Skip to main content
SpringerLink
Log in

Human Disorders of Peroxisome Biogenesis: Zellweger Spectrum and Rhizomelic Chondrodysplasia Punctata

  • Chapter
  • First Online:
Molecular Machines Involved in Peroxisome Biogenesis and Maintenance

Abstract

The human peroxisome biogenesis disorders (PBD) are caused by autosomal recessive mutations in any of the 14 PEX genes, which encode peroxins, or PEX proteins, that act cooperatively to assemble functional peroxisomes. Mutations in PEX genes affect the import of peroxisome matrix enzymes and formation of new peroxisomes. The consequences are multiple enzyme deficiencies causing developmental malformations and progressive postnatal tissue injury. The PBD are classified into two distinct groups: Zellweger spectrum disorders (ZSD) and Rhizomelic Chondrodysplasia Punctata spectrum type 1 (RCDP1). The term “spectrum” is preferred because there is a gradation of phenotypes from severe to mild in these disorders, as well as newly recognized atypical phenotypes. In general, the milder the phenotype, the greater are the residual functions of the defective peroxin.

Tissues most affected in the PBD include the brain, peripheral nerves, eye, liver, kidney, heart, adrenal glands, bone, and lung. The severe form is distinguished by developmental malformations and early demise. In the intermediate and milder phenotypes, malformations may not be present and prominent disease features reflect postnatal peroxisome dysfunction over time. It is this latter group of patients that would benefit most from targeted therapies. In this chapter, we will review clinical phenotypes, diagnoses, supportive management, and research approaches to developing targeted therapies. In the overall theme of this chapter, we will highlight how patient studies have contributed to our knowledge of peroxisome disorders and normal peroxisome biology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

PBD:

Peroxisome biogenesis disorders

ZSD:

Zellweger spectrum disorder

ZS:

Zellweger syndrome

NALD:

Neonatal adrenoleu kodystrophy

IRD:

Infantile Refsum disease

RCDP:

Rhizomelic chondro dysplasia punctata

References

  • Acharya BS, Ritwik P, Velasquez GM, Fenton SJ (2012) Medi-cal-dental findings and management of a child with infantile Refsum disease: a case report. Spec Care Dentist 32:112–117

    PubMed  Google Scholar 

  • Aubourg P, Scotto J, Rocchiccioli F, Feldmann-Pautrat D, Robain O (1986) Neonatal adrenoleukodystrophy. J Neurol Neurosurg Psychiatry 49:77–86

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baldwin EJ, Gibberd FB, Harley C, Sidey MC, Feher MD, Wierzbicki AS (2010) The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry 81:954–957

    PubMed  Google Scholar 

  • Bams-Mengerink AM, Majoie CB, Duran M, Wanders RJ, Van Hove J, Scheurer CD, Barth PG, Poll-The BT (2006) MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punc-tata. Neurology 66:798–803, discussion 789

    CAS  PubMed  Google Scholar 

  • Barkovich AJ, Peck WW (1997) MR of Zellweger syndrome. AJNR Am J Neuroradiol 18:1163–1170

    CAS  PubMed  Google Scholar 

  • Barth PG, Majoie CB, Gootjes J, Wanders RJ, Waterham HR, van der Knaap MS, de Klerk JB, Smeitink J, Poll-The BT (2004) Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 62:439–444

    CAS  PubMed  Google Scholar 

  • Berendse K, Ebberink MS, Ijlst L, Poll-The BT, Wanders RJ, Waterham HR (2013) Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder. Orphanet J Rare Dis 8:138

    PubMed Central  PubMed  Google Scholar 

  • Bove KE, Heubi JE, Balistreri WF, Setchell KD (2004) Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol 7:315–334

    PubMed  Google Scholar 

  • Bowen P, Lee CS, Zellweger H, Lindenberg R (1964) A familial syndrome of multiple congenital defects. Bull Johns Hopkins Hosp 114:402–414

    CAS  PubMed  Google Scholar 

  • Braverman N, Moser A (2012) Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta 1822(9):1442–1452

