You are working in the Paediatric Emergency Department and are called in to see a neonate with a history of irritability and seizures. You enter the room and are told the following: “Emma is a 3 day old, term baby who has been refusing feeds and crying excessively. Her mother says she has been irritable since birth. There has been no history of fever or cough. At home she had seizure-like activity with tonic posturing”. When you examine her, you find an awake, extremely irritable baby with flexed upper limbs flexed, extended lower limbs and global hyperreflexia. She is not dysmorphic and has no cardiac murmurs, respiratory distress or abdominal organomegaly.

Babies cry (a lot!) and we all know that, however Emma is presenting some red flags: she’s irritable and has an acute onset of seizures, without any obvious trigger.

The basics

In this post we will discuss some acute metabolic presentations in the neonatal period, how to identify potential problems and emergency treatment in the ED. You don’t need to make a diagnosis (bonus points if you do) but do need to remember that spotting the zebra will lead to more favourable outcomes. Metabolic diseases / disorders are also called inborn errors of metabolism (IEM).

How common are metabolic conditions?

Individually, metabolic conditions are rare, most having an incidence of less than 1 per 100,000 births. However, when considered collectively, the incidence may reach 1 in 800 to 1 in 2500 births (Applegarth et. al, 2000; Sanderson et.al, 2006). 

Remember: some symptoms can be unspecific and can mimic sepsis; or a child with an undiagnosed metabolic condition can decompensate with an intercurrent infection. 

An easy-to-understand classification by Saudubray divides the IEM in three groups of disorders, depending on how they present. 

Intoxication disorders

An acute or progressive intoxication from the accumulation of toxic compounds, usually small molecules. 

These usually present with a symptom-free interval and clinical signs of ‘intoxication’, which may be acute, although can be intermittent.

• disorders of amino acid catabolism: e.g. phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia 
• most organic acidurias: e.g. methylmalonic, propionic, isovaleric acidaemia
• urea cycle defects: e.g. Ornithine transcarbamylase deficiency (OTC deficiency), Citrullinemia type I (ASS1 deficiency).
• sugar intolerances: galactosemia
• metals: Wilson’s, Menkes, hemochromatosis
• porphyrias

Disorders involving energy metabolism

A deficiency in energy production or utilization, within the liver, myocardium, muscle, brain or other tissues. 

Common symptoms include hypoglycemia, hyperlactatemia, hepatomegaly, failure to thrive and cardiac failure. 

• Mitochondrial defects: congenital lactic acidemias (defects of pyruvate transporter, pyruvate carboxylase, pyruvate dehydrogenase, and the Krebs cycle), mitochondrial respiratory chain disorders and the fatty acid oxidation defects (MCAD deficiency).
• Cytoplasmic energy defects: disorders of glycogen metabolism (collectively known as glycogen storage diseases), hyperinsulinism.  

Complex molecules disorders

Problems in the synthesis or catabolism of complex molecules, leading to storage of big molecules. 

Symptoms are chronic, progressive and independent of intercurrent events or food intake. 

• Mucopolysaccharidosis (I-IV, VI and VII). The eponymous names are used less frequently now, particularly in the literature, but you might come across them in clinical practice (MPS I, Hurler’s Syndrome; MPS II, Hunter’s Syndrome; MPS VI, Maroteaux- Lamy) 
• Gaucher disease
• Peroxisomal disorders: e.g. X-linked adrenoleukodystrophy (X-ALD) and Zellweger’s Syndrome.

Treatment strategies

Remember your biochemistry: a substrate is transformed by an enzyme into a product .

If there is a problem with the enzyme, the substrate will accumulate. If this substrate accumulation is a problem, we eliminate it, like avoiding protein in the diet or removing toxins with treatments such as ammonia scavengers.  If a lack of the product is the problem, we can supplement it (for example the administration of carbohydrate in glycogen storage disease). And for some diseases the  enzyme can be “corrected” with organ transplantation or enzyme replacement therapy.

A bonus on smells

Due to accumulation of “unusual” products in their body fluids, people with certain metabolic conditions have distinctive odours (better observed in urine, for practical reasons):

• Maple syrup, burnt sugar, curry: Maple syrup urine disease
• Sweaty feet: glutaric aciduria type II, isovaleric acidaemia
• Cabbage: tyrosinemia
• Mousy, musty: phenylketonuria
• Rotting fish: trimethylaminuria
• Swimming pool: Hawkinsinuria 

Back to Emma. You explain to Emma’s mother that there are lots of things that could be making her unwell so you’re going to send some tests to help work out what the problem is. You put in a cannula, take a gas, send some bloods to the lab and set her and her mother up to collect a urine.

Just as you’re pondering the causes of a raised anion gap, the lab phones with Emma’s blood results… Her ammonia is 184!

Emma has an acute neurological presentation, with metabolic acidosis, increased anion gap and mildly elevated ammonia, suggestive of an organic acidaemia.  In the context of a sick neonate with a raised anion gap, a normal lactate and normal ketones, think organic acids.

Are you familiar with ammonia?

A normal ammonia level is <50 mol/l but mildly raised values are common, up to 80 mol/l.

In neonates, any illness may be responsible for values up to 180 mol/l.

Artifactually high values can be caused by muscle activity, haemolysis or delay in separating the sample. Capillary samples are often haemolysed or contaminated and therefore should not be used.

There’s debate as to whether a level of >100 or 200 should be discussed with a metabolic specialist, but if in doubt, follow the RCPCH DeCon guideline and seek advice for any patient presenting with a level >100 mmol/l.

Urine organic acids and blood acylcarnitines will also be sent as part of this baby’s metabolic work-up. Although the results won’t be available in ED, the urine organic acid profile will confirm a diagnosis of an organic acidaemia, while the blood acylcarnitine profile will support the diagnosis as the organic acids conjugate with carnitines creating compounds such as isovalerylcarnitine.

