|Year : 2020 | Volume
| Issue : 3 | Page : 196-197
New heterozygous mutation of protoporphyrinogen oxidase gene in a case of variegate porphyria in Taiwan
Meng-Han Shen1, Min-Hui Chi1, Tseng-Tong Kuo2
1 Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taipei, and Linkou Branches, Taiwan
2 Department of Pathology, Chang Gung Memorial Hospital, Taipei, Taiwan
|Date of Submission||08-Feb-2019|
|Date of Decision||06-Mar-2020|
|Date of Acceptance||23-Mar-2020|
|Date of Web Publication||03-Jun-2020|
Dr. Min-Hui Chi
Department of Dermatology, Chang Gung Memorial Hospital, No. 199, Tung Hwa North Road, Taipei
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Shen MH, Chi MH, Kuo TT. New heterozygous mutation of protoporphyrinogen oxidase gene in a case of variegate porphyria in Taiwan. Dermatol Sin 2020;38:196-7
|How to cite this URL:|
Shen MH, Chi MH, Kuo TT. New heterozygous mutation of protoporphyrinogen oxidase gene in a case of variegate porphyria in Taiwan. Dermatol Sin [serial online] 2020 [cited 2021 Oct 23];38:196-7. Available from: https://www.dermsinica.org/text.asp?2020/38/3/196/285719
Variegate porphyria (VP), one of the neurocutaneous porphyrias, is an autosomal dominant inherited disease which is caused by decreased activity of protoporphyrinogen oxidase (PPOX). Mutations in the PPOX gene may affect the structure of the enzyme PPOX, and reduce enzyme activity. VP is mainly reported in South Africa whites of Dutch descent (1/300). Prevalence of VP has been estimated at 0.3/100,000 in Europe. In 2017, the first VP case in China was reported. Here, we report a new heterozygous mutation of the PPOX gene in a Taiwanese VP patient.
A 28-year-old Taiwanese woman with Meniere's disease and bipolar disorder presented with itchy hyperpigmented macules, excoriation, and scars on her face, upper chest [Figure 1]a, bilateral dorsal hands and lateral side of upper limbs for 2 years. Intermittent attacks of vesicles with an itching sensation were recently noted on bilateral dorsal side of hands, particularly after sun exposure [Figure 1]b. Simultaneously, one episode of acute onset of hearing impairment on the right side suddenly occurred. The patient also fainted several times, and experienced tremors of four limbs in the last 2 months. A review of her medical history showed she had been receiving valproic acid for 6 months for her psychiatric disorder with one tablet a day for 3 months and then 1.5 tablets a day for 3 months before she came to our clinic. No obvious change in her living environment and eating habit, nor significant psychological stress was found. Acute intermittent porphyria (AIP) was suspected by the neurologist initially. Monitoring through 24-hour electroencephalogram and brain computed tomography did not discover specific brain lesions.
|Figure 1: Clinical images of the patient. (a) The lesions were itchy brown macules with excoriation on her chest, (b) hands. Tense vesicle was noted on bilateral hands. The lesions were predominantly on the sun-exposed area. (c) The hematoxylin–eosin histology shows subepidermal vesicles containing mononuclear cells, festooning of the dermal papillae protruding into the vesicle, and thickened dermal vessels surrounded by lymphocytes. (Hematoxylin and Eosin staining, original magnification ×100) (d) A PAS stain which was marked in black circle in the Figure 1c showed PAS-positive vessels in the dermis.(PAS staining, original magnification ×200)|
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Skin biopsy of one vesicular lesion on her left hand illustrated a subepidermal vesicle containing mononuclear cells, festooning of the dermal papillae protruding into the vesicle, and thickened dermal vessels surrounded by lymphocytes [Figure 1]c. Periodic acid-Schiff (PAS) staining showed PAS-positive vessels in the dermis and PAS-positive basement membrane on the floor of the vesicle [Figure 1]d. The dermatopathology presentation was consistent with that of porphyria cutanea tarda. An increase in the level of urinary porphobilinogen (3.4 mg/L; normal range <2.0 mg/L) and urinary 5′-aminolevulinic acid (5.7 mg/L; normal value <4.5 mg/L) with increased urinary coproporphyrin I and III levels (331.7 μg/L; normal value <152.8 μg/L) were present. The plasma scan with a fluorescence emission peak was detected at 626 nm. Based on the findings above, the patient was diagnosed with VP. A review of the patient's family history disclosed that none of her family members exhibited similar manifestations, and no ancestor was from South Africa. Furthermore, we performed gene analysis for this patient, and her PPOX gene revealed a missense variant rs776885557: C.850A>G, p. Ser284Gly in the heterozygous state [Figure 2]. Following the diagnosis, she was advised to avoid sun exposure, crash dieting, alcohol consumption, and the use of unsafe drugs, including valproic acid. The patient's skin lesions completely subsided with residual postinflammatory hyperpigmentation. Moreover, seizure attacks did not occur thereafter.
|Figure 2: Mutation of c.850A>G in the protoporphyrinogen oxidase gene (the lower panel shows the patient's gene analysis) compared with the wild-type allele (top panel)|
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VP is caused by a decrease in the activity of PPOX by 43% of the normal activity. The neuropsychiatric manifestations of VP are variable, and attacks of VP are less severe and considerably less frequent than those of AIP. Therefore, VP is rarely considered by neurologists during diagnosis. Plasma, excited using the wavelength of 405 ± 1 nm, with a fluorescence emission peak at 626 ± 1 nm, can be used as a diagnostic marker for VP. According to the information from American Porphyria Foundation, genetic testing can determine specific porphyria if a mutation is found in a characteristic gene location. Screening of the patient's PPOX gene revealed a novel missense variant rs776885557: C.850A>G, p. Ser284Gly in the heterozygous state. The minor allele frequency of this missense variant is 0.000008/1. The variant is located in 13th beta sheet, a component of flavin adenine dinucleotide (FAD)-binding domain. Protoporphyrinogen IX oxidase (PPOX) converts protoporphyrinogen to protoporphyrin with the coenzyme FAD. A similar reported missense mutation, p. S284I, decreases catalytic activity of PPOX. Consequently, our patient's missense variant, p. Ser284Gly, may affect the secondary structure of PPOX, its activity, and exhibit pathologic effects. Our patient's clinical presentation and gene mutation verified that this mutational variant induces VP.
In conclusion, we reported a novel heterozygous single-nucleotide missense mutation of the PPOX gene in a Taiwanese VP patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Brenner DA, Bloomer JR. The enzymatic defect in variegate prophyria. Studies with human cultured skin fibroblasts. N
Engl J Med 1980;302:765-9.
Qin X, Tan Y, Wang L, Wang Z, Wang B, Wen X, et al
. Structural insight into human variegate porphyria disease. FASEB J 2011;25:653-64.
Ramanujam VM, Anderson KE. Porphyria diagnostics – Part 1: A brief overview of the porphyrias. Curr Protoc Hum Genet 2015;86:17,20,11-26.
Zhou S, Zhao X, Kang H, Xu R, Yu Y, Zheng J, et al
. Novel heterozygous mutation of protoporphyrinogen oxidase gene in a Chinese patient with variegate porphyria. J Dermatol 2017;44:e317-8.
Tracy JA, Dyck PJ. Porphyria and its neurologic manifestations. In: Biller J, Ferro JM, editors. Handb Clin Neurol 2014;120:839-49.
[Figure 1], [Figure 2]