11 Inherited Hyperammonaemias James V. Leonard 11.1 Introduction Several syndromes are associated with symptomatic hyperammonaemia (Table 11.1; Scriver et al. 2000; Fernandes et al. 2000). The patterns of clini- cal presentation are broadly similar and rather characteristic for all disorders, with certain exceptions (for example arginase deficiency). These are discussed separately. Patients with hyperammonaemia may present at almost any age, but they are more likely to do so in the neonatal period, during late infancy and around puberty. The early symptoms are often not specific and therefore easily over- looked. Nevertheless it is important to think of hyperammonaemia to establish the diagnosis quickly and reduce complications. Table 11.1. Nomenclature No. Disorder Definitions/comment Gene symbol OMIM No. 11.1 Carbamyl phosphate synthetase Autosomal recessive CPS1 237300 deficiency (CPS) 11.2 Ornithine transcarbamylase X-linked OTC 311250 deficiency (OTC) 11.3 Citrullinaemia (argininosuccinate Autosomal recessive ASS 215700 synthetase deficiency; CIT1or ASS) 11.4 Argininosuccinic aciduria (argini- Autosomal recessive ASL 207900 nosuccinate lyase deficiency; ASL) 11.5 Arginase deficiency (ARG) Autosomal recessive ARG1 207800 11.6 N-Acetylglutamate synthetase Autosomal recessive NAGS 237310 deficiency (NAGS) 11.7 Lysinuric protein intolerance (LPI) Autosomal recessive SLC7A7 222700 11.8 Hyperammonaemia- Autosomal recessive SLC25A15 238970 hyperornithinaemia- homocitrullinuria syndrome (HHH) 11.9 Pyrroline-5-carboxylate synthase Autosomal recessive PYCS 138250 (PYCS) 11.10 Hyperinsulinaemia- See Chap. 35 Hyperammonaemia syndrome (HIHA) 11.11 Citrullinaemia type 2 (CIT 2) Autosomal recessive SLC25A13 603471, 605814 118 Inherited Hyperammonaemias In the neonatal period, babies with hyperammonaemia, most commonly those with urea cycle disorders, appear normal, but they soon become progres- sively unwell, with poor feeding, vomiting, lethargy, irritability and tachypnoea. The babies may deteriorate rapidly, with neurological and autonomic problems, including vasomotor instability, fits, apnoea and coma. In infancy the symptoms are generally less acute and more variable than in the neonatal period. These include anorexia, lethargy, vomiting and failing to thrive with poor developmental progress. Irritability and behavioural problems are also common. In children and adults, patients commonly present with a more obvious neurological illness. These may be acute and may be precipitated by “metabolic stress” such as infection or anaesthesia. Symptoms may be episodic and of- ten the patient is initially anorexic and lethargic, but sometimes they may be agitated and irritable. Vomiting and headaches may be prominent or the pa- tient may be ataxic. The patient may then recover completely but may progress to develop a fluctuating level of consciousness with focal neurological signs. Alternatively the patients may have chronic neurological illness with learn- ing difficulties and sometimes with neurological signs such as ataxia that are worsewithintercurrentinfections.Thefirststepistoestablishthediagnosisby measuring plasma ammonia, amino acids and urine organic acids and orotate. Arginase deficiency most commonly presents with a spastic diplegia that is commonly initially diagnosed as cerebral palsy. Some patients may present with fits and a subacute encephalopathy. Those with lysinuric protein intolerance (LPI) usually have typical symptoms of hyperammonaemia, but they may also present with failure to thrive and an aversion to high-protein foods. Later presentation includes growth failure and hepatosplenomegaly. Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) often presents with typical symptoms of hyperammonaemia, most commonly in infancy. Pyrroline-5-carboxylate synthetase deficiency is a very rare disorder, the features of which may include joint hypermobility, skin hyperelasticity, cataract and mental retardation. Hyperammonaemia is preprandial. Citrin deficiency (citrullinaemia type 2) may present as cholestatic jaundice in early infancy or as hyperammonaemic encephalopathy in adults. Treatment 119 11.2 Treatment Hyperammonaemia has a high morbidity and mortality. Early intervention can prevent many of the complications so that treatment should never be delayed. The treatment of hyperammonaemic syndromes has two phases: that of the acute hyperammonaemia and the long-term management (Brusilow 1991; Urea Cycle Disorders Conference Group 2001). I Acute Hyperammonaemia Severe hyperammonaemic encephalopathy is a major emergency because of the risk of cerebral oedema (Table 11.2). Table 11.2. Emergency treatment of severe acute hyperammonaemia Treatment 1 General supportive care e. g. ventilation (particularly prior to transfer) treat- ment of sepsis, seizures etc. 2 Stop protein intake 3 Give a high energy intake, either (a) oral: (i) 10–25% soluble glucose poly- mer, depending on age, or (ii) protein-free formula (80056, Mead Johnson; Duocal, SHS); or (b) intravenously: (i) 10% glucose by peripheral infusion, or (ii) 10–25% glucose by central venous line. Fluid volumes may be restricted if there is concern about cerebral oedema 4 Alternative pathways for nitrogen excretion (if diagnosis known) Sodium benzoate up to 500 mg/kg perday–oralorintravenously Sodium phenylbutyrate up to 600 mg/kg per day l-Arginine In citrullinaemia and ASA – up to 700 mg/kg per day OTC at CPS deficiencies – up to 50 mg/kg per day For the emergency treatment of hyperammonaemia before the diagnosis is known, some centres consider the following to be a safer alternative: 300 mg l-arginine/kg per day; 200 mg l-carnitine/kg per day. Both can be given orally or intravenously 5 Dialysis (haemodialysis, haemodiafiltration or haemofiltration). Start imme- diately if plasma ammonia > 500 µmol/l or if ammonia does not fall with the above measures. In very small babies, haemofiltration may not be technically possible and it may be necessary to resort to peritoneal dialysis, but this is less efficient At conventional doses of 250 mg/kg,sodiumbenzoatecontains1.74mmol/kg of sodium and sodium phenylbutyrate 1.35 mmol/kg These regimens are not nutritionally complete and will cause malnutrition if prolonged. They must not be continued longer than absolutely necessary 120 Inherited Hyperammonaemias I Long-Term Treatment The aim of long-term treatment is to control the metabolic disorder whilst at the same time giving a nutritionally complete diet to achieve as near normal growth and development as possible. The major components of the treatment are diet, replacement of missing metabolites and medication that utilises alternative pathways for nitrogen removal (Table 11.3). Table 11.3. Summary of treatment of hyperammonaemic syndromes No. Disorder Long-term diet Emergency Medication regimen 11.1 Carbamyl phosphate synthetase Low protein Yes Sodium benzoate deficiency Sodium phenylbutyrate Arginine (citrulline) 11.2 Ornithine carbamyl transferase Low protein Yes Sodium benzoate deficiency Sodium phenylbutyrate Arginine (citrulline) 11.3 Citrullinemia Low protein Yes Sodium benzoate Sodium phenyl butyrate Arginine 11.4 Argininosuccinic aciduria Low protein Yes Sodium benzoate Sodium phenylbutyrate Arginine 11.5 Arginase deficiency Low arginine Yes Sodium benzoate Sodium phenylbutyrate 11.6 N-Acetylglutamate synthetase Normal/reduced Ye s N-Carbamylglutamate deficiency protein 11.7 Lysinuric protein intolerance Low protein Citrulline 11.8 HHH syndrome Low protein 11.9 PYCS Uncertain 11.10 Hyperinsulinemia- hyperammonaemia syndromea 11.11 Citrullinaemia type 2 Galactose-free diet Yes Galactose restriction (citrin deficiency) Sodium benzoate Sodium phenylbutyrate Arginine a See Chap. 35 G Low-Protein Diet and Essential Amino Acid Supplements Diet forms an essential part of the management of most patients with hy- perammonaemic syndromes. Some patients self-select low-protein diets, while others do not. The aim should be restrict protein to attain good metabolic control while at the same time ensuring that the diet is nutritional complete and requirements for normal growth are met. Protein requirements vary with age, being highest in infancy (FAO/WHO/UNU Expert Committee 1985; Dewey Treatment 121 et al. 1996). There is considerable individual variation in requirements, and the values widely quoted in nutritional texts are usually the “safe” values, being mean + 2 SDs. Some patients may be treated with considerably less that these values (Table 11.4). Table 11.4. Protein requirements by age (expressed as grams per kilogram per day) Age FAO/WHO/UNU FAO/WHO/UNU Revised meanb Revised safe 1985a (Mean) 1985a valuesb (safe: mean +2 SD) 0–1 months 1.99 2.69 1–2 months 2.25 1.54 2.04 2–3 months 1.82 1.19 1.53 3–4 months 1.47 1.86 1.06 1.37 4–5 months 1.34 1.86 0.98 1.25 5–6 months 1.3 1.86 0.92 1.19 6–9 months 1.25 1.65 0.85 1.09 9–12 months 1.15 1.48 0.78 1.02 1–1.5 years 1.0 1.26 0.79 1.0 1.5–2 years 0.94 1.17 0.76 0.94 2–3 years 0.91 1.13 0.74 0.92 3–4 years 0.88 1.09 0.73 0.9 4–5 years 0.86 1.06 0.71 0.88 5–6 years 0.83 1.02 0.69 0.86 6–7 years 0.82 1.01 0.69 0.86 7–8 years 0.81 1.01 0.69 0.86 8–9 years 0.81 1.01 0.69 0.86 9–10 years 0.80 0.99 0.69 0.86 Girls 10–11 years 0.81 1.00 0.71 0.87 11–12 years 0.79 0.98 0.69 0.86 12–13 years 0.77 0.96 0.69 0.85 13–14 years 0.75 0.94 0.68 0.84 14–15 years 0.72 0.9 0.66 0.81 15–16 years 0.7 0.87 0.66 0.81 16–17 years 0.66 0.83 0.63 0.78 17–18 years 0.64 0.8 0.63 0.77 Boys 10–11 years 0.79 0.99 0.69 0.86 11–12 years 0.79 0.98 0.69 0.86 12–13 years 0.81 1.0 0.71 0.88 13–14 years 0.78 0.97 0.69 0.86 14–15 years 0.77 0.96 0.69 0.86 15–16 years 0.74 0.92 0.68 0.84 16–17 years 0.72 0.9 0.67 0.83 17–18 years 0.69 0.86 0.66 0.81 a FAO/WHO/UNU 1985 b Dewey et al.