Archives of Academic Emergency Medicine. 2022; 10(1): e74 CA S E RE P O RT Acute Intermittent Porphyria as a Rare Challenging Neuro-Metabolic Disease; a Case Report Elsayed Abed1∗, Omer M. Saeed2, Basem Abd El-Hamid3, Mohamed A. Elsayed3, Heba Dawoud4, Nahla Mohamed Heikal4, Ahmed Hanei Elshafie5, Aya Hagar6, Hossam Emam1, Ahmed Farag El-adawey1, Abdel-Ghaffar Fayed1, Ahmed Hassan Elsheshiny1, Mahmoud Galal Ahmed1 1. Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, 11651, Egypt. 2. Department of Neurology, Al-Araby international hospital, Monufia, 32951, Egypt. 3. Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, 11651, Egypt. 4. Department of pediatrics, Faculty of Medicine, Tanta University, 31511, Egypt. 5. Department of Neurology, Shebin Elkom teaching hospital, Monufia, 32951, Egypt. 6. Egyptian intensive care fellowship, Shebin Elkom teaching hospital, Monufia, 32951, Egypt. Received: July 2022; Accepted: August 2022; Published online: 13 September 2022 Abstract: Porphyria is a challenging metabolic disease due to its heterogeneous presentation symptoms and its difficult diagnosis. Many affected individuals can complain of recurrent neuro-visceral attacks per year, some of which may be persistent and life-threatening, which is confusing if there is no established diagnosis. Although the motor manifestations, autonomic changes and seizure are highly suggestive, the diagnosis is often overlooked and needs confirmatory genetic testing. To the best of our knowledge, the acute intermittent porphyria (AIP) reported in this case, involving severe electrolyte disturbances and rapid severe weakness is a challenging neuro- metabolic case and is extremely rare worldwide. Here, we reported a case of AIP in a young girl who presented to the emergency department of Al-Araby international Hospital, Monufia, Egypt with severe abdominal pain, constipation, and headache which had started 10 days ago. It seems that the diagnosis of porphyria should be considered particularly in those patients with abdominal complaints associated with electrolyte disturbances, seizures, and severe progressive neuropathy. Keywords: Electrolyte Imbalance; Porphyria, Acute Intermittent; Polyneuropathies Cite this article as: Abed E, Saeed MO, El-Hamid BA, Elsayed AM, Dawoud H, Heikal NM, et al. Acute Intermittent Porphyria as a Rare Challenging Neuro-Metabolic Disease; a Case Report. Arch Acad Emerg Med. 2022; 10(1): e74. https://doi.org/10.22037/aaem.v10i1.1780. 1. Introduction Porphyrias are a group of rare metabolic disorders presenting a wide range of clinical manifestations. As a result of the ge- netic mutation in the enzymatic pathway involved in heme biosynthesis, a specific subtype of acute porphyrias can arise (1). The acute porphyrias can be either autosomal domi- nant, such as acute intermittent porphyria (AIP), variegate porphyria, and hereditary coproporphyria, or autosomal re- cessive, such as delta-aminolevulinic acid (ALA) dehydratase ∗Corresponding Author: Elsayed Abed; Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, 11651, Egypt. Email: elsayed- abed.226@azhar.edu.eg, Tel: 00201062635615, ORCID: https://orcid.org/0000- 0001-6494-3874. deficiency. Enzymatic defect in the porphobilinogen deami- nase (PBGD) can cause AIP; a rare autosomal dominant dis- ease that can be easily confused with other diseases (2). Clin- ical presentation of AIP is rare before puberty and the diag- nosis is suggested by a triad of symptoms; severe abdomi- nal pain, quadriparesis due to peripheral nerve involvement, delirium, and depression as the most common neuropsy- chiatric manifestation, which dominates the clinical picture. Despite the rarity of the disease, the diagnosis may be con- firmed by a decreasing level of porphobilinogen in the ery- throcytes. However, although the autonomic changes and seizure are highly suggestive, the diagnosis is often over- looked and needs confirmatory genetic testing (3). Moreover, early diagnosis may considerably improve patients’ progno- sis through proper management. Here we reported a case of AIP presenting to emergency department with severe elec- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem E. Abed et al. 2 Table 1: The laboratory findings as well as cerebrospinal fluid and genetic analyses of the patient Variable Value Complete blood count Red blood cells (cells/mcL) 4 million White blood cells (cells/mcL) 55000 Platelets count (/mcL) 226,000 Hemoglobin (gm/dl) 13 Venus blood gas analysis pH 7.31 pCO2 (mm Hg) 42 pO2(mm Hg) 40 Electrolyte Sodium (mEq/L) 108 Potassium (mEq/L) 2.7 Total calcium (mg/dl) 4.9 Ionized calcium (mg/dl) 3.5 Magnesium (mEq/L) 0.7 Phosphorus (mEq/L) 2.1 Osmolality Urine osmolality (mOml/kg) 277 Serum osmolality (mOml/kg) 252 Serum chloride (mEq/L) 73 Urinary Calcium/creatinine ratio 1.053 CSF analysis CSF appearance Clear, colorless CSF protein (mg/100 ml) 35 CSF glucose (mmol/l) 4.2 CSF chloride (mmol/l) 125 CSF lactate (mmol/l) 2.1 CSF culture and sensitivity negativ Gene analysis HBMS gene NM_000190.3:c.76C>T CSF: cerebrospinal fluid. trolyte disturbances and rapid severe weakness. It seems that, the diagnosis of AIP should be considered when pa- tients present with severe electrolyte imbalance and progres- sive neuropathy. 