    CAS  PubMed  Google Scholar 

  • Braverman N, Dodt G, Gould SJ, Valle D (1998) An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes. Hum Mol Genet 7:1195–1205

    CAS  PubMed  Google Scholar 

  • Braverman N, Steel G, Lin P, Moser A, Moser H, Valle D (2000) PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics 63:181–192

    CAS  PubMed  Google Scholar 

  • Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D (2002) Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat 20:284–297

    CAS  PubMed  Google Scholar 

  • Braverman N, Zhang R, Chen L, Nimmo G, Scheper S, Tran T, Chaudhury R, Moser A, Steinberg S (2010) A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton. Mol Genet Metab 99:408–416

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brites P, Ferreira AS, da Silva TF, Sousa VF, Malheiro AR, Duran M, Waterham HR, Baes M, Wanders RJ (2011) Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice. PLoS One 6:e28539

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Levy N, Girard N, Sarda P, Boespflug-Tanguy O, Villard L (2013) Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet 93:579–586

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chang CC, South S, Warren D, Jones J, Moser AB, Moser HW, Gould SJ (1999) Metabolic control of peroxisome abundance. J Cell Sci 112(Pt 10):1579–1590

    CAS  PubMed  Google Scholar 

  • Cohen SM, Brown FR 3rd, Martyn L, Moser HW, Chen W, Kistenmacher M, Punnett H, de la Cruz ZC, Chan NR, Green WR (1983) Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome (Zellweger’s syndrome) and its relationship to neonatal adrenoleukodystrophy. Am J Ophthalmol 96:488–501

    CAS  PubMed  Google Scholar 

  • Collins CS, Gould SJ (1999) Identification of a common PEX1 mutation in Zellweger syndrome. Hum Mutat 14:45–53

    CAS  PubMed  Google Scholar 

  • Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD, Watkins PA, Moser AB, Moser HW, Steinberg SJ (2002) Contig-uous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet 70:1520–1531

    CAS  PubMed Central  PubMed  Google Scholar 

  • Danks DM, Tippett P, Adams C, Campbell P (1975) Cerebro-hepato-renal syndrome of Zellweger. J Pediatr 86:382–387

    CAS  PubMed  Google Scholar 

  • Das AK, Holmes RD, Wilson GN, Hajra AK (1992) Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents. Lipids 27:401–405

    CAS  PubMed  Google Scholar 

  • Datta NS, Wilson GN, Hajra AK (1984) Deficiency of enzymes catalyzing the biosynthesis of glycerol-ether lipids in Zellweger syn-drome. A new category of metabolic disease involving the absence of peroxisomes. N Engl J Med 311:1080–1083

    CAS  PubMed  Google Scholar 

  • De Duve C, Baudhuin P (1966) Peroxisomes (microbodies and related particles). Physiol Rev 46:323–357

    PubMed  Google Scholar 

  • Demyer W, Zeman W, Palmer CG (1964) The face predicts the brain: diagnostic significance of median facial anomalies for holo-prosencephaly (arhinencephaly). Pediatrics 34:256–263

    CAS  PubMed  Google Scholar 

  • Distel B, Erdmann R, Gould SJ, Blobel G, Crane DI, Cregg JM, Dodt G, Fujiki Y, Goodman JM, Just WW, Kiel JA, Kunau WH, Lazarow PB, Mannaerts GP, Moser HW, Osumi T, Rachubinski RA, Roscher A, Subramani S, Tabak HF, Tsukamoto T, Valle D, van der Klei I, van Veldhoven PP, Veenhuis M (1996) A unified nomenclature for peroxisome biogenesis factors. J Cell Biol 135:1–3

    CAS  PubMed  Google Scholar 

  • Dodt G, Braverman N, Valle D, Gould SJ (1996) From ex-pressed sequence tags to peroxisome biogenesis disorder genes. Ann N Y Acad Sci 804:516–523

    CAS  PubMed  Google Scholar 

  • Dranchak PK, Di Pietro E, Snowden A, Oesch N, Braverman NE, Steinberg SJ, Hacia JG (2011) Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations. J Cell Biochem 112:1250–1258

