Introduction. Overview

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1 Disorders of peroxisome assembly Steven J Steinberg PhD (Dr. Steinberg of Johns Hopkins University School of Medicine has no relevant financial relationships to disclose.) Nancy E Braverman MD (Dr. Braverman of the Institute for Genetic Medicine at Johns Hopkins University School of Medicine has no relevant financial relationships to disclose.) Raphael Schiffmann MD, editor. (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Sanofi Genzyme.) Originally released December 28, 1993; last updated August 9, 2007; expires August 9, 2010 Notice: This article has expired and is therefore not available for CME credit. Introduction This article includes discussion of disorders of peroxisome assembly, peroxisomal polyenzymopathies, group 1 peroxisomal disorders, disorders of peroxisome biogenesis, generalized peroxisomal disorders, disorders of peroxisome assembly, Zellweger syndrome, cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview The peroxisome biogenesis disorders are a heterogeneous group of rare autosomal recessive diseases. The underlying defect is the failure to form functional peroxisomes, resulting in deficiencies of multiple enzymes targeted to this organelle and progressive, multisystem diseases. Two clinical categories of disease are distinguished, Zellweger spectrum and Rhizomelic chondrodysplasia punctata spectrum. The authors describe the 2 clinical spectra of peroxisome assembly defects and highlight the marked strides in understanding the molecular pathology made over the past decade. Historical note and terminology Microbodies were first described in mouse kidney by Rhodin in Purified microbodies from rat liver were active in peroxide-linked oxidation reactions, leading to the name "peroxisomes" (Lazarow and Moser 1995). The ubiquitous presence of these single-membraned organelles, their role in fatty acid oxidation, and their absence in patients with Zellweger syndrome (Goldfischer et al 1973) stimulated interest in peroxisome biology. A reliable assay for peroxisome dysfunction based on elevated serum very long-chain fatty acids defined a new category of human metabolic disease (Moser et al 1999). The peroxisome biogenesis disorders may affect the brain, retina, craniofacies, kidney, and skeleton (Zellweger 1987; Brown et al 1993; Lazarow and Moser 1995). The failure to assemble normal peroxisomes and the impaired ability to import peroxisome matrix proteins result in multiple deficiencies of peroxisomal enzymes. Disorders of peroxisome assembly can be divided into 2 classes: the Zellweger syndrome spectrum and rhizomelic chondrodysplasia punctata. Zellweger spectrum is defined by the clinical disorders of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. These disorders were described before the relationship to peroxisome deficiency was known and thus the terms do not relate directly to the underlying gene defect. In order to determine the genes involved in the peroxisome biogenesis disorders, patient fibroblast cell lines were collected and fused for biochemical complementation. This approach defined at least 13 complementation groups, each predicted to represent a different gene defect (Moser et al 1995). Many PEX genes were subsequently identified by screening human cdna libraries (Dodt et al 1996). PEX genes encode proteins referred to as peroxins. In sum, 12 PEX genes are associated with Zellweger spectrum disorders (Steinberg et al 2004). In contrast, rhizomelic chondrodysplasia type 1 is associated exclusively with a defect in the PEX7 gene (Braverman et al 1997). A variety of historic labels have been ascribed to the Zellweger spectrum (cerebrohepatorenal syndrome, hyperpipecolic acidemia). In addition, some patients initially diagnosed with Usher syndrome or Leber congenital amaurosis were later shown to have assembly defects (Ek et al 1986; Raas-Rothschild et al 2002).

