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For initial test options for disorders of peroxisomal biogenesis and/or function, refer to the Laboratory Test Directory.
Peroxisomal disorders are a group of diseases caused by gene defects impairing the formation (peroxisome biogenesis disorders) or function of the peroxisomes, with symptoms that impact a wide range of body systems. Peroxisome biogenesis disorders include Zellweger spectrum disorders (ZSDs) and rhizomelic chondrodysplasia punctata (RCDP). Single enzyme defects include Refsum disease, peroxisomal acyl-CoA oxidase deficiency, peroxisomal bifunctional deficiency, defects of bile acid synthesis, and primary hyperoxaluria. Some single enzyme defects present with similar clinical features to ZSD (eg, ACOX1, HSD17B4) or RCDP (eg, AGPS, GNPAT), although these often can be distinguished by extensive biochemical testing.
Disease Overview
Symptoms
Common features of peroxisomal disorders include:
- Hypotonia, seizures, peripheral neuropathy, and ataxia
- Abnormal brain magnetic resonance imaging (MRI) findings such as neuronal migration defects, leukodystrophy, or cerebellar atrophy
- Poor growth, feeding problems, and fat-soluble vitamin deficiency
- Hepatic dysfunction, hepatomegaly, and cholestasis
- Progressive adrenal insufficiency
- Renal cortical cysts or kidney stones
- Skeletal abnormalities such as stippling of the growth plates, chondrodysplasia punctata, or progressive loss of bone mineral density
- Deafness or progressive hearing loss
- Visual impairment due to cataracts, glaucoma, optic nerve hypoplasia, band keratopathy, or progressive retinal dystrophy
- Developmental delay and intellectual disability
Testing Strategy
When a peroxisomal disorder is suspected, the following screening tests may be considered:
- Very long-chain fatty acids in plasma
- C26-lysophosphatidylcholine (LPC) in whole blood or plasma
- Phytanic and pristanic acids in plasma
- Plasmalogens in erythrocytes
- Pipecolic acid in urine (neonates) and plasma (older children or adults)
- Bile acid intermediates in plasma and urine
These biochemical tests may not detect individuals with moderate or mild disease. Some assays are sensitive to age or diet and the complexity of biochemical profiles associated with different peroxisomal disorders requires expertise for optimal interpretation. Therefore, multigene panels are often used to confirm a diagnosis of a peroxisomal disorder.
Genetics
Etiology
Pathogenic variants in genes related to the structure and function of peroxisomes (see the Genes Tested table)
Incidence
At least 1 in 50,000 live births
Genes Tested
| Gene | MIM # | Associated Disorder | Inheritance |
|---|---|---|---|
|
ABCD3 |
170995 |
Congenital bile acid synthesis defect |
AR |
|
ACBD5 |
616618 |
Retinal dystrophy with leukodystrophy |
AR |
|
ACOX1 |
609751 |
Peroxisomal acyl-CoA oxidase deficiency |
AR |
|
Mitchell Syndrome |
AD |
||
|
AGPS |
603051 |
RCPD type 3 |
AR |
|
AGXT |
604285 |
Primary hyperoxaluria |
AR |
|
AMACR |
604489 |
Alpha-methylacyl-CoA racemase deficiency |
AR |
|
DNM1L |
603850 |
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission |
AD, AR |
|
Optic atrophy |
AR |
||
|
FAR1 |
616107 |
Peroxisomal fatty acyl-CoA reductase (RCDP type 4) |
AR |
|
GNPAT |
602744 |
RCDP type 2 |
AR |
|
HSD17B4 |
601860 |
D-bifunctional protein deficiency, Perrault syndrome |
AR |
|
PEX1 |
602136 |
ZSD |
AR |
|
PEX10 |
602859 |
ZSD |
AR |
|
PEX11B |
603867 |
ZSD |
AR |
|
PEX12 |
601758 |
ZSD |
AR |
|
PEX13 |
601789 |
ZSD |
AR |
|
PEX14 |
601791 |
ZSD |
AR |
|
PEX16 |
603360 |
ZSD |
AR |
|
PEX19 |
600279 |
ZSD |
AR |
|
PEX2 |
170993 |
ZSD |
AR |
|
PEX26 |
608666 |
ZSD |
AR |
|
PEX3 |
603164 |
ZSD |
AR |
|
PEX5 |
600414 |
ZSD |
AR |
|
RCDP type 5 |
AR |
||
|
PEX6 |
601498 |
ZSD |
AR, AD |
|
PEX7 |
601757 |
RCDP type 1 |
AR |
|
PHYH |
602026 |
Refsum disease |
AR |
|
SCP2 |
184755 |
Leukoencephalopathy with dystonia and motor neuropathy |
AR |
Genotype-Phenotype Correlations
The majority of PEX5 variants are associated with ZSD. One variant, c.722dupA in coding exon 7, has been associated with RCDP type 5.
