Zellweger Spectrum Disorder

Steven J Steinberg, Gerald V Raymond, Nancy E Braverman, Ann B Moser, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya, Steven J Steinberg, Gerald V Raymond, Nancy E Braverman, Ann B Moser, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya

Excerpt

Clinical characteristics: Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.

Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress.

Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.

Diagnosis/testing: The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes. One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.

Management: Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation; varices can be treated with sclerosing therapies; anti-seizure medication, early intervention services for developmental delay and intellectual disability; adrenal replacement therapy; vitamin D supplementation and consideration of bisphosphonates for osteopenia; treatment as per dentist for ameliogenesis imperfecta. Supportive treatment for renal oxalate stones has included hydration, lithotripsy, and surgical intervention. Annual influenza and respiratory syncytial virus vaccines should be provided.

Surveillance: Growth and nutrition should be assessed at each visit. Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture; monitor for changes in seizure activity; head MRI to evaluate for white matter changes that may explain changes in cognitive and/or motor ability; monitor developmental progress and educational needs; ACTH and cortisol levels by age one year and annually thereafter. Dental examinations every six months. Annual urine oxalate-to-creatinine ratio with consideration of renal imaging when performing liver imaging. Assessment of family needs at each visit.

Genetic counseling: ZSD is typically inherited in an autosomal recessive manner (one PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state). At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in an affected family member. Prenatal testing for a pregnancy at increased risk is possible by DNA testing if both ZSD-related pathogenic variants have been identified in an affected family member, or by biochemical testing if the biochemical defects have been confirmed in cultured fibroblasts from an affected family member.

