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Investigation of metabolic encephalopathy: encephalopathy may be a presenting sign in a wide range of medical conditions.

Encephalopathy may be a presenting sign in a wide range of medical conditions. This review focuses only on the diagnosis and initial management of those inherited metabolic diseases (IMDs) prevalent in South Africa that may present with encephalopathy in childhood. Metabolic encephalopathy is a medical emergency, and appropriate empirical intervention can often improve outcome, provided a timely working diagnosis is made based on clinical suspicion and targeted laboratory investigations.


Most IMDs are caused by autosomal recessive (AR) single enzyme deficiencies. Some follow an X-linked recessive pattern, affecting mainly boys, or in the case of some mitochondrial disorders, a strictly maternally inherited pattern. The spectrum and frequency of IMDs in a population are strongly influenced by consanguinity and the prevalence of founder mutations. Clinicians should be aware of disorders that are more likely to occur within the population they are treating. A family history, evidence of previous siblings with similar presentations or consanguinity should always be sought. Genetic population studies have shown, for example, that high carrier frequencies of single mutations in the South African black population are responsible for most cases of glutaric aciduria type 1 (GA1), galactosaemia and cystinosis. (1-3) Furthermore, our experience has shown that whereas propionic acidaemia (PA) is frequently encountered across all population groups, isovaleric acidaemia (IVA) is mostly confined to Afrikaners. Furthermore, common European disorders such as phenylketonuria and medium chain acyl dehydrogenase deficiency (MCADD) are relatively uncommon in South Africa.

By far the most common of the urea cycle defects is the X-linked recessive disorder, ornithine transcarbamylase deficiency (OTC). X-linked recessive disorders usually arise as novel maternal germ-line mutations and therefore occur with similar frequencies worldwide. Mitochondrial cytopathies can be caused either by AR deficiency of many nuclear encoded genes or by mutations in the smaller mitochondrial genome. Because mitochondria derive exclusively from the maternal oocyte, the latter disorders are only passed from a mother to her children and are perpetuated through her daughters.

Table 1 presents a series of selected IMDs diagnosed at the Red Cross Children's Hospital Metabolic Disease Laboratory over the preceding 6 years that may potentially present with metabolic encephalopathy. These cases represent over 60% of all IMDs diagnosed in this period and the majority fall into 3 main categories, namely the organic acidaemias (OAs), the urea cycle defects (UCDs) and the mitochondrial cytopathies. Not included in this series are those cases where encephalopathy may be secondary to failure of other organs such as hepatorenal failure in tyrosinaemia type 1 and galactosaemia, adrenal failure in adrenoleukodystrophy (X-ALD) or hypoglycaemia in glycogen storage disease type 1.
Table 1. Confirmed IMD cases associated with metabolic
encephalopathy diagnosed at Red Cross Children's Hospital
Metabolic Disease Laboratory, 2006 - 2012

Name of disorder Number of cases

Glutaric aciduria type 1 (GA1)* 23

Mitochondrial cytopathies (all) 11

Propionic acidaemia (PA)* 11

Urea cycle defects (all) 7

Non-ketotic hyperglycinaemia (NKH) 5

Pyruvate dehydrogenase deficiency (PDH)* 5

Ketone utilisation defects (all)* 4

Fatty acid oxidation defects (FAODs - all)* 4

Biotinidase deficiency* 3

Isovaleric acidaemia* 3

Multiple acyl dehydrogenase deficiency* 3

Glutathione synthetase deficiency* 2

Methylmalonic acidaemia (MMA)* 2

Maple syrup urine disease (MSUD)* 2

Molybdenum cofactor deficiency 2

l-2-hydroxyglutaric aciduria* 1

HMG-CoA-lyase deficiency* 1

Malonyl-CoA decarboxylase deficiency* 1

*Organic acidaemias.

