Peroxisome Biogenesis Disorder 8b

A number sign (#) is used with this entry because this form of peroxisome biogenesis disorder (PBD8B) is caused by homozygous mutation in the PEX16 gene (603360) on chromosome 11p11.

Mutations in PEX16 also cause Zellweger syndrome (PBD8A; 614876).

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 PEX16 gene have cells of complementation group 9 (CG9, equivalent to CGD). For information on the history of PBD complementation groups, see 214100.

Clinical Features

Ebberink et al. (2010) studied 6 patients, including 1 previously reported by Pineda et al. (1999), with a relatively mild peroxisome biogenesis disorder. Two sibs presented between age 1 and 2 years with delayed walking and frequent falls after normal initial development. The disorder was progressive and was characterized by lower limb spasticity and ataxia resulting in wheelchair dependence in the first decade. Other features included optic atrophy, cataracts, dysarthria, dysphagia, constipation, and a peripheral demyelinating motor and sensory neuropathy. Brain imaging showed progressive white matter abnormalities involving many brain regions. Cognition was relatively preserved. Studies of skin fibroblasts showed that peroxisomes were markedly enlarged in size and reduced in number compared to controls. However, biochemical studies showed only mild abnormalities, such as increased very long chain fatty acids (VLCFA), increased bile acid intermediates, and increased branched chain fatty acids (only found in 1 sib). Phytanic acid alpha-oxidation, pristanic acid beta-oxidation, and red cell plasmalogen were normal. Peroxisomal enzymes were normal, and the peroxisomes were import-competent. The other patients displayed similar symptoms.

Molecular Genetics

In 6 patients with a mild PBD, Ebberink et al. (2010) sequenced all known PEX genes and identified mutations in PEX16 in each patient (603360.0003-603360.0005). Expression of wildtype PEX16 restored the number and size of peroxisomes in patient fibroblasts to normal. Ebberink et al. (2010) emphasized that even though PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with a relatively mild phenotype showing import-competent peroxisomes in fibroblasts.