Peroxisome Biogenesis Disorder 4b

A number sign (#) is used with this entry because of evidence that this form of peroxisome biogenesis disorder (PBD4B) is caused by homozygous or compound heterozygous mutation in the PEX6 gene (601498) on chromosome 6p21.1, or overexpression of a heterozygous mutation in PEX6 due to allelic expression imbalance (AEI) resulting from a polymorphism on the mutant allele in the PEX6 3-prime UTR.

Mutations in the PEX6 gene also cause Zellweger syndrome (PBD4A; 614862) and Heimler syndrome-2 (HMLR2; 616617).

Description

Peroxisome biogenesis disorder-4B (PBD4B) includes the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012).

For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539.

Individuals with mutations in the PEX6 gene have cells of complementation group 4 (CG4, equivalent to CG6 and CGC). For information on the history of PBD complementation groups, see 214100.

Clinical Features

Najmabadi et al. (2011) studied 5 sibs (family M331) with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children.

Falkenberg et al. (2017) studied 7 unrelated patients and 1 half-brother who all exhibited characteristic features of a Zellweger spectrum disorder. Most had visual impairment and/or sensorineural hearing loss, and liver dysfunction was also frequently noted. One patient had adrenal insufficiency. All affected individuals showed neurologic involvement, including profound hypotonia, gait abnormalities, developmental delay, and neuropathy, as well as white matter abnormalities on brain MRI. Biochemical analysis revealed aberrant peroxisomal metabolite levels in patient blood and fibroblasts, and patient fibroblasts showed an import defect of peroxisomal matrix proteins. The clinical course was progressive, without a clear episode of rapid deterioration. Four patients died between 8 and 20 years of age, whereas 4 patients were still alive and in their first decade of life at the time of the study.

Molecular Genetics

Matsumoto et al. (2001) found compound heterozygosity for mutations in the PEX6 gene (601498.0007, 601498.0008) in a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) of PBD complementation group 6. This patient was Patient 6 of Kelley et al. (1986).

The 5 sibs in the study of Najmabadi et al. (2011) carried a homozygous frameshift mutation in the PEX6 gene (601498.0009).

In 4 unrelated patients with a phenotype consistent with a Zellweger spectrum disorder (ZSD), Falkenberg et al. (2017) performed functional genetic complementation of patient fibroblasts or fused cell complementation and identified defective PEX6 as the cause of the disease. Sanger sequencing identified a heterozygous R860W mutation (601498.0015) in the PEX6 gene in all 4 individuals, but no second mutation was detected. Heterozygosity for the same R860W mutation was independently identified by Sanger sequencing in 3 more unrelated patients with a similar phenotype and 1 affected half-brother. Peroxisome-specific gene-panel sequencing in 4 of the patients and whole-exome sequencing in 2 other patients did not reveal additional pathogenic variants in other genes encoding peroxisomal proteins. In 2 patients, the PEX6 mutation was shown to have occurred de novo, but in 3 families, it was inherited from an unaffected parent (parental DNA was unavailable in the remaining 2 families). Analysis of PEX6 mRNA from affected individuals demonstrated allelic expression imbalance (AEI), with levels of mutant cDNA that were consistently 3 to 5 times higher than those of wildtype PEX6. In contrast, the cDNA levels of wildtype and mutant PEX6 alleles were equal in an unaffected mother who carried the R860W mutation. Comparison of common variants in PEX6 between the affected individuals and the unaffected carrier parents identified a c.*442_445delTAAA polymorphism (rs144286892) in the 3-prime UTR that correlated with AEI of PEX6 when present in heterozygosity but not homozygosity; the polymorphism was heterozygous and in cis with the R860W mutation in all 8 affected individuals, but homozygous in the 3 unaffected carrier parents. Functional analysis indicated that the PEX6 R860W mutation has a negative effect on PEX1 (602136)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6.