Taciane Alegra. Metabolic presentations part 2: children and adolescents, Don't Forget the Bubbles, 2020. Available at:
Neurological symptoms in a healthy teen
Jane, 14 years old, is brought in by ambulance, unconscious after a 20-minute generalized tonic-clonic seizure at home. She’s wheeled into resus, and while she has a cannula inserted, you take a history from her father. You learn that she has been a healthy child who’s never had a seizure before, with no chronic conditions, no history of drug abuse, no acute illness, and no sick contacts. She’s a vegetarian and enjoys dancing. She’s started a new ‘intermittent fasting diet’ and yesterday hadn’t eaten since brunch. She went to bed early and this morning her mother was woken early by strange sounds coming from Jane’s room and found her seizing on the floor.
Her primary survey shows that she’s maintaining her airway, is tachypnoeic with oxygen saturations of 98% in air and clear lungs, a normal cardiovascular examination and a GCS of 10, with global hyperreflexia.
This adolescent has an acute onset of neurological symptoms. The differential diagnoses are broad, but her symptoms were precipitated by a new diet that required prolonged fasting. This case is a red flag for a metabolic condition!
The RCPCH Decreased Consciousness (DeCon) guideline lays out an approach to the child with a decreased conscious level, including differentials, investigations and management (take a look at the DeCon poster and summary guidance).
You send some bloods and, as suggested by the RCPCH DeCon guideline, you include an ammonia.
Some points to remember
Common things are common: sepsis, CNS infections, intoxication (prescribed and recreational drugs), and primary seizure disorders should all be considered here, but extend your differentials to conditions that can be individually rare but are common as a group: metabolic diseases.
All children presenting with a decreased conscious level, regardless of age, should have an ammonia sent as part of their initial investigation in ED… this could be a case of an undiagnosed urea cycle defect.
In late onset urea cycle defects, acute metabolic encephalopathy develops following metabolic stress precipitated by a rapid increase in nitrogen load from:
- rapid weight loss and auto-catabolism
- increase in protein turnover from steroids
- surgery and childbirth
- or other precipitants of protein catabolism.
Adolescents and adults with an undiagnosed urea cycle defect may be completely fit and well, but may have chronic symptoms such as headache, cyclical vomiting, behavioural difficulties, psychiatric symptoms or mild learning difficulties.
They may be selective vegetarians, restricting their protein intake.
Between episodes patients are relatively well. However, acute presentations can be fatal or patients may be left with a neurological deficit.
For more information about cycle urea disorders, check out Metabolic presentations part 1.
The take home
Always send an ammonia in any child presenting with an acute encephalopathy or decreased GCS.
Disorders involving energy metabolism
Next up is Liz, a patient with a diagnosed metabolic disorder.
Liz is a 3-year-old girl from the countryside, who is visiting her grandmother in the city. She has had diarrhoea since yesterday and started vomiting last night. In the last 3 hours, she hasn’t been able to tolerate anything orally. There has been no fever or respiratory symptoms and she is passing urine as normal. Her 5-year-old cousin has similar symptoms.
Her Grandmother informs you that Liz has MCAD deficiency and her emergency plan was tried at home, without success. Liz is not usually treated at your hospital and you don’t have her chart. Unfortunately, Liz’s grandmother didn’t bring the plan to the hospital.
Liz looks tired and is mildly dehydrated, but smiles at you. Her heart sounds are normal and her chest is clear. She has increased bowel sounds, a soft abnormal with mild diffuse pain on deep palpation and no masses or organomegaly. She’s afebrile but tachycardic at 165, her capillary refill time is 3 seconds, and her systolic BP is 104mmHg.
You put in a cannula and measure bedside glucose and ketones. Liz has a hypoketotic hypoglycaemia.
What is MCAD deficiency?
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Caucasians in Northern Europe and the United States. Most children are now diagnosed through newborn screening. In fatty acid oxidation disorders, the body can only partially break down fat.
