Anita MacDonald
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from oral glucose polymer solutions or intrave- nous glucose) to reduce production of potentially toxic metabolites or to prevent hypoglycaemia [1] . This is essential for a variety of conditions in- cluding MSUD, organic acidaemias, UCD, long- chain and medium-chain fatty acid oxidation disorders and GSD.
Disorders of Amino Acid Metabolism
Deficiencies in enzymes involved in amino acid metabolism cause abnormalities in the break- down of amino acids, resulting in the accumula- tion of toxic substances, e.g. phenylalanine, phe- nylpyruvate and phenylacetic acid in PKU, and subsequent organ damage ( table 1 ) [2] . The brain, liver and kidney are the most frequently affected organs. Some disorders cause chronic neurologi- cal damage without acute decompensation (e.g.
PKU), others cause acute symptoms associated with catabolic states leading to endogenous pro- tein breakdown and release of amino acids (MSUD) [3] . Dietary treatment is essential for PKU, homocystinuria (HCU), MSUD and tyro- sinaemia type 1 (HT1) [4] .
Dietary treatment involves:
• Avoidance of foods high in natural protein to prevent excess accumulation of the ‘precursor’
amino acid(s); foods such as meat, fish, eggs, cheese, nuts and seeds are not permitted un- less it is a very mild disorder phenotype • A limited amount of natural protein is given to
maintain ‘precursor’ blood amino acids within the target treatment range; natural food sourc- es allocated for substrate amino acids are from cereal, potato, some vegetables and milk • Provision of L -amino acids that are free of
‘precursor’ amino acids to meet at least safe levels of protein/nitrogen requirements with an additional amount to compensate for the inefficiency of L -amino acid utilisation • Provision of indispensable/conditionally in-
dispensable amino acids that may become de-
ficient as a result of the enzyme block or di- etary treatment (e.g. phenylalanine in HT1, cystine in HCU)
• Maintenance of a normal energy intake by en- couraging the use of foods naturally low in protein and of specially manufactured low- protein foods such as bread and pasta • Prevention of catabolism and metabolic de-
compensation during illness/trauma, particu- larly in MSUD
Diet may be the sole form of therapy or used in combination with other treatments. In mild or moderate PKU, adjunct therapy in the form of tetrahydrobiopterin, a coenzyme in the hydrox- ylation reaction of phenylalanine to tyrosine, may help to enhance natural protein tolerance or improve blood phenylalanine control. It acts as a chaperone to increase the activity of the defective enzyme [4] . In HT1, the drug nitisinone inhibits the accumulation of the catabolic intermediates which are converted to succinyl acetone and suc- cinyl acetoacetate, which are responsible for liver and kidney toxicity [5] .
Organic Acidurias
Organic acidurias are a diverse group of disor- ders, typically in the degradative pathways of amino acids, carbohydrates and fatty acids, char- acterised by increased excretion of organic acids in the urine. They include the conditions affect- ing abnormal catabolism of branched-chain ami- no acids: methylmalonic aciduria (MMA), pro- pionic aciduria (PA) and isovaleric aciduria ( table 2 ). Clinical features frequently include en- cephalopathy and episodic metabolic acidosis, caused not only by the accumulation of toxic in- termediates but also by disturbances of mito- chondrial energy metabolism and carnitine ho- moeostasis [3] . Symptoms commonly develop between days 2 and 5 of life, although they can commence at any age. Major goals of therapy are the reversal of catabolism, the promotion of anab-
228 MacDonald ConditionIncidenceClassificationSymptoms in untreated patientsTreatment PKUVariesClassicorseverePKU–Severe intellectual and neurological impairment–Low phenylalanine diet (classic PKU, children: betweenPlasma phenylalanine–Mousy odourtolerate 200–500 mg daily) populations: concentrations >1,200 μmol/l–Infantile spasms–Phenylalanine-free L-amino acid supplement 1 in 4,000 toModeratePKU–Lightly pigmented (hair, eyes and skin)–Tyrosine supplementations (usually already 1 in 200,000Plasma phenylalanine–Eczemaadded to L-amino acid supplement) concentrations >600–1,200 μmol/l–Microcephaly–Vitamins/minerals/essential and LC PUFA MildPKUorhyperphenylalaninaemia–Delayed speech development–Use of low-protein foods (special and natural) Phenylalanine concentrationsOlderpatientsto maintain ‘normal’ energy requirements <600 μmol/l–Hyperactivity–Patients with mild/moderate PKU may –Disturbed behaviourrespond to 5–20 mg/kg sapropterin daily –Austistic features –Self-injury –Abnormalities of gait –Tremor –Grand mal seizures MSUD1 in 116,000Classic MSUDClassic(neonatalonset)–Diet low in BCAA (leucine, valine, isoleucine; Intermediate