Abstract
Conventionally, diagnosis of peroxisomal disorders (PD) has been performed by enzymatic and genetic analysis after measurement of peroxisomal metabolites in blood. With the progress of genome analysis technology accompanying the advent of the next generation sequencer, including whole-exome sequencing (WES), the approach of undiagnosed diseases by comprehensive genomic analysis has become a global trend. In PD also, not only new phenotypes of known pathogenic genes but also newly identified PD have been reported by WES, mainly in the patients with undiagnosed neurological diseases. Therefore, PD diagnostic system combining screening of peroxisomal metabolites and WES should be useful for efficient diagnosis.
On the one hand, diagnosis of adrenoleukodystrophy (ALD) should be done as soon as possible, as early hematopoietic stem cell transplantation is critically important for improving the prognosis of brain-type ALD. We have established a rapid diagnostic system combined with measurement of very long chain fatty acids and detection of ABCD1 mutations. Furthermore, the pre-symptomatic diagnosis by family analysis of probands as well as newborn screening, combined with long-term follow-up system are also important for overcoming this intractable disease. In this chapter, we describe the efficient and prompt approach for diagnosis of PD and ALD and introduce our diagnostic system in Japan.
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References
Abu-Safieh L, Alrashed M, Anazi S et al (2013) Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res 23:236–247
Bacino C, Chao YH, Seto E, Lotze T, Xia F, Jones RO, Moser A, Wangler MF (2015) A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey. Mol Genet Metab Rep 5:15–18
Barøy T, Koster J, Strømme P et al (2015) A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Hum Mol Genet 24:5845–5854
Bjørgo K, Fjær R, Mørk HH, Ferdinandusse S, Falkenberg KD, Waterham HR, Øye AM, Sikiric A, Amundsen SS, Kulseth MA, Selmer K (2017) Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder. Mol Genet Metab 121:325–328
Blomqvist M, Ahlberg K, Lindgren J, Ferdinandusse S, Asin-Cayuela J (2017) Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report. J Med Case Rep 11:218
Buchert R, Tawamie H, Smith C, Uebe S, Innes AM, Al Hallak B, Ekici AB, Sticht H, Schwarze B, Lamont RE, Parboosingh JS, Bernier FP, Abou Jamra R (2014) A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet 95:602–610
Corzo D, Gibson W, Johnson K et al (2002) Contiguous 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
Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT (2012) X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 7:51
Huffnagel IC, Laheji FK, Aziz-Bose R, Tritos NA, Marino R, Linthorst GE, Kemp S, Engelen M, Eichler F (2019) The natural history of adrenal insufficiency in x-linked adrenoleukodystrophy: an international collaboration. J Clin Endocrinol Metab 104:118–126
Kumar KR, Wali GM, Kamate M, Wali G, Minoche AE, Puttick C, Pinese M, Gayevskiy V, Dinger ME, Roscioli T, Sue CM, Cowley MJ (2016) Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing. Neurogenetics 17:265–270
McMillan HJ, Worthylake T, Schwartzentruber J et al (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 7:1–9
Ohba C, Osaka H, Iai M (2013) Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. Neurogenetics 14:225–232
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
Ratbi I, Falkenberg KD, Sommen M et al (2015) Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet 97:535–545
Renaud M, Guissart C, Mallaret M, Ferdinandusse S, Cheillan D, Drouot N, Muller J, Claustres M, Tranchant C, Anheim M, Koenig M (2016) Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. J Neurol 263:1552–1558
Schabhüttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, Erwa W, Trajanoski S, Strom TM, Auer-Grumbach M (2014) Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. J Neurol 261:970–982
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 (2016) Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet 24:1565–1571
Shimozawa N, Tsukamoto T, Suzuki Y, Orii T, Shirayoshi Y, Mori T, Fujiki Y (1992) A human gene responsible for Zellweger syndrome that affects peroxisome assembly. Science 255:1132–1134
Shimozawa N, Tsukamoto T, Nagase T, Takemoto Y, Koyama N, Suzuki Y, Komori M, Osumi T, Jeannette G, Wanders RJ, Kondo N (2004) Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene. Hum Mutat 23:552–558
Shimozawa N (2011) Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain and Development 33:770–776
Shimozawa N, Honda A, Kajiwara N, Kozawa S, Nagase T, Takemoto Y, Suzuki Y (2011) X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan. J Hum Genet 56:106–109
Takashima S, Toyoshi K, Itoh T, Kajiwara N, Honda A, Ohba A, Takemoto S, Yoshida S, Shimozawa N (2017) Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. Mol Genet Metab 120:255–268
Takashima S, Saitsu H, Shimozawa N (2019) Expanding the concept of peroxisomal diseases and efficient diagnostic system in Japan. J Hum Genet 64:145–152
Takemoto Y, Suzuki Y, Horibe R, Shimozawa N, Wanders RJ, Kondo N (2003) Gas chromatography/mass spectrometry analysis of very long chain fatty acids, docosahexaenoic acid, phytanic acid and plasmalogen for the screening of peroxisomal disorders. Brain and Development 25:481–487
Ventura MJ, Wheaton D, Xu M, Birch D, Bowne SJ, Sullivan LS, Daiger SP, Whitney AE, Jones RO, Moser AB, Chen R, Wangler MF (2016) Diagnosis of a mild peroxisomal phenotype with next-generation sequencing. Mol Genet Metab Rep 9:75–78
Vilarinho S, Sari S, Mazzacuva F, Bilgüvar K, Esendagli-Yilmaz G, Jain D, Akyol G, Dalgiç B, Günel M, Clayton PT, Lifton RP (2016) ACOX2 deficiency: a disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment. Proc Natl Acad Sci 113:11289–11293
Wang Y, Busin R, Reeves C, Bezman L, Raymond G, Toomer CJ, Watkins PA, Snowden A, Moser A, Naidu S, Bibat G, Hewson S, Tam K, Clarke JT, Charnas L, Stetten G, Karczeski B, Cutting G, Steinberg S (2011) X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab 104:160–166
Yamashita T, Mitsui J, Shimozawa N et al (2017) Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype. J Neurol Sci 375:424–429
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The diagnostic studies of PD are approved by the Ethical Committee of the Graduate School of Medicine, Gifu University.
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Shimozawa, N. (2019). Diagnosis of Peroxisomal Disorders. In: Imanaka, T., Shimozawa, N. (eds) Peroxisomes: Biogenesis, Function, and Role in Human Disease. Springer, Singapore. https://doi.org/10.1007/978-981-15-1169-1_7
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DOI: https://doi.org/10.1007/978-981-15-1169-1_7
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