Peroxisomal Disorders Panel, Sequencing

Content Review: September 2021 Last Update:

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.

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