form–Poor feeding‘classic’ children with MSUD tolerate 400–600 mg daily) Intermittent form–Sweet, malty, caramel-like smell–BCAA-free L-amino acid supplement Thiamin-responsive form–Episodic vomiting–Valine/isoleucine supplements if blood levels low (a cofactor for BCKD complex)–Irritability(dosage titrated to valine/isoleucine –Hypoglycaemiablood concentrations) –Lethargy–Vitamin/minerals/essential and LC PUFA –Encephalopathy–Use of low-protein foods (special and natural) –Cerebral oedemato maintain ‘normal’ energy requirements –Seizures–Requires emergency regimen during illness, –Delay in diagnosis may result infasting, infection or surgery neurological damage or death Intermediateform –Presents at any age (infancy to adulthood) –Failure to thrive –Hypotonia –Progressive developmental delay –Ketoacidosis Intermittentform –Episodic ataxia and ketoacidosis (often with intercurrent illness or increased protein intake) HT11 in 100,000Acute or chronic formAcute–Diet low in tyrosine and phenylalanine –Early infancy–May tolerate up to 0.5 g/kg natural protein daily, but –Severe liver failureamount to be titrated to tyrosine/phenylalanine –Cirrhosisconcentrations –Hepatocellular carcinoma–Tyrosine/phenylalanine-free amino acid supplement –Renal Fanconi syndrome–Phenylalanine supplements if blood levels low –Glomerulosclerosis(dosage titrated according to blood levels) –Vitamin D-resistant rickets–Use of low-protein foods (special and natural) to –Neurological crisismaintain ‘normal’ energy requirements Chronic–Vitamin/minerals/essential and LC PUFA –Slight enlargement of liver–Nitisinone (1 mg/kg/day) –Mild growth retardation –Renal tubular dysfunction and rickets –Hepatosplenomegaly –Liver cirrhosis –Hepatocellular carcinoma
Table 1. Incidence, classification and symptoms of amino acid disorders
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 226–233 DOI: 10.1159/000360344
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olism and, as a consequence, the reversal of the breakdown of endogenous protein [3] .
Treatment strategies include: (1) natural pro- tein restriction of precursor amino acids (aiming to provide safe levels of protein intake [6] ); (2) maintaining an optimal energy intake; and (3) use of adjunctive compounds to dispose of toxic metabolites (e.g. carnitine) or to increase activity of deficient enzymes (e.g. vitamin B 12 in MMA).
Some inherited metabolic disease centres pre- scribe precursor-free amino acids to supplement natural protein intake, although the long-term value of these supplements remains uncertain. In MMA and PA, to reduce the production of pro- pionate, it is also necessary to avoid prolonged fasting (with the use of overnight tube feeding) in order to limit oxidation of odd-chain fatty acids liberated from triglyceride stores during lipoly- sis. Also in MMA/PA, metronidazole is given to reduce intestinal production of propionate. Met- abolic decompensation caused by catabolic stress (e.g. from vomiting and decreased oral intake) re- quires prompt intervention with an emergency regimen.
Urea Cycle Disorders
UCD are rare defects in waste nitrogen metabo- lism associated with the breakdown of protein and other nitrogen-containing molecules [7] . Partial deficiency or total absence of any of the enzyme activities in the urea cycle (including car- bamoyl-phosphate synthetase 1, ornithine car- bamoyltransferase, argininosuccinate synthetase, argininosuccinate lyase and arginase) causes ac- cumulation of ammonia and glutamine, and nor- mal arginine biosynthesis is interrupted. The re- sulting hyperammonaemia and central nervous system dysfunction is associated with high mor- tality and morbidity. Although symptoms mainly develop in the neonatal period, patients differ in age at presentation, in the character and severity of symptoms and in their susceptibility to meta-
Table 1 (continued) ConditionIncidenceClassificationSymptoms in untreated patientsTreatment HCU1 in 344,000Pyridoxine responsive–Dislocation of the optic lens, myopia –Classic HCU only in classicNon-pyridoxine responsiveand glaucoma–Low-methionine diet (classic HCU tolerates a HCU–Osteoporosis, scoliosis, thinning andmedian of 230 mg/day) (varies from lengthening of the long bones–Methionine-free L-amino acid supplement 1 in 65,000 to –Learning difficulties, developmental delay, –Cystine supplements if blood levels low 1 in 900,000)psychiatric problems, EEG abnormalities (dosage titrated according to blood levels) and epilepsy–Use of low-protein foods (special and natural) to maintain –Thromboembolism‘normal’ energy requirements –Vitamin/minerals/essential and LC PUFA –Folic acid supplementation –Betaine supplementation BCKD = Branched-chain α-keto acid dehydrogenase; BCAA = branched-chain amino acids; LC PUFA = long-chain polyunsaturated fatty acids.
