Peroxisome Biogenesis Disorder 3b

A number sign (#) is used with this entry because this form of peroxisome biogenesis disorder (PBD3B) is caused by homozygous or compound heterozygous mutation in the PEX12 gene (601758) on chromosome 17. Mutations in the PEX12 gene also cause Zellweger syndrome (PBD3A; 614859).

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 PEX12 gene have cells of complementation group 3 (CG3). For information on the history of PBD complementation groups, see 214100.

Clinical Features

Christensen et al. (1990) described a patient with ataxia, dysarthric speech, dry skin, hypotonia, and absent reflexes.

Gootjes et al. (2004) reinvestigated the patient of Christensen et al. (1990), a girl from unrelated parents. At age 5 years, an elevated plasma level of phytanic acid was found, and physical examination revealed psychomotor retardation, hypotonia, ataxia, dysarthria, convergent strabismus, nystagmus, and absent deep tendon reflexes. CT of the brain, EMG, nerve conduction velocity (NCV), visual evoked potential (VEP), electroretinogram (ERG), auditory brainstem response (ABR), and somatosensory evoked potential (SSEP) were within normal limits. She was unable to walk without support. After treatment with a phytanic acid-restricted diet, she was able to take 3 or 4 steps without support. Bilateral sensory hearing loss was detected at age 8 years. Mental evaluation at age 15 years revealed a functional level of 7 to 8 years. Bilateral Achilles tendon extensions were performed at age 16 years. Because of persistent ataxia and instability of the lower extremities, triple arthrodeses of the ankles was done at age 20 and 22 years. She was eventually able to take approximately 30 steps without support. Electroretinogram at age 18 years showed lack of flicker response at 32 Hz, and ophthalmoscopy suggested early retinitis pigmentosa. She had no dysmorphic features.

Gootjes et al. (2004) described a patient, the child of consanguineous Arab Muslim parents, with a comparatively mild peroxisomal biogenesis disorder who was alive at the age of 8 years. The patient had broad nasal bridge, hypertelorism, external ear deformity, hypotonia, and psychomotor retardation. No cataract was present but there was nystagmus and hearing deficit. By age 4 years the patient could not sit or walk unsupported and had no intentional hand use.

Biochemical Features

Christensen et al. (1990) found that their patient had elevated plasma levels of phytanic acid and bile acid intermediates, but normal phytanic acid oxidation in fibroblasts. Furthermore, C26:0 beta-oxidation, very long chain fatty acids (VLCFA) levels, dihydroxyacetonephosphate-acyltransferase (DHAPAT) activity, and de novo plasmalogen biosynthesis in fibroblasts were normal.

Ten Brink et al. (1994) found that pristanic acid was also elevated in plasma from this patient. Phytanic acid levels in plasma normalized after the patient was prescribed a phytanic acid-restricted diet, whereas pristanic acid remained elevated. It was concluded that the patient had a deficiency of the enzyme responsible for the first step of beta-oxidation of DHCA, THCA, and pristanic acid.

Clinical Management

Gootjes et al. (2004) reported that a phytanic acid-restricted diet in their patient caused plasma phytanic acid to decrease to trace levels, where they remained. The diet improved motor strength and balance, and she was able to take 3 or 4 steps without support.

Molecular Genetics

In a patient with a mild peroxisomal biogenesis disorder of complementation group 3 who had originally been diagnosed with trihydroxycholestanoyl-CoA oxidase deficiency, Gootjes et al. (2004) detected compound heterozygosity for a nonsense mutation (R180X; 601758.0005) and a missense mutation (L317F; 601758.0010) in the PEX12 gene.

Gootjes et al. (2004) studied 8 patients with peroxisomal biogenesis disorder (PBD) of relatively mild types compared to the entire PBD spectrum. Seven of these patients came from consanguineous families; in the eighth patient this was unknown. All patients had been diagnosed with neonatal adrenoleukodystrophy or infantile Refsum disease, or had overlapping symptoms. In all of these patients a homozygous missense mutation (S320F; 601758.0006) in the PEX12 gene was found.