Let’s recap some basic biochemistry: in prolonged fasting, the body’s normal response is to break down fat to create ketones, as an alternative source of energy. However, children with MCAD deficiency can’t produce large amounts of ketones, so their ketone response is not appropriate to the degree of hypoglycaemia.
Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma, triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. These children appear well at birth and, if not identified through newborn screening, typically present between 3 and 24 months of age, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting (Merritt and Chang, 2019).
Children with fatty acid oxidation disorders (medium, long and short chain defects) have typical acylcarnitine patterns. This is one of the reasons acylcarnitines are sent as part of metabolic and hypoglycaemia work-ups.
What is the priority in acute presentations?
Children who have MCADD, like Liz, need extra calories when sick. The most important intervention is to give simple carbohydrates by mouth, such as glucose tablets or sweetened, non-diet beverages, or intravenously if needed to reverse catabolism and sustain anabolism. In Liz’s case, she’s vomiting all oral intake so cannot tolerate oral carbohydrates, so the intravenous route is necessary.
The key priorities are:
- Correct hypoglycaemia immediately with 200mg/kg glucose: 2 ml/kg of 10% glucose or 1ml/kg of 20% glucose, over a few minutes.
- Treat shock or circulatory compromise with a bolus of 20ml/kg 0.9% sodium chloride.
- Give maintenance fluids with potassium once the plasma potassium concentration is known and the child is passing urine.
Where can you find resources?
The British Inherited Metabolic Disease Group, BIMDG, has specific guidance on their website.
Disorders involving storage of complex molecules
Mike is 12 years old, presenting to the ED with cough and fever. He has been coughing for 10 days, worse progressively in the last 5 and febrile for the last 3 days. He’s been lethargic since yesterday and even when afebrile he looks unwell. His appetite is poor and he has been “sipping some apple juice”. You learn from his mother that he has a condition called Mucopolysaccharidosis (MPS) type I and is receiving treatment with “the enzyme”. Every now and again, “he is chesty and needs to come to hospital”.
You examine Mike. He’s pink and well hydrated, but looks sick. You notice that he is shorter than an average 12 year old boy, has hand contractures and coarse facial features.
He has a soft systolic cardiac murmur with good pulse volume. On auscultating his chest you hear creps and rhonchi on the right side. He has mild hepatomegaly and an umbilical hernia.
His temperature is 37.5ºC, heart rate is132, respiratory rate 30, and oxygen saturations are just 88% in air.
A bit about mucopolysaccharidoses (MPS)
In mucopolysaccharidosis disorders, the body is unable to break down mucopolysaccharide sugar chains. These mucopolysaccharide sugars build up in cells, blood and connective tissue: hence the name, ‘storage disorders’.
In general, most affected people appear healthy at birth and experience a period of normal development, followed by a decline in physical and/or mental function.
As the condition progresses, it may affect appearance; physical abilities; organ function; and, in most cases, cognitive development.
Most cases are inherited in an autosomal recessive manner, although one specific form (Type II) follows an X-linked pattern of inheritance.
Specific treatment can be provided via enzyme replacement therapy or haematopoietic stem cell transplantation in the early stages.
Presently, enzyme replacement therapy is available for MPS I, II and VI and is given as an intravenous infusion either weekly or biweekly, depending on the disease.
Both enzyme-replacement and haemotopoietic stem cell treatments still have gaps and few clinical trials supporting them. (rarediseases.info; Dornelles et.al, 2014).
What treatment should be started in the ED?
Patients with Mucopolysaccharidosis don’t require any emergency treatment in the ED for their underlying metabolic disease. They are, however, at increased risk of respiratory infections.
Mike is likely to have a community acquired pneumonia and needs to be treated accordingly with oxygen and antibiotics.
Adam , HH. Ardinger, RA. Pagon, S. E. Wallis, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews® [online book]
Merritt JL, Chang IJ. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews® [online book], June 2019. Available at https://www.ncbi.nlm.nih.gov/books/NBK1424/
Genetic and Rare Diseases Information Center (GARD) https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis
Dornelles AD et al. Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network. Genet Mol Biol. 2014