Inherited Metabolic Disorders Module

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.

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, there will be more substrate. If accumulation of the substrate is the problem, we remove it (like avoiding protein in the diet).  Or, if the problem is the lack of the product, we can supplement it. And for some diseases the  enzyme can be “corrected” (by organ transplantation, enzyme replacement).

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 

• Irritability and excessive crying
• Acute onset of seizures, without any obvious trigger. 

• Blood gas, glucose, U&E, LFTs, CRP, blood culture, urine ketones and MC&S, metabolic screen. Consider CT brain.

FBC, CRP, U&E, LFTs  – normal

Venous blood gas:

• pH: 7.33 
• pCO2: 3.1 kPa*
• HCO₃^–: 14 mmol/L
• Na+: 142 mmol/L
• K+: 4 mmol/L
• Chloride: 100 mmol/L

Glucose: 5 mmol/L

Ketones: 2.1mmol/L

Ammonia 184

Urine: Ketones +2, and smells of sweaty feet.

Metabolic screen: plasma amino acids, urine organic acids, acylcarnitine profile sent 

*1kPa = 7.5mmHg

This baby has an acute neurological presentation, with metabolic acidosis, increased anion gap and mildly elevated ammonia –  suggestive of an organic acidemia

• 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.

• Manage seizures in the usual way. 
• Specific emergency treatment of her metabolic presentation requires 

• stopping sources of protein (milk)
• avoiding catabolism (by giving glucose IV – 2mL/kg 10% glucose) 
• rehydration (IV fluids resuscitation and maintenance)

• The “sweaty feet” smell is a clue to 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.

• Sick neonates with metabolic acidosis, increased anion gap and mildly elevated ammonia may have an organic acidemia.
• Treatment is to stop feeds, prevent catabolism with 10% dextrose (and standard electrolytes for IV maintenance) and cover for sepsis with IV antibiotics, whilst considering other differentials.

• Lucy is tachypnoeic and has a respiratory alkalosis
• Emma, on the other hand, had a metabolic acidosis with a normal respiratory rate

• AG = 16 mEq/L
• (Na + K) – (HCO3 + Cl) = (135 + 4) – (99 + 24) = 139 – 123 = 16
• Unlike Lucy’s case, this baby has a normal anion gap.

Hyperventilation

• This baby have a neurological acute presentation, with respiratory alkalosis and extremely elevated ammonia –  suggestive of a urea cycle disorder
• High ammonia stimulates the brain stem respiratory centre, causing hyperventilation and, as consequence, respiratory alkalosis 

• Overall treatment is similar to case 1: cover for sepsis, manage seizures and consider differentials. 

• As with organic acidaemias, the initial (specific) treatment requires 

• stopping sources of protein (milk)
• avoiding catabolism (by giving glucose IV – 2mL/kg 10% glucose) 
• rehydration (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 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. 

• 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.

• 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. 

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 can be given – they offer alternative pathways for ammonia excretion through urinary pathways.
• Phenylglutamine and hippurate are produced and are excreted in urine.

• Sick neonates with respiratory alkalosis, normal anion gap and very elevated ammonia may have a urea cycle defect. 

• Emergency treatment is the same as for an organic acidaemia plus ammonia scavengers.

• This adolescent has an acute onset of neurological symptoms. The differential diagnoses are broad but a red flag for a metabolic condition is that her encephalopathy was precipitated by prolonged fasting. 

• The RCPCH 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). 

• All children presenting with a decreased conscious level, regardless of age, should have an ammonia sent as part of their initial investigation in ED.

• In late onset urea cycle defects, acute metabolic encephalopathy develops following metabolic stress precipitated by a rapid increase in nitrogen load from
• infection, trauma, rapid weight loss and auto-catabolism, increase in protein turnover from steroids, surgery, 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, so the learning point is to always send an ammonia in any child presenting with an acute encephalopathy.

• Two cases reports your team may find interesting

• https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-015-0741-2
• https://www.mja.com.au/journal/2015/203/11/initial-presentation-urea-cycle-disorder-adulthood-under-recognised-cause

Send ammonia as part of your investigation of adolescents presenting with a decreased conscious level 

• History: vomiting and lethargy
• 16% weight loss by day 6 of life
• Examination: jaundice and a palpable liver

• Discuss your institution’s hypoglycaemia guideline – which tests to send, where to find the bottles and Guthrie cards.

• Discuss the differential diagnoses of hypoglycaemia. Refer to the following material:
  • https://www.rch.org.au/clinicalguide/guideline_index/Hypoglycaemia/
  • https://www.paediatricfoam.com/2017/04/neonatal-hypoglycaemia/

• Hypoglycaemia, this neonate has hepatomegaly and raised liver enzymes point towards a diagnosis of galactosaemia.