230 MacDonald Table 2. Incidence, classification and symptoms of organic acidaemias ConditionPrevalenceClassificationSigns and SymptomsTreatmentComplications PAUncertain Estimates: 1 in 50,000 to 1 in 500,000 High in regions of Saudi Arabia (1 in 2,000 to 1 in 5,000)
Early onset Presenting in neonatal period; severe illness follows introduction of protein- containing feeds Late onset (>6 weeks) Less common, and variable clinical presentation
Life-threatening illness Poor feeding/feed refusal Faltering growth Vomiting Dehydration Dyspnoea Hypothermia Lethargy Hypotonia Hepatomegaly Developmental delay Seizures Somnolence Coma 1. Low-protein diet ± amino acid supplements free of methionine, threonine, valine and isoleucine 2. Carnitine 3. Metronidazole 4. Sodium bicarbonate for acidosis 5. Sodium benzoate for hyperammonaemia 6. Emergency regimen during intercurrent infections
Neurological damage Movement disorders and dystonia Developmental delay Poor growth Hair loss Nutritional deficiencies, e.g. selenium and zinc Acute protein malnutrition Dermatitis Candida infections Recurrent infections Osteoporosis Acute and recurrent pancreatitis Hypocalcaemia due to parathyroid hormone resistance Cardiomyopathy MMAUncertain Estimates: 1 in 50,000
Methylmalonyl-CoA mutase phenotypes: Mut0 (no mutase activity) Mut– (residual mutase activity) Cobalamin disorders cblA cblB Cobalamin reduction pathway disorders cblC cblD Poor feeding/feed refusal Faltering growth Vomiting Candida infections Hypotonia Dehydration Dyspnoea Lethargy Progressive encephalopathy Hepatomegaly Developmental delay Seizures 1. Vitamin B12 for responsive patients 2. Low-protein diet ± amino acid supplements free of methionine, threonine, valine and isoleucine 3. Carnitine 4. Metronidazole 5. Sodium bicarbonate for acidosis 6. Sodium benzoate for hyperammonaemia 7. Emergency regimen during intercurrent infections
Neurological damage Hypotonia Neurodevelopmental delay Learning difficulties Basal ganglion damage and stroke-like symptoms Poor growth Hair loss Nutritional deficiencies, e.g. selenium and zinc Acute protein malnutrition Osteoporosis Acute and recurrent pancreatitis Tubular acidosis with hyperuricaemia Chronic renal failure Cardiomyopathy Isovaleric acidaemiaUnknownAcute, severe neonatal form Chronic intermittent formEpisodic vomiting Poor feeding/feed refusal Hypotonia Dehydration Dyspnoea Lethargy Hypothermia Sweaty feet odour Progressive encephalopathy Psychomotor delay Seizures
1. Low-protein diet ± amino acid supplements free of leucine 2. Carnitine 3. Glycine 4. Emergency regimen during intercurrent infections Neurological damage Natural aversion to protein-containing foods Pancreatitis Faltering growth Learning difficulties
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 226–233 DOI: 10.1159/000360344
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bolic derangement depending on the affected en- zyme and its residual activity [8] .
Treatment for UCD involves reducing protein intake, supplementing essential amino acids and avoiding catabolic states. Drug therapy produces alternative pathways for nitrogen excretion and includes ammonia-scavenging drugs (e.g. sodi- um phenylbutyrate or sodium benzoate) and ar- ginine (except in arginase deficiency), which pro- motes incorporation of ammonia into citrulline and arginosuccinate. L -Citrulline may be given as an alternative to arginine in ornithine carbam- oyltransferase and carbamoyl-phosphate syn- thase deficiency [7] .
