A novel mutation in HMBS associated with a leukoencephalopathy and review of literature

Abstract

Purpose: Hydroxy-methyl-bilane synthase (HMBS), also known as porphobilinogen deaminase, is the third enzyme in the heme biosynthesis pathway, which catalyzes the condensation of four porphobilinogen molecules to yield hydroxy-methyl-bilane. Heterozygous HMBS pathogenic variants cause acute intermittent porphyria (AIP). In contrast, biallelic pathogenic variants in HMBS cause a spectrum of porphyria-related encephalopathy or leukoencephalopathy. In this study, we presented a previously unidentified mutation in HMBS and anticipated contributing to the literature with this novel mutation in terms of genotype-phenotype correlation. In contrast to the nomenclature of HMBS-related clinics described in the literature, the present study aimed to demonstrate that biallelic HMBS mutations can cause leukoencephalopathy without being associated with porphyria. Materials and methods: We reported an adult patient who presented with cystic leukoencephalopathy on brain magnetic resonance imaging (MRI) without porphyria symptoms. We performed whole-exome analysis (WES) on the patient and evaluated the variants with recommended guidelines. Results: The missense likely pathogenic variant was detected in the homozygous state in the HMBS gene NM_000190.4: c.271G>A; p.Asp91Asn; in WES analysis. We presented the patient’s clinical and radiological features and compared them with patients previously described with leukoencephalopathy and biallelic HMBS variants. Conclusion: Our case is presented as the 13. patient with biallelic HMBS pathogenic variants, and the patient’s variation is the seventh novel pathogenic variant (c.271G>A) in the literature. In addition to this novel mutation, we anticipate that our patient's clinical and radiological findings will contribute to the genotype-phenotype correlation. This study demonstrates that clinical manifestations, caused by biallelic variants of the HMBS gene, can occur without porphyria, contrary to the previous definitions of diseases associated with porphyria. Based on the findings of our case and patients in the literature, we recommend that the nomenclature of current HMBS-related clinics caused by biallelic mutations be reconsidered.

Keywords

• HMBS
• biallelic
• leukoencephalopathy
• porphyria

HMBS geninde lökoensefalopati ile ilişkili yeni bir mutasyon ve literatürün gözden geçirilmesi

Öz

Amaç: Porfobilinogen deaminaz olarak da bilinen hidroksi-metil-bilan sentaz (HMBS), hem biyosentez yolunda yer alan üçüncü enzimdir ve dört porfobilinogen molekülünün yoğunlaşmasını katalize ederek hidroksi-metil-bilan oluşumunu sağlar. Heterozigot HMBS patojenik varyantları, akut intermitan porfiriye (AIP) neden olur. Buna karşın, HMBS'deki biallelik patojenik varyantlar, porfiriye bağlı ensefalopati veya lökoensefalopati spektrumuna neden olur. Bu çalışmada, HMBS'de daha önce tanımlanmamış bir mutasyonu sunduk ve genotip-fenotip korelasyonu açısından bu yeni mutasyon ile literatüre katkıda bulunmayı öngördük. Literatürde tanımlanan HMBS ile ilişkili kliniklerin isimlendirilmesinden farklı olarak, bu çalışma, biallelik HMBS mutasyonlarının porfiri ile ilişkili olmadan da lökoensefalopatiye neden olabileceğini göstermeyi amaçlamıştır. Gereç ve yöntem: Porfiri semptomları göstermeyen, beyin manyetik rezonans görüntüleme (MRG) sonuçlarında kistik lökoensefalopati saptanan bir yetişkin hasta sunduk. Hastaya tüm ekzom analizi (WES) yaptık ve önerilen kılavuzlara göre varyantları değerlendirdik. Bulgular: WES analizinde, HMBS geni NM_000190.4: c.271G>A; p.Asp91Asn'de homozigot durumda muhtemelen patojenik olan bir missense varyant tespit edildi. Hastanın klinik ve radyolojik özelliklerini sunduk ve bunları daha önce lökensefalopati ve biallelik HMBS varyantları ile tanımlanan hastalarla karşılaştırdık. Sonuç: Bizim vakamız, biallelik HMBS patojenik varyantları olan 13. hasta olarak sunulmaktadır ve hastanın varyantı literatürdeki yedinci yeni patojenik varyanttır (c.271G>A). Yeni sunulan bu mutasyona ek olarak, hastamızın sunulan klinik ve radyolojik bulguları ile genotip-fenotip korelasyonuna katkıda bulunduğumuzu öngörmekteyiz. Bu çalışma, HMBS geninin biallelik varyantlarının neden olduğu klinik belirtilerin, porfiri ile ilişkili hastalıkların önceki tanımlarının aksine, porfiri olmadan da ortaya çıkabileceğini göstermektedir. Bizim vakamızın ve literatürdeki hastaların bulgularına dayanarak, biallelik mutasyonların neden olduğu HMBS ile ilgili mevcut kliniklerin isimlendirilmesinin yeniden gözden geçirilmesi öneriyoruz.

Anahtar Kelimeler

• HMBS
• biallelik
• lökoensefalopati
• porfiri

References

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