2. Case presentation A 13-year-old girl with no history of medical or familial dis- eases presented to the emergency department of Al-Araby in- ternational Hospital, Monufia, Egypt with severe abdominal pain, constipation, and headache, which had started 10 days ago. Within the next few days following admission, the pa- tient developed an attack of generalized tonic-clonic seizure associated with low-grade fever. On examination, the pa- tient was confused in post ictal state. Otherwise, the neu- rological and general examination was unremarkable. Pa- tient was hemodynamically stable. Urgent brain computed tomography (CT) scan showed brain edema (figure 1). Cere- brospinal fluid (CSF) analysis, routine blood chemistry tests, blood culture, and serum electrolyte evaluation were per- formed. On a clinical basis, central nervous system infec- tion was suspected and the patient started to receive acy- clovir. Due to severe abdominal pain, abdominopelvic CT scan with contrast was done, which revealed marked disten- tion of large bowel, and no definite air-fluid level or obstruct- ing masses (figure 1). The initial results of laboratory inves- tigation revealed marked electrolyte disturbances; sodium level: 108 milliequivalents per liter (mEq/L), potassium level: 2.7 mEq/L, total calcium level: 4.9 mg/dl, ionized calcium level: 3.5 mg/dl, magnesium level: 0.7 mEq/L, and phos- phorus level: 2.1 mEq/L (table 1). Within the next few days, the patient began to become agitated and developed gen- eralized muscle pain despite proper correction of resistant hyponatremia with hypertonic saline 3%. In addition, the patient started to develop polyuria, and polydipsia, despite the normovolemic state, confirmed by clinical examination and central venous pressure monitoring. High suspicion to Bartter-like syndrome was raised as the renal tubular de- fect with increased renal loss of electrolyte was confirmed by the following laboratory investigation: urine osmolarity 277mOml/kg, serum osmolality 252 mmol/kg, serum chlo- ride 73 mEq/L, and urinary Calcium/creatinine ratio 1.053 (table 1). Within the next few days, she developed weak- ness in both lower limbs, right more than left, which was rapidly progressing to involve upper limbs associated with trunk muscle affection till the patient became quadriplegic. The rest of the examination was normal. Our opinion about the case changed and we had a rising concern about ge- netic disease. At that time, the whole-exome sequencing was sent abroad to CENTOGENE GmbH (Rostock, Germany) for genetic analysis. Electrophysiological studies were done, which revealed evidence of purely motor axonal polyneu- ropathy affecting upper and lower limbs with bilateral facial axonal neuropathy (prolonged first time (F) wave latencies with reduced amplitude of compound motor action poten- tials). Unfortunately, the condition worsened till the patient became intubated and mechanically ventilated due to respi- ratory muscle involvement. The CSF examination showed cytoalbuminous dissociation, and this made the diagnosis more in favor of Guillain-Barre Syndrome (GBS). The patient received intravenous immunoglobulin (IV IG) (2gm per Kg divided over 5 days) with partial improvement. Due to the failure of multiple trials for weaning from mechanical ven- tilation, tracheostomy was performed. Genetic sequencing results showed a heterozygous pathogenic variant in the hy- droxymethylbilane synthase (HMBS) gene, which confirmed the diagnosis of autosomal dominant AIP (figure 2). The pa- tient received dextrose 25% and 2 doses of hemin 250 mg once daily for four days, 2 weeks apart followed by another dose after 2 months. There was a marked improvement re- garding the weakness, and abdominal pain, and we managed to wean her from mechanical ventilation. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e74 Figure 1: left image: Brain computed tomography scan without contrast showed grey-white matter differentiation of the cerebrum and cere- bellum is preserved, however there is subtly reduced density of the cerebrum relative to the cerebellum, suggesting mild/early diffuse edema. No sulcal effacement and ventricles are normal in appearance. Right and middle image: Abdominal computed tomography scan with intra- venous contrast reveals marked distension of stomach and duodenum. Figure 2: Summary of genetic testing findings (left) and its interpretation (right). 