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S (2010) Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet 47:608–615

    CAS  PubMed  Google Scholar 

  • Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR (2011) Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat 32:59–69

    CAS  PubMed  Google Scholar 

  • Ebberink MS, Koster J, Visser G, Spronsen F, Stolte-Dijkstra I, Smit GP, Fock JM, Kemp S, Wanders RJ, Waterham HR (2012) A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11beta gene. J Med Genet 49:307–313

    CAS  PubMed  Google Scholar 

  • El-Bassyouni HT, Abdel Maksoud SA, Salem FA, Badr El-Deen R, Abdel Aziz H, Thomas MM (2012) Evidence of oxidative stress in peroxisomal disorders. Singapore Med J 53:608–614

    PubMed  Google Scholar 

  • Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Al-len JT, McLean BN, Brown AY, Vreken P, Waterham HR, Wan-ders RJ (2000) Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24:188–191

    CAS  PubMed  Google Scholar 

  • Ferdinandusse S, Finckh B, de Hingh YC, Stroomer LE, Denis S, Kohlschutter A, Wanders RJ (2003) Evidence for increased oxidative stress in peroxisomal D-bifunctional protein deficiency. Mol Genet Metab 79:281–287

    CAS  PubMed  Google Scholar 

  • Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, Reith W, Haas D, Wanders RJ, Duran M, Marziniak M (2006) Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet 78:1046–1052

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fourcade S, Lopez-Erauskin J, Ruiz M, Ferrer I, Pujol A (2014) Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy. Biochimie 98:143–149

    CAS  PubMed  Google Scholar 

  • Fransen M (2012) Peroxisome dynamics: molecular players, mechanisms, and (Dys)functions. ISRN Cell Biol 2012:24 p

    Google Scholar 

  • Fransen M, Nordgren M, Wang B, Apanasets O (2011) Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta 1822:1363–1373

    PubMed  Google Scholar 

  • Fujiki Y, Okumoto K, Kinoshita N, Ghaedi K (2006) Lessons from peroxisome-deficient Chinese hamster ovary (CHO) cell mutants. Biochim Biophys Acta 1763:1374–1381

    CAS  PubMed  Google Scholar 

  • Geisbrecht BV, Collins CS, Reuber BE, Gould SJ (1998) Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleu-kodystrophy, and infantile Refsum disease. Proc Natl Acad Sci USA 95:8630–8635

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gilbert EF, Opitz JM, Spranger JW, Langer LO Jr, Wolfson JJ, Viseskul C (1976) Chondrodysplasia punctata–rhizomelic form. Pathologic and radiologic studies of three infants. Eur J Pediatr 123:89–109

    CAS  PubMed  Google Scholar 

  • Gilchrist KW, Gilbert EF, Goldfarb S, Goll U, Spranger JW, Opitz JM (1976) Studies of malformation syndromes of man XIB: the cerebro-hepato-renal syndrome of Zellweger: comparative pathology. Eur J Pediatr 121:99–118

    CAS  PubMed  Google Scholar 

  • Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK, Ritch RH, Norton WT, Rapin I, Gartner LM (1973) Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. Science 182:62–64

    CAS  PubMed  Google Scholar 

  • Gootjes J, Schmohl F, Mooijer PA, Dekker C, Mandel H, Topcu M, Huemer M, Von Schutz M, Marquardt T, Smeitink JA, Waterham HR, Wanders RJ (2004) Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism. Hum Mutat 24:130–139

    CAS  PubMed  Google Scholar 

  • Heymans HS, Oorthuys JW, Nelck G, Wanders RJ, Schutgens RB (1985) Rhizomelic chondrodysplasia punctata: another peroxisomal disorder. N Engl J Med 313:187–188

    CAS  PubMed  Google Scholar 

  • Horn MA, van den Brink DM, Wanders RJ, Duran M, Poll-The BT, Tallaksen CM, Stokke OH, Moser H, Skjeldal OH (2007) Phenotype of adult Refsum disease due to a defect in peroxin 7. Neurology 68:698–700