Organic acidaemias

The OAs are largely represented by deficiencies of enzymes involved in the catabolism of amino and fatty acids for fuel. During catabolism, organic acid intermediates accumulate and clinical decompensation is mostly ascribed to the inherent toxicity of these intermediates or the fact that they may disrupt other critical metabolic pathways. Diagnostic metabolites can be measured in blood or in urine and, together with elevated precursor amino or fatty acids, are used to make a diagnosis. Typically patients are far more likely to decompensate when the affected pathway is stressed during major catabolic episodes as seen with inter-current infections, or the early neonatal transition to extra-uterine life, or if the child is fed the compounds that they are unable to metabolise. Typically, the resultant metabolic derangements, all of which can contribute to depressed neurological function, are the following:

* high anion-gap metabolic acidosis due to the accumulated organic acids themselves

* hyperammonaemia due to secondary disruption of the urea cycle

* hypoglycaemia due to secondary inhibition of hepatic gluconeogenesis

* lactataemia due to failed gluconeogenesis

* ketonaemia where intermediates may feed into ketone biosynthesis.

It is important to note that in some disorders such as PA and biotinidase deficiency, all the above metabolic derangements may be present. Others, such as the fatty acid oxidation defects (FAODs), typically only present with the first 3 and maple syrup urine disease (MSUD) usually presents only with a severe anion-gap acidosis. Further, clinical clues to some OAs may be the distinct smell of caramelised sugar in MSUD and the offensive goat-like cheesy odour of isocaproate that accumulates in IVA and multiple acyl dehydrogenase deficiency. Glutaric aciduria type 1 is the most common OA in South Africa and is caused by AR deficiency of glutaryl-CoA dehydrogenase (GCDH), a critical enzyme in the infantile neuronal lysine catabolic pathway. (1) Due to a relatively large size and limited hepatic glucose production, the infantile brain relies heavily on ketones and amino acids like lysine as a fuel source during times of catabolic stress. Children with GA1 are born and develop normally, until they typically present during infancy with hypotonia and encephalopathy associated with an episode of catabolic stress. During these episodes, massive levels of the toxic lysine metabolites, 3-OH glutarate and glutarate accumulate in the brain, causing disruption of neuronal mitochondrial function and irreversible damage to the basal ganglia.

Children go on to develop a severely debilitating form of choreo-athetoid cerebral palsy, often with retention of a normal intellect. In addition, GA1 can be associated with microencephalic-macrocephaly, with a high risk of repeated intracranial and even retinal haemorrhages. The clinical and radiological profile is easily confused with repeated blunt non-accidental head injury. (4) If GA1 is diagnosed prior to the first acute episode, the outcome can be significantly altered by dietary lysine restriction, carnitine supplementation, and most importantly an 'emergency regimen' consisting of the provision of liberal glucose during periods of catabolic stress. (5) After 24 months, the risk of acute episodes drops dramatically as the liver is able to supply brain glucose requirements. Appropriately treated children may have an entirely normal outcome. (3)

GA1 is easily diagnosed by analysis of urine organic acids and confirmed by GCDH mutation analysis. In South Africa, 1 in 35 to 1 in 50 black people are carriers for the same A293T mutation in the GCDH gene and at least 60 children are estimated to be born with this disorder each year - most of them never receive a correct diagnosis! (1)

Urea cycle defects

The UCDs as a group constitute approximately 12% of emergency admissions due to IMDs. (6) They all involve deficiencies of enzymes or transporters involved in the hepatic cyclical conversion of neuro-toxic ammonia, to urea. All are exacerbated by increased protein intake or catabolic stress, in much the same manner as the OAs. Isolated hyperammonaemia is the hallmark of the UCDs and clinical presentations vary from acute encephalopathy with brain oedema to milder symptoms such as learning difficulties, drowsiness and avoidance of high-protein foods. Proximal defects in the urea cycle are generally associated with higher ammonia levels. (7)