2 Clinical manifestations Presentation and course Both Zellweger spectrum and rhizomelic chondrodysplasia punctata show an overlapping range of phenotypes from severe to mild. The variation in disease severity is secondary to the effect of the mutation on protein function, but not to the specific PEX gene involved. A summary of clinical and biochemical phenotypes are found in table 1. Table 1. Clinical and Biochemical Phenotypes in Peroxisome Biogenesis Disorder Patients Syndrome Clinical Biochemical Zellweger syndrome Neonatal adrenoleukodystrophy Infantile Refsum disease Rhizomelic chondrodysplasia punctata Hypotonia Seizures Cataracts Dysmorphic facies Liver disease Demise months Hypotonia Seizures +/- dysmorphia Demise months Mental retardation Hearing loss Pigmentary retinopathy Survive at least several years Prominent skeletal abnormalities with proximal shortening of long bones and coronal clefts in vertebrae Ichthyosis Cataracts Mental retardation VLCFA = very long-chain fatty acids * Phytanic acid levels are age and diet dependent, and are normal in infancy. VLCFA plasmalogens phytanic acid* VLCFA plasmalogens phytanic acid* VLCFA plasmalogens phytanic acid* Normal VLCFA plasmalogens phytanic acid* Zellweger spectrum. This spectrum includes, from most severe to more mild, Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Children with these disorders have significant morbidity including retinopathy, hearing loss, liver and adrenal dysfunction, seizures, and mental retardation. Although these disease names remain useful for teaching purposes, individual patients can exhibit a great deal of variation from the stereotyped category. Zellweger patients are distinguished by facial dysmorphology, chondrodysplasia punctata (limited compared to rhizomelic chondrodysplasia punctata), profound hypotonia, and minimal psychomotor development. They are diagnosed early and most die within the first year of life secondary to infection, aspiration, progressive liver disease, or their underlying neurologic dysfunction. Infantile Refsum disease patients may survive through adolescence and manifest moderate to severe mental retardation, progressive retinopathy, and deafness. General appearance. The classic Zellweger patient has a normal birth weight but exhibits striking hypotonia and growth failure. They have a characteristic facial appearance with a high forehead, large anterior fontanel, flat supraorbital ridges, epicanthal folds, broad nasal bridge, small nose with anteverted nares, and external ear abnormalities (Lazarow and Moser 1995). The stereotypic Zellweger facies is less apparent in milder patients. Eye abnormalities. Visual defects are common and include corneal clouding, cataracts and congenital glaucoma, as well as optic atrophy and pigmentary retinopathy. Virtually all infantile Refsum disease patients have pigmentary degeneration of the retina and a depressed ERG. Leopard spot pigmentation, characterized by areas of photoreceptor degeneration with patchy hypertrophy, nodular hyperplasia, and atrophy of the pigment epithelium is observed in neonatal adrenoleukodystrophy patients (Lyons et al 2004).

3 Neurologic features. There are 3 major types of neurologic involvement: neuronal migration abnormalities, white matter abnormalities, and selective neuronal involvement (Powers and Moser 1998). This is reflected on exam by profound hypotonia, poor suck, and depressed neonatal and deep tendon reflexes. In Zellweger syndrome, seizures are common and there is minimal psychomotor development. Hearing loss and retinal degeneration occur in all milder patients. Leukodystrophy may develop in longer surviving patients. The EEG, brainstem auditory evoked responses, and somatosensory evoked responses are typically abnormal in Zellweger syndrome (Govaerts et al 1985). MRI of the brain can show impaired myelination, abnormal cortical gyral patterns, ventricular dilatation, and germinolytic cysts (Barkovich and Peck 1997). Visceral abnormalities. Hepatocellular disease with liver enlargement is observed in 78% of Zellweger cases, fibrosis in 76%, micronodular cirrhosis in 37%, and cholestasis in 59%. Liver biopsy may reveal striking iron storage and periportal inflammation, but the iron storage is diminished after age 20 weeks. There are renal cortical cysts best visualized by CT scan, with 78 of 80 patients demonstrating renal cysts at autopsy. Renal functional defects include generalized aminoaciduria and proteinuria. Adrenal function may be deficient on provocative testing or during crises, and severe infections are frequent. Cardiac anomalies are also increased, with 32% of patients having ventricular septal defects and 22% having aortic abnormalities. Genital anomalies include cryptorchidism or labial hypoplasia and clitoromegaly (Lazarow and Moser 1995). Rhizomelic chondrodysplasia punctata spectrum. Rhizomelic chondrodysplasia punctata spectrum includes classic severe disease, milder variants, and some cases of adult Refsum disease (Braverman et al 2002). Around 90% of patients have severe disease and rarely survive beyond childhood; 25% die in early infancy. Rhizomelic chondrodysplasia punctata is distinguished by shortening of the proximal limbs (rhizomelia), extensive punctate calcifications in cartilage (chondrodysplasia punctata), congenital cataracts, and profound growth and developmental delays. Most children have seizures. Cervical spine stenosis may be under appreciated, and spinal cord compression secondary to the chondrodysplasia is reported (Khanna et al 2001). Ichthyotic skin changes are noted in less than one third of individuals. As in Zellweger spectrum, there is a slightly increased incidence over that in the general population for congenital malformations such as cleft palate, and renal and cardiac malformations. Death is often secondary to respiratory complications from chronic aspiration, restricted chest wall movement, and a small pulmonary cage (White