    CAS  PubMed  Google Scholar 

  • Hubbard WC, Moser AB, Liu AC, Jones RO, Steinberg SJ, Lorey F, Panny SR, Vogt RF Jr, Macaya D, Turgeon CT, Tortorelli S, Raymond GV (2009) Newborn screening for X-linked adrenoleu-kodystrophy (X-ALD): validation of a combined liquid chromatog-raphy-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab 97:212–220

    CAS  PubMed  Google Scholar 

  • Huffnagel IC, Clur SA, Bams-Mengerink AM, Blom NA, Wanders RJ, Waterham HR, Poll-The BT (2013) Rhizomelic chondro-dysplasia punctata and cardiac pathology. J Med Genet 50:419–424

    CAS  PubMed  Google Scholar 

  • Iwasa M, Yamagata T, Mizuguchi M, Itoh M, Matsumoto A, Hironaka M, Honda A, Momoi MY, Shimozawa N (2012) Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology 33:292–298

    PubMed  Google Scholar 

  • Kelley RI (1983) Review: the cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 16:503–517

    CAS  PubMed  Google Scholar 

  • Khanna AJ, Braverman NE, Valle D, Sponseller PD (2001) Cervical stenosis secondary to rhizomelic chondrodysplasia punctata. Am J Med Genet 99:63–66

    CAS  PubMed  Google Scholar 

  • Krause C, Rosewich H, Woehler A, Gartner J (2013) Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis. Hum Mol Genet 22:3844–3857

    CAS  PubMed  Google Scholar 

  • Kulkarni KS, Baranano KW, Lin DD, Raymond GV (2011) Contrast enhancement of brainstem tracts in Zellweger spectrum disorder: evidence of inflammatory demyelination? Neuropediatrics 42:32–34

    CAS  PubMed  Google Scholar 

  • Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY, Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K, Braverman NE (2012) A founder mutation in the PEX6 gene is re-sponsible for increased incidence of Zellweger syndrome in a French Canadian population. BMC Med Genet 13:72

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lopez-Erauskin J, Fourcade S, Galino J, Ruiz M, Schluter A, Naudi A, Jove M, Portero-Otin M, Pamplona R, Ferrer I, Pujol A (2011) Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol 70:84–92

    CAS  PubMed Central  PubMed  Google Scholar 

  • MacCollin M, De Vivo DC, Moser AB, Beard M (1990) Ataxia and peripheral neuropathy: a benign variant of peroxisome dysgenesis. Ann Neurol 28:833–836

    CAS  PubMed  Google Scholar 

  • Maeda K, Kimura A, Yamato Y, Nittono H, Takei H, Sato T, Mitsubuchi H, Murai T, Kurosawa T (2002) Oral bile acid treatment in two Japanese patients with Zellweger syndrome. J Pediatr Gastroenterol Nutr 35:227–230

    PubMed  Google Scholar 

  • Majewski J, Wang Z, Lopez I, Al Humaid S, Ren H, Racine J, Bazinet A, Mitchel G, Braverman N, Koenekoop RK (2011) A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing. J Med Genet 48:593–596

    CAS  PubMed  Google Scholar 

  • Maxwell MA, Nelson PV, Chin SJ, Paton BC, Carey WF, Crane DI (1999) A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype. Hum Genet 105:38–44

    CAS  PubMed  Google Scholar 

  • McMillan HJ, Worthylake T, Schwartzentruber J, Gottlieb CC, Lawrence SE, Mackenzie A, Beaulieu CL, Mooyer PA, Wanders RJ, Majewski J, Bulman DE, Geraghty MT, Ferdinandusse S, Boycott KM (2012) Specific combination of compound heterozygous mutations in 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis 7:90

    PubMed Central  PubMed  Google Scholar 

  • Michelakakis HM, Zafeiriou DI, Moraitou MS, Gootjes J, Wanders RJ (2004) PEX1 deficiency presenting as Leber congenital amaurosis. Pediatr Neurol 31:146–149

