Test Id : PGRBC

If peroxisomal biogenesis disorders (Zellweger syndrome spectrum) are suspected, also order very long chain fatty acids (POX / Fatty Acid Profile, Peroxisomal [C22-C26], Serum; or POXP / Fatty Acid Profile, Peroxisomal [C22-C26], Plasma), bile acids (BAIPD / Bile Acids for Peroxisomal Disorders, Serum), and pipecolic acid (PIPU / Pipecolic Acid, Random, Urine).

If rhizomelic chondrodysplasia punctata (RCDP) is suspected, also order very long chain fatty acids (POX / Fatty Acid Profile, Peroxisomal [C22-C26], Serum), which includes phytanic and pristanic acid analysis.

Whole blood should be sent refrigerated.

1. Reason for testing is required

2. Date of blood transfusion, if performed.

3. Biochemical Genetics Patient Information (T602) is recommended, but not required, to be filled out and sent with the specimen to aid in the interpretation of test results.

Patient Preparation: Specimen must be collected either prior to or 6 weeks after a blood transfusion.

Specimen Type: Whole Blood

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Green top (sodium or lithium heparin), yellow top (ACD solution A or B)

Specimen Volume: 5 mL

Collection Instructions: Send specimen in original tube. Do not aliquot.

• Biochemical Genetics Patient Information

1. Biochemical Genetics Patient Information (T602) (recommended, but not required)

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

3 mL

Diagnosing patients with possible peroxisomal disorders, such as peroxisomal biogenesis disorders (Zellweger syndrome spectrum) and rhizomelic chondrodysplasia punctata (RCDP), including fatty acyl-CoA reductase 1 (FAR1) deficiency

Evaluating patients with abnormal newborn screen results for X-linked adrenoleukodystrophy who appear to have a different type of peroxisomal disorder, such as a Zellweger syndrome spectrum disorder.

Aiding in the assessment of peroxisomal function

This test measures plasmalogens and plasmalogen to fatty acid ratios for the purpose of diagnosis of peroxisomal biogenesis disorders (Zellweger syndrome spectrum) and rhizomelic chondrodysplasia punctata (RCDP), including fatty acyl-CoA reductase 1 (FAR1) deficiency.

Peroxisomes are organelles that carry out essential metabolic functions, including beta-oxidation of very long-chain fatty acids (VLCFA), alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include disorders of peroxisomal biogenesis with defective assembly of the entire organelle, and disorders of peroxisome function with single peroxisomal enzyme/transporter defects where the organelle is intact but a specific function is disrupted.

Biochemical abnormalities in peroxisomal biogenesis disorders can include accumulations of VLCFA, phytanic acid, pristanic acid, pipecolic acid, bile acids, and reduced plasmalogens. The differential diagnosis of these disorders is based on recognition of clinical phenotypes combined with a series of biochemical tests to assess peroxisomal function and structure. These include measurements and ratios of VLCFA, phytanic acid, and its metabolite pristanic acid (POX / Fatty Acid Profile, Peroxisomal [C22-C26], Serum; or POXP / Fatty Acid Profile, Peroxisomal [C22-C26], Plasma), pipecolic acid (PIPA / Pipecolic Acid, Serum; or PIPU / Pipecolic Acid, Random, Urine), bile acids (BAIPD / Bile Acids for Peroxisomal Disorders, Serum), and plasmalogens.

Peroxisomal biogenesis disorders (PBD) include Zellweger syndrome spectrum disorders, which are clinically diverse and range in severity from neonatal lethal (Zellweger syndrome) to more variable clinical courses in neonatal adrenoleukodystrophy and infantile Refsum disease. Affected children typically have hypotonia, poor feeding, distinctive facial features, seizures, and liver dysfunction. Other features can include retinal dystrophy, hearing loss, developmental delays, and bleeding episodes.

