Test Id : LPCBS

For more information see Newborn Screen Follow-up for X-linked Adrenoleukodystrophy.

If the patient has an abnormal newborn screening result for X-linked adrenoleukodystrophy, immediate action should be taken. Refer to the appropriate ACMG Newborn Screening ACT Sheet.(1)

Supplies: Card-Blood Spot Collection (Filter Paper) (T493)

Container/Tube:

Preferred: Blood Spot Collection Card

Acceptable: PerkinElmer 226 filter paper, Munktell filter paper, Whatman Protein Saver 903 Paper, local newborn screening card, or blood collected in tubes containing ACD or EDTA, and then spotted and dried on filter paper

Specimen Volume: 2 Blood spots

Collection Instructions:

1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.

2. Completely fill at least 2 circles on the filter paper card (approximately 100 microliters blood per circle).

3. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.

4. Do not expose specimen to heat or direct sunlight.

5. Do not stack wet specimens.

6. Keep specimen dry.

Additional Information:

1. For collection instructions, see Blood Spot Collection Instructions.

2. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777).

3. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800.

Forms

1. Biochemical Genetics Patient Information (T602)

2. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.

• Biochemical Genetics Patient Information
• Blood Spot Collection Card-Spanish Instructions
• Newborn Screen Follow-up for X-Linked Adrenoleukodystrophy
• Blood Spot Collection Card-Chinese Instructions
• Blood Spot Collection Instructions

1. Biochemical Genetics Patient Information (T602)

2. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.

1 Blood spot

Second-tier newborn screen for X-linked adrenoleukodystrophy

This test is not intended for metabolic screening of symptomatic patients.

This test is supplemental and not intended to replace state mandated newborn screening.

This test is used as a second-tier newborn screen for X-linked adrenoleukodystrophy (X-ALD).

For more information see Newborn Screen Follow-up for X-linked Adrenoleukodystrophy.

If the patient has an abnormal newborn screening result for X-linked adrenoleukodystrophy, immediate action should be taken. Refer to the appropriate ACMG Newborn Screening ACT Sheet.(1)

This assay measures C20, C22, C24, and C26 lysophosphatidylcholine (LPC) species in dried blood spots by liquid chromatography tandem mass spectrometry.

Peroxisomes are organelles present in all human cells except mature erythrocytes. They carry out essential metabolic functions, including beta-oxidation of very long-chain fatty acids, alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include 2 major subgroups: disorders of peroxisomal biogenesis and single peroxisomal enzyme/transporter defects. Peroxisome biogenesis defects, such as Zellweger spectrum disorder (ZSD), are characterized by defective assembly of the entire organelle, whereas in single enzyme/transporter defects, such as X-linked adrenoleukodystrophy (XALD), the organelle is intact but a specific function is disrupted. These disorders are clinically diverse and range in severity from neonatal lethal to later onset milder variants.

XALD is a disorder affecting the nervous system, adrenal cortex, and testis. It is the most common of the peroxisomal disorders, affecting 1 in 17,000 to 1 in 21,000 male patients. At least 50% of all female patients who are heterozygous for XALD are symptomatic. A defect in the ABCD1 gene is responsible for the disease. XALD shows a wide range of phenotypic expressions. The clinical phenotypes occurring in male patients can be subdivided in 4 main categories: cerebral inflammatory, adrenomyeloneuropathy (AMN), Addison only, and asymptomatic. The first 2 phenotypes account for almost 80% of the patients, while the frequency of the asymptomatic category diminishes with age, and it is very rare after 40 years of age. It is estimated that approximately 50% of heterozygous individuals develop an AMN-like syndrome. Treatment options are hormone replacement therapy, dietary intervention, or hematopoietic stem cell transplantation.

Elevations of C24 LPC and C26 LPC may be indicative of XALD. In 2016, XALD was added to the US Recommended Uniform Screening Panel, a list of conditions that are nationally recommended for newborn screening by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. Therefore, measurement of LPCs is a useful second-tier test for newborn screening for XALD.

ZSD are a continuum of severe disorders affecting the nervous system, vision, hearing, and liver function. Most individuals present in infancy, but adult patients have been identified. The prevalence of ZSD is 1 in 50,000. ZSD follows autosomal recessive inheritance. At least 12 different genes have been implicated in ZSD, with approximately 60% to 70% of genetic variants occurring in PEX1. The clinical phenotypes include Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD).

Individuals with Zellweger syndrome typically die within the first year of life without making any developmental progress. Individuals with NALD or IRD typically present in childhood with developmental delays, vision loss, hearing loss, and have a much slower disease progression. There is no specific treatment for ZSD. Although ZS are not a primary disease target for testing, this test will detect infants with these disorders.

In female patients: Elevations of C24 lysophosphatidylcholine (LPC) or C26 LPC may be indicative of heterozygosity for X-linked adrenoleukodystrophy (XALD) or other forms of peroxisomal disorders.

In male patients: Elevations of C24 LPC or C26 LPC may be indicative of XALD or other forms of peroxisomal disorders.

Abnormal results are not sufficient to conclusively establish a diagnosis of a particular disease. To verify a preliminary diagnosis based on the analysis, independent biochemical (eg, in vitro enzyme assay) or molecular genetic analyses are required.

This test cannot reliably detect carrier status (heterozygosity) for these conditions.

A positive test result is strongly suggestive of a diagnosis but requires follow-up by stand-alone biochemical or molecular assay, which is best coordinated by local genetics providers.

1. ACMG Newborn Screening ACT Sheets. Accessed February 6, 2024. Available at www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_and_Algorithms/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_and_Algorithms.aspx?hkey=9d6bce5a-182e-42a6-84a5-b2d88240c508

2. Huffnagel IC, van de Beek MC, Showers AL, et al. Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy. Mol Genet Metab. 2017;122(4):209-215. doi:10.1016/j.ymgme.2017.10.012

3. Klouwer FCC, Ferdinandusse S, van Lenthe H, et al. Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders. J Inherit Metab Dis. 2017;40(6):875-881. doi:10.1007/s10545-017-0064-0

4. Sandlers Y, Moser AB, Hubbard LE, Kratz LE, Jones RO, Raymond GV. Combined extraction of acyl carnitines and 26:0 lysophosphatidylcholine from dried blood spots: prospective newborn screening for X-linked adrenoleukodystrophy. Mol Genet Metab. 2012;105(3)416-420

Internal standard in methanol is added to a dried blood spot. The extract is evaporated and reconstituted prior to injection onto a liquid chromatography tandem mass spectrometry (LC-MS/MS) system. The lysophosphatidylcholine (LPC) concentrations are measured by MS/MS analysis in the multiple reaction monitoring positive mode to follow the precursor to product species transitions. The ratio of the extracted peak area to internal standard as determined by LC-MS/MS is used to calculate the concentration of LPC species in the sample.(Unpublished Mayo method)

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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