Diagnosis of Peroxisomal Disorders
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.
KeywordsPeroxisomal disorders VLCFA Plasmalogen Phytanic acid Next generation sequencing Whole-exome sequencing Undiagnosed diseases Chromatography/mass spectrometry Adrenoleukodystrophy Genetic testing Presymptomatic diagnosis Carrier detection ABCD1 Newborn screening
The diagnostic studies of PD are approved by the Ethical Committee of the Graduate School of Medicine, Gifu University.
Conflict of Interest
The author declares no conflict of interest.
- 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 95:602–610CrossRefGoogle Scholar
- 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 261:970–982CrossRefGoogle Scholar
- 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 120:255–268CrossRefGoogle Scholar
- 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 25:481–487CrossRefGoogle Scholar
- 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 113:11289–11293CrossRefGoogle Scholar
- 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 104:160–166CrossRefGoogle Scholar