    PubMed  Google Scholar 

  • Mignarri A, Vinciguerra C, Giorgio A, Ferdinandusse S, Waterham H, Wanders R, Bertini E, Dotti MT, Federico A (2012) Zellweger spectrum disorder with mild phenotype caused by PEX2 gene mutations. JIMD Rep 6:43–46

    PubMed Central  PubMed  Google Scholar 

  • Moser AE, Singh I, Brown FR III, Solish GI, Kelley RI, Benke PJ, Moser HW (1984) The cerebrohepatorenal (Zellweger) syndrome. Increased levels and impaired degradation of very-long-chain fatty acids and their use in prenatal diagnosis. N Engl J Med 310:1141–1146

    CAS  PubMed  Google Scholar 

  • Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, Chen G, Raymond G, Liu A, Gordon D et al (1995) Phenotype of patients with peroxisomal disorders subdivided into six-teen complementation groups. J Pediatr 127:13–22

    CAS  PubMed  Google Scholar 

  • Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, Waterham HR (2002) Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet 70:612–624

    CAS  PubMed Central  PubMed  Google Scholar 

  • Muller CC, Nguyen TH, Ahlemeyer B, Meshram M, Santram-purwala N, Cao S, Sharp P, Fietz PB, Baumgart-Vogt E, Crane DI (2010) PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxida-tive stress. Dis Model Mech 4:104–119

    PubMed Central  PubMed  Google Scholar 

  • Muntau AC, Mayerhofer PU, Paton BC, Kammerer S, Roscher AA (2000) Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am J Hum Genet 67:967–975

    CAS  PubMed Central  PubMed  Google Scholar 

  • Noguer MT, Martinez M (2010) Visual follow-up in peroxisomal-disorder patients treated with docosahexaenoic acid ethyl ester. Invest Ophthalmol Vis Sci 51:2277–2285

    PubMed  Google Scholar 

  • Nordgren M, Wang B, Apanasets O, Fransen M (2013) Peroxisome degradation in mammals: mechanisms of action, recent advances, and perspectives. Front Physiol 4:145

    PubMed Central  PubMed  Google Scholar 

  • Opitz J, Rhein GZ, Vitale L, Shahidi N, Howe J, Chou S, Shanklin D, Sybers H, Dood A, Gerritsen T (1969) The Zellweger syndrome (cerebro-hepato-renal syndrome). Birth Defects 2:1–15844

    Google Scholar 

  • Osumi T, Imamura A, Tsukamoto T, Fujiwara C, Hashiguchi N, Shimozawa N, Suzuki Y, Kondo N (2000) Temperature sensitivity in peroxisome assembly processes characterizes milder forms of pe-roxisome biogenesis disorders. Cell Biochem Biophys 32(Spring):165–170

    CAS  PubMed  Google Scholar 

  • Oswald G, Lawson C, Raymond G, Golden WC, Braverman N (2011) Rhizomelic chondrodysplasia punctata type 1 and fulminant neonatal respiratory failure, a case report and discussion of patho-physiology. Am J Med Genet A 155A:3160–3163

    PubMed  Google Scholar 

  • Otera H, Okumoto K, Tateishi K, Ikoma Y, Matsuda E, Nishi-mura M, Tsukamoto T, Osumi T, Ohashi K, Higuchi O, Fujiki Y (1998) Peroxisome targeting signal type 1 (PTS1) receptor is involved in import of both PTS1 and PTS2: studies with PEX5-defective CHO cell mutants. Mol Cell Biol 18:388–399

    CAS  PubMed Central  PubMed  Google Scholar 

  • Paker AM, Sunness JS, Brereton NH, Speedie LJ, Albanna L, Dharmaraj S, Moser AB, Jones RO, Raymond GV (2010) Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial. Neurology 75:826–830

    CAS  PubMed Central  PubMed  Google Scholar 

  • Passarge E, McAdams AJ (1967) Cerebro-hepato-renal syndrome. A newly recognized hereditary disorder of multiple congenital defects, including sudanophilic leukodystrophy, cirrhosis of the liver, and polycystic kidneys. J Pediatr 71:691–702

