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Investigation of Metabolic Encephalopathy Encephalopathy May Be a Presenting Sign in a Wide Range of Medical Conditions

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Investigation of Metabolic Encephalopathy Encephalopathy May Be a Presenting Sign in a Wide Range of Medical Conditions Investigation of metabolic encephalopathy Encephalopathy may be a presenting sign in a wide range of medical conditions. G F van der Watt, FCPath (SA) Chem, MMed, MB ChB, DA (SA) Principal Pathologist (Chemical), Division of Chemical Pathology, Groote Schuur Hospital and Red Cross War Memorial Children’s Hospital, University of Cape Town and National Health Laboratory Service George van der Watt is an academic chemical pathologist with an interest in paediatric inherited metabolic disease. He co-ordinates a biochemical diagnostic laboratory for these disorders in Cape Town and is also chairman of the South African Inherited Metabolic Disease Group. Correspondence to: George van der Watt ([email protected]) Encephalopathy may be a presenting sign Genetic population studies have shown, encephalopathy may be secondary to failure in a wide range of medical conditions. for example, that high carrier frequencies of other organs such as hepatorenal failure This review focuses only on the diagnosis of single mutations in the South African in tyrosinaemia type 1 and galactosaemia, and initial management of those inherited black population are responsible for adrenal failure in adrenoleukodystrophy metabolic diseases (IMDs) prevalent most cases of glutaric aciduria type 1 (X-ALD) or hypoglycaemia in glycogen in South Africa that may present with (GA1), galactosaemia and cystinosis.1-3 storage disease type 1. encephalopathy in childhood. Metabolic Furthermore, our experience has shown encephalopathy is a medical emergency, and that whereas propionic acidaemia (PA) Clinical clues to some appropriate empirical intervention can often is frequently encountered across all improve outcome, provided a timely working population groups, isovaleric acidaemia OAs may be the distinct diagnosis is made based on clinical suspicion (IVA) is mostly confined to Afrikaners. smell of caramelised and targeted laboratory investigations. Furthermore, common European disorders sugar in MSUD and such as phenylketonuria and medium chain the offensive goat- Clinicians should be acyl dehydrogenase deficiency (MCADD) are relatively uncommon in South Africa. like cheesy odour aware of disorders that of isocaproate that are more likely to occur By far the most common of the urea accumulates in IVA within the population cycle defects is the X-linked recessive disorder, ornithine transcarbamylase and multiple acyl they are treating. A deficiency (OTC). X-linked recessive dehydrogenase family history, evidence disorders usually arise as novel maternal deficiency. of previous siblings with germ-line mutations and therefore occur with similar frequencies worldwide. similar presentations or Mitochondrial cytopathies can be caused Organic acidaemias consanguinity should either by AR deficiency of many nuclear The OAs are largely represented by always be sought. encoded genes or by mutations in the deficiencies of enzymes involved in the smaller mitochondrial genome. Because catabolism of amino and fatty acids for mitochondria derive exclusively from the fuel. During catabolism, organic acid Introduction maternal oocyte, the latter disorders are intermediates accumulate and clinical Most IMDs are caused by autosomal only passed from a mother to her children decompensation is mostly ascribed to the recessive (AR) single enzyme deficiencies. and are perpetuated through her daughters. inherent toxicity of these intermediates or Some follow an X-linked recessive pattern, the fact that they may disrupt other critical affecting mainly boys, or in the case of Table 1 presents a series of selected IMDs metabolic pathways. Diagnostic metabolites some mitochondrial disorders, a strictly diagnosed at the Red Cross Children’s Hospital can be measured in blood or in urine and, maternally inherited pattern. The spectrum Metabolic Disease Laboratory over the together with elevated precursor amino or and frequency of IMDs in a population are preceding 6 years that may potentially present fatty acids, are used to make a diagnosis. strongly influenced by consanguinity and the with metabolic encephalopathy. These cases Typically patients are far more likely to prevalence of founder mutations. Clinicians represent over 60% of all IMDs diagnosed in decompensate when the affected pathway should be aware of disorders that are more this period and the majority fall into 3 main is stressed during major catabolic episodes likely to occur within the population they categories, namely the organic acidaemias as seen with inter-current infections, or the are treating. A family history, evidence of (OAs), the urea cycle defects (UCDs) early