et al 2003). Cranial imaging and MR spectroscopy have shown delayed myelination, decreased choline to creatine ratios, and increased levels of mobile lipids, thought to reflect the deficiency of plasmalogens, which are substantial components of myelin (Alkan et al 2003). Prognosis and complications The average age at death for Zellweger syndrome patients was around 12 weeks with liver failure and respiratory infections as common precipitating factors (Wilson et al 1986). Patients with neonatal adrenoleukodystrophy and infantile Refsum disease vary in prognosis; although they have multiple disabilities, they survive longer. Complications include refractory seizures, liver disease with gastrointestinal bleeding and coagulopathy, failure to thrive, adrenal insufficiency, susceptibility to routine infection, and osteopenia secondary to hepatorenal disease. Surviving patients usually have progressive visual and hearing loss. Nearly all patients are mentally retarded. A recent study has suggested that in combination the activities of dihydroxyacetonephosphate: acyltransferase and C26:0 acid oxidation correlate with life expectancy (Gootjes et al 2002). These studies require corroboration. Homozygosity for PEX1-I700fs and PEX1-G843D are associated with severe and mild disease, respectively. The majority of rhizomelic chondrodysplasia punctata patients show early demise. Of those that survive infancy, 50% are alive at age 5 years, but only a fraction are alive at 10 years. The majority of children do not progress in their development beyond the 3-month level (White et al 2003). The grave prognosis has severely curtailed the degree of interventions. Seizures and respiratory complications are the typical causes of death. Homozygosity for PEX7-L292X predicts a severe course. Clinical vignette A newborn female was referred for evaluation of severe hypotonia, poor feeding, large anterior fontanel, bilateral talipes equinovarus, and an unusual face with bitemporal hollowing, broad nasal root, and down-turned corners of the mouth. The family and gestational histories were normal. Ophthalmology examination revealed retinitis pigmentosa, and there was hepatomegaly (liver edge 4 cm below the right costal margin) with elevated liver enzyme levels

4 including serum alanine aminotransferase (237 U/mL), alkaline phosphatase (1380 U/mL), and lactic dehydrogenase (610 U/mL). A skeletal survey revealed large patellae with punctate calcification around the hips and a delayed bone age. A normal karyotype, elevated urinary pipecolic acid, decreased red blood cell plasmalogens, and increased serum very long-chain fatty acids were consistent with the diagnosis of Zellweger syndrome (Moser et al 1999). The child exhibited minimal developmental progress and died at age 6 months with disseminated intravascular coagulation and hepatic failure. Biological basis Etiology and pathogenesis Disorders of peroxisome assembly are inherited in an autosomal recessive fashion. About 85% of patients with a Zellweger spectrum phenotype and elevated plasma very long-chain fatty acids have a defect in peroxisome assembly. The remaining patients have single enzyme defects in 1 of 2 enzymes required for peroxisomal fatty acid metabolism: Acyl-CoA oxidase or D-bifunctional protein (Watkins et al 1995). About 95% of patients with rhizomelic chondrodysplasia punctata have a defect in PEX7, referred to as type 1 (Braverman et al 1997; Motley et al 1997). The remaining patients have single enzyme defects in 1 of the first 2 peroxisomal steps of plasmalogen synthesis: dihydroxyacetone phosphate: acyltransferase (type 2) and alkyl-dihydroxyacetone phosphate synthase (type 3) (Hebestreit et al 1996; de Vet et al 1998). The Zellweger spectrum is associated with defects in at least 12 different PEX genes that encode proteins required for peroxisome biogenesis. It is not possible to predict the PEX gene defect of a Zellweger spectrum patient based on phenotype alone. In contrast, biochemical testing distinguishes the 3 types of rhizomelic chondrodysplasia punctata. The estimated frequency of each gene defect in Zellweger spectrum patients is shown in Table 2. PEX1 is by far the most common cause of Zellweger spectrum defects and approximately 96% of these patients have a defect in 1 of 6 genes: PEX1, PEX2, PEX6, PEX10, PEX12, or PEX26 (Steinberg et al 2004). Table 2. PEX Gene Defects Associated with Peroxisome Biogenesis Disorders Role in peroxisome assembly Membrane synthesis PEX gene Estimated frequency in spectrum PEX16 PEX19 PEX3 <1% <1% <1% Peroxisome targeting signal-1 receptor PEX5 2% Docking site for matrix protein import Translocation site for protein import Recycling of targeting receptors Peroxisome targeting signal-2 PEX13 PEX14 PEX2 PEX10 PEX12 PEX26 PEX6 PEX1 PEX7 <1% <1% 3% 3% 5% 5% 10% 70% 95% of rhizomelic chondrodysplasia punctata General model of peroxisome assembly and matrix import. The cellular origin of peroxisomes has been controversial. Previously it was believed that peroxisomes arose from fission of pre-existing peroxisomes (Lazarow 2003), but there is recent evidence suggesting that peroxisomes can also arise de novo from endoplasmic reticulum membranes (Kunau 2005). The key steps of peroxisome matrix protein import are listed in Table 2. The import process begins when matrix proteins are synthesized on free cytosolic ribosomes. PEX5 and PEX7 encode the peroxisome targeting signal receptors, and escort matrix proteins bearing the signals PTS1 (C-terminal-SKL) and PTS2 (N-termina- -R/KX5Q/HL-) to the peroxisome membrane. PEX13 and PEX14 encode peroxisome membrane proteins that are the putative docking site for the receptor-matrix protein complex. Peroxisome membrane proteins encoded by the genes PEX10, PEX12, and PEX2 provide the site of matrix protein transport across the membrane. PEX1, PEX6, and PEX26 play an important role in recycling PEX5 and PEX7 for another round of import (Weller et al 2003).

