Is genetic testing required to diagnose a metabolic disorder?

From the Guidelines

Genetic testing is not always necessary to secure a diagnosis of a metabolic problem, but it can be a valuable tool in certain cases, particularly when the diagnosis is unclear or when specific genetic mutations are suspected. According to the American Academy of Child and Adolescent Psychiatry 1, genetic testing can be helpful in diagnosing metabolic disorders, but it is not always the first step. The diagnosis of metabolic disorders typically involves a combination of clinical evaluation, biochemical testing, and genetic testing.

Some metabolic disorders can be diagnosed through biochemical testing, such as serum amino acids and urine organic acids, which can detect abnormalities in metabolite levels or enzyme activity 1. For example, disorders like phenylketonuria (PKU) can be diagnosed through newborn screening that detects elevated phenylalanine levels in blood. Other diagnostic approaches include clinical evaluation of symptoms, family history assessment, and specialized tests like glucose tolerance tests for diabetes or liver function tests for certain metabolic conditions.

However, genetic testing can be important for confirming diagnoses, identifying specific mutations, determining inheritance patterns, and guiding treatment decisions 1. In some complex or rare metabolic disorders, genetic testing may be the only definitive way to establish a diagnosis, especially when biochemical markers are ambiguous or symptoms overlap with multiple conditions. The American College of Medical Genetics, the American Academy of Neurology, and the American Academy of Pediatrics recommend a chromosomal microarray in all individuals with intellectual disability of undetermined etiology, which can also help diagnose certain metabolic disorders 1.

Key points to consider when deciding whether to use genetic testing to diagnose a metabolic disorder include:

• The presence of suggestive clinical features, such as developmental regression or episodic decompensation 1
• Physical examination findings, such as hepatosplenomegaly or coarse facial features 1
• Family history, including consanguinity or a history of metabolic disorders 1
• The results of biochemical testing, such as serum amino acids or urine organic acids 1

In summary, while genetic testing is not always required to diagnose a metabolic disorder, it can be a valuable tool in certain cases, and its use should be considered on a case-by-case basis, taking into account the individual's clinical presentation, family history, and the results of biochemical testing. The decision to use genetic testing should be based on the individual's specific needs and circumstances, and should be guided by the latest clinical guidelines and evidence-based recommendations.

From the Research

Genetic Testing for Metabolic Disorders

• Genetic testing can be useful in diagnosing certain metabolic disorders, such as familial hypercholesterolemia (FH) 2.
• FH is a genetic disorder characterized by high levels of low-density lipoprotein (LDL) cholesterol, which can increase the risk of cardiovascular disease 3, 4.
• Genetic testing can help identify individuals with FH and guide treatment decisions, such as the use of PCSK9 inhibitors 3, 4.
• However, genetic testing is not always necessary for diagnosing metabolic disorders, and other factors such as medical history, physical examination, and laboratory tests should also be considered 2.

Diagnosis of Metabolic Disorders

• The diagnosis of metabolic disorders, such as FH, typically involves a combination of clinical evaluation, laboratory tests, and genetic testing 2.
• Laboratory tests, such as lipid profiles, can help identify individuals with high levels of LDL cholesterol, which is a characteristic of FH 3, 4.
• Genetic testing can help confirm the diagnosis of FH and identify the specific genetic mutation responsible for the condition 2.
• Other tests, such as pulse wave velocity (PWV) measurements, can also be used to assess cardiovascular risk in individuals with FH 5.

Treatment of Metabolic Disorders

• The treatment of metabolic disorders, such as FH, typically involves a combination of lifestyle modifications, such as diet and exercise, and medication 3, 4.
• PCSK9 inhibitors are a type of medication that can be used to lower LDL cholesterol levels in individuals with FH 3, 4.
• Other medications, such as statins and ezetimibe, can also be used to lower LDL cholesterol levels and reduce cardiovascular risk 3, 4, 5.
• Genetic testing can help guide treatment decisions and ensure that individuals with FH receive the most effective treatment for their specific condition 2.