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Porphyria-induced posterior reversible encephalopathy syndrome and central

nervous system dysfunction

Article in Molecular Genetics and Metabolism · November 2019

DOI: 10.1016/j.ymgme.2019.10.011

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 Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Molecular Genetics and Metabolism

journal homepage: www.elsevier.com/locate/ymgme

Review article

Porphyria-induced posterior reversible encephalopathy syndrome and

central nervous system dysfunction
⁎
Daniel A. Jaramillo-Callea,b, Juan M. Solanoc, Alejandro A. Rabinsteind, Herbert L. Bonkovskye,
a
IPS Universitaria, Universidad de Antioquia, Medellin, Colombia
b
Institute of Medical Research, Universidad de Antioquia, School of Medicine, Medellin, Colombia
c
Department of Neurology, Universidad de Antioquia, School of Medicine, Medellin, Colombia
d
Department of Neurology, Mayo Clinic, Rochester, MN, United States of America
e
Section on Gastroenterology & Hepatology, Wake Forest University School of Medicine/NC Baptist Hospital, Winston-Salem, United States of America.

A R T I C LE I N FO A B S T R A C T

Keywords: Background and aim: An association between neuropsychiatric manifestations and neuroimaging suggestive of
Central nervous system posterior reversible encephalopathy syndrome (PRES) during porphyric attacks has been described in numerous
Neuroimaging case reports. We aimed to systematically review clinical-radiological features and likely pathogenic mechanisms
Neuropsychiatry of PRES in patients with acute hepatic porphyrias (AHP) and porphyric attacks.
Physiopathology
Methods: PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched (July 30, 2019). We included
Porphyria
Posterior leukoencephalopathy syndrome
articles describing patients with convincing evidence of an AHP, confirmed porphyric attacks, and PRES in
neuroimaging.
Results: Forty-three out of 269 articles were included, which reported on 46 patients. Thirty-nine (84.8%) pa-
tients were women. The median age was 24 ± 13.8 years. 52.2% had unspecified AHP, 41.3% acute inter-
mittent porphyria, 4.3% hereditary coproporphyria, and 2.2% variegate porphyria. 70.2% had systemic arterial
hypertension. Seizures, mental changes, arterial hypertension, and hyponatremia occurred more frequently than
expected for porphyric attacks (p < .001). Seizures and hyponatremia were also more frequent than expected
for PRES. The most common distributions of brain lesions were occipital (81.4%), parietal (65.1%), frontal
(60.5%), subcortical (40%), and cortical (32.5%). Cerebral vasoconstriction was demonstrated in 41.7% of the
patients who underwent angiography. 19.6% of the patients had ischemic lesions, and 4.3% developed long-term
sequelae (cognitive decline and focal neurological deficits).
Conclusions: Brain edema, vasoconstriction, and ischemia in the context of PRES likely account for central
nervous symptoms in some porphyric attacks.

1. Introduction regions, which is often reversible in follow-up images. PRES was in-
itially observed in association with preeclampsia/eclampsia, renal
Posterior reversible encephalopathy syndrome (PRES) is a clinical- failure, cytotoxic drugs, autoimmune disorders, and organ transplan-
radiological condition characterized by neurological symptoms and tation. However, the increasing availability of advanced imaging
cerebral vasogenic edema. Clinical manifestations include seizures, technologies in emergency rooms is broadening the spectrum of dis-
headaches, altered mental status, visual disturbances, and other focal eases in which PRES is recognized, such as the acute hepatic porphyrias
neurological deficits. Neuroimaging often shows asymmetric and bi- (AHPs) [1,2].
lateral vasogenic edema, predominantly affecting parieto-occipital AHPs are rare genetic disorders characterized by partial enzymatic

Abbreviations: ADH, Antidiuretic hormone; AHPs, Acute hepatic porphyrias; AIP, Acute intermittent porphyria; ALA, 5-aminolevulinic acid; ALAS1, 5-aminole-
vulinic acid synthase 1; BBB, Blood-brain barrier; CNS, Central nervous system; CSF, Cerebrospinal fluid; GABA, γ; ICAM1, Intracellular adhesion molecule-1; IL,
Interleukin; IQR, Interquartile range; MAP, mean arterial pressure; NO, Nitric oxide; NOS, Nitric oxide synthase; PEPT2, Peptide transporter 2; PRES, Posterior
reversible encephalopathy syndrome; PTX3, Pentraxin-3; ROS, Reactive oxygen species; SIADH, Inappropriate secretion of ADH; TCAC, Tricarboxylic acid cycle; TNF,
Tumor necrosis factor; ULN, Upper limit of normal; UPBG, Urinary porphobilinogen; VCAM1, Vascular cell adhesion protein-1; VEGF, Vascular endothelial growth
factor
⁎
Corresponding author at: Wake Forest University, School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, United States of America.
E-mail addresses: daniel.jaramillo2@udea.edu.co (D.A. Jaramillo-Calle), hbonkovs@wakehealth.edu (H.L. Bonkovsky).

https://doi.org/10.1016/j.ymgme.2019.10.011
Received 12 August 2019; Received in revised form 29 October 2019; Accepted 30 October 2019
1096-7192/ © 2019 Published by Elsevier Inc.