    CAS  PubMed  Google Scholar 

  • Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC (2010) Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet 87:282–288

    CAS  PubMed Central  PubMed  Google Scholar 

  • Poll-The BT, Gootjes J, Duran M, De Klerk JB, Wenniger-Prick LJ, Admiraal RJ, Waterham HR, Wanders RJ, Barth PG (2004) Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet A 126A:333–338

    PubMed  Google Scholar 

  • Poulos A, Sheffield L, Sharp P, Sherwood G, Johnson D, Beckman K, Fellenberg AJ, Wraith JE, Chow CW, Usher S et al (1988) Rhizomelic chondrodysplasia punctata: clinical, pathologic, and biochemical findings in two patients. J Pediatr 113:685–690

    CAS  PubMed  Google Scholar 

  • Powers JM, Moser HW, Moser AB, Upshur JK, Bradford BF, Pai SG, Kohn PH, Frias J, Tiffany C (1985) Fetal cerebrohepato-renal (Zellweger) syndrome: dysmorphic, radiologic, biochemical, and pathologic findings in four affected fetuses. Hum Pathol 16:610–620

    CAS  PubMed  Google Scholar 

  • Raas-Rothschild A, Wanders RJ, Mooijer PA, Gootjes J, Waterham HR, Gutman A, Suzuki Y, Shimozawa N, Kondo N, Eshel G, Espeel M, Roels F, Korman SH (2002) A PEX6-defective peroxi-somal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents. Am J Hum Genet 70:1062–1068

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ratzel SE, Lingard MJ, Woodward AW, Bartel B (2010) Reducing PEX13 expression ameliorates physiological defects of late-acting peroxin mutants. Traffic 12:121–134

    PubMed Central  PubMed  Google Scholar 

  • Regal L, Ebberink MS, Goemans N, Wanders RJ, De Meirleir L, Jaeken J, Schrooten M, Van Coster R, Waterham HR (2010) Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol 68:259–263

    CAS  PubMed  Google Scholar 

  • Rizzo WB (1998) Inherited disorders of fatty alcohol metabolism. Mol Genet Metab 65:63–73

    CAS  PubMed  Google Scholar 

  • Roels F, Saudubray JM, Giros M, Mandel H, Eyskens F, Sara-cibar N, Atares Pueyo B, Prats JM, De Prest B, De Preter K, Pineda M, Krystkowiak P, Gootjes J, Wanders RJ, Espeel M, Poll-The BT (2003) Peroxisome mosaics. Adv Exp Med Biol 544:97–106

    PubMed  Google Scholar 

  • Rosewich H, Ohlenbusch A, Gartner J (2005) Genetic and clini-cal aspects of Zellweger spectrum patients with PEX1 mutations. J Med Genet 42:e58

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schrader M, Bonekamp NA, Islinger M (2012) Fission and proliferation of peroxisomes. Biochim Biophys Acta 1822:1343–1357

    CAS  PubMed  Google Scholar 

  • Setchell KD, Bragetti P, Zimmer-Nechemias L, Daugherty C, Pelli MA, Vaccaro R, Gentili G, Distrutti E, Dozzini G, Morelli A et al (1992) Oral bile acid treatment and the patient with Zellweger syn-drome. Hepatology 15:198–207

    CAS  PubMed  Google Scholar 

  • Sevin C, Ferdinandusse S, Waterham HR, Wanders RJ, Aubourg P (2011) Autosomal recessive cerebellar ataxia caused by muta-tions in the PEX2 gene. Orphanet J Rare Dis 6:8

    PubMed Central  PubMed  Google Scholar 

  • Shimozawa N, Tsukamoto T, Suzuki Y, Orii T, Fujiki Y (1992) Animal cell mutants represent two complementation groups of peroxi-some-defective Zellweger syndrome. J Clin Invest 90:1864–1870

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smith DW, Opitz JM, Inhorn SL (1965) A syndrome of multiple developmental defects including polycystic kidneys and intrahepatic biliary dysgenesis in 2 siblings. J Pediatr 67:617–624

