Peroxisome Biogenesis Disorder 6b

A number sign (#) is used with this entry because of evidence that this form of peroxisome biogenesis disorder (PBD6B) is caused by compound heterozygous mutation in the PEX10 gene (602859) on chromosome 1p36.

Mutations in the PEX10 gene also cause the more severe phenotype Zellweger syndrome (PBD6A; 614870).

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. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (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 PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.

Clinical Features

Clayton et al. (1996) reported an 8-year-old girl who presented with progressive ataxia, tremor, and dysarthria at 3.5 years of age after normal early development. She had no other neurologic abnormalities. Brain imaging showed cerebellar atrophy and focal white matter lesions in the cerebral hemispheres. Laboratory studies showed a mild increase in liver enzymes, increased phytanic and pristanic acids, and increases in the bile acid intermediates THCA and DHCA, consistent with a peroxisomal disorder. However, beta-oxidation of branched-chain fatty acids was normal. Treatment with a low-phytanic acid diet resulted in normalization of the biochemical parameters and arrested the progression of ataxia. Steinberg et al. (2009) reported follow-up of the patient (PBD687) reported by Clayton et al. (1996). At age 17 years, she had slow speech and difficulty with handwriting, spelling, and calculations. She did not have nystagmus, but showed breakdown of pursuits and dysmetric saccades. She had marked ataxia, mild hypotonia, and a history of delayed menarche. Liver function was normal. Laboratory studies showed increased plasma pipecolic acid, DHCA, and THCA, but fibroblasts did not show any defects in peroxisome metabolism or assembly, even at higher temperatures.

Regal et al. (2010) reported 2 unrelated patients who presented around age 5 to 6 years with slowly progressive cerebellar ataxia, dysarthria, and a sensorimotor axonal neuropathy. Clinical features included gait ataxia, limb ataxia, impaired smooth pursuit, distal sensory impairment, and hypo- or areflexia in the lower limbs. Neither patient had mental retardation. Brain imaging showed cerebellar atrophy. Laboratory studies showed increased phytanic, pristanic, and pipecolic acids as well as increased bile acid intermediates. One patient had mildly abnormal liver function tests. Very long-chain fatty acids were normal. Fibroblasts from 1 patient showed peroxisomal mosaicism, with 20% of fibroblasts lacking normal peroxisomes. Regal et al. (2010) emphasized the mild phenotype in these patients.

Inheritance

The transmission pattern of PBD6B in the families reported by Clayton et al. (1996) and Regal et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient (PBD052) with NALD, Warren et al. (1998) identified compound heterozygous mutations in the PEX10 gene (H290Q; 602859.0002 and R125X; 602859.0003). Clinical features of the patient were not provided, but patient cells retained significant import of peroxisomal targeting signal-1 (PTS1)- and PTS2-containing matrix proteins, consistent with residual functional activity. Peroxisomal catalase, which carries an unusual form of PTS1, was found to be cytosolic in patient cells, and this defect was rescued by expression of wildtype PEX10.

In a young woman (PBD687) with a mild form of PBD6B manifest as cerebellar ataxia (Clayton et al., 1996), Steinberg et al. (2009) identified compound heterozygous mutations in the PEX10 gene (602859.0007 and 602859.0008). Steinberg et al. (2009) noted the mild and atypical phenotype associated with the peroxisomal disorder in this patient.

In 2 unrelated patients with PBD6B manifest as childhood-onset cerebellar ataxia and neuropathy, Regal et al. (2010) identified compound heterozygous mutations in the PEX10 gene (602859.0005; 602859.0009-602859.0011). Functional studies of the variants were not performed, but transfection of patient fibroblasts with wildtype PEX10 rescued the mildly abnormal peroxisomal phenotype.