Metabolic disorders

Metabolic disorders, synonymous with inborn errors of metabolism (IEM) are inherited genetic disorders relating to enzymes or transport proteins that disrupt metabolic pathways. They lead to accumulation or deficiencies in substances which can lead to clinical manifestations.

Guthrie testing (the newborn blood spot test) screens for 6 inherited metabolic diseases:

1. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
2. Phenylketonuria (PKU)
3. Maple syrup urine disease (MSUD)
4. Isovaleric acidaemia (IVA)
5. Glutaric aciduria type 1 (GA1)
6. Homocystinuria (HCU)

As mentioned, they are inherited genetic disorders. It is most commonly an autosomal recessive mutation and therefore consanguineous relationships increase the risk of inheriting one of the disorders. De novo mutations and mitochondrial disorders do occur, however.

🔢 Classification

There are 3 broad pathophysiological groups: disorders of intoxication, energy metabolism, and complex organelles.

😷 Presentation

We will discuss some of the presentations of specific IEMs later but let’s look at some general presentations.

IEM's present at any age, although many present in early childhood.

They should be considered in all children with:

• Severe presentations of common ilnesses
• Significant metabolic acidosis
• Unexplained respiratory alkalosis
• Hypoglycaemia
• Cardiac failure or cardiomyopathy
• Hepatomegaly or hepatosplenomegaly or liver dysfunction
• Unexpected drowsiness coma or irritability
• Early onset seizures
• Dysmorphic features
• Developmental regression
• Sudden infant death syndrome

💡 Infections are common trigger for IEMs and so the child may present with symptoms of the infection as well.

🔍 Investigations

💡 Specific diagnostic tests and genetic testing can be performed if there is a clear diagnosis.

When taking the history, specifically ask about:

• A family history of inborn error of metabolism; draw a family tree (pedigree)
• A family history of sudden unexplained death(s), particularly in childhood, epilepsy, or learning difficulties
• Consanguinity detailing if first, second, or third cousins

On examination, there may not be any specific clinical findings. However, examination including the skin, musculoskeletal, and ophthalmological systems are required.

🧰 Management

Management primarily involves pharmacological medications and dietary measures.

Let’s take a look at some specific IEMs now:

Phenylketonuria

Phenylketonuria (PKU) is an IEM that affects the processing of phenylalanine - an essential amino acid. Essential amino acids are amino acids that are not produced by the body and need to be acquired through diet.

Sources of phenylalanine include:

• Meat
• Eggs
• Chicken and poultry
• Seafood
• Dairy

• Nuts and seeds
• Legumes
• Soy
• Whole grains

Pathphysiology

PKU is inherited in an autosomal recessive fashion. It most commonly is due to defects in the phenylalanine hydroxylase enzyme which normally converts phenylalanine → tyrosine. However, when it is defective the phenylalanine accumulates. Accumulation of phenylalanine is toxic. It converts to phenylpyruvate which is able to cross the blood-brain-barrier → seizures and learning difficulties.

😷 Presentation

It presents by 6 months as the baby will have signs of developmental delay.

• Fairer skin, hair and eyes - as tyrosine is involved in the body's production of melanin.
• Learning difficulties
• Behavioural difficulties
• Seizures and infantile spasm
• Eczema
• Musty urine sweat and breath.

💡 Pregnant women with PKU often fail to adhere to the dietary restrictions for PKU which leads to accumulation of phenylalanine that then gets passed onto the baby. So a healthy baby without PKU may initially present with a phenotype similar to PKU due to the high levels of phenylalanine from the mother.

🔍 Investigations

• 🥇 Guthrie testing (newborn blood spot test) done at 5-9 days of life.
• Bloods - show hyperphenylalaninaemia.
• Urinary organic acids test (OAT) - testing for phenylpyruvic acid.

🧰 Management

🏆 Low phenylalanine diet + nutritional supplementation - seeing as phenylalanine is present in many foods, it is sometimes difficult to stick to it.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

MCADD is also an autosomal recessive disorder affecting the ability to break down medium-chain fatty acids → acetyl-CoA as their is no MCAD enzyme. Acetyl-CoA is a substrate for the Krebs cycle which in turn produces energy through oxidative phosphorylation.

😷 Presentation

• Hypoketotic hypoglycaemia - low ketones and low glucose. As acetyl-CoA gets converted into ketones.
• Lethargy
• Seizures and coma

🔍 Investigations

• 🥇 Guthrie testing (newborn blood spot test) done at 5-9 days of life.
• Enzymatic assay or genetic testing

🧰 Management

• Avoid prolonged fasting (no longer than 6 hours without feeding) and maintain regular intake of simple carbohydrates to prevent hypoglycaemia.

Maple syrup urine disease (MSUD)

MSUD is a rarer IEM of autosomal recessive inheritance that causes accumulation of branched-chain amino acids.

There are 3 branched chain amino acids:

1. Leucine
2. Isoleucine
3. Valine

Foods that are high in these amino acids include:

• Meat
• Fish
• Chicken
• Eggs

• Yoghurts
• Soya
• Nuts
• Bread

• Pasta
• Chocolate
• Milk
• Cheese

It is known as “maple syrup urine disease” as the urine excreted from patients with this condition is sweet-smelling.

😷 Presentation

It is newborns that present with MSUD, with the following:

• Lethargy
• Poor feeding
• Irritability
• Seizures and coma
• Focal neurological signs

🔍 Investigations

• 🥇 Guthrie testing (newborn blood spot test) done at 5-9 days of life.
• Enzymatic assay or genetic testing

🧰 Management

• Lifelong dietary control to prevent the build-up of branched-chain amino acids.