    CAS  PubMed  Google Scholar 

  • Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, Bernard Otte J, Evrard V, Latinne D, Vincent MF, Moser A, Soriano HE (2003) Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation 76:735–738

    PubMed  Google Scholar 

  • Steinberg SJ, Raymond GV, Braverman NE, Moser AB (1993) Peroxisome biogenesis disorders, Zellweger syndrome spectrum. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; [updated 2012 May 10]

    Google Scholar 

  • Steinberg S, Chen L, Wei L, Moser A, Moser H, Cutting G, Braverman N (2004) The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. Mol Genet Metab 83:252–263

    CAS  PubMed  Google Scholar 

  • Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW (2006) Peroxisome biogenesis disorders. Biochim Biophys Acta 1763:1733–1748

    CAS  PubMed  Google Scholar 

  • Steinberg S, Jones R, Tiffany C, Moser A (2008) Investigational methods for peroxisomal disorders. Curr Protoc Hum Genet, Chapter 17, Unit 17.6

    Google Scholar 

  • Steinberg SJ, Snowden A, Braverman NE, Chen L, Watkins PA, Clayton PT, Setchell KD, Heubi JE, Raymond GV, Moser AB, Moser HW (2009) A PEX10 defect in a patient with no detectable de-fect in peroxisome assembly or metabolism in cultured fibroblasts. J Inherit Metab Dis 32:109–119

    CAS  PubMed  Google Scholar 

  • Sugarman GI (1974) Chondrodysplasia punctata (rhizomelic type): case report and pathologic findings. Birth Defects Orig Artic Ser 10:334–340

    CAS  PubMed  Google Scholar 

  • Sun Y, Wang L, Wei X, Zhu Q, Yang Y, Lan Z, Qu N, Chu Y, Wang Y, Yang S, Liang Y, Wang W, Yi X (2012) Analysis of a Chinese pedigree with Zellweger syndrome reveals a novel PEX1 mutation by next-generation sequencing. Clin Chim Acta 417:57–61

    PubMed  Google Scholar 

  • Tran D, Greenhill W, Wilson S (2011) Infantile refsum disease with enamel defects: a case report. Pediatr Dent 33:266–270

    PubMed  Google Scholar 

  • van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ (2003) Identification of PEX7 as the second gene in-volved in Refsum disease. Am J Hum Genet 72:471–477

    PubMed Central  PubMed  Google Scholar 

  • Van Maldergem L, Moser AB, Vincent MF, Roland D, Reding R, Otte JB, Wanders RJ, Sokal E (2005) Orthotopic liver transplan-tation from a living-related donor in an infant with a peroxisome bio-genesis defect of the infantile Refsum disease type. J Inherit Metab Dis 28:593–600

    PubMed  Google Scholar 

  • van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJ, Barth PG, Poll-The BT (2006) High incidence of hyperox-aluria in generalized peroxisomal disorders. Mol Genet Metab 88:346–350

    PubMed  Google Scholar 

  • Viseskul C, Opitz JM, Spranger JW, Hartmann HA, Gilbert EF (1974) Pathology of chondrodysplasia punctata rhizomelic type. Birth Defects Orig Artic Ser 10:327–333

    CAS  PubMed  Google Scholar 

  • Walter C, Gootjes J, Mooijer PA, Portsteffen H, Klein C, Waterham HR, Barth PG, Epplen JT, Kunau WH, Wanders RJ, Dodt G (2001) Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet 69:35–48

    CAS  PubMed Central  PubMed  Google Scholar 

  • Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356:1736–1741

    CAS  PubMed  Google Scholar 

  • Wei H, Kemp S, McGuinness MC, Moser AB, Smith KD (2000) Pharmacological induction of peroxisomes in peroxisome biogenesis disorders. Ann Neurol 47:286–296

    CAS  PubMed  Google Scholar 

  • Wells TR, Landing BH, Bostwick FH (1992) Studies of vertebral coronal cleft in rhizomelic chondrodysplasia punctata. Pediatr Pathol 12:593–600

    CAS  PubMed  Google Scholar 

  • White AL, Modaff P, Holland-Morris F, Pauli RM (2003) Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A 118A:332–342

