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DECODING PORPHYRIA IN MALAYSIA: BIOCHEMICAL AND MOLECULAR CHARACTERISATION
Corresponding Author(s) : Dr. Sofwatul MN.
Malaysian Journal of Clinical Biochemistry,
Vol. 3 No. 1 (2026): Young Scientists Award (35th MACB Conference 2025)
Abstract
Porphyria is a group of rare inherited or acquired disorders arising from enzyme deficiencies in the heme biosynthesis pathway. Accurate diagnosis requires integration of clinical, biochemical, and genetic data to differentiate between subtypes. This study aimed to characterise porphyria subtypes among Malaysian patients using a multi-modal diagnostic approach involving urinary and plasma porphyrin analysis and molecular testing. Thirteen patients with clinical suspicion of porphyria underwent biochemical screening using high-performance liquid chromatography (HPLC) to analyse urinary and plasma porphyrins. Molecular investigations included whole-exome sequencing (WES), Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) targeting key porphyria-related genes. All patients showed elevated urinary porphyrins, with levels correlating to clinical severity. Plasma porphyrin profiling supported diagnosis in acute intermittent porphyria (AIP) but was less informative for erythropoietic protoporphyria (EPP). Genetic analysis confirmed one AIP case with a pathogenic HMBS gene variant (c.673C>T), two cases suggestive of EPP with homozygous low-penetrance FECH gene variants (c.315-48T>C), and one case with a heterozygous pathogenic HFE gene variant (c.187C>G) linked to the risk of acquired porphyria cutanea tarda (PCT). Four cases had inconclusive genetic findings, while five showed no pathogenic variants, indicating the possibility of acquired porphyria or alternative diagnoses. This study highlights the value of combining biochemical and molecular tools in the diagnosis of porphyria. The presence of low-penetrance or absent variants in some patients underscores the need for thorough clinical evaluation and consideration of environmental triggers in suspected porphyria cases.
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- Aarsand, A. K., To-Figueras, J., Whatley, S., Sandberg, S., & Schmitt, C. (2024). Practical recommendations for biochemical and genetic diagnosis of the porphyrias. In Liver International. John Wiley and Sons Inc. https://doi.org/10.1111/liv.16012
- Adams, P. C., Horgan-Bell, C., Walsh, S., & Sadikovic, B. (2020). Porphyria cutanea tarda associated with elevated serum ferritin, iron overload, and a bone morphogenetic protein 6 genetic variant. Canadian Liver Journal, 3(2), 232–234. https://doi.org/10.3138/canlivj-2019-0018
- Barman-Aksoözen, J., Cwiek, P., Bansode, V. B., Koentgen, F., Truöb, J., Pelczar, P., Cinelli, P., Schneider-Yin, X., Schuömperli, D., & Minder, E. I. (2017). Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice. DMM Disease Models and Mechanisms, 10(3), 225–233. https://doi.org/10.1242/dmm.027755
- Bonkovsky, H. L., Dixon, N., & Rudnick, S. (2019). Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). In Molecular Genetics and Metabolism (Vol. 128, Issue 3, pp. 213–218). Academic Press Inc. https://doi.org/10.1016/j.ymgme.2019.03.002
- Bonkovsky, H. L., & Rudnick, S. R. (2025). Erythropoietic Protoporphyria and X-linked Protoporphyria (Vol. 2025). MSD Manual. https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/the-porphyrias/erythropoietic-protoporphyria-and-x-linked-protoporphyria
- Bygum, A., Christiansen, L., Petersen, N. E., Hørder, M., Thomsen, K., & Brandrup, F. (2003). Familial and sporadic porphyria cutanea tarda: Clinical, biochemical and genetic features with emphasis on iron status. Acta Dermato-Venereologica, 83(2). https://doi.org/10.1080/00015550310007454
- Colombi, A., Maroni, M., Ferioli, A., Valla, C., Coletti, G., & Fob, V. (1983). Liquid Chromatography of Urinary Porphyrins for the Biological Monitoring of Occupational Exposure to Porphyrinogenic Substances. In American Journal of Industrial Medicine.