5 Cellular and molecular pathogenesis. PEX gene defects can be characterized based on their impact on peroxisome assembly at the cellular level. For example, patients with PEX3, PEX16, and PEX19 defects appear to have no residual peroxisome structures in cell culture. In contrast, PEX7 defects do not affect peroxisome morphology, but fail only to import PTS2 matrix proteins. The remaining PEX gene defects perturb peroxisome metabolism globally, but retain residual peroxisome structures, termed ghosts (Santos et al 1988). Most of what is known about peroxisome morphology comes from the study of liver biopsies or cultured skin fibroblasts. Interestingly, there is not always concordance between these in the same patient, with liver usually displaying more severe abnormalities. In the majority of Zellweger samples, hepatic peroxisomes were not detectable or were present in small numbers (Depreter et al 2003). This is different from cultured fibroblasts, in which most Zellweger cells have peroxisomes that are reduced in number, but enlarged in size as compared to normal controls (Santos et al 1988). In rhizomelic chondrodysplasia punctata hepatic peroxisomes appear enlarged, but have normal morphology in fibroblasts (Depreter et al 2003). Furthermore, the assembly defect is strongly influenced by the class of gene mutation. PEX mutations predicted to result in null alleles are associated with Zellweger syndrome, and missense mutations are more often associated with neonatal adrenoleukodystrophy or infantile Refsum disease. Around 80% of patients with PEX1 defects have at least 1 of 2 common mutations, I700fs and G843D. Homozygosity for the nonsense allele I700fs is associated more often with Zellweger syndrome, whereas homozygosity for the missense allele G843D is associated with infantile Refsum disease (Poll-The et al 2004). PEX7-L292X homozygosity is also severe. Histological abnormalities. In Zellweger spectrum, neuropathological studies have demonstrated a defect in neuronal migration that begins about the third month of gestation. Macroscopically brains frequently have polymicrogyria and pachygyria, hypoplasia of the corpus callosum, and deficient olfactory lobes (Wilson et al 1986). Microscopically detectable changes include heterotopias of the cerebral neurons and Purkinje cells of the cerebellum, dysplasia of the olivary complex, and hypomyelination. Demyelination is a frequent complication of older patients. Trilamellar inclusions can be detected in the brain, adrenal gland, and kidney. In rhizomelic chondrodysplasia punctata, routine brain imaging is normal or has shown delayed myelination with cerebral and cerebellar atrophy. Lens pathology has not been reported. In the CNS, there is a general decrease in neuron number and white matter, dysplastic olives, and progressive cerebellar degeneration (Powers et al 1999). In epiphyseal bone, the most marked abnormalities are in the resting cartilage, which shows focal areas of degenerating chondrocytes, calcification, cyst formation, and vascularization. The zone of hypertrophic chondrocytes is diminished and disorganized (Dimmick and Applegarth 1993). Animal models. Null mouse models have been developed for PEX2, PEX5, PEX7, PEX11beta, and PEX13.These mice have severe phenotypes, as expected. PEX2 Zellweger mice have been useful for defining the neuropathology that is observed in these disorders (Faust 2003; Faust et al 2005). Biochemical analysis of PEX2 mutant mice shows the characteristic accumulation of very longchain fatty acids and deficient plasmalogens in a wide variety of tissues. These mice have severe growth retardation, hypotonia, spasticity, microencephaly, failure to thrive, malnutrition attributed to abnormal bile acid formation, and severe gait abnormalities. In the CNS, peroxisomes are more abundant in differentiating neurons and constitute important factors determining neuronal polarity and migration. Cerebellar foliation is abnormal in PEX2 mice and there are an increased number of granular neurons that undergo apoptosis. Cerebellar layer formation is delayed and there is increased thickness in the internal and external granular layers, compatible with delays in neuronal migration. Purkinje cell morphology is abnormal. PEX5 null mice lacked morphologically identifiable peroxisomes and have biochemical abnormalities consistent with Zellweger syndrome. Intrauterine growth retardation, hypotonia at birth, and demise within 72 hours were prominent phenotypic features (Baes et al 1997). The brain showed impaired neuronal migration, maturation, and extensive neuronal apoptosis. Cellular studies showed proliferation of pleomorphic mitochondria with functional mitochondrial abnormalities (Baumgart et al 2001). These might relate to increased oxidation secondary to deficient peroxisomal catalase and superoxide dismutase, and was suggested as a factor in the pathogenesis of Zellweger syndrome. Of note, mitochondrial dysfunction was implicated in the first Zellweger syndrome patients described (Goldfischer et al