Disorders of Fatty Acid Oxidation
Mitochondrial fatty acid oxidation is required for energy during fasting, either through com- plete oxidation or through production of ke- tones in the liver that then serve as an alternative energy source for the brain. Disorders are main- ly precipitated by fasting and typically present as hypoketotic hypoglycaemia, which leads to coma or convulsions. The most common fatty acid disorder in Northern Europe is medium- chain acyl-CoA dehydrogenase deficiency (MCADD) [5] . In unscreened populations, MCADD is associated with 25% mortality on presentation. Most children identified through newborn screening remain well without long- term sequelae. Precipitating factors of acute metabolic episodes in infancy include prolonged fasting caused by vomiting/diarrhoea/fever, and in teenagers/adults strenuous exercise, alcohol and drugs (with vomiting/fasting), surgery and pregnancy [9] . Treatment consists of avoidance of fasting and use of an emergency regimen with illness/surgery/trauma. See table 3 for suggested safe fasting times.
Disorders of Carbohydrate Metabolism The disorders of carbohydrate metabolism dis- play a wide range of clinical features: symptoms caused by toxicity (galactosaemia and hereditary fructose intolerance, HFI) or hypoglycaemia (GSD).
Disorders of Galactose and Fructose Metabolism Galactosaemia is a disorder of galactose metabo- lism causing abnormal glycosylation of glycopro- teins and glycolipids [10] . In HFI, accumulation of fructose 1-phosphate causes inhibition of gly- cogen breakdown and glucose synthesis, thereby causing severe hypoglycaemia following fructose ingestion [11] . Both conditions are potentially life threatening on presentation. Children with galactosaemia and HFI typically develop evi- dence of severe damage to the liver and kidneys after dietary intake of lactose (milk, milk prod- ucts) in galactosaemia or of fructose (fruits, su- crose) in HFI [5] . Treatment includes the elimi- nation of the intake of galactose or fructose, re- spectively. In HFI, an aversion to fructose is common.
Children with galactosaemia often present in the first week of life. Children with HFI develop symptoms after the introduction of fruits, vege- tables and particularly table sugar (the fructose- glucose disaccharide sucrose) to their diet, often between 4 and 8 months of age [12] . Long-term complications are common in galactosaemia and appear to be independent of the severity of ill- ness, type of diet therapy or dietary adherence, and there is debate about how stringent dietary restriction should be later in life. In contrast, in HFI outcome is good, with normal growth, intel- ligence and life span [12] .
Disorders of Gluconeogenesis and Glycogen Storage
GSD are defects of a number of different en- zymes involved in glycogen synthesis and degra- dation [13] . Glycogen is primarily stored in the
232 MacDonald Table 3. Incidence, classification and symptoms of MCADD and carbohydrate disorders ConditionPrevalenceClassificationSigns and SymptomsTreatment Complications MCADD1 in 12,000– 20,000 in the UK, USA and Australia
Common mutation is c.985A>G and is associated with clinically severe presentation Milder forms have uncertain clinical relevance Acute ‘hypoketotic’ hypoglycaemic encephalopathy and liver dysfunctionFrequent regular feeds in 1st year of life >1 year: avoid fasting for >12–14 h Dietary fat restriction unnecessary Emergency protocol for intercurrent infections, surgery or other conditions requiring prolonged fasting (regular feeds from glucose polymer); if not tolerated or feasible, will require glucose-containing IV fluids) Developmental delay secondary to acute metabolic event Galacto- saemia1 in 16,000 to 1 in 40,000 in Western Europe
Deficiency of GALT Classic galactosaemia: GALT enzyme activity <5% of controls Duarte variant: GALT activity is approx. 25% of control values
Feeding problems Faltering growth Hepatocellular damage Bleeding Liver failure Sepsis Neonatal death Cataracts Intellectual disability Developmental delay Verbal dyspraxia Abnormalities of motor function Low-galactose diet (lactose free) Lactose-free medicationsPremature ovarian dysfunction Delayed growth Osteopenia Osteoporosis HFI1 in 20,000 (1 in 11,000 to 1 in 100,000)