- Di Pierro, E., De Canio, M., Mercadante, R., Savino, M., Granata, F., Tavazzi, D., Nicolli, A. M., Trevisan, A., Marchini, S., & Fustinoni, S. (2021). Laboratory diagnosis of porphyria. In Diagnostics (Vol. 11, Issue 8). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/diagnostics11081343
- Elder, G. H. (2012). Porphyria Cutanea Tarda and Related Disorders. In The Porphyrin Handbook: Medical Aspects of Porphyrins (Vol. 14, pp. 67–92). Elsevier Inc. https://doi.org/10.1016/B978-0-08-092388-8.50010-8
- Hindmarsh, J. T., Oliveras, L., & Greenway, D. C. (1999). Plasma porphyrins in the porphyrias. Clinical Chemistry, 45(7). https://doi.org/10.1093/clinchem/45.7.1070
- Katrin Baumann, R. K. (2022). Long-term follow-up of acute porphyria in female patients: Update of clinical outcome and life expectancy. Molecular Genetics and Metabolism Reports. https://doi.org/10.1016/j.ymgmr.2022.100842
- Keyfi, F., Alaei, A., Daryasari, H. M., Hakimi, A., & Gharavi, P. (2024). Utilizing High-Performance Liquid Chromatography (HPLC) in Clinical Diagnostics. In O. Núñez (Ed.), Relevant Applications of High-Performance Liquid Chromatography in Food, Environmental, Clinical and Biological Fields. IntechOpen. https://doi.org/10.5772/intechopen.1008238
- Leaf, R. K., & Dickey, A. K. (2024). Porphyria cutanea tarda: a unique iron-related disorder. Hematology, 2024(1), 450–456. https://doi.org/10.1182/hematology.2024000664
- Linenberger, M., & Fertrin, K. Y. (2020). Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. ASH Education Program. https://doi.org/10.1182/hematology.2020000124
- Macours, P., & Cotton, F. (2006). Improvement in HPLC separation of porphyrin isomers and application to biochemical diagnosis of porphyrias. Clinical Chemistry and Laboratory Medicine, 44(12), 1433–1440. https://doi.org/10.1515/CCLM.2006.266
- Minder, A. E., Kluijver, L. G., Barman-Aksözen, J., Minder, E. I., & Langendonk, J. G. (2024). Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management. In Liver International. John Wiley and Sons Inc. https://doi.org/10.1111/liv.16027
- Neeleman, R. A., Wensink, D., Wagenmakers, M. A. E. M., Mijnhout, G. S., Friesema, E. C. H., & Langendonk, J. G. (2020). Diagnostic and therapeutic strategies for porphyrias. The Netherlands Journal of Medicine, 78, 149–160.
- Ogun, A. S., Joy, N. V, & Valentine, M. (2023). Biochemistry, Heme Synthesis. In StatPearls. StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.
- Pallet, N., Karras, A., Thervet, E., Gouya, L., Karim, Z., & Puy, H. (2018). Porphyria and kidney diseases. In Clinical Kidney Journal (Vol. 11, Issue 2, pp. 191–197). Oxford University Press. https://doi.org/10.1093/ckj/sfx146
- Poli, A., Manceau, H., Nguyen, A. L., Moulouel, B., Dessendier, N., Talbi, N., Puy, H., Junot, C., Gouya, L., Schmitt, C., & Lefebvre, T. (2023). Quantification of Urine and Plasma Porphyrin Precursors Using LC–MS in Acute Hepatic Porphyrias: Improvement in Routine Diagnosis and in the Monitoring of Kidney Failure Patients. Clinical Chemistry, 69(10), 1186–1196. https://doi.org/10.1093/clinchem/hvad117
- Ruthirago, D., Julayanont, P., & Rassameehiran, S. (2016). Presentations associated with porphyrias in intensive care units. The Southwest Respiratory and Critical Care Chronicles, 4(16), 51–55. https://doi.org/10.12746/swrccc2016.0416.220
- Singal, A. K. (2022). Porphyria Cutanea Tarda Disease Overview.