One PEX6 complex variant, p.Arg860Trp with *442_445delTAAA in cis, has been associated with autosomal dominant ZSD. However, p.Arg860Trp with homozygosity for *442_445delTAAA has been reported in unaffected individuals.
Loss-of-function variants in ACOX1 are associated with peroxisomal acyl-CoA oxidase deficiency. One gain-of-function variant, p.Asn237Ser, is associated with Mitchell syndrome.
Test Interpretation
Analytic Sensitivity
For massively parallel sequencing:
| Variant Class | Analytic Sensitivity (PPA) Estimatea (%) | Analytic Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
99.9 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
99.9 |
62.1-100 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
One or more pathogenic or likely pathogenic variants detected |
Confirms a diagnosis of a heritable peroxisomal disorder or related disorder Specific diagnosis depends on the variant(s) detected |
|
Inconclusive |
One or more variants of uncertain significance detected |
Unknown if the variant(s) are disease-causing or benign |
|
Negative |
No pathogenic variants detected |
Diagnosis of a peroxisomal disorder or related disorder is less likely, though not excluded |
Limitations
- A negative result does not exclude a heritable form of peroxisomal dysfunction.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
- Regulatory region and deep intronic variants
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
- ACBD5(NM_001352568) exon(s) 6
- ACBD5(NM_001352569) exon(s) 6
- ACBD5(NM_001352570) exon(s) 13
- ACBD5(NM_001352571) exon(s) 5
- ACBD5(NM_001352573) exon(s) 6
- ACBD5(NM_001352574) exon(s) 6
- ACBD5(NM_001352575) exon(s) 6
- ACBD5(NM_001352576) exon(s) 6
- ACBD5(NM_001352581) exon(s) 6
- ACBD5(NM_001352585) exon(s) 5
- ACBD5(NM_001352586) exon(s) 5
- ACBD5(NM_001352568) partial exon(s) 1(Chr10:27529638-27529648)
- ACBD5(NM_001352572) partial exon(s) 1(Chr10:27529638-27529648)
- SCP2(NM_001007098) exon(s) 11
- SCP2(NM_001330587) exon(s) 12
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
References
-
26220973
Barøy T, Koster J, Strømme P, et al. A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Hum Mol Genet. 2015;24(20):5845-5854.
-
29220678
Falkenberg KD, Braverman NE, Moser AB, et al. Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder. Am J Hum Genet. 2017;101(6):965-976.
-
32169171
Chung HL, Wangler MF, Marcogliese PC, et al. Loss- or gain-of-function mutations in ACOX1 cause axonal loss via different mechanisms. Neuron. 2020;106(4):589-606.e6.
Use to confirm a suspected diagnosis of a peroxisomal disorder, including peroxisome biogenesis disorders such as ZSDs and RCDP type 1 or single enzyme disorders such as Refsum disease. This test will not detect ABCD1 defects associated with X-linked adrenoleukodystrophy/adrenomyeloneuropathy.