6 1973). Detailed analysis of the PEX5 null murine model has demonstrated that docosahexaenoic acid and isoprenoid/cholesterol deficiency are unlikely to make a major contribution to pathogenesis (Janssen et al 2000; Vanhorebeek et al 2001). PEX13 null mice are similar to PEX2 and PEX5 deficient mice (Maxwell et al 2003). PEX11beta null mice have neuronal migration defects, enhanced neuronal apoptosis, hypotonia, and neonatal lethality. Surprisingly, there are no defects in peroxisomal matrix protein import and only mild deficiencies of beta-oxidation and ether lipid biosynthesis, challenging the idea that the clinical features are directly related to these cellular abnormalities (Li et al 2002). PEX7 null mice mimic the severe rhizomelic chondrodysplasia punctata clinical and biochemical phenotype. These mice are hypotonic with growth impairment and the majority do not survive weaning. Neuronal density is increased in the intermediate zone of the cerebral cortex; these mice also have a delay in neuronal migration (Brites et al 2003). Endochondral ossification is also delayed. These mouse models are useful to study therapeutic applications. Docosahexaenoic acid supplementation in the PEX5 mouse did not result in clinical improvement (Baes et al 2000). In contrast, bile acid supplementation of the PEX2 mouse increased survival, growth, and cerebellar development (Faust et al 2005). Epidemiology" Danks has estimated a 1 in 100,000 incidence of Zellweger syndrome in Australia. When considering the full spectrum, the panethnic incidence is estimated to be 1 in 50,000 (Moser et al 1995). PEX1 deficiency has an estimated incidence of 1 in 71,000 in North American and European populations. The other causes of Zellweger spectrum are much more rare (1 in 300,000 to 1,000,000). Population differences are known; for example, Zellweger spectrum is less common in Japan (1 in 500,000) and the most common underlying gene defect is PEX10 deficiency. Rhizomelic chondrodysplasia type1 has an estimated incidence of 1 in 100,000. There is a common mutation, L292X, representing a founder allele in the northern European Caucasian population. Prevention Prenatal diagnosis is generally performed using cultured chorionic villus cells or amniocytes after an index case is proven to have a peroxisome assembly defect. Prenatal testing can also be performed directly on uncultured amniocytes or chorionic villi by DNA, enzyme, or immunoblot analysis. If the gene defect is known, it may be possible to perform preimplantation genetic diagnosis. Differential diagnosis Severe hypotonia in infancy associated with eye, liver, or brain demyelination can also be seen in glutaric aciduria type II and muscle-eye-brain disease, a defect in O-mannosyl glycan synthesis. Other entities associated with severe hypotonia include Prader-Willi syndrome and congenital myopathies. The differential diagnosis for neonatal seizures also includes molybdenum cofactor deficiency, sulfite oxidase deficiency, nonketotic hyperglycinemia, Aicardi syndrome, disorders of the mitochondrial respiratory chain, and chromosomal abnormalities. Diagnoses that have been considered in Zellweger spectrum patients with an atypical presentation include Werdnig-Hoffman disease (Baumgartner et al 1998), Niemann-Pick type C (Schedin et al 1997), Charcot Marie Tooth, ataxia and cholestasis (Clayton et al 1996), Usher syndrome, and late onset leukodystrophy (Moser et al 1995). Other causes of chondrodysplasia punctata include defects in arylsulfatase E (CDPX1) (Brunetti-Pierri et al 2003), sterol isomerase (CDPX2) (Braverman et al 1999), maternal vitamin K deficiency or warfarin use, and maternal autoimmune disease (Wessels et al 2003). Diagnostic workup Biochemical investigation of peroxisomal function is warranted if the clinical picture includes abnormalities in the following systems: craniofacial, neurologic (hypotonia, seizures, peripheral neuropathy), neurosensory (visual or hearing abnormalities), hepatic, skeletal, hypocholesterolemia, and failure to thrive (Poggi-Travert et al 1995). A patient suspected to have a Zellweger spectrum disorder should have a fasting or preprandial blood collected for the measurement of plasma very-long chain fatty acids and the branched-chain fatty acids, phytanic and pristanic (Moser and Raymond 1998). False positive results can be associated with non-fasting specimens, sample hemolysis, or

