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disorders: investigation presenting with a severe acute encephalopathy may have had
previous episodes, commonly much milder, precipitated by
*
Notes: This chapter is a short introduction and cannot cover all situ- Seizures and Stroke-like episodes: the metabolic disorders that
ations. If in doubt, consult your local specialist metabolic centre. Detailed most commonly present with seizures or stroke-like episodes are
and free instructions on the management of acute illness in specific listed in Tables 2 and 3 with appropriate investigations. The list
inborn errors of metabolism can be found on the British Inherited Meta-
is not exhaustive as seizures are a late feature in many metabolic
bolic Disease Group Website (BIMDG) http://www.bimdg.org.uk/.
disorders.
AAM Morris PHD FRCPCH is a Consultant in Paediatric Metabolic Medicine
Investigation of the CSF is often useful but, if this is done,
at the Manchester Centre for Genomic Medicine, St Mary’s Hospital,
ensure that samples are collected correctly for all likely possi-
Manchester, UK. Conflict of interest: none
bilities, to avoid the need for a repeat lumbar puncture.
J V Leonard PHD FRCP FRCPCH is a Former Professor of Paediatric Metabolic
Disease at UCL Institute of Child Health, London, UK. Conflict of Acute ataxia: occasionally patients will present with an episodic
interest: none ataxia. These patients should be screened for maple syrup urine
PAEDIATRICS AND CHILD HEALTH --:- 1 Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/j.paed.2014.10.005
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Reference values are less than 50 mmol/l but any difficulty with
Causes of acute metabolic encephalopathy the venepuncture, including a child struggling or a haemolysed
Causes Investigations sample, may increase the plasma ammonia concentration.
Values more than 100 mmol/l suggest an inborn error although in
C Hypoglycaemia C Blood gases the newborn the threshold is usually taken to be 200 mmol/l.
C Hyperammonaemia C Blood glucose However it must be emphasised that the interpretation of plasma
C Disorders of fatty acid oxidation C Blood lactate ammonia concentrations requires careful assessment of the
C Amino acids disorders including C Plasma electrolytes conditions under which the blood was collected as well as the
maple syrup urine disease & anion gap effect of any treatment, such as intravenous glucose. The meta-
C Organic acidaemias and biotinidase C Plasma ammonia bolic causes of hyperammonaemia and investigations are listed
deficiency C Plasma amino acids in Table 5.
C Mitochondrial respiratory chain C Blood spot acylcarnitines
disorders C Liver function tests Disorders of acid-base regulation
C Plasma biotinidase Metabolic acidosis is a common complication of almost any
C Urine organic acids illness and is usually secondary to tissue hypoxia. However, if
the history suggests previous episodes, there is marked ketosis or
Biotinidase deficiency is very rare but responds dramatically to treatment if
the acidosis persists after tissue perfusion is corrected, the patient
started early.
should be investigated for a metabolic problem. The major cau-
Table 1 ses and the investigations are listed in the Table 6.
Respiratory alkalosis is uncommon in patients who are not
disease, hyperammonaemia, GLUT1 deficiency and organic on a ventilator and they should be investigated for
acidaemias. hyperammonaemia.
Hyperammonaemia Rhabdomyolysis
Plasma ammonia should be measured in every undiagnosed This presents with acute muscle pain, dark brown discolouration
encephalopathic patient since early intervention is essential. of the urine (myoglobinuria) and often acute renal failure. The
VLCFA ¼ very long chain fatty acids, NCL ¼ Neuronal ceroid lipofuscinosis, PPT1 ¼ palmitoyl protein thioesterase 1, TPP1 ¼ Tripeptidyl peptidase 1.
Table 2
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Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
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SYMPOSIUM: INBORN ERRORS OF METABOLISM
Metabolic disorders that may present with a stroke-like Metabolic causes of hyperammonaemia
illness
Causes Investigations
Causes Investigations
C Urea cycle disorders C Plasma ammonia
Homocystinuria Plasma amino acids and total C Organic acidaemias C Plasma aminoacids
homocysteine C Fatty acid oxidation disorders C Urine organic acids and
C Transport defects e Lysinuric aminoacids
Organic acidaemias Urine organic acids
protein intolerance, C Blood spot acylcarnitines
Ornithine transcarbamylase Plasma ammonia HHH syndrome, C Blood lactate
deficiency Citrin deficiency
C Others: Ornithine aminotransferase
Mitochondrial disorders Mitochondrial DNA mutations
deficiency, Pyruvate carboxylase
(eg MELAS) (blood)
deficiency, etc
Congenital disorders of Serum transferrin isoelectric
For a full list of causes of hyperammonaemia see Table 20.2 in Saudubray et
glycosylation focussing al., 2012.
HHH ¼ Hyperornithinaemia, hyperammonaemia, homocitrullinuria syndrome.