Deficiency of fructose 1-phosphate aldolase activityNausea Vomiting Restlessness Pallor, sweating, trembling Lethargy Hepatomegaly, jaundice Haemorrhage Proximal renal tubular syndrome Hepatic failure and death 1. Fructose-, sucrose- and sorbitol-free diet 2. Sucrose-/fructose-free multivitamin supplement 3. Fructose-, sucrose- and sorbitol-free medications
Liver and kidney dysfunction GSD1 in 100,000 1 in 8 GSD I patients have type Ib 1 in 100,000
GSD Ia (von Gierke) Glucose-6-phosphatase deficiency GSD Ib (von Gierke) Glucose-6-phosphate translocase deficiency GSD III (Cori/Forbes) Deficiency of debranching enzyme and of subtypes GSD IIIa: 85% of all GSD III GSD IIIb: 15% of all GSD III Hepatomegaly Hypoglycaemia Hyperlipidaemia Lethargy Seizures Development delay Protuberant abdomen Same as in GSD Ia Neutropenia Infections Inflammatory bowel disease Hepatomegaly (Cardio)myopathy Short stature Hypoglycaemia GSD IIIa: symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement GSD IIIb: symptoms primarily related to liver disease 1. Lactose-free (± sucrose-/fructose-free) formula (but breast milk not contraindicated) 2. Frequent, small daytime feedings with avoidance of fasting (high in complex carbohydrate) 3. Continuous overnight tube feedings of glucose 4. Uncooked cornstarch >1 year (starting dose of 1 g/kg/dose): titrate dose according to glucose/lactate monitoring 5. Protein (10–15%) of recommended total energy intake 6. Vitamins/minerals/essential and LC PUFA 7. Emergency protocol for intercurrent infections (continuous tube feedings from glucose polymer) 8. Xanthine-oxidase inhibitor (allopurinol) to prevent gout 9. Lipid-lowering medications 1. High-protein diet 2. Uncooked cornstarch >1 year (starting dose of 1 g/kg/dose): titrate dose according to glucose/lactate monitoring; regular feeding 3. Vitamins/minerals/essential and LC PUFA 4. Emergency protocol for intercurrent infections (continuous tube feedings from glucose polymer) Short stature Osteoporosis Delayed puberty Gout Renal disease Pulmonary hypertension Hepatic adenomas Polycystic kidneys Pancreatitis Neurocognitive effects Menorrhagia Cardiomyopathy Myopathy Poor growth Osteoporosis and osteopenia Polycystic ovary disease GALT = Galactose-1-phosphate uridylyltransferase; LC PUFA = long-chain polyunsaturated fatty acids.
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liver and muscle, and disorders of glycogen deg- radation may affect the liver or muscle or both [14] . The liver GSD include GSD I and the he- patic presentation of GSD III [15] . Typical meta- bolic features are lactic acidaemia and hypogly- caemia. Variable organ dysfunction, most fre- quently hepatomegaly, occurs. The goal of treatment is to maintain normoglycaemia, pre- vent hypoglycaemia and prevent secondary complications. Treatments include frequent meals, cornstarch supplementation and/or con- tinuous overnight tube feeding to avoid hypo- glycaemia. In GSD I, allopurinol reduces uric acid levels in the blood to prevent gout and kid- ney stones [14] .
Conclusions
• The treatment goal for all IEM is to achieve optimal development and nutritional status during childhood, and maximal indepen- dence, social integration and self-esteem in adolescence and adulthood
• All conditions require diligent care, and IEM are best managed by a multidisciplinary team led by a physician
• Attentive nutritional support with the provi- sion of macronutrients and micronutrients to meet dietary reference values/requirements is essential
• Frequent monitoring of growth, nutritional intake, development and biochemical control is necessary
11 Bouteldja N, Timson DJ: The biochemi- cal basis of hereditary fructose intoler- ance. J Inherit Metab Dis 2010; 33: 105–
112.
12 Steinmann B, Santer R: Disorders of fructose metabolism; in Saudubray JM, van den Berghe G, Walter JH (eds): In- born Metabolic Diseases: Diagnosis and Treatment, ed 5. Berlin, Springer, 2012, pp 157–165.
13 van den Berghe G: Disorders of gluco- neogenesis. J Inherit Metab Dis 1996; 19:
470–477
14 Laforet P, Weinstein DA, Smit PA: The glycogen storage diseases and related disorders; in Saudubray JM, van den Berghe G, Walter JH (eds): Inborn Meta- bolic Diseases: Diagnosis and Treat- ment, ed 5. Berlin, Springer, 2012, pp 115–116.
15 Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS; ACMG:
Glycogen storage disease type III diag- nosis and management guidelines. Gen- et Med 2010; 12: 446–463.
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