- Stölzel, U., Doss, M. O., & Schuppan, D. (2019). Clinical Guide and Update on Porphyrias. In Gastroenterology (Vol. 157, Issue 2, pp. 365-381.e4). W.B. Saunders. https://doi.org/10.1053/j.gastro.2019.04.050
- Varghese, M. V., James, J., Rafikova, O., & Rafikov, R. (2021). Glucose-6-phosphate dehydrogenase deficiency contributes to metabolic abnormality and pulmonary hypertension. American Journal of Physiology - Lung Cellular and Molecular Physiology, 320(4), L508–L521. https://doi.org/10.1152/AJPLUNG.00165.2020
- Vassiliou, D. (2023). Studies on the Acute Porphyrias – with special reference to women’s health. Karolinska University Hospital.
References
Aarsand, A. K., To-Figueras, J., Whatley, S., Sandberg, S., & Schmitt, C. (2024). Practical recommendations for biochemical and genetic diagnosis of the porphyrias. In Liver International. John Wiley and Sons Inc. https://doi.org/10.1111/liv.16012
Adams, P. C., Horgan-Bell, C., Walsh, S., & Sadikovic, B. (2020). Porphyria cutanea tarda associated with elevated serum ferritin, iron overload, and a bone morphogenetic protein 6 genetic variant. Canadian Liver Journal, 3(2), 232–234. https://doi.org/10.3138/canlivj-2019-0018
Barman-Aksoözen, J., Cwiek, P., Bansode, V. B., Koentgen, F., Truöb, J., Pelczar, P., Cinelli, P., Schneider-Yin, X., Schuömperli, D., & Minder, E. I. (2017). Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice. DMM Disease Models and Mechanisms, 10(3), 225–233. https://doi.org/10.1242/dmm.027755
Bonkovsky, H. L., Dixon, N., & Rudnick, S. (2019). Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). In Molecular Genetics and Metabolism (Vol. 128, Issue 3, pp. 213–218). Academic Press Inc. https://doi.org/10.1016/j.ymgme.2019.03.002
Bonkovsky, H. L., & Rudnick, S. R. (2025). Erythropoietic Protoporphyria and X-linked Protoporphyria (Vol. 2025). MSD Manual. https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/the-porphyrias/erythropoietic-protoporphyria-and-x-linked-protoporphyria
Bygum, A., Christiansen, L., Petersen, N. E., Hørder, M., Thomsen, K., & Brandrup, F. (2003). Familial and sporadic porphyria cutanea tarda: Clinical, biochemical and genetic features with emphasis on iron status. Acta Dermato-Venereologica, 83(2). https://doi.org/10.1080/00015550310007454
Colombi, A., Maroni, M., Ferioli, A., Valla, C., Coletti, G., & Fob, V. (1983). Liquid Chromatography of Urinary Porphyrins for the Biological Monitoring of Occupational Exposure to Porphyrinogenic Substances. In American Journal of Industrial Medicine.