Fabry diseasea Leukocyte a-galactosidase
Table 4 Table 6
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Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/j.paed.2014.10.005
SYMPOSIUM: INBORN ERRORS OF METABOLISM
C Galactosaemia (newborn period) C Liver function tests, clotting Disorders of fatty acid oxidation Blood spot acylcarnitines
C Tyrosinaemia type 1 studies
Organic acidaemias Urine organic acids
C Fructosaemia C blood glucose, lactate
C Mitochondrial respiratory chain C blood spot acylcarnitines Mitochondrial respiratory chain Blood lactate
disorders C plasma amino acids disorders including Barth Plasma monolysocardiolipin
C Fatty acid oxidation disorders C serum a-fetoprotein syndrome mtDNA mutations and
C Wilson disease C serum a-1-antitrypsin, mitochondrial studies on
C Urea cycle disorders C plasma copper and muscle
C a-1 antitrypsin deficiency caeruloplasmin
Lysosomal storage disorders Urine GAGs, Blood film for
C Niemann Pick type C C urine organic acids including
including Pompe, Hurler & vacuolated leukocytes, Enzyme
C Disorders of bile acid synthesis succinylacetone
Fabrya diseases studies
C plasma and urine bile acids
Glycogen storage disease type Leukocyte debrancher enzyme,
Further investigations including liver scans and biopsy may be necessary.
IIIb mutation analysis
Table 7 GAGs ¼ glycosaminoglycans.
a
rare in childhood
Sudden death is most commonly a presentation for fatty acid b
rarely a presenting feature.
oxidation disorders. Sadly, newborn screening does not
completely prevent this. The screening program in the UK only Table 9
includes one fatty acid oxidation disorder - medium chain acyl-
organic acid analysis. Blood and bile should also be sent for
CoA dehydrogenase deficiency (MCADD). Moreover, some ba-
acylcarnitine analysis but the results must be interpreted by
bies with MCADD die in the first 48 h, before screening has been
biochemists familiar with post-mortem samples because there
undertaken. Sudden death also occurs in mitochondrial disor-
are a number of pitfalls. Any residual bloodspots from newborn
ders, organic acidaemias and other metabolic conditions but it is
screening should be retrieved, as acylcarnitine analysis of these
seldom the presenting event.
gives much clearer results. It is also now possible to do mutation
If a metabolic disorder is suspected, liver and muscle biopsies
analysis for many disorders including all known fatty acid
should be obtained as soon as possible post-mortem and stored
oxidation defects.
at 70 C. A sterile skin biopsy should be sent for fibroblast
culture and blood should be taken for DNA extraction. An au-
Management
topsy may also give valuable clues, such as increased lipid
droplets in multiple tissues. The management these patients is divided into two sections;
Unfortunately, most biochemical tests are uninterpretable firstly the management of acute illness and secondly the pre-
post-mortem. If urine can be obtained, it should be sent for vention of such illness in the first place. All patients who are at
risk of decompensation should have a plan that starts at home to
try to prevent episodes of decompensation.
Metabolic causes of acute rhabdomyolysis
Acute illness
Causes Investigations After resuscitation and stabilisation it is important to document
the clinical state. For patients with neurological illness, the
Fatty acid oxidation disorders Blood spot acylcarnitines
Glasgow coma score should be noted. Efforts should be made to
especially partial CPT II CPT II assay (in fibroblasts)
identify the factor that has precipitated the illness, such as
deficiency Mutation analysis
infection or fasting. This is not always possible as sometimes
McArdle’s disease and defects Forearm exercise test (in adults) patients become ill for reasons that are not clear.
of glycolysis Mutation analysis The steps that should be taken in the treatment of acute illness
Histochemistry on muscle biopsy are listed in Table 10, together with notes about each stage of the
Enzyme assays on erythrocytes or process.
muscle Some inborn errors will improve markedly if given pharma-
cological doses of cofactor of the defective enzyme. The most
Lipin1 deficiency LPIN1 mutation analysis
important disorders that may respond are listed in the Table 11.
Mitochondrial respiratory Ubiquinone measurement Standard treatment should not be delayed whilst waiting to see if
chain disorders Mitochondrial studies on muscle there is a response as delay may prove disastrous.
biopsy
Special problems: hypoglycaemia: it is important to document
CPT II ¼ carnitine palmitoyltransferase II.
hypoglycaemia correctly. Bedside strip tests only give approximate
Table 8 value despite the apparent accuracy of the meters so that blood
PAEDIATRICS AND CHILD HEALTH --:- 4 Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/j.paed.2014.10.005
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH --:- 5 Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/j.paed.2014.10.005
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH --:- 6 Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morris AAM, Acute presentations of inherited metabolic disorders: investigation and initial management,
Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/j.paed.2014.10.005