The classic neonatal presentation of OTC involves an apparently healthy male neonate who develops feeding difficulties, lethargy and hypersomnolence within the early neonatal period that rapidly progresses to life-threatening hyperammonaemic encephalopathy. Respiratory alkalosis is typically found due to stimulation of the respiratory centre by ammonia. Measuring plasma ammonia is critical for the early detection of UCDs and the prognosis is significantly improved if ammonia can be controlled quickly by protein restriction, renal replacement therapy and agents such as sodium benzoate and phenylbutyrate that can clear ammonia through alternate pathways. Liver transplant is curative, especially for severe defects. Milder defects are often managed with a combination of protein restriction, ammonia clearing agents and supplementation with arginine, an essential amino acid produced by the intact urea cycle. After demonstrating hyperammonaemia, a specific diagnosis can be made by analysing plasma amino acids, including citrulline and argininosuccinate, and by measuring orotate in urine. The diagnosis is confirmed by gene sequencing or tissue enzyme assay. Making a molecular diagnosis in X-linked recessive disorders such as OTC is particularly important as it allows for prenatal screening and the detection of female carriers in the family.

Mitochondrial cytopathies

The mitochondrial cytopathies represent a diverse group of IMDs that typically involve organ systems with high aerobic energy requirements such as muscle and nervous tissue. They are caused either by mutations in the maternally inherited mitochondrial genome (mtDNA), or by nuclear DNA mutations. (8) Due to the fact that mitochondria are not uniformly distributed and that mutated and normal mtDNA can occur in the same mitochondria (heteroplasmy), these disorders can present variably, even if the same mutation is involved. Some mitochondrial cytopathies may present with relatively acute-onset encephalopathy and lactic acidosis but this is usually preceded by progressive neurological deterioration with movement disorders, seizures, strokelike episodes and neuropathy as examples. (10)

Mitochondrial cytopathies often also present with evidence of other progressive organ system dysfunction such as myopathy/ cardiomyopathy, renal tubulopathy, hepatopathy, hearing and visual defects and endocrinopathies. Unfortunately a single effective screening test for this group of disorders does not exist. (9) Demonstration of lactataemia has poor specificity and sensitivity and the diagnosis is often made only after exclusion of other disorders. Working these patients up includes selective molecular screening for common mtDNA and nuclear DNA mutations, light and electron microscopy of affected tissues and specific mitochondrial enzyme respiratory complex enzyme assays performed on fresh tissue. Very few mitochondrial cytopathies are significantly amenable to treatment.

Laboratory work-up of suspected metabolic encephalopathy

Metabolic disease should be considered in any child presenting with progressive or acute-onset neurological deterioration. Clinical suspicion must remain high where a reasonable alternative diagnosis is not immediately apparent, where the deterioration is associated with recognised catabolic stress, in neonates and infants presenting for the first time, or where a family history of similarly affected siblings is apparent. (11)

A tentative diagnosis can often be made on clinical grounds together with the results of the Tier 1 investigations outlined in Table 2. Where clinical suspicion is high or where initial investigations support a metabolic diagnosis, Tier 2 investigations are appropriate. Tier 3 investigations are usually performed later to confirm a diagnosis or where clinical suspicion remains despite nonspecific results obtained at Tiers 1 and 2. The laboratory investigations listed will detect or infer a diagnosis in the majority of IMDs presenting with encephalopathy that may occur in South Africa, but clinicians need to remain cognizant of the fact that many other IMDs such as galactosaemia require directed diagnostic testing and may be missed by these screening tests.
Table 2. Laboratory investigation of suspected metabolic encephalopathy

Laboratory Sample requirements Rationale

investigations Tier 1

Arterial blood gas Capped heparin blood on High anion gap acidosis
plus plasma ice, plus 1 ml heparin in OAs, respiratory
[Na.sup.+], tube alkalosis in UCDs
[K.sup.+] and
[Cl.sup.-] for anion
gap calculation

Plasma ammonia 1 ml EDTA tube, on ice, >600 [micro]mol/l
 to reach laboratory typical of UCDs
 within 30 minutes 150 - 600 [micro]
 mol/l typical of
 many OAs and Reye-like
 syndrome associated
 with FAODs

Plasma lactate 1 ml fluoride blood Increase suspicion of
 OA where lactate and
 ketones are unable to
 explain the extent of
 an anion gap acidosis

