Peroxisome Biogenesis Disorder 5b

A number sign (#) is used with this entry because of evidence that this form of peroxisome biogenesis disorder (PBD5B) is caused by homozygous or compound heterozygous mutation in the PEX2 gene (170993) on chromosome 8q21. Mutations in the PEX2 gene also cause the more severe disorder Zellweger syndrome (PBD5A; 614866).

Description

The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. 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 PEX2 gene have cells of complementation group 5 (CG5, equivalent to CG10 and CGF). For information on the history of PBD complementation groups, see 214100.

Clinical Features

Shimozawa et al. (1999) studied a Welsh female with IRD who presented at the age of 1 year with delayed milestones and joint laxity. Later, retinitis pigmentosa manifested and biochemical investigation showed accumulation of very long chain fatty acids (VLCFAs) and phytanic acid and an abnormal bile acid profile. The activities of dihydroxyacetone phosphate acyltransferase (DHAP-AT) were reduced in platelets and fibroblasts. The patient died at 3 years of age following an episode of bronchiolitis.

Mandel et al. (1994) reported 2 brothers, aged 5 and 9 years, with neurodegenerative symptoms after the first year of life. They were born to consanguineous Israeli Arab parents. Both sibs were found to have elevated levels of plasma very long chain fatty acids, pipecolic and phytanic acids, and abnormal bile acid intermediates, suggesting a generalized peroxisome deficiency disorder. Peroxisomes were absent in 90% of hepatocytes, but normal peroxisomal functions were found in fibroblasts. Gootjes et al. (2004) reported further on the older brother. His development was described as normal in infancy, but by the age of 22 months, he had hypotonia, could not walk unassisted, and had cerebellar and vermian atrophy on MRI. The patient continued to deteriorate and died from pneumonia at age 13.

Sevin et al. (2011) reported 2 brothers, born of unrelated parents, who developed isolated progressive cerebellar ataxia at ages 3.5 and 18 years, respectively. The younger brother developed mild dysarthria at age 2.5 years and gait disturbances at age 3.5 years. He had a broad-based gait, but was able to run and climb stairs at age 7. The symptoms worsened at age 9: he was unable to run, had difficulty writing, and showed tremor, nystagmus, slow saccades, and hyporeflexia. Cognition was reported as normal. The older brother developed cerebellar signs with ataxia, dysmetria, dysarthria, hyporeflexia, and slow saccades with oculomotor apraxia at age 18 years. Brain imaging in both patients showed cerebellar atrophy. Laboratory studies showed increased phytanic and pristanic acid and moderately increased bile acid intermediates (DHCA and THCA). Very long-chain fatty acids were near normal, and pipecolic acid and plasmalogen synthesis were normal. These findings were consistent with a mild peroxisomal disorder.

Mignarri et al. (2012) reported a 51-year-old Italian man with a mild form of PBD5B, who had experienced childhood onset of slowly progressive cerebellar ataxia characterized by increased falls and unsteady walking at age 3 years. Clinical features as an adult included gait ataxia, gaze-evoked nystagmus, hypoacusis, dysarthria, dysmetria, areflexia, and pes cavus. Electrophysiologic studies showed a severe axonal sensorimotor polyneuropathy. Cognition was intact. Brain imaging showed cerebellar and pontine atrophy without signal abnormalities. Laboratory studies showed increased very long chain fatty acids, increased pristanic and phytanic acid, and increased bile acid intermediates, consistent with a mild peroxisomal defect.

Inheritance

The transmission pattern of PBD5B in the families reported by Sevin et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Welsh patient with IRD, Shimozawa et al. (1999) detected compound heterozygosity for a missense mutation (E55K; 170993.0002) and a nonsense mutation (R118X; 170993.0001) in the PEX2 gene.

In 1 of the sibs reported by Mandel et al. (1994) with a peroxisomal disorder, Gootjes et al. (2004) identified a homozygous mutation in the PEX2 gene (W223X; 170993.0005).

In 2 brothers with isolated cerebellar ataxia and biochemical evidence of a mild peroxisomal disorder, Sevin et al. (2011) identified a homozygous truncating mutation in the PEX2 gene (c.865_866insA; 170993.0006). Patient fibroblasts showed normal peroxisomes and contained catalase, suggesting that the mutant protein is localized correctly in the peroxisomal membrane and retains some activity. Further functional studies were not performed. The report expanded the phenotypic spectrum associated with PEX2 mutations to include mild and isolated autosomal recessive cerebellar ataxia.

In a 51-year-old Italian man, born of unrelated parents, with PBD5B manifest as childhood-onset cerebellar ataxia and an axonal sensorimotor polyneuropathy, Mignarri et al. (2012) identified compound heterozygosity for 2 previously identified mutations in patients with PBD5B (170993.0001 and 170993.0006). Patient fibroblasts showed mosaicism for a peroxisomal defect.