    PubMed  Google Scholar 

  • Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB (2002) Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem 80:727–735

    CAS  PubMed  Google Scholar 

  • Wilson GN, Holmes RG, Custer J, Lipkowitz JL, Stover J, Datta N, Hajra A (1986) Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy. Am J Med Genet 24:69–82

    CAS  PubMed  Google Scholar 

  • Wood PL, Khan MA, Smith T, Ehrmantraut G, Jin W, Cui W, Braverman NE, Goodenowe DB (2011) In vitro and in vivo plas-malogen replacement evaluations in rhizomelic chrondrodysplasia punctata and Pelizaeus-Merzbacher disease using PPI-1011, an ether lipid plasmalogen precursor. Lipids Health Dis 10:182

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JG (2009) Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat 30:E467–E480

    PubMed Central  PubMed  Google Scholar 

  • Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D'Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukaddes NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, LeClair E, Poduri A, Oner O, Al-Saad S, Al-Awadi SA, Bastaki L, Ben-Omran T, Teebi AS, Al-Gazali L, Eapen V, Stevens CR, Rappaport L, Gabriel SB, Markianos K, State MW, Greenberg ME, Taniguchi H, Braverman NE, Morrow EM, Walsh CA (2013) Using whole-exome sequencing to identify inherited causes of autism. Neuron 77:259–273

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zeharia A, Ebberink MS, Wanders RJ, Waterham HR, Gutman A, Nissenkorn A, Korman SH (2007) A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C. J Hum Genet 52:599–606

    CAS  PubMed  Google Scholar 

  • Zellweger H, Maertens P, Superneau D, Wertelecki W (1988) History of the cerebrohepatorenal syndrome of Zellweger and other peroxisomal disorders. South Med J 81:357–364

    CAS  PubMed  Google Scholar 

  • Zhang R, Chen L, Jiralerspong S, Snowden A, Steinberg S, Braverman N (2010) Recovery of PEX1-Gly843Asp peroxisome dys-function by small-molecule compounds. Proc Natl Acad Sci USA 107:5569–5574

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zolman BK, Bartel B (2004) An Arabidopsis indole-3-butyric ac-id-response mutant defective in PEROXIN6, an apparent ATPase im-plicated in peroxisomal function. Proc Natl Acad Sci USA 101:1786–1791

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zwijnenburg PJ, Deurloo KL, Waterham HR, Meijers-Heijboer EJ, van Vugt JM, Tan-Sindhunata MB (2010) Second trimester prenatal diagnosis of rhizomelic chondrodysplasia punctata type 1 on ultrasound findings. Prenat Diagn 30:162–164

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

CA is a PhD candidate in Human Genetics at McGill University, NB is funded by the Canadian Institutes of Health Research and Alberta Collaborative Research and Innovation Opportunities. AM is supported by the Peroxisomal Diseases Laboratory at the Kennedy Krieger Institute and the Neurosciences Core C of the Intellectual and Developmental Disabilities Research Center, NIH/NICHD 5P30HD024061-22. The authors are grateful to all the physicians, scientists, and families who work together to advance knowledge and treatment of peroxisomal diseases.

Author information

Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Nancy Braverman & Catherine Argyriou

  2. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Nancy Braverman

  3. Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA

    Ann Moser

Authors
  1. Nancy Braverman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine Argyriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy Braverman .

Editor information

Editors and Affiliations

  1. Mauerbach, Austria

    Cecile Brocard

  2. Max F. Perutz Laboratories University of Vienna, Vienna, Austria

    Andreas Hartig

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Wien

About this chapter

Cite this chapter

Braverman, N., Argyriou, C., Moser, A. (2014). Human Disorders of Peroxisome Biogenesis: Zellweger Spectrum and Rhizomelic Chondrodysplasia Punctata. In: Brocard, C., Hartig, A. (eds) Molecular Machines Involved in Peroxisome Biogenesis and Maintenance. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1788-0_4

Download citation

Publish with us

Policies and ethics

Search

Navigation