7 patients on a ketogenic diet. The branched-chain fatty acids accumulate with dietary exposure to dairy, meat, and other food sources containing phytol. Thus, branched-chain fatty acids are normal in the newborn period. Additional studies on the blood should be performed if the plasma fatty acid analysis is consistent with a defect in peroxisomal beta-oxidation (increased C26:0, C26:0/C22:0, and C24:0/C22:0) and/or alpha-oxidation (increased phytanic acid), or if the biochemical results are equivocal and the clinical features are suggestive of Zellweger spectrum. These studies include measurement of erythrocyte plasmalogen levels, plasma pipecolic acid, and plasma bile acids. An expanded fatty acid profile usually shows a deficiency in docosahexaenoic acid. In addition, urine can be submitted for organic acid analysis (2-hydroxysebacic acid and epoxydicarboxylic acids), pipecolic acid measurement, and bile acid studies. Zellweger newborns generally have very high urine pipecolic acid levels due to an inability to reabsorb this metabolite, but this reverses after the first 6 months of life. Further characterization of peroxisome abnormalities should be performed in cultured skin fibroblasts. Useful studies include measurement of very long-chain fatty acid content, betaoxidation (substrates: C24:0, C26:0, or pristanic acid), phytanic acid alpha-oxidation, total plasmalogen synthesis, or the single enzymes needed for plasmalogen biosynthesis, or catalase solubility. In addition, immunohistochemistry can be used to visualize peroxisomes and matrix proteins to determine the extent of the peroxisome assembly defect. If the only demonstrable defects involve fatty acid metabolism, then the patient more likely has a single enzyme defect. DNA analysis is available on a clinical service basis, and can be useful for confirmation of the diagnosis, carrier testing of at-risk relatives, and prenatal testing. Patients suspected of rhizomelic chondrodysplasia punctata should have erythrocyte plasmalogen levels measured (Heymans et al 1983). If plasmalogens are deficient, it is advisable to measure plasma very long-chain fatty acid and phytanic acid (these are typically part of 1 test). Although plasma phytanic acid is elevated only after dietary exposure to phytol, it is important to demonstrate plasma very long-chain fatty acids are normal due to some clinical overlap between this disorder and Zellweger spectrum. A skin fibroblast cell line should be established to document the defect in plasmalogen synthesis and to measure phytanic acid oxidation. If phytanic acid oxidation is deficient, then the patient has a PEX7 defect. A variety of common alleles are associated with PEX7 exons 7 and 9 (Braverman et al 2002). Management Systematic evaluation of patients with Zellweger spectrum disorder should include visual and auditory evoked response testing, comprehensive eye examination, brain MRI, renal and cardiac ultrasound, skeletal survey, and evaluation of hepatic enzymes and clotting factors. ACTH and cortisol levels should be measured to determine the extent of adrenal dysfunction. There is no known specific therapy for these disorders and any therapy should address the fact that features begin prenatally. Dietary approaches to resolve specific biochemical abnormalities include dietary restriction of metabolites that accumulate and replacement of those that are deficient. Reports of these approaches are mostly anecdotal and have not been studied systematically in patients. For example, repletion of erythrocyte plasmalogen levels has been achieved by dietary administration of plasmalogen precursors such as batyl alcohol, but this has not improved the clinical status. Oral bile acid administration improved hepatobiliary function in 1 infant with Zellweger syndrome (Noetzel 1998). More recently patients have received docosahexaenoic acid supplementation, but there is not yet a proven clinical benefit to this therapy (Martinez and Vazquez 1998). An infantile Refsum disease patient has received an orthotopic liver transplant and although biochemical parameters improved, it is too early to tell whether there is clinical benefit (Van Maldergem et al 2005). Due to the benefit of dietary phytanic acid restriction in adult Refsum disease, this is often prescribed for surviving peroxisome biogenesis disorder patients. Supportive management of affected children must be tailored to disease severity. Infants may require gastrostomy tube placement to ensure appropriate nourishment. Vitamin K supplementation and water-miscible preparations of fatsoluble vitamins should be provided. It is recommended that cataracts be extracted in early infancy to preserve some visual function. Orthopedic referral may be useful to follow skeletal defects. Pediatric care in early childhood should include monitoring of growth and nutrition, yearly screening of thyroid, hearing, and visual function, and periodic visits to genetics and neurology clinics. Early intervention, family support services, and hospice care may be required. Evaluation of patients with rhizomelic chondrodysplasia punctata should include eye examination, auditory evoked responses, renal and cardiac ultrasound, and skeletal survey. These patients do not have abnormal liver or adrenal functions. Supportive management should be instituted as discussed above for the Zellweger spectrum.

