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To date, four congenital defects of monosaccharide transport are known (Fig. 11.1). Their clinical picture depends on tissue-specific expression and substrate specificity of the affected transporter. SGLT1 deficiency causes intestinal , a condition that presents with severe osmotic diarrhea and dehydration soon after birth. SGLT2 mutations result in isolated , a harmless renal transport defect with normal blood glucose concentrations. In GLUT1 deficiency, also termed , clinical symptoms, usually microcephaly and an epileptic encephalopathy, are caused by impaired glucose transport at the blood brain barrier and thus into neurons and glia cells. The key finding is a low CSF glucose. is the result of a deficiency of GLUT2, an important glucose and galactose carrier within liver, kidney and pancreatic β-cells. Patients typically present with a combination of hepatic glycogen storage and a generalized renal tubular dysfunction which includes severe glucosuria.

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.

More than a dozen genetic defects in the fatty acid oxidation pathway are currently known. Nearly all of these defects present in early infancy as acute life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting or febrile illness (for recent reviews, see [] [] [] []). In some of the disorders there also may be chronic skeletal muscle weakness or acute exerciseinduced rhabdomyolysis and acute or chronic cardiomyopathy. Recognition of the fatty acid oxidation disorders is often difficult because patients can appear well until exposed to prolonged fasting, and screening tests of metabolites may not always be diagnostic. Rare related disorders include a transport defect of fatty acids, and secondary (as in the Sjögren-Larsson syndrome), or primary defects in the metabolism of leukotrienes.

Disorders of ketone body metabolism present either in the first few days of life or later in childhood, during an infection or some other metabolic stress. In defects of ketogenesis, decompensation leads to encephalopathy, with vomiting and a reduced level of consciousness, often accompanied by hepatomegaly. The biochemical features — hypoketotic hypoglycaemia, with or without hyperammonaemia — resemble those seen in fatty acid oxidation disorders. In defects of ketolysis, the clinical picture is dominated by severe ketoacidosis. This is often accompanied by decreased consciousness and dehydration.

Respiratory chain deficiencies have long been regarded as neuromuscular diseases only. However, (i.e. ATP synthesis by the respiratory chain) is not restricted to the neuromuscular system but proceeds in all cells that contain mitochondria (Fig. 15.1). Most non-neuromuscular organs and tissues are, therefore, also dependent upon mitochondrial energy supply. Due to the twofold genetic origin of respiratory enzymes [nuclear DNA and mitochondrial (mtDNA)], a respiratory chain deficiency can theoretically give rise to any symptom in any organ or tissue at any age and with any mode of inheritance.

The diagnosis of a respiratory chain deficiency is difficult to consider initially when only one abnormal symptom is present. In contrast, this diagnosis is easier to consider when two or more seemingly unrelated symptoms are observed. The treatment, mainly dietetic, does not markedly influence the usually unfavorable course of the disease.

Creatine deficiency syndromes (CDS) are a novel group of inborn errors of creatine synthesis and transport including autosomal recessive arginine:glycine amidino transferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies, and the X-linked creatine transporter (SLC6A8) deficiency. In all these disorders the common clinical hallmark is mental retardation, expressive speech delay and epilepsy; the common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Increased levels of guanidinoacetic acid (GAA) in body fluids are pathognomonic for GAMT deficiency whereas these levels are reduced in AGAT deficiency. An increased urinary creatine/creatinine ratio is associated with SLC6A8 deficiency. Oral supplementation of creatine leads to partial restoration of the cerebral creatine pool and improvement of clinical symptoms in GAMT and AGAT deficiency. Reduction of GAA by additional dietary restriction of arginine (and supplemen tation of ornithine) appears to be of additional benefit for the long-term outcome of GAMT deficient patients. For SLC6A8 deficient patients no effective treatment is currently available. CDS may account for a considerable fraction of children and adults with mental retardation of unknown cause and, therefore, screening for these disorders (by urinary/plasma metabolites, brain H-MRS and/or DNA approach) should be included in the investigation of this population.