3. Discussion Porphyria is a challenging metabolic disease due to its het- erogeneous presentation symptoms and its difficult diag- nosis. It is a common term incorporating many inborn metabolic diseases affecting heme biosynthesis. For each of the eight enzymes included in this pathway, there is an as- sociated known defect. Due to these defects, an intermedi- ate precursor is accumulated (1, 4). There are multiple clas- sifications for porphyria but distinctly it is attributed to ei- ther the site of accumulation of the metabolite or the pheno- typically dominant manifestations (5). The commonest type was AIP (3). It occurs mainly due to an autosomal dominant enzymatic defect in the third cascade of the heme synthesis pathway. Defects of the HMBS gene, which encodes PBGD enzyme, lead to the accumulation of porphyrin precursors such as ALA and porphobilinogen. These toxic metabolites accumulate in the liver and become deposited in many sys- tems causing problems with a wide range of severity and af- fecting different organs. Renal failure and electrolyte imbal- ances are also among the possible emerging heterogeneous presentation sequelae. In the present report, we introduced a case of AIP, in which a young girl presented with a rare pre- sentation. Due to the strong association between hormonal changes and precipitation of attacks, AIP is more prevalent in females. Our case showed severe weakness in both upper and lower limbs that progressed to involve the respiratory mus- cles due to severe peripheral neuropathy. This could be at- tributed to axonal dysfunction due to Na+/K+ pump energy dysfunction resulting from the lack of heme availability and the direct neurotoxic effect of porphyrin precursors (6). Se- vere resistant hyponatremia was observed in our case either due to primary salt wasting or the syndrome of inappropri- ate antidiuretic hormone secretion as reported in a previous study (7). The degree of axonal damage probably predicts the ultimate prognosis. However, some patients with the GBS variant remain permanently quadriparetic (8). Once a por- phyria attack is diagnosed, precipitating factors or provok- ing agents such as dietary changes with low caloric intake, certain drugs, stressful conditions, and infections should be avoided (4, 5). Treatment for AIP includes both support- ive and specific therapies. In addition, glucose supplements or parenteral administration of hematin are suggested (8). Clinical evaluation and parental targeted testing are recom- mended to establish whether the detected variant is inher- ited or de novo. Although some attacks may be persistent and life-threatening, early diagnosis may considerably improve This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem E. Abed et al. 4 patient prognosis through proper management. 4. Conclusion Porphyric neuropathy is a predominantly motor neuropathy with different clinical presentations that may mimic various neuropathies, such as GBS with diffuse axonal involvement, or lead neuropathy with specific nerve involvement, or bi- lateral radial neuropathy. A diagnosis of porphyria should be considered particularly in patients with abdominal com- plaints associated with electrolyte disturbances, seizures, and severe progressive neuropathy. Moreover, early diag- nosis may considerably improve patient prognosis through proper management. 5. Declarations 5.1. Acknowledgments The authors would like to express their gratitude to the De- partment of Neurology, Faculty of Medicine, Al-Azhar Uni- versity, Cairo, Egypt. 5.2. Authors’ contributions All authors participated in manuscript writing and editing. All authors have read and approved the manuscript. 5.3. Funding and supports This study was self-funded by the authors. 5.4. Competing interests The authors declare that they have no competing interests. 5.5. Ethics approval and consent to participate This study was conducted in concordance with declaration of Helsinki and the participant signed a written informed con- sent before the submission of the case report. The institu- tional review board (IRB) approval was obtained from the ethical committee of Faculty of Medicine, Al-Azhar Univer- sity, Cairo, Egypt. References 1. Spiritos Z, Salvador S, Mosquera D, Wilder J. Acute inter- mittent porphyria: current perspectives and case presen- tation. Ther Clin Risk Manag. 2019;15:1443-51. 2. 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Medicine. 2005;84(1):48-60. 8. Schutte C-M, Van der Meyden CH, Van Niekerk L, Kakaza M, Van Coller R, Ueckermann V, et al. Severe porphyric neuropathy-importance of screening for porphyria in Guillain-Barre syndrome: clinical alert. S Afr Med J. 2016;106(1):44-7. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Case presentation Discussion Conclusion Declarations References