Di Pierro, E., De Canio, M., Mercadante, R., Savino, M., Granata, F., Tavazzi, D., Nicolli, A. M., Trevisan, A., Marchini, S., & Fustinoni, S. (2021). Laboratory diagnosis of porphyria. In Diagnostics (Vol. 11, Issue 8). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/diagnostics11081343
Elder, G. H. (2012). Porphyria Cutanea Tarda and Related Disorders. In The Porphyrin Handbook: Medical Aspects of Porphyrins (Vol. 14, pp. 67–92). Elsevier Inc. https://doi.org/10.1016/B978-0-08-092388-8.50010-8
Hindmarsh, J. T., Oliveras, L., & Greenway, D. C. (1999). Plasma porphyrins in the porphyrias. Clinical Chemistry, 45(7). https://doi.org/10.1093/clinchem/45.7.1070
Katrin Baumann, R. K. (2022). Long-term follow-up of acute porphyria in female patients: Update of clinical outcome and life expectancy. Molecular Genetics and Metabolism Reports. https://doi.org/10.1016/j.ymgmr.2022.100842
Keyfi, F., Alaei, A., Daryasari, H. M., Hakimi, A., & Gharavi, P. (2024). Utilizing High-Performance Liquid Chromatography (HPLC) in Clinical Diagnostics. In O. Núñez (Ed.), Relevant Applications of High-Performance Liquid Chromatography in Food, Environmental, Clinical and Biological Fields. IntechOpen. https://doi.org/10.5772/intechopen.1008238
Leaf, R. K., & Dickey, A. K. (2024). Porphyria cutanea tarda: a unique iron-related disorder. Hematology, 2024(1), 450–456. https://doi.org/10.1182/hematology.2024000664
Linenberger, M., & Fertrin, K. Y. (2020). Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. ASH Education Program. https://doi.org/10.1182/hematology.2020000124
Macours, P., & Cotton, F. (2006). Improvement in HPLC separation of porphyrin isomers and application to biochemical diagnosis of porphyrias. Clinical Chemistry and Laboratory Medicine, 44(12), 1433–1440. https://doi.org/10.1515/CCLM.2006.266
Minder, A. E., Kluijver, L. G., Barman-Aksözen, J., Minder, E. I., & Langendonk, J. G. (2024). Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management. In Liver International. John Wiley and Sons Inc. https://doi.org/10.1111/liv.16027
Neeleman, R. A., Wensink, D., Wagenmakers, M. A. E. M., Mijnhout, G. S., Friesema, E. C. H., & Langendonk, J. G. (2020). Diagnostic and therapeutic strategies for porphyrias. The Netherlands Journal of Medicine, 78, 149–160.
Ogun, A. S., Joy, N. V, & Valentine, M. (2023). Biochemistry, Heme Synthesis. In StatPearls. StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.
Pallet, N., Karras, A., Thervet, E., Gouya, L., Karim, Z., & Puy, H. (2018). Porphyria and kidney diseases. In Clinical Kidney Journal (Vol. 11, Issue 2, pp. 191–197). Oxford University Press. https://doi.org/10.1093/ckj/sfx146
Poli, A., Manceau, H., Nguyen, A. L., Moulouel, B., Dessendier, N., Talbi, N., Puy, H., Junot, C., Gouya, L., Schmitt, C., & Lefebvre, T. (2023). Quantification of Urine and Plasma Porphyrin Precursors Using LC–MS in Acute Hepatic Porphyrias: Improvement in Routine Diagnosis and in the Monitoring of Kidney Failure Patients. Clinical Chemistry, 69(10), 1186–1196. https://doi.org/10.1093/clinchem/hvad117
Ruthirago, D., Julayanont, P., & Rassameehiran, S. (2016). Presentations associated with porphyrias in intensive care units. The Southwest Respiratory and Critical Care Chronicles, 4(16), 51–55. https://doi.org/10.12746/swrccc2016.0416.220
Singal, A. K. (2022). Porphyria Cutanea Tarda Disease Overview.
Stölzel, U., Doss, M. O., & Schuppan, D. (2019). Clinical Guide and Update on Porphyrias. In Gastroenterology (Vol. 157, Issue 2, pp. 365-381.e4). W.B. Saunders. https://doi.org/10.1053/j.gastro.2019.04.050
Varghese, M. V., James, J., Rafikova, O., & Rafikov, R. (2021). Glucose-6-phosphate dehydrogenase deficiency contributes to metabolic abnormality and pulmonary hypertension. American Journal of Physiology - Lung Cellular and Molecular Physiology, 320(4), L508–L521. https://doi.org/10.1152/AJPLUNG.00165.2020
Vassiliou, D. (2023). Studies on the Acute Porphyrias – with special reference to women’s health. Karolinska University Hospital.