whereas the pentose phosphate pathway involves D stereoisomers, glucuronic acid gives rise to L-xylulose which is subsequently converted into xylitol and D-xylulose. Affected individuals excrete large amounts of L-xylulose in urine. This is a benign disorder and not discussed further.

Three inborn errors are known in the pathway of fructose metabolism depicted in Fig. 9.1. is a harmless anomaly characterized by the appearance of fructose in the urine after the intake of fructose-containing food. In (HFI), fructose may provoke prompt gastrointestinal discomfort and hypoglycemia upon ingestion, symptoms that may vary from patient to patient and depend on the ingested dose. Fructose may cause liver and kidney failure when taken persistently, and its intake becomes life-threatening when given intravenously. (FBPase) is also usually considered an inborn error of fructose metabolism although, strictly speaking, it is a defect of gluconeogenesis. The disorder is manifested by the appearance of hypoglycemia and lactic acidosis (neonatally, or later during fasting or induced by fructose) and may also be life-threatening.

Hyperinsulinism can occur throughout childhood but is most common in infancy. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most important cause of hypoglycemia in early infancy. The excessive secretion of insulin is responsible for profound hypoglycemia and requires aggressive treatment to prevent severe and irreversible brain damage. Onset can be in the neonatal period or later, with the severity of hypoglycemia decreasing with age. PHHI is a heterogeneous disorder with two histopathological lesions, diffuse (DiPHHI) and focal (FoPHHI), which are clinically indistinguishable. FoPHHI is sporadic and characterized by somatic islet-cell hyperplasia. DiPHHI corresponds to a functional abnormality of insulin secretion in the whole pancreas and is most often recessive although rare dominant forms can occur, usually outside the newborn period. Differentiation between focal and diffuse lesions is important because the therapeutic approach and genetic counselling differ radically. PET scanning with 18-fluoro-dopa can distinguish between focal and diffuse PHHI. A combination of glucose and glucagon is started as an emergency treatment as soon as a tentative diagnosis of PHHI is made. This is followed by diazoxide and other medication. Patients who are resistant to medical treatment require pancreatectomy; FoPHHI can be definitively cured by a limited pancreatectomy, but DiPHHI requires a subtotal pancreatectomy, following which there is a high risk of diabetes mellitus. Persistent hyperinsulinism in older children is most commonly caused by pancreatic adenoma.