Inborn errors of metabolism

Question 1

Describe the overview of the history of inborn errors of metabolism and understand the concept of one gene mutation altering an enzyme in a specific metabolic pathway that can give rise to a disease

Answer 1

The concept of IEM was introduced by Archiblad Garrod in the early 20th century, who worked on alkaptonuria which he recognised as a genetic trait passed along specific family lines

Garrod suggested that such diseases resulted from a “block” in a metabolic pathway that was due to the loss or modification of a specific enzyme’s function

He proposed that genes dictate the function of enzymes, and that a mutation in a gene could lead to an abnormal or non-functional enzyme, leading to a buildup of specific metabolites - Garrod’s “one gene-one enzyme” hypothesis

Examples of IEMs include phenylketonuria (PKU), where a deficiency in the enzyme phenylalanine hydroxylase leads to an accumulation of phenylalanine and its metabolites, leading to intellectual disability if not treated

In these diseases, as in many other inborn errors of metabolism, the key defect is a mutation in a single gene, leading to a deficiency or total absence of a key enzyme in a metabolic pathway

This leads to an accumulation of substrate or a deficiency of product, causing the signs and symptoms of the disease

Question 2

Explain that there are several mechanisms of inheritance of IEM and give examples of disorders of each inheritance pattern

Answer 2

IEM can be inherited through different patterns depending on the genes involved. The main modes of inheritance are:

1) Autosomal Recessive Inheritance:

• Both parents must be carriers of a mutated gene to pass on the disorder, and the affected individual has two copies of the mutated gene
• E.g. Phenylketonuria (PKU), Sickle Cell Disease, and Cystic Fibrosis

2) Autosomal Dominant Inheritance:

• In this pattern, an individual needs to inherit only one copy of the defective gene from either parent to develop the disorder.
• A parent with the disorder has a 50% chance of passing the disorder to each of their children.
• An example of an IEM with this pattern of inheritance is Acute Intermittent Porphyria

3) X-linked Recessive Inheritance:

• In this pattern, the mutated gene is located on the X chromosome.
• Males are more likely to be affected because they have one X and one Y chromosome (XY), while females have two X chromosomes (XX) and therefore have a backup if one X chromosome carries the mutation.
• E.g. Lesch-Nyhan syndrome and Haemophilia A and B

4) Mitochondrial Inheritance:

• In this rare pattern of inheritance, the mutations are in the mitochondrial DNA, which is only passed down from the mother
• Disorders resulting from mutations in mitochondrial DNA affect the energy production of the cell and can cause a wide range of symptoms.

E.g. Leber’s Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)

Question 3

Explain that IEM are individually rare disorders but are collectively common and contribute to significant mortality and disease burden

Answer 3

Inborn Errors of Metabolism (IEM) refer to a large group of genetic disorders that interfere with the body’s metabolism

These disorders are individually rare but, taken as a group, they are not uncommon

The prevalence estimates for IEMs range from 1 in 800 to 1 in 2,500 births, which collectively represent a significant fraction of newborns

Despite their rarity, IEMs contribute significantly to pediatric disease and mortality due to the severity of their presentation

Depending on the specific disorder, they can cause a wide range of symptoms, such as developmental delay, mental retardation, failure to thrive, hypoglycemia, seizures, metabolic acidosis, and even sudden death

The early identification of these disorders, using techniques such as newborn screening, can lead to interventions that significantly reduce morbidity and mortality

Treatment strategies for IEMs can include dietary restrictions, medications to reduce the accumulation of toxic substances or replace deficient substances, and, in some cases, organ transplantation

Question 4

Explain how IEM are classified and describe the differences between neonatal and adult presentations of IEM

Answer 4

Broadly specified according to the specific type of metabolic pathway that is affected:

1) Disorders of intermediary metabolism:

• These affect the metabolism of proteins, carbohydrates, or fats
• E.g. phenylketonuria (affecting protein metabolism), glycogen storage diseases (affecting carbohydrate metabolism), and fatty acid oxidation disorders (affecting fat metabolism)

2) Disorders of complex molecules:

• These affect the metabolism of complex substances, like glycoproteins, lysosomal storage diseases, and peroxisomal disorders

3) Disorders of vitamins, metal and others:

• These affect the metabolism of various other substances such as vitamins (e.g., B12 deficiency) and trace elements (e.g., Wilson disease affecting copper metabolism)

Neonatal presentations of IEMs often involve severe, acute symptoms that can be life-threatening if not promptly diagnosed and treated

Symptoms can be nonspecific but may include poor feeding, vomiting, lethargy, seizures, and failure to thrive

Adult presentations of IEMs can be more variable and can often involve more chronic or progressive symptoms

Adults can also present with a mild form of an IEM that was not diagnosed during childhood

Symptoms can include muscle weakness, developmental delay, neurological symptoms, or organ damage

The onset of symptoms can be triggered by factors like illness, stress, or changes in diet

Question 5

Describe how the laboratory can help identify IEM and give examples of specialist tests and confirmatory tests for the diagnosis of IEM

Answer 5

1) Biochemical Tests:

These tests measure levels of particular substances in a patient’s blood, urine, or other tissues that can be indicators of specific metabolic disorders

They can detect abnormal metabolites or changes in enzyme activities.

Examples include:

1. Plasma amino acid analysis: Used to diagnose conditions like phenylketonuria and maple syrup urine disease
2. Urine organic acid analysis: Useful for conditions like methylmalonic acidemia and glutaric aciduria
3. Acylcarnitine profile: Useful for diagnosing disorders of fatty acid oxidation and organic acidurias

2) Enzyme Assays:

• These tests assess the activity of specific enzymes that are affected by metabolic disorders
• They are often performed on blood cells, fibroblasts, or liver biopsies

3) Genetic Tests:

• These tests look for specific mutations in the genes associated with metabolic disorders
• NGS panels or whole-exome sequencing can be used for diagnosis when multiple genes could be causing the observed clinical phenotype

4) Newborn Screening:

• Many countries have newborn screening programs that test for a range of IEMs shortly after birth
• This is typically done through a heel prick blood sample collected on filter paper (Guthrie card)
• The testing methodology often involves tandem mass spectrometry, which can screen for multiple IEMs simultaneously

Question 6

Describe the criteria required for a successful screening programme and know which disorders are tested for in the UK Newborn blood spot screening programme

Answer 6

For a screening program to be effective, it must satisfy a number of criteria, often known as Wilson’s criteria, which are:

1. The condition should be an important health problem
2. The natural history of the condition should be well understood
3. There should be a recognisable early stage or latent period
4. There should be a recognizable early stage or latent period
5. A suitable test or examination should be available
6. The test should be acceptable to the population
7. The health care system should be capable of handling the extra clinical workload resulting from screening
8. The risks, both physical and psychological, should be less than the benefits
9. The costs should be balanced against the benefits

UK Newborn Blood Spot Screening Programme screens for:

• Sickle cell disease
• Cystic fibrosis
• Congenital hypothyroidism
• Phenylketonuria (PKU)
• Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
• Maple syrup urine disease (MSUD)