Peroxisome Biogenesis Disorder 14b

A number sign (#) is used with this entry because this form of peroxisome biogenesis disorder (PBD14B) is caused by homozygous mutation in the PEX11B gene (603867) on chromosome 1q21. One such patient has been reported.

Description

PBD14B is an autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy (Ebberink et al., 2012), all of which had been observed in patients with mild peroxisomal biogenesis disorders (e.g., Kelley et al., 1986; Poll-The et al., 1987). Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, was reported.

Thoms and Gartner (2012) classified the disorder described by Ebberink et al. (2012) in their patient as a mild 'Zellweger syndrome (214100) spectrum' (ZSS) disorder. See PBD1B (601539) for a phenotypic description and discussion of genetic heterogeneity of less severe phenotypes on the Zellweger syndrome spectrum. See PBD9B (614879) for another atypical peroxisome biogenesis disorder.

Clinical Features

Ebberink et al. (2012) described a 26-year-old Dutch man with mild intellectual disability and a normal karyotype who was the fourth child of nonconsanguineous parents and had 2 healthy brothers and 1 healthy sister. The mother had had 3 miscarriages. After uncomplicated delivery and birth, with normal growth parameters, he was noted at 6 weeks of age to have bilateral congenital cataracts; these were extracted at 4 and 5 months, respectively. Early development was normal but after a surgery for hydrocele he underwent a remarkable regression, losing speech and ability to walk, and it took half a year for him to reach his former level. In general, when ill his condition became rather poor and he took a long time to recover. He had dry skin with scaling of the hands and feet. He developed progressive bilateral sensorineural hearing loss starting at the age of 7 years. At age 12, he was noted to have nystagmus with a rotatory component, normal strength, normal sensation, but symmetrically reduced reflexes in the upper extremities, areflexia in the lower extremities, and sensory abnormalities. Cardiac function was normal. Cerebral magnetic resonance imaging (MRI) showed a Chiari I malformation. Electroencephalogram (EEG) was normal. Electromyography (EMG) showed low normal motor conduction velocity and absent sensory responses. Over time he became wheelchair-bound and suffered from gastrointestinal problems and urinary incontinence. Since the age of 15, he had recurrent severe migraine-like episodes of photophobia, headaches, and vomiting, often following mental stress or physical exertion. Since the age of 16.5 years, he had been treated with valproic acid, coenzyme Q10, and carnitine.

Biochemical Features

Because of clinical features, Ebberink et al. (2012) suspected a mitochondrial or peroxisomal disorder in their patient and undertook extensive metabolic investigations. While microscopic examination of the patient's fibroblasts indicated a clear defect in peroxisomal division, all other biochemical parameters were normal, including very long chain fatty acids, phytanic acid, pristanic acid, bile acid intermediates, and erythrocyte plasmalogens. Immunofluorescence microscopy revealed an aberrant peroxisomal phenotype, with peroxisomes that varied markedly in size and number. Few fibroblasts had normal numbers of normal sized peroxisomes, but most fibroblasts had lower numbers of enlarged and elongated peroxisomes. In about 10% of patients fibroblasts, catalase was not located in peroxisomes but in the cytosol, although all fibroblasts of the patient contained peroxisomal membranes. After 3 days of culturing the cells at 40 degrees C, a complete absence of catalase-containing peroxisomes was noted in about 90% of fibroblasts. When cells cultured at 40 degrees C were shifted to 37 degrees C, it took 8 days for catalase-containing peroxisomes to reappear in about 90% of the cells.

Molecular Genetics

In a 26-year-old Dutch man with mild intellectual disability and a normal karyotype, Ebberink et al. (2012) found a homozygous nonsense mutation in the PEX11B gene resulting in no PEX11-beta protein (603867.0001). Overexpression of wildtype PEX11-beta in the patient's fibroblasts cultured at 40 degrees C changed the mutant peroxisome-deficient phenotype to the normal wildtype phenotype, and this defect could not be complemented by PEX11-alpha (603866). However, overexpression of wildtype PEX11-gamma (607583) in patient fibroblasts cultured at 40 degrees C showed partial compensation and resulted in elongated and enlarged peroxisomes in approximately 50% of transfected cells. The peroxisomal phenotype in patient cells overexpressing PEX11-gamma appeared similar to that observed in patient fibroblasts cultured at 37 degrees C, which suggested that the occurrence of the enlarged, elongated catalase-containing peroxisomes is related to the levels of PEX11-gamma.

Animal Model

Pex11-beta knockout mice show neonatal lethality and the severe pathologic features typical of Zellweger syndrome (see 214100), although biochemically they appeared only mildly affected in peroxisome metabolism (Li et al., 2002). Ebberink et al. (2012) hypothesized that the relatively mild phenotype of the patient was the result of partial compensation of PEX11G for the PEX11B defect.