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References

    1. Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–47.
    1. Acharya BS, Ritwik P, Velasquez GM, Fenton SJ. Medical-dental findings and management of a child with infantile Refsum disease: a case report. Spec Care Dentist. 2012;32:112–7.
    1. Berendse K, Engelen M, Linthorst GE, van Trotsenburg AS, Poll-The BT. High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders. Orphanet J Rare Dis. 2014;9:133.
    1. Berendse K, Klouwer FC, Koot BG, Kemper EM, Ferdinandusse S, Koelfat KV, Lenicek M, Schaap FG, Waterham HR, Vaz FM, Engelen M, Jansen PL, Wanders RJ, Poll-The BT. Cholic acid therapy in Zellweger spectrum disorders. J Inherit Metab Dis. 2016;39:859–68.
    1. Berendse K, Koot BGP, Klouwer FCC, Engelen M, Roels F, Lacle MM, Nikkels PGJ, Verheij J, Poll-The BT. Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder. J Inherit Metab Dis. 2019;42:955–65.
    1. Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313–21.
    1. Collins CS, Gould SJ. Identification of a common PEX1 mutation in Zellweger syndrome. Hum Mutat. 1999;14:45–53.
    1. 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. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002;70:1520–31.
    1. 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. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet. 2010;47:608–15.
    1. Ebberink MS, Koster J, Visser G, Spronsen F, Stolte-Dijkstra I, Smit GP, Fock JM, Kemp S, Wanders RJ, Waterham HR. A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene. J Med Genet. 2012;49:307–13.
    1. Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat. 2011;32:59–69.
    1. Ebberink MS, Mooyer PA, Koster J, Dekker CJ, Eyskens FJ, Dionisi-Vici C, Clayton PT, Barth PG, Wanders RJ, Waterham HR. Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines. Hum Mutat. 2009;30:93–8.
    1. Falkenberg KD, Braverman NE, Moser AB, Steinberg SJ, Klouwer FCC, Schlüter A, Ruiz M, Pujol A, Engvall M, Naess K, van Spronsen F, Körver-Keularts I, Rubio-Gozalbo ME, Ferdinandusse S, Wanders RJA, Waterham HR. Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder. Am J Hum Genet. 2017;101:965–76.
    1. Ferdinandusse S, Falkenberg KD, Koster J, Mooyer PA, Jones R, van Roermund CWT, Pizzino A, Schrader M, Wanders RJA, Vanderver A, Waterham HR. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J Med Genet. 2017;54:330–7.
    1. Fujiki Y. Peroxisome biogenesis and human peroxisome-deficiency disorders. Proc Jpn Acad Ser B Phys Biol Sci. 2016;92:463–77.
    1. Gootjes J, Skovby F, Christensen E, Wanders RJ, Ferdinandusse S. Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder. Neurology. 2004;62:2077–81.
    1. Gould SJ, Raymond GV, Valle D. The peroxisome biogenesis disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:3181-218.
    1. Heubi JE, Bishop WP. Long-term cholic acid treatment in a patient with Zellweger spectrum disorder. Case Rep Gastroenterol. 2018;12:661–70.
    1. Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97.
    1. Hubbard WC, Moser AB, Tortorelli S, Liu A, Jones D, Moser H. Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings. Mol Genet Metab. 2006;89:185–7.
    1. 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. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab. 2009;97:212–20.
    1. Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22.
    1. Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151.
    1. Lines MA, Jobling R, Brady L, Marshall CR, Scherer SW, Rodriguez AR, Lee L, Lang AE, Mestre TA, Wanders RJ, Ferdinandusse S, Tarnopolsky MA, et al. Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology. 2014;82:963–8.
    1. Lyons CJ, Castano G, McCormick AQ, Applegarth D. Leopard spot retinal pigmentation in infancy indicating a peroxisomal disorder. Br J Ophthalmol. 2004;88:191–2.
    1. Majewski J, Wang Z, Lopez I, Al Humaid S, Ren H, Racine J, Bazinet A, Mitchel G, Braverman N, Koenekoop RK. 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. 2011;2011;48:593–6.
    1. Moser AB, Jones RO, Hubbard WC, Tortorelli S, Orsini JJ, Caggana M, Vogel BH, Raymond GV. Newborn Screening for X-Linked Adrenoleukodystrophy. Int J Neonatal Screen. 2016;2:15.
    1. Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, Chen G, Raymond G, Liu A, Gordon D, et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr. 1995;127:13–22.
    1. Moser HW. Genotype-phenotype correlations in disorders of peroxisome biogenesis. Mol Genet Metab. 1999;68:316–27.
    1. Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, McNeill NH, Helman G, Simons C, Schmidt JL, Rizzo WB, Patterson MC, Taft RJ, Vanderver A. GLIA Consortium. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab. 2015;114:501–15.
    1. Patay Z. Diffusion-weighted MR imaging in leukodystrophies. Eur Radiol. 2005;15:2284–303.
    1. Pierce SB, Walsh T, Chisholm KM, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010;87:282–8.
    1. Plecko B, Stockler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol. 2000;48:121–5.
    1. Poll-The BT, Gootjes J, Duran M, De Klerk JB, Wenniger-Prick LJ, Admiraal RJ, Waterham HR, Wanders RJ, Barth PG. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet A. 2004;126A:333–8.
    1. 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. 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;70:1062–8.
    1. Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet. 2015;97:535–45.
    1. Ratbi I, Jaouad IC, Elorch H, Al-Sheqaih N, Elalloussi M, Lyahyai J, Berraho A, Newman WG, Sefiani A. Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene. Eur J Med Genet. 2016;59:507–11.
    1. Régal L, Ebberink MS, Goemans N, Wanders RJ, De Meirleir L, Jaeken J, Schrooten M, Van Coster R, Waterham HR. Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol. 2010;68:259–63.
    1. Renaud M, Guissart C, Mallaret M, Ferdinandusse S, Cheillan D, Drouot N, Muller J, Claustres M, Tranchant C, Anheim M, Koenig M. Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. J Neurol. 2016;263:1552–8.
    1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
    1. Rush ET, Goodwin JL, Braverman NE, Rizzo WB. Low bone mineral density is a common feature of Zellweger spectrum disorders. Mol Genet Metab. 2016;117:33–7.
    1. Sevin C, Ferdinandusse S, Waterham HR, Wanders RJ, Aubourg P. Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet J Rare Dis. 2011;6:8.
    1. Sheffer R, Douiev L, Edvardson S, Shaag A, Tamimi K, Soiferman D, Meiner V, Saada A. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function. Am J Med Genet A. 2016;170:1603–7.
    1. Shimozawa N, Nagase T, Takemoto Y, Ohura T, Suzuki Y, Kondo N. Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: Evidence for a founder haplotype for the most common PEX10 gene mutation. Am J Med Genet. 2003;120A:40–3.
    1. Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016;24:1565–71.
    1. Steinberg SJ, Snowden A, Braverman NE, Chen L, Watkins PA, Clayton PT, Setchell KD, Heubi JE, Raymond GV, Moser AB, Moser HW. A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. J Inherit Metab Dis. 2009;32:109–19.
    1. Taylor RL, Handley MT, Waller S, et al. Novel PEX11B mutations extend the peroxisome biogenesis disorder 14B phenotypic spectrum and underscore congenital cataract as an early feature. Invest Ophthalmol Vis Sci. 2017;58:594–603.
    1. Tran D, Greenhill W, Wilson S. Infantile refsum disease with enamel defects: a case report. Pediatr Dent. 2011;33:266–70.
    1. Tran C, Hewson S, Steinberg SJ, Mercimek-Mahmutoglu S. Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-linked adrenoleukodystrophy. Pediatr Neurol. 2014;51:262–5.
    1. van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJ, Barth PG, Poll-The BT. High incidence of hyperoxaluria in generalized peroxisomal disorders. Mol Genet Metab. 2006;88:346–50.
    1. Vanstone JR, Smith AM, McBride S, Naas T, Holcik M, Antoun G, Harper ME, Michaud J, Sell E, Chakraborty P, Tetreault M, Majewski J, Baird S, Boycott KM, Dyment DA, MacKenzie A, Lines MA, et al. DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur J Hum Genet. 2016;24:1084–8.
    1. Ventura MJ, Wheaton D, Xu M, Birch D, Bowne SJ, Sullivan LS, Daiger SP, Whitney AE, Jones RO, Moser AB, Chen R, Wangler MF. Diagnosis of a mild peroxisomal phenotype with next-generation sequencing. Mol Genet Metab Rep. 2016;9:75–78.
    1. Vogel BH, Bradley SE, Adams DJ, D'Aco K, Erbe RW, Fong C, Iglesias A, Kronn D, Levy P, Morrissey M, Orsini J, Parton P, Pellegrino J, Saavedra-Matiz CA, Shur N, Wasserstein M, Raymond GV, Caggana M. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. 2015;114:599–603.
    1. Waterham HR, Koster J, van Roermund CWT, Mooyer PAW, Wanders RJA, Loenard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007;356:1736–41.
    1. Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822:1430–41.
    1. Watkins PA, McGuinness MC, Raymond GV, Hicks BA, Sisk JM, Moser AB, Moser HW. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol. 1995;38:472–7.
    1. Yoon G, Malam Z, Paton T, Marshall CR, Hyatt E, Ivakine Z, Scherer SW, Lee KS, Hawkins C, Cohn RD, Finding of Rare Disease Genes (FORGE) in Canada Consortium Steering Committee Lethal disorder of mitochondrial fission caused by mutations in DNM1L. J Pediatr. 2016;171:313–6.e1.

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