Rhizomelic chondrodysplasia punctata (RCDP) is a malformation disorder characterized by rhizomelic shortening, chondrodysplasia punctata, cataracts, intellectual disability, and seizures; however, it can have a milder phenotype with only cataracts and chondrodysplasia punctata. Currently, there are 5 clinical types of rhizomelic chondrodysplasia punctata: RCDP 1, 2, 3, 4 (also known as FAR1 deficiency) and 5. RCDP 1 is the classical form that presents in infancy with skeletal manifestations, including rhizomelic shortening, cataracts, and severe to profound postnatal growth deficiency. Infants with RCDP 1 have developmental delay, and later, intellectually disability. The majority of children with RCDP 1 do not survive beyond the first decade of life. RCDP 1 is an autosomal recessive disorder caused by disease-causing variants in the PEX7 gene. RCDP 2 and 3 have clinical phenotypes similar to RCDP 1 and may be distinguished by plasmalogen deficiency. RCDP 2 and 3 are autosomal recessive conditions caused by disease-causing variants in GNPAT and AGPS genes, respectively. Individuals with RCDP 5 have a milder phenotype when compared to classic RCDP 1, with most individuals able to achieve self-feeding, independent ambulation, and development of limited language skills. RCDP5 results in less pronounced reduction in plasmalogens compared to RCDP 1. This newly recognized subtype of RCDP is an autosomal recessive disorder caused by disease-causing variants in the PEX5 gene.

The typical biochemical profile for RCDP shows reduced plasmalogens, elevated phytanic acid, and normal VLCFA. Confirmatory testing via molecular analysis for all types of RCDP is available (PDGP / Peroxisomal Disorder Gene Panel, Varies).

Fatty acyl-CoA reductase 1 (FAR1) deficiency, also known as RCDP type 4, is an autosomal recessive peroxisomal disorder caused by disease-causing variants in the FAR1 gene that result in early-onset epilepsy, microcephaly, cataracts, postnatal growth deficiency, and intellectual disability. Unlike RCDP, however, infants with FAR1 deficiency have no skeletal abnormalities. The biochemical profile for FAR1 deficiency includes reduced plasmalogens, normal to elevated phytanic acid, and normal VLCFA.

Hexadecanal-Dimethylacetal, C16:0 DMA:

> or =6.00 mcg/mL

Octadecanal-Dimethylacetal, C18:0 DMA:

> or =9.00 mcg/mL

9Z-Octadecenal-DiMethylacetal C18:1 DMA:

> or =2.00 mcg/mL

C16:0 DMA/C16:0:

> or =0.018

C18:0 DMA/C18:0:

> or =0.040

Reports include concentrations of C16:0, C18:0 and C18:1 plasmalogens and the ratio of the C16:0 and C18:0 plasmalogens to the respective fatty acid. When no significant abnormalities are detected, a simple descriptive interpretation is provided.

A profile of reduced plasmalogens and abnormal very long-chain fatty acids (VLCFA), as well as possible abnormalities in pipecolic acid and bile acids, can be consistent with a diagnosis of a peroxisomal biogenesis disorder (Zellweger syndrome spectrum).

A profile of reduced plasmalogens, elevated phytanic acid, and normal VLCFA is consistent with a diagnosis of rhizomelic chondrodysplasia punctata, such as RCDP type 1 or 2, FAR1 deficiency (RCDP type 4), or other types of RCDP.

Positive test results could be due to a genetic or nongenetic condition. Additional confirmatory testing would be required to differentiate between these causes.

The results of testing performed in erythrocytes are invalid following a transfusion; therefore, collect specimen either prior to or 6 weeks after a blood transfusion.

1. Braverman NE, Moser AB, Steinberg SJ, Fallatah WF, Duker A, Bober M. Rhizomelic chondrodysplasia punctata type 1. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2001. Updated January 30, 2020. Accessed May 25, 2023. Available at: www.ncbi.nlm.nih.gov/books/NBK1270/

2. Buchert R, Tawamie H, Smith C, et al. A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet. 2014;95(5):602-610

3. Baroy T, Koster J, Stromme P, et al: A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by a loss of the PEX5 long isoform. Hum Mol Genet. 2015;24(20):5845-5854

4. Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822(9):1442-1452

This test measures C16:0, C18:1 and C18:0 plasmalogens in red blood cells as a diagnostic marker for peroxisomal disorders as well as C16:0 and C18:0 fatty acids for normalization. Briefly, samples, standards and quality control are mixed with internal standards and derivatization and extraction is performed. Plasmalogens and fatty acids are then extracted from solution, transferred to a new tube, dried down under nitrogen, reconstituted, and analyzed by gas chromatography mass spectrometry.(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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