Urine or plasma 1 ml heparin blood on
ketones ice 1 ml plain urine

Plasma laboratory 1 ml fluoride blood Confirm hypoglycaemia.
glucose Glucometers are
 unreliable during
 hypoglycaemia and can
 crossreact with
 galactose, giving
 erroneously elevated
 glucose levels in

Laboratory investigations Tier 2

Urine organic acid 2 ml urine in a plain Confirms OAs. Detection
analysis tube, on ice of orotate in most
 UCDs. Increases
 suspicion for

Plasma amino acid 1 ml heparin blood, on Confirms MSUD. Specific
analysis ice diagnosis in UCDs
Plasma acyl-carnitine 1ml heparin blood, on Confirms most OAs.
analysis ice Essential for
 confirmation of FAODs

Laboratory investigations Tier 3

Plasma very long 1 ml heparin blood, on Essential for diagnosis
chain fatty acids ice of X-ALD, pyridoxine -
 responsive epilepsy and
 peroxisomal disorders
 (e.g. Zellweger's

Plasma lactate / 1 ml fluoride blood on A normal lactate /
pyruvate ratio ice to reach laboratory pyruvate ratio [less
 immediately or blood than or equal to]20
 collected in obtained during lactic
 pre-prepared perchloric acidosis suggests
 acid tube pyruvate dehydrogenase
 deficiency or a
 gluconeogenic defect

Specific tissue or Plasma, leukocytes, Confirmation of
plasma enzyme assays erythrocytes, skin specific enzyme
 fibroblasts or deficiency
 hepatocytes collected
 as per testing
 laboratory protocol

Molecular gene 1 ml EDTA blood for Confirmation of genetic
sequencing or nuclear gene mutations. defect Family screening
mutational analysis Mitochondrial DNA for carriers Antenatal
 preferably analysed in diagnosis in future
 DNA extracted from pregnancies
 affected tissue

Empirical management of metabolic encephalopathy

Emergency empirical management of a child with metabolic encephalopathy can significantly reduce morbidity, pending confirmation of the diagnosis by specialised investigations. The principles of empirical management are outlined in Table 3. These interventions are based on the control of life-threatening metabolic derangements, where benefits outweigh the potential risks. General supportive therapy should always be provided concomitantly. In patients where pyruvate dehydrogenase deficiency is strongly suspected, these guidelines should be adapted. These patients can present with encephalopathy and/or seizures, and may have subtle cephalic and facial dysmorphisms similar to fetal alcohol syndrome together with anatomical brain abnormalities and typically have very high cerebrospinal fluid and plasma lactate levels with normal plasma lactate/pyruvate ratios of [less than or equal to]20. (12) They may respond to treatment with high fat and low carbohydrate intake. As soon as a specific metabolic diagnosis is available, interventions must be altered as per accepted guidelines. (13), (14)
Table 3. Empirical management of suspected metabolic encephalopathy.
(6), (13), (14)

Intervention Directions Rationale

Halt protein and fat Dextrose IV at 10 Insulin and glucose
intake and replace mg/kg/min [+ or -] promote anabolism and
calories with insulin to maintain inhibit
glucose normoglycaemia. If proteolysis/lipolysis
 lactate >3 mmol/l and that aggravate
 hyperglycaemia develops decompensation in OAs
 reduce glucose infusion and UCDs. Glucose may
 rate and avoid insulin stimulate hepatic
 glycolysis and lactate

Manage Ammonia >150 [micro] Ammonia is a potent
hyperammonaemia mol/l: sodium-benzoate neurotoxin and can be
aggressively 250mg/kg/day IV/O, and effectively controlled
 phenylbutyrate (450 with timely
 mg/kg/day O) Ammonia intervention
 >250 umol/l: begin
 renal replacement
 therapy (dialysis)

Correct metabolic Ventilatory support, Renal replacement
acidosis renal replacement therapy can
 therapy and significantly reduce
 NaHC[O.sub.3] infusion toxic organic anion
 can be considered if levels
 plasma HC[O.sub.3]-
 [less than or equal
 to]15 mmol/l

Empirical Carnitine 100 mg/kg/day Some disorders may
administration of IV/O Hydroxycobalamin respond dramatically
metabolic (vit [B.sub.12]) 1 mg to replacement of
co-factors IM Biotin 10 mg/day O co-factors that have
 Thiamine 10 mg/kg/day low toxicity and can
 IV Pyridoxine 10 be administered
 mg/kg/day IV empirically pending a

References available at


* Clinicians in South Africa need to rely on a high level of clinical awareness, combined with a low threshold for ordering basic metabolic investigations, to effectively diagnose and treat patients presenting with potential metabolic encephalopathy.