8 Special considerations Pregnancy Couples with an affected child have a 25% recurrence risk. Prenatal diagnosis is possible by biochemical or molecular testing. Biochemical testing has a higher sensitivity if cultured fibroblasts from the index case are characterized. It is possible to perform biochemical testing on pregnancies considered at-risk based on fetal abnormalities detected during routine prenatal care. Molecular testing should be performed only if PEX gene mutations have been identified in the index case, the parents are shown to be carriers of pathogenic mutations, or both. Anesthesia Provided coincident infections or coagulopathies are treated, no specific risks for anesthesia or surgery have been documented for patients with disorders of peroxisome assembly. Attention to respiratory status is critical due to the extreme hypotonia in Zellweger spectrum and restrictive lung disease in rhizomelic chondrodysplasia punctata. References cited Alkan A, Kutlu R, Yakinci C, Sigirci A, Aslan M, Sarac K. Delayed myelination in a rhizomelic chondrodysplasia punctata case: MR spectroscopy findings. Magn Reson Imaging 2003;21: PMID Baes M, Gressens P, Baumgart E, et al. A mouse model for Zellweger syndrome. Nat Genet 1997;17(1): PMID Barkovich AJ, Peck WW. MR of Zellweger syndrome. AJNR Am J Neuroradiol 1997;18: PMID Baumgart E, Vanhorebeek I, Grabenbauer M, et al. Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse). Am J Pathol 2001;159: PMID Baumgartner MR, Verhoeven NM, Jakobs C, et al. Defective peroxisome biogenesis with a neuromuscular disorder resembling Werdnig-Hoffmann disease. Neurology 1998;51: PMID Braverman N, Chen L, Lin P, et al. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat 2002;20: PMID Braverman N, Lin P, Moebius FF, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7- isomerase cause X-linked dominant Conradi-Hunermann syndrome. Nat Genet 1999;22: PMID Braverman N, Steel G, Obie C, et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet 1997;15(4): PMID Brites P, Motley AM, Gressens P, et al. Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata. Hum Mol Genet 2003;12: PMID Brown FR 3rd, Voigt R, Singh AK, Singh I. Peroxisomal disorders. Neurodevelopmental and biochemical aspects. Am J Dis Child 1993;147: PMID Brunetti-Pierri N, Andreucci MV, Tuzzi R, et al. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet 2003;117: PMID Clayton PT, Johnson AW, Mills KA, et al. Ataxia associated with increased plasma concentrations of pristanic acid, phytanic acid and C27 bile acids but normal fibroblast branched-chain fatty acid oxidation. J Inherit Metab Dis 1996;19: PMID de Vet EC, Ijlst L, Oostheim W, Wanders RJ, van den Bosch H. Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency. J Biol Chem 1998;273(17): PMID

9 Depreter M, Espeel M, Roels F. Human peroxisomal disorders. Microsc Res Tech 2003;61: PMID Dimmick JE, Applegarth DA. Pathology of peroxisomal disorders. Perspect Pediatr Pathol 1993;17: PMID Dodt G, Braverman N, Valle D, Gould SJ. From expressed sequence tags to peroxisome biogenesis disorder genes. Ann NY Acad Sci 1996;804: PMID Ek J, Kase BF, Reith A, Bjorkhem I, Pedersen JI. Peroxisomal dysfunction in a boy with neurologic symptoms and amaurosis (Leber disease): clinical and biochemical findings similar to those observed in Zellweger syndrome. J Pediatr 1986;108: PMID Faust PL. Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency. J Comp Neurol 2003;461(3): PMID Faust PL, Banka D, Siriratsivawong R, Ng VG, Wikander TM. Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain. J Inherit Metab Dis 2005;28: PMID Goldfischer S, Moore CL, Johnson AB, et al. Peroxisomal and mitochondrial defects in the cerebrohepatorenal syndrome. Science 1973;182:62-4. PMID Gootjes J, Mooijer PA, Dekker C, et al. Biochemical markers predicting survival in peroxisome biogenesis disorders. Neurology 2002;59(11): PMID Govaerts L, Colon E, Rotteveel J, Monnens L. A neurophysiological study of children with the cerebro-hepato-renal syndrome of Zellweger. Neuropediatrics 1985;16: PMID Heymans HS, Schutgens RB, Tan R, van den Bosch H, Borst P. Severe plasmalogen deficiency in tissues of infants without peroxisomes(zellweger syndrome). Nature 1983;306: PMID Janssen A, Baes M, Gressens P, Mannaerts GP, Declercq P, Van Veldhoven PP. Docosahexaenoic acid deficit is not a major pathogenic factor in peroxisome-deficient mice. Lab Invest 2000;80:31-5. PMID Khanna AJ, Braverman NE, Valle D, Sponseller PD. Cervical stenosis secondary to rhizomelic chondrodysplasia punctata. Am J Med Genet 2001;99:63-6. PMID Kunau WH. Peroxisome biogenesis: end of the debate. Curr Biol 2005;15:R PMID Lazarow PB. Peroxisome biogenesis: advances and conundrums. Curr Opin Cell Biol 2003;15: PMID Lazarow PB, Moser HW. Disorders of peroxisome biogenesis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited diseases. 