• Some countries screen for galactosaemia in their newborn screening programmes (Ireland, UK, New Zealand, some parts of Australia). Because of its autosomal recessive inheritance, galactosaemia is more common in some ethnic groups. 

• In the Irish travelling community, for example, the incidence is higher than the rest of the populations, so babies born to parents from the travelling community are specifically screened on day 1 of life in Irish maternity hospitals. The baby’s diet should exclude galactose, so newborn babies of Irish travelling families are given soy-based formula rather than breast feeds or standard formula until their screening test result is known.

• The initial investigation and management of hypoglycaemia: this baby needs Glucose 10% 2mL/kg IV as soon as possible. Collect blood prior to treatment.

• Management is similar to the previous cases:
  • Clinical stabilisation
  • Antibiotics
  • stop feeds
  • Correct hypoglycaemia with 2ml/kg 10% 
  • Give maintenance fluids with electrolytes to maintain hydration as per your local policy

Galactosaemia occurs due to a defect in the enzyme galactose-1-phosphate uridyl transferase (GALT). It presents after the affected patient receives the sugar galactose, present in milk. Accumulation of galactose-1-phosphate results in damage to the brain, liver, and kidney. The affected neonate presents with vomiting, hypoglycaemia due to an inability to metabolise glucose, feeding difficulty, seizures, irritability, jaundice, hepatomegaly, liver failure, cataracts, splenomegaly, and Escherichia coli sepsis. The condition presents with metabolic acidosis. Source: Gene Reviews 

Liz has MCADD and needs extra calories when she is sick. The most important intervention is to give simple carbohydrates by mouth (e.g. glucose tablets or sweetened, non-diet beverages) or intravenously if needed to reverse catabolism and sustain anabolism. Liz is vomiting all oral intake so cannot tolerate oral carbohydrates, so the intravenous route is necessary.

No, it’s not. The body’s response to prolonged fasting is to break down fat to create ketones to be used as an alternative source of energy. Liz has not produced ketones, because she is unable to break down fat.

• 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. 

• 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. 

• 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. 

• Children appear well at birth and, if not identified through newborn screening, typically present between three 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. Gene reviews https://www.ncbi.nlm.nih.gov/books/NBK1424/

• The British Inherited Metabolic Disease Group, BIMDG, has specific guidance on their website, including
  • 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. 

• 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.

• In mucopolysaccharidosis disorders, the body is unable to break down mucopolysaccharide sugar chains. These mucopolysaccharide sugars buildup 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 and system functioning; 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).

A neonate presents with extreme irritability and vomiting. Which laboratory tests can be most helpful in identifying an underlying inherited metabolic condition?

A: Ammonia

B: Glucose

C: LDH

D: Coagulation profile

The correct answer is A.

Irritability and vomiting are unspecific presentations for a broad range of neonatal conditions. Elevated ammonia can help differentiate towards a metabolic condition, such as organic acidemias and urea cycle disorders.

Hypoglycaemia with low ketones are an _______ response, it can lead us to think of _______ diagnosis. 

A: Appropriate, sepsis

B: Appropriate, diabetes

C: Inappropriate, diabetes

D: Inappropriate, fatty acid oxidation disorders.

The correct answer is D.

The body’s response to prolonged fasting is to break down fat to create ketones that will be used as an alternative source of energy. So in hypoglycaemic states, high ketones will be observed. If ketones are low, it’s because the body is unable to break down fat properly, such as in fatty acid oxidation disorders.

Which tests are part of the investigation of hypoglycemia?

A: Insulin and GH

B: Amino acids (plasma)

C: Ketones

D: All the above

The correct answer is D.

The basic screen aims to identify the most common endocrine or metabolic conditions responsible for hypoglycemia. Usually it involves: glucose, ketones (Beta-hydroxybutyrate), insulin, cortisol, Growth Hormone (GH), ammonia, lactate, free fat acids, serum amino acids, acylcarnitines profile (Guthrie card) and urine for organic acids and ketones.

Extremely high ammonia can be usually found in which condition?

A: Hyperinsulinism

B: Phenylketonuria

C: Urea Cycle disorders

D: MSUD

The correct answer is C.

Although ammonia can be increased for a range of reasons (muscle activity, haemolysis, neonatal sepsis), however in urea cycle disorders these levels are the highest observed. The urea cycle is responsible for the metabolism of nitrogen waste from the breakdown of proteins, as one of these enzymes are deficient, it leads to an accumulation of ammonia as nitrogen cannot be metabolised to urea.

Which of the following is incorrect regarding Anion Gap (AG)?

A: The AG is the difference between primary measured cations and the primary measured anions.

B: Potassium (K⁺) is the most important cation for AG calculation. 

C: Commonly measured anions are Chloride and Bicarbonate.

D: AG is useful in understanding causes of metabolic acidosis. 

The correct answer is B.

If not available, the anion gap can be calculated without potassium, in this situation the reference range will be different (12 ±  4mEq/L).