Fast Facts: Long-Chain Fatty Acid Oxidation Disorders

Understand, Identify and Support

Barbara K. Burton, Anne Daly, B.K. Burton, A. Daly

• Publisher: S. Karger
• Year: 2021
• Print ISBN:
  9783318068306
• eBook ISBN:
  9783318068313
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Disorders affecting the oxidation of long-chain fatty acids are complex, potentially life-threatening, metabolic conditions. A number of genetically distinct conditions exist, depending on the gene and protein affected, but there are some common clinical and biochemical features. Newborn screening, which allows early intervention to prevent long-term morbidity, is not universally available. Even with screening, it is important that health professionals recognize the symptoms that may manifest at different stages of life. This concise guide to these rare conditions will be of value to all health professionals who may encounter or care for an individual with a long-chain fatty acid oxidation disorder. As well as explaining the underlying defects, inheritance and how the conditions manifest, the book describes the diagnosis and differential diagnosis of the disorders. The final chapter gives some guidance on genetic counseling and supporting patients.

4

Diagnosis

Individuals with an LC-FAOD may be diagnosed after clinical presentation or after newborn screening while asymptomatic.

Newborn screening

Newborn screening for LC-FAODs is conducted by analysis of acylcarnitines in the dried blood spot obtained from a baby during the first few days of life. Mortality resulting from FAODs has been significantly reduced in countries in which this is available.^1,2

Following a positive newborn screen for one of these conditions, diagnostic testing must be performed. For most disorders this includes a plasma acylcarnitine profile and urine organic acid analysis. Measurement of free and total carnitine levels is essential when the newborn screen shows findings suggestive of carnitine uptake defect.

It is important to note that both the plasma acylcarnitine profile and urine organic acids are most likely to yield abnormal results when a patient is acutely symptomatic or following fasting. Therefore, normal results of these tests following a positive newborn screen do not rule out the diagnosis of an LC-FAOD.

While patients with the most severe defects will typically have an abnormal acylcarnitine profile regardless of when it is obtained, individuals with milder defects may exhibit abnormalities only when stressed. Newborn screening specimens are typically obtained shortly after the stress of labor and delivery, when feeding may not yet be well established. In contrast, by the time of follow-up testing, infants are typically feeding frequently so are essentially always in a fed state.

Normalization of the acylcarnitine profile has been most commonly observed in infants with a positive newborn screen for VLCAD and LCHAD/TFP deficiencies. These infants should have either some assessment of enzyme activity or molecular testing of the relevant gene or genes, regardless of the biochemical test results.

In some countries, enzyme assays can be performed on blood samples or cultured fibroblasts obtained from a skin biopsy. In other circumstances, indirect evidence of impaired β-oxidation can be obtained by incubating fibroblasts with ¹³C-labeled or unlabeled palmitate and carnitine, with subsequent acylcarnitine profiling of the cells. This type of study is often referred to as an in-vitro probe study.

Specific algorithms for follow-up of an abnormal newborn screen for each of the LC-FAODs can be found on the website of the American College of Medical Genetics and Genomics (www.acmg.net) under newborn screening and the steps are summarized, with additional notes from the authors, in Table 4.1.

Clinical presentation

If an individual presents with symptoms suggestive of an LC-FAOD, the following studies should be obtained:

•plasma free and total carnitine levels

•plasma acylcarnitine profile

•urine organic acids.

There are characteristic acylcarnitine abnormalities associated with the various disorders (Table 4.2). The acylcarnitine profile is reliably abnormal in all patients only during an acute episode of decompensation and may normalize in some individuals when they are well. Therefore, if a person is seen for evaluation after recovery from the initial episode that prompted concern, it is important that the test be repeated when the patient again develops symptoms.

Urine organic acids are often abnormal during acute episodes but are commonly normal dur...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• List of abbreviations and glossary
• Introduction
• Fatty acid metabolism
• Epidemiology and genetics
• Clinical presentation
• Diagnosis
• Genetic counseling, newborn screening and patient support
• Useful resources
• Index