7th ed. New York: McGraw-Hill, 1995: Li X, Baumgart E, Morrell JC, Jimenez-Sanchez G, Valle D, Gould SJ. PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function. Mol Cell Biol 2002;22: PMID Lyons CJ, Castano G, McCormick AQ, Applegarth D. Leopard spot retinal pigmentation in infancy indicating a peroxisomal disorder. Br J Ophthalmol 2004;88(2): PMID Martinez M, Vazquez E. MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders. Neurology 1998;51: PMID Maxwell M, Bjorkman J, Nguyen T, et al. Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. Mol Cell Biol 2003;23(16): PMID Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999;45: PMID Moser AB, Rasmussen M, Naidu S, et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 1995;127: PMID

10 Moser HW, Raymond GV. Genetic peroxisomal disorders: why, when, and how to test. Ann Neurol 1998;44: PMID Motley AM, Hettema EH, Hogenhout EM. Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. Nat Genet 1997;15(4): PMID Noetzel MJ. Fish oil and myelin: cautious optimism for treatment of children with disorders of peroxisome biogenesis. Neurology 1998;51:5-7. PMID Poggi-Travert F, Fournier B, Poll-The BT, Saudubray JM. Clinical approach to peroxisomal disorders. J Inherit Metab Dis 1995;18(suppl 1):1-18. PMID Poll-The BT, Gootjes J, Duran M, et al. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. AM J Med Genet A 2004 May;126(4): Powers JM, Kenjarski TP, Moser AB, Moser HW. Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells. Acta Neuropathol (Berl) 1999;98: Powers JM, Moser HW. Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 1998;8: PMID Raas-Rothschild A, Wanders RJ, Mooijer PA, et al. A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents. Am J Hum Genet 2002;70: PMID Santos MJ, Imanaka T, Shio H, Small GM, Lazarow PB. Peroxisomal membrane ghosts in Zellweger syndrome--aberrant organelle assembly. Science 1988;239: PMID Schedin S, Sindelar PJ, Pentchev P, Brunk U, Dallner G. Peroxisomal impairment in Niemann-Pick type C disease. J Biol Chem 1997;272: PMID Steinberg S, Chen L, Wei L, et al. The PEX gene screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. Mol Genet Metab 2004;83: PMID Van Maldergem L, Moser AB, Vincent MF, et al. Orthotopic liver transplantation from a living-related donor in an infant with a peroxisome biogenesis defect of the infantile Refsum disease type. J Inherit Metab Dis 2005;28: PMID Vanhorebeek I, Baes M, Declercq PE. Isoprenoid biosynthesis is not compromised in a Zellweger syndrome mouse model. Biochim Biophys Acta 2001;1532: PMID Watkins PA, McGuinness MC, Raymond GV, et al. Distinction between peroxisomal bifunctional enzyme and acyl-coa oxidase deficiencies. Ann Neurol 1995;38: PMID Weller S, Gould SJ, Valle D. Peroxisome biogenesis disorders. Annu Rev Genomics Hum Genet 2003;4: PMID Wessels MW, Den Hollander NJ, De Krijger RR, et al. Fetus with an unusual form of nonrhizomelic chondrodysplasia punctata: case report and review. Am J Med Genet A 2003;120: PMID White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A 2003;118(4): PMID Wilson GN, Holmes RD, Custer J, et al. Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy. Am J Med Genet 1986;24: PMID Zellweger H. The cerebro-hepato-renal (Zellweger) syndrome and other peroxisomal disorders [review]. Dev Med Child Neurol 1987;29(6): PMID **References especially recommended by the author or editor for general reading.

11 Former authors Golder Wilson MD (original author), Mario A Cabrera-Salazar MD, and John A Barranger MD PhD ICD and OMIM codes ICD codes ICD-9: Cerebrohepatorenal syndrome: Zellweger syndrome: ICD-10: Cerebrohepatorenal syndrome: Q89.8 Zellweger syndrome: Q87.8 OMIM numbers Zellweger syndrome: # Profile Age range of presentation 0-01 month months years Sex preponderance male=female Family history family history may be obtained Heredity heredity may be a factor heredity typical autosomal recessive Population groups selectively affected none selectively affected Occupation groups selectively affected none selectively affected Differential diagnosis list glutaric aciduria type II muscle-eye-brain disease Prader-Willi syndrome congenital myopathies molybdenum cofactor deficiency sulfite oxidase deficiency nonketotic hyperglycinemia Aicardi syndrome

12 disorders of the mitochondrial respiratory chain chromosomal abnormalities Werdnig-Hoffman disease Niemann-Pick type C Charcot Marie Tooth Ataxia cholestasis Usher syndrome late onset defects in arylsulfatase E (CDPX1) sterol isomerase (CDPX2) maternal vitamin K deficiency maternal warfarin use maternal autoimmune disease Associated disorders Hepatocellular disease Infantile Refsum disease Other topics to consider Adrenoleukodystrophy Chondrodystrophies Single enzyme defects of peroxisomal beta-oxidation Copyright MedLink Corporation. All rights reserved.