neonatal transition to extra-uterine previous siblings with similar presentations and the mitochondrial cytopathies. Not life, or if the child is fed the compounds or consanguinity should always be sought. included in this series are those cases where that they are unable to metabolise. Typically, 11 CME January 2013 Vol. 31 No. 1 Metabolic encephalopathy neuronal lysine catabolic pathway.1 Table 1. Confirmed IMD cases associated with metabolic encephalopathy Due to diagnosed at Red Cross Children's Hospital Metabolic Disease a relatively large size and limited hepatic Laboratory, 2006 - 2012 glucose production, the infantile brain relies heavily on ketones and amino acids Name of disorder Number of cases like lysine as a fuel source during times of Glutaric aciduria type 1 (GA1)* 23 catabolic stress. Children with GA1 are born Mitochondrial cytopathies (all) 11 and develop normally, until they typically Propionic acidaemia (PA)* 11 present during infancy with hypotonia and encephalopathy associated with an episode Urea cycle defects (all) 7 of catabolic stress. During these episodes, Non-ketotic hyperglycinaemia (NKH) 5 massive levels of the toxic lysine metabolites, Pyruvate dehydrogenase deficiency (PDH)* 5 3-OH glutarate and glutarate accumulate in Ketone utilisation defects (all)* 4 the brain, causing disruption of neuronal Fatty acid oxidation defects (FAODs – all)* 4 mitochondrial function and irreversible Biotinidase deficiency* 3 damage to the basal ganglia. Isovaleric acidaemia* 3 Children go on to develop a severely Multiple acyl dehydrogenase deficiency* 3 debilitating form of choreo-athetoid Glutathione synthetase deficiency* 2 cerebral palsy, often with retention of a Methylmalonic acidaemia (MMA)* 2 normal intellect. In addition, GA1 can Maple syrup urine disease (MSUD)* 2 be associated with microencephalic- macrocephaly, with a high risk of repeated Molybdenum cofactor deficiency 2 intracranial and even retinal haemorrhages. l-2-hydroxyglutaric aciduria* 1 The clinical and radiological profile is HMG-CoA-lyase deficiency* 1 easily confused with repeated blunt non- Malonyl-CoA decarboxylase deficiency* 1 accidental head injury.4 If GA1 is diagnosed prior to the first acute episode, the outcome *Organic acidaemias. can be significantly altered by dietary lysine restriction, carnitine supplementation, and the resultant metabolic derangements, of isocaproate that accumulates in IVA and all of which can contribute to depressed multiple acyl dehydrogenase deficiency. neurological function, are the following: • high anion-gap metabolic acidosis due to the accumulated organic acids The classic neonatal themselves presentation of OTC • hyperammonaemia due to secondary disruption of the urea cycle involves an apparently • hypoglycaemia due to secondary healthy male neonate inhibition of hepatic gluconeogenesis who develops feeding • lactataemia due to failed gluconeogenesis • ketonaemia where intermediates may difficulties, lethargy and feed into ketone biosynthesis. hypersomnolence within the early neonatal period It is important to note that in some disorders such as PA and biotinidase deficiency, all that rapidly progresses the above metabolic derangements may to life-threatening be present. Others, such as the fatty acid hyperammonaemic oxidation defects (FAODs), typically only present with the first 3 and maple syrup encephalopathy. urine disease (MSUD) usually presents only with a severe anion-gap acidosis. Further, Glutaric aciduria type 1 is the most common clinical clues to some OAs may be the OA in South Africa and is caused by AR distinct smell of caramelised sugar in MSUD deficiency of glutaryl-CoA dehydrogenase and the offensive goat-like cheesy odour (GCDH), a critical enzyme in the infantile 12 CME January 2013 Vol. 31 No. 1 Metabolic encephalopathy most importantly an ‘emergency regimen’ the GCDH gene and at least 60 children Isolated hyperammonaemia is the hallmark consisting of the provision of liberal glucose are estimated to be born with this disorder of the UCDs and clinical presentations during periods of catabolic stress.5 After 24 each year – most of them never receive a vary from acute encephalopathy with months, the risk of acute episodes drops correct diagnosis!1 brain oedema to milder symptoms such dramatically as the liver is able to supply as learning difficulties, drowsiness and brain glucose requirements. Appropriately Urea cycle defects avoidance of high-protein foods. Proximal treated children may have an entirely The UCDs as a group constitute defects in the urea cycle are generally normal outcome.3 approximately 12% of emergency admissions associated with higher ammonia levels.7 due to IMDs.6 They all involve deficiencies GA1 is easily diagnosed by analysis of enzymes or transporters involved in the The classic neonatal presentation of OTC of urine organic acids and confirmed hepatic cyclical conversion of neuro-toxic
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