Galactosaemia

Galactosaemia is an autosomal recessive IEM that affects the body’s ability to break down galactose (a monosaccharide found in milk and dairy products). The inability to break it down leads to galactose accumulation which is toxic and can lead to organ damage.

😷 Presentations

Newborns with galactosaemia within the first 1-2 weeks of life:

• Diarrhoea
• Vomiting
• Lethargy
• Hypotonia
• Liver damage

🔍 Investigations

• Enzymatic assay or genetic testing

• Dietary control - removal of galactose and lactose from the diet. This will most likely require a soy-based formula for babies.

Patients would need close monitoring and regular follow-up to monitor complications.

Hyperammonaemia

Ammonia is a highly toxic chemical that derives from nitrogen. It is detoxifed to urea (NH3 → CO(NH₂)₂) via the ornithine cycle/urea cycle. This primarily occurs in the liver.

Ammonia is elevated in severe illness, liver disease, certain medications, transient rise in the newborn.

An ammonia level should be measured when there is:

1. Unexplained encephalopathy
2. Respiratory alkalosis
3. Recurrent vomiting
4. Unexplained severe illness in a baby or child.
5. Unexplained seizures (due to cerebral oedema)

🔍 Investigations

• Plasma ammonia levels

🧰 Management

1. Stop feeding
2. Start 10% dextrose
3. IV ammonia scavenging medications - such sodium phenylacetate and sodium benzoate.
4. Arginine - it is a substrate in the urea cycle and is used in the production of ornithine which is subsequently converted into urea.
5. Haemofiltration

Hypoglycaemia

Hypoglycaemia is defined as a blood glucose of <2.6mmol/L

Hypoglycaemia is common in the first day of life in infants who are:

• Preterm
• Growth restricted or ill

Blood glucose measurements are checked routinely in these circumstances.

After that, blood glucose should be checked in any child who appears seriously ill, has a prolonged seizure, or develops an altered state of consciousness.

🔍 Investigations

• Hypoglycaemia screen at the time of hypoglycaemia is required to identify an IEM or endocrine cause.
• Ketones should be checked as their absence is an abnormal response.
• Physical examination for hepatomegaly - indicates glycogen storage disorder

Glycogen storage disorders:

The glycogen storage disorders (GSD) are a diverse group and can be divided into 3 subgroups:

1. Hepatic GSD:

The hepatic forms are associated with hypoglycaemia, such as GSD type 1a.

GSD type 1a is due to deficiency of glucose-6-phosphatase (G6PD) and leads to severe hypoglycaemia because of the inability to mobilise glucose from glycogen, or to utilise glucose from gluconeogenesis.

2. Muscle GSD:

The most common muscle GSD is GSD V, also called McArdle disease. It is due to deficiency of myophosphorylase.

Patients characteristically have exercise intolerance relieved by rest, the ‘second wind’ phenomena. This reflects the ability of the muscles to ‘switch’ to using other energy sources, e.g. free fatty acids or free glucose in the blood stream.

They are at risk of exercise-induced breakdown of muscle tissue (rhabdomyolysis) and its complications, particularly AKI.

3. Cardiac GSD

Lysosomal storage disorders

The lysosome is the recycling centre of the cell and contains a number of enzymes.

Pathophysiology

Deficiency of one of these enzymes results in the inability to break down a specific chemical leading to its accumulation within the cell.

This accumulation typically leads to signs of visceral storage (hepatosplenomegaly) and/or central nervous system involvement with developmental regression or seizures or both.

Let’s take a look at mucopolysaccharidosis:

• Mucopolysaccharidosis:

They are progressive multisystem disorders which may affect the neurological, ocular, cardiac, and skeletal systems, due to defective breakdown of glycosaminoglycans (GAGs). The different forms of MPS have highly variable clinical features.

The majority present with growth faltering, developmental delay, dysmorphism (coarsening of facial features, frontal bossing) and/or hepatosplenomegaly in the first 6–12 months of life.

Treatment is supportive according to the child’s needs and a number of the conditions have enzyme replacement therapies available. Successful enzyme replacement by haemopoietic stem cell transplantation has been performed for MPS type I, but it cannot reverse any established neurological abnormality and has a minimal effect on the skeletal component.

Mitochondrial disease

The Krebs cycle (also known as the tricarboxylic acid cycle) is found in all cells except red blood cells, which lack mitochondria.

The primary function of this system is the production of ATP (adenosine triphosphate) from the process of oxidative phosphorylation.

Pathophysiology

Mitochondrial disorders are those directly resulting from deficits in energy production by oxidative phosphorylation and therefore affect those organs with the greatest energy demands such as the brain, heart, kidney, retina, skeletal muscle.

Lipid storage disorders

Lipid storage diseases are a group of IEM's in which enzyme deficiency causes lipid accumulation in cells and tissues.

This excessive storage of fats can cause permanent cellular and tissue damage, affecting the brain, nervous system, liver, spleen and bone marrow.

The most common lipid storage disorder is Gaucher disease.

Lipid metabolism disorders

The most common reason for raised cholesterol in childhood is obesity.

However, familial hypercholesterolaemia is the most common inherited disorder of lipid metabolism.

A few children with homozygous familial hypercholesterolaemia may be the index case. They typically present before 5 years of age to dermatologists with lipid deposits. These deposits classically occur in the natal cleft and the extensor surfaces of the elbows.

Read more about familial hypercholestrolaemia here.