Secondary creatine deficiency can be found in OAT deficiency (▸ Chap. 22).

Mutations within the gene for the hepatic enzyme phenylalanine hydroxylase (PAH) and those involving enzymes of pterin metabolism are associated with hyperphenylalaninaemia (HPA). Phenylketonuria (PKU) is caused by a severe deficiency in PAH activity and untreated leads to permanent central nervous system damage. Dietary restriction of phenylalanine (PHE) along with aminoacid, vitamin and mineral supplements, started in the first weeks of life and continued through childhood, is an effective treatment and allows for normal cognitive development. Continued dietary treatment into adulthood with PKU is generally recommended but, as yet, there is insufficient data to know whether this is necessary. Less severe forms of PAH deficiency may or may not require treatment depending on the degree of HPA. High blood levels in mothers with PKU leads to fetal damage. This can be prevented by reducing maternal blood PHE throughout the pregnancy with dietary treatment. Disorders of pterin metabolism lead to both HPA and disturbances in central nervous system amines. Generally they require treatment with oral tetrahydrobiopterin and neurotransmitters.

Five inherited disorders of tyrosine metabolism are known, depicted in Fig. 18.1. Hereditary tyrosinaemia type I is characterised by progressive liver disease and renal tubular dysfunction with rickets. Hereditary tyrosinaemia type II (Richner-Hanhart syndrome) presents with keratitis and blisterous lesions of the palms and soles. Tyrosinaemia type III may be asymptomatic or associated with mental retardation. Hawkinsinuria may be asymptomatic or presents with failure to thrive and metabolic acidosis in infancy. In alkaptonuria symptoms of osteoarthritis usually appear in adulthood. Other inborn errors of tyrosine metabolism include oculocutaneous albinism caused by a deficiency of melanocyte-specific tyrosinase, converting tyrosine into DOPA-quinone; the deficiency of tyrosine hydroxylase, the first enzyme in the synthesis of dopamine from tyrosine; and the deficiency of aromatic L-amino acid decarboxylase, which also affects tryptophan metabolism. The latter two disorders are covered in ▸ Chap. 29.

Branched-chain organic acidurias or organic acidemias are a group of disorders that result from an abnormality of specific enzymes involving the catabolism of branched-chain amino acids (BCAAs). Collectively, the most commonly encountered are maple syrup urine disease (MSUD), isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA). They can present clinically as a severe neonatal onset form of metabolic distress, an acute, intermittent, late-onset form, or a chronic progressive form presenting as hypotonia, failure to thrive, and developmental delay. Other rare disorders involving leucine, isoleucine, and valine catabolism are 3-methylcrotonyl glycinuria, 3-methylglutaconic (3-MGC) aciduria, short/branched-chain acyl-CoA dehydrogenase deficiency, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, 3-hydroxyisobutyric aciduria, and malonic aciduria. All the disorders can be diagnosed by identifying acylcarnitines and other organic acid compounds in plasma and urine by gas chromatography-mass spectrometry (GC-MS) or tandem MS and all can be detected by newborn screening using tandem MS.

Six inherited disorders of the urea cycle are well described (Fig. 20.1). These are the deficiencies of , and . Deficiencies of and of have also been described. All these defects are characterised by hyperammonaemia and disordered amino acid metabolism. The presentation is highly variable: those presenting in the newborn period usually have an overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy or irritability and tachypnoea to fits, coma and respiratory failure. In infancy, the symptoms are less severe and more variable. Poor developmental progress, behavioural problems, hepatomegaly and gastrointestinal symptoms are common. Children and adults frequently have a chronic neurological illness that is characterised by variable behavioural problems, confusion, irritability and episodic vomiting. However, during any metabolic stress the patients may become acutely unwell. Arginase deficiency has more specific symptoms, such as spastic diplegia, dystonia, ataxia and fits. All these disorders have autosomal- recessive inheritance except ornithine transcarbamoylase deficiency, which is X-linked.