Spotting the zebras among the horses: Understanding metabolic disorders

Metabolic disorders – also known as inborn errors of metabolism – are a heterogenous group of genetic conditions, which are individually rare but collectively common (see BioNews 1315, 1319 and 1329).

These conditions can present at any age, and they have certain recognisable characteristics in their clinical presentation. There are more than 1000 well-established metabolic diseases and more than 100 provisional ones, subdivided into around 130 groups. It is important to learn to spot these zebras among horses – the rare metabolic disorders – in a timely manner, so that we can optimise patient outcomes.

Metabolic disorders relate to metabolic pathways – complex, interconnected chemical reactions in our bodies. These chemical reactions are crucial to energy production and to the synthesis of proteins, fats and carbohydrates.

The complexity of metabolic pathways, as famously visualised by the late Dr Donald Nicholson, can seem terrifying. Here is one of his charts, and the reaction that it sometimes provokes.

However, the following simplified approach can help us to understand both metabolic pathways and metabolic disorders.

Normal metabolism involves conversion of one type of chemical substance (known as a 'substrate') to a different type of chemical substance (known as a 'product'), with the help of a third type of chemical substance (an enzyme) and sometimes also a fourth (known as a 'cofactor').

In an inborn error of metabolism, a mutation in a person's DNA results in the deficiency of an enzyme or a cofactor. This, in turn, results in an accumulation of the substrate (and sometimes accumulation of a related substance known as a 'metabolite'), and in a deficiency of the product.

For example, in a child with urea cycle disorder, the toxin ammonia is not broken down to urea as it should be. An excess of ammonia then leads to symptoms that can include irritability, vomiting, seizures and coma.

Another example is metabolic disorders related to glycogenolysis, a metabolic process that breaks down glycogen to release glucose during fasting. If enzymes or cofactors involved in glycogenolysis are deficient, this can result in glycogen accumulation in the liver (causing abdominal distension) and in glucose deficiency (causing symptoms of hypoglycaemia).

Metabolic disorders can present at any age, and age of onset of symptoms is usually related to the severity of the enzyme deficiency. If a child has little or no enzyme activity, then the disorder will present soon after birth or during infancy. If a child has greater (but still deficient) enzyme activity, then the disorder might present later on – during childhood, adolescence or adulthood.

Clinical presentation of metabolic disorders can be varied, non-specific, acute or chronic. Such disorders can share features with common childhood illnesses, but there are certain clues that suggest a metabolic disorder (see the table at the end of this article).

Features such as loss of skills or developmental regression, self-mutilation or injurious behaviour, episodic confusion, cyclical vomiting and unusual body odours are strong pointers to metabolic disorders. Unexplained liver disease, cardiomyopathy, arrhythmia or unusual heart rhythms require metabolic investigation.

Metabolic investigation usually entails – as a first line – targeted biochemical or metabolite testing in blood or urine, based on the clinical presentation or examination findings. Measuring the deficient or absent enzyme helps to predict the severity of clinical presentation. Genetic testing is confirmatory, and is vital in order to access services including genetic counselling, antenatal testing and preimplantation genetic testing.

Treatment strategies are varied, and depend on the specific disorder. For example:

• Taking the vitamin biotin in the case of biotinidase deficiency, adhering to a protein-restricted diet in the case of amino acid disorders, and regular feeding (as per the fasting tolerance) in the case of glycogen storage disorders.
• Enzyme replacement therapy (to deliver a deficient enzyme), substrate reduction therapy (to reduce accumulated substrate or metabolites), or chaperone therapy (targeting misfolded proteins) in the case of lysosomal storage disorders.
• Bone marrow transplantation and liver transplantation play a curative role for some metabolic disorders, and gene therapy has recently been approved as a disease-modifying strategy for metachromatic leukodystrophy (see BioNews 1132 and 1179).
• Gene therapy using viral vectors or genome editing (see BioNews 1272, 1289 and 1324) and mRNA therapy using lipid nanoparticles (see BioNews 1296) are advancing rapidly and bring hope to the future of metabolic disorders.

It is crucial not to miss a metabolic disorder. Many such disorders are treatable once diagnosed, and early diagnosis can help in many ways. For example:

• Initiating presymptomatic testing of siblings.
• Enabling access to gene therapy (if this is appropriate and available).
• Encouraging genetic counselling in relation to future pregnancies.

Even in instances where a metabolic disorder is not (currently) treatable, early diagnosis can still help in the following ways:

• Avoiding invasive tests, if these are futile.
• Initiating supportive multidisciplinary team management.
• Reorientation towards palliative care, if this is in the patient's best interests.

In conclusion, patients and professionals alike stand to benefit from improved understanding of metabolic disorders. Improved understanding encourages timely recognition and better management, helping us to deliver high-quality, holistic care to our patients and their families.

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