The emergency treatment of suspected organic acidaemias

It’s important to think about your differentials. Sepsis is the most common – these conditions can mimic sepsis, or decompensation can be triggered by an infection, always cover with broad spectrum antibiotics. But don’t forget non-accidental injury and other differentials – the baby is likely to need a CT head if presenting encephalopathic or with seizures. If she continues to seize, load with an anticonvulsant.

 Specific emergency treatment of her metabolic presentation requires:

What about that urine?

The “sweaty feet” smell of the urine points towards the diagnosis of Isovaleric Acidaemia. Remember that this condition can be part of the Newborn Screening in some countries (Ireland, UK, Australia, New Zealand).

Isovaleric acidaemia is a type of organic acidemia, inherited in an autosomal recessive way. It is caused by a problem with the enzyme that usually breaks down the amino acid leucine. This amino acid accumulates and is toxic at high levels, causing an ‘intoxication’ encephalopathy. The sweaty feet smell is stronger without treatment or  during acute exacerbations.

Maple Syrup Urine Disease (MSUD) is another organic acidaemia, associated with sweet smelling urine during decompensation. These children cannot break down leucine, valine and isoleucine. They may not have hypoglycaemia, hyperammonemia or acidosis and, if not picked up on newborn screening, can be diagnosed late, resulting in neurological sequelae.

Organic acidaemias: the take homes

The next case feels like déjà vu…

The next baby you see is remarkably like Emma but with a subtle difference. Lucy is a 3 day old baby, presenting with poor feeding, irritability and seizures at home. There has been no fever, cough, coryza, or sick contacts. On examination she’s awake, extremely irritable, with upper limbs, extended lower limbs extended and global hyperreflexia. She has no dysmorphic features, cardiac murmur or abdominal organomegaly. You notice that she seems tachypnoeic at 70, although her lungs are clear. The rest of her observations are normal. 

The key differences between Emma and Lucy’s presentations is that Lucy is tachypnoeic and has a respiratory alkalosis; this should make you suspicious of hyperventilation. Always check an ammonia level in sick babies, but particularly in this case as hyperammonemia stimulates the brain stem respiratory centre, causing hyperventilation and, as consequence, respiratory alkalosis. 

The lab phones you with Lucy’s ammonia result…

Acute neurological presentations, with respiratory alkalosis and extremely elevated ammonia point towards a urea cycle disorder. Respiratory alkalosis is a common early finding caused by hyperventilation secondary to the effect of hyperammonemia on the brain stem, although later the respiratory rate slows as cerebral oedema develops and an acidosis is seen. Lucy also has a low urea and mildly deranged liver enzymes and INR, all of which support the diagnosis of a urea cycle disorder.

The emergency treatment of suspected urea cycle disorders

Overall the acute treatment is similar to the first case: cover for sepsis, manage seizures and consider differentials.

And as in the first suspected metabolic case:

• stop sources of protein – stop feeds 
• avoid catabolism – giving glucose IV – 2mL/kg 10% glucose 
• rehydrate – IV fluids resuscitation and maintenance

In urea cycle disorders, the toxic metabolite is ammonia, so ammonia scavengers are used, all given intravenously:

• sodium benzoate
• phenylbutyrate 
• arginine

A nice guideline on the management of hyperammonemia secondary to an undiagnosed cause can be found on the British Inherited and Metabolic Disease Group website.

Urea cycle disorders are autosomal recessive inborn errors of metabolism. A defect in one of the enzymes of the urea cycle, which is responsible for the metabolism of nitrogen waste from the breakdown of proteins, leads to an accumulation of ammonia as it cannot be metabolised to urea. The urea cycle is also the only endogenous source of the amino acids arginine, ornithine and citrulline.   The most common urea cycle disorder is Ornithine Transcarbamylase (OTC) deficiency. Unlike the other urea cycle disorders (which are autosomal recessive), OTC deficiency is x-linked recessive, meaning most cases occur in male infants. Female carriers tend to be asymptomatic.

Classically, urea cycle disorders present in the neonatal period with vomiting, anorexia and lethargy that rapidly progresses to encephalopathy, coma and death if untreated. In these circumstances, ammonia accumulates leading to a very high plasma ammonia. 

Children presenting in infancy generally have less acute and more variable symptoms than in the neonatal period and include anorexia, lethargy, vomiting and failure to thrive, with poor developmental progress. Irritability and behavioural problems are also common. The liver is often enlarged but, as the symptoms are rarely specific, the illness is initially attributed to many different causes that include gastrointestinal disorders. The correct diagnosis is often only established when the patient develops a more obvious encephalopathy with changes in consciousness level and neurological signs. 

Adolescents and adults can present with encephalopathy and or chronic neurological signs. 

What are ammonia scavengers?

In urea cycle defects, ammonia cannot be converted to urea so instead is converted to glutamine and glycine. 

Ammonia scavengers phenylbutyrate and sodium benzoate offer alternative pathways for ammonia excretion through urinary pathways.

Phenylglutamine and hippurate are produced and are excreted in urine.

Urea cycle disorders: the take homes

Thank you to Dr Roshni Vara, Consultant in Paediatric Inherited Metabolic Disease at the Evelina London Children’s Hospital for her help with this post.

References

Adam , HH. Ardinger, RA. Pagon, S. E. Wallis, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews® [online book].

Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;105(1):e10.

Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK.Arch Dis Child. 2006 Nov;91(11):896-9. 

Saudubray J-M, Baumgartner MR, Walter JH. (editors) Inborn Metabolic Diseases. Diagnosis and treatment. 6th Edition. Springer 2016.