* Some treatable IMDs are relatively common in South Africa.

* The assumption that these disorders are collectively rare must be dispelled.

* As awareness increases, we hope that clinicians will increasingly utilise available laboratory and NBS resources, enabling more of these patients to receive the correct timely diagnosis and appropriate management.


Hungry Africa's breadbasket needs to grow

Home-grown wheat could be the solution to a growing hunger problem in sub-Saharan Africa. The region is one of the few in which the number of undernourished people is rising, bucking a global trend. But a new analysis suggests wheat production there falls a long way short of what's possible.

A report from the UN Food and Agriculture Organization (FAO) concludes that the number of chronically undernourished people in the world has dropped in the last four years. Africa is the only region where the number has actually risen - by 20 million over the same period. The FAO says that agricultural growth there is essential.

Wheat could be the answer, say researchers at the International Maize and Wheat Improvement Center. At a recent conference in Addis Ababa, Ethiopia, they presented an analysis of 12 sub-Saharan countries. They conclude that in areas where conditions favour wheat growing, the yields are only hitting 10 - 25 per cent of their potential.

'[Extra wheat] would free locals from dependence on markets, where the price can rise by 50 per cent in a few months,' says Hans-Joachim Braun, head of the centre's global wheat programme. Braun says African ministers have contacted him, saying they want to grow wheat. The FAO report gives broad-brush guidance on where this might be feasible.


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(2.) Henderson H, Leisegang F, Brown R, et al. The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa. BMC Pediatr 2002; 2:7.

(3.) Nandhlal J, Owen EP, Leisegang F, et al. A single mutation causes cystinosis in 90% of African Black and Cape Coloured race patients from the Western Cape South Africa. FSASP Conference proceedings 2012, Cape Town, South Africa.

(4.) Carman KB, Aydogdu SD, Yakut A, et al. Glutaric aciduria type 1 presenting as subdural haematoma. J Paediatr Child Health 2012; 48(8):712.

(5.) Heringer J, Boy SP, Ensenauer R, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 2010;68(5):743-52.

(6.) Haeberle J, Boddaert N, Burlina A, et al. Suggested Guidelines for the Diagnosis and Management of Urea Cycle Disorders. Orphanet J Rare Dis 2012; 29;7(1):32.

(7.) Ah Mew N, Krivitzky L, McCarter R, et al. Clinical Outcomes of Neonatal Onset Proximal versus Distal Urea Cycle Disorders Do Not Differ. J Pediatr 2012. Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network.

(8.) Scaglia F. Nuclear gene defects in mitochondrial disorders. Methods Mol Biol 2012; 837:17-34.

(9.) Graham BH. Diagnostic challenges of mitochondrial disorders: complexities of two genomes. Methods Mol Biol 2012; 837:35-46.

(10.) Uziel G, Ghezzi D, Zeviani M. Infantile mitochondrial encephalopathy. Semin Fetal Neonatal Med. 2011; 16 (4):205-15.

(11.) Saudubray JM, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis. 2006; 29(2-3):261-74.

(12.) Patel KP, O'Brien TW, Subramony SH, et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012; 106(3):385-94.

(13.) New England Consortium of Metabolic Programs. Acute Illness Protocols. (accessed 2 November 2012).

(14.) British Inherited Metabolic Disease Group. Emergency Protocols. (accessed 02 November 2012).

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 (
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Publication:CME: Your SA Journal of CPD
Geographic Code:6SOUT
Date:Jan 1, 2013
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