Please cite this article as: Daniel A. Jaramillo-Calle, et al., Molecular Genetics and Metabolism, https://doi.org/10.1016/j.ymgme.2019.10.011
D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

deficiencies in the heme biosynthetic pathway. The most common 2.3. Study selection and data collection
forms are autosomal dominant inherited disorders, named acute inter-
mittent porphyria (AIP, OMIM:176000), hereditary coproporphyria Two reviewers (DAJC and JMS) independently screened abstracts
(OMIM:121300), and variegate porphyria (OMIM:176200). A fourth and collected the data. Articles in languages other than Spanish and
and very rare recessive form is caused by a severe deficiency of 5- English were translated. Extracted data included age, sex, medical
aminolevulinic acid dehydratase (OMIM:125270). The clinical pre- history, clinical manifestations, laboratory tests, medications, imaging
sentation consists of life-threatening attacks of neurovisceral symptoms studies, and outcomes. Unreported data were considered absent.
due to autonomic, peripheral and central neuropathy. Signs and Disagreements were resolved by discussion to a consensus between
symptoms are nonspecific, typically comprising abdominal pain, ta- reviewers. Relevant missing data were requested from authors.
chycardia, systemic arterial hypertension, bladder dysfunction, vo-
miting, pain, and muscle weakness. Central nervous system (CNS) 2.4. Methodological quality assessment
dysfunction and neuropsychiatric manifestations similar to those of
PRES may also occur in a minority of cases. Attacks are triggered by We used the tool to assess the methodological quality of case reports
factors (e.g., drugs, fasting, stress, alcohol, hormones) that induce he- by Murad et al. [9], which was adapted for this review. The quality was
patic 5-aminolevulinic acid synthase 1 (ALAS1, E.C. 2.3.1.37) and cause judged according to the number of criteria fulfilled as high (5 criteria),
excessive production of the porphyrin precursors, 5-aminolevulinic acid moderate (4 criteria), and low (≤3 criteria).
(ALA) and porphobilinogen. Symptoms rarely occur before puberty and
are more common in women, probably related to the inducing effect of 2.5. Diagnosis of porphyric attacks
sex hormones (predominantly progesterone) on ALAS1. Diagnosis relies
on the demonstration of significantly elevated urinary ALA and/or To establish that a group of nonspecific clinical manifestations is
porphobilinogen (UPBG). Intravenous hemin is considered the most caused by a dominant AHP, significantly elevated UPBG must be de-
effective treatment available for attacks, but carbohydrate loading may monstrated [10]. In this review, confirmed porphyric attacks were de-
also be useful in mild cases [3]. fined as concentrations of UPBG ≥ 4-fold the upper limit of normal
The pathogenesis of attacks is not entirely understood [4]. The most (ULN) or positive qualitative tests. Quantitative UPBG tests are best
widely accepted hypothesis suggests that ALA produced excessively in normalized to urine creatinine concentrations, which adjust to the
the liver is the main pathogenic factor [5]. ALA can inhibit or activate marked variability related to the concentration or dilution of urine.
γ-aminobutyric acid receptors and is also pro-oxidative so that it may Quantitative UPBG tests reported as elevated without reference ranges
lead to neuro and cytotoxicity [6,7]. The fact that liver transplantation were considered positive.
stops recurrences of attacks and normalizes the urinary excretion of
porphyrin precursors supports that the liver is the primary pathogenic 2.6. Study parameters
site. However, an important unresolved issue regarding this hypothesis
is to what extent excessive ALA synthesized in the liver is involved in Severe porphyric attacks were defined by the presence of hypona-
the pathogenesis of CNS dysfunction given that the blood-brain barrier tremia (serum Na < 130 mEq/L), seizures, or paresis. Otherwise, they
(BBB) is almost impermeable to porphyrin precursors, and there is a were considered mild. Porphyria types were reassessed based on DNA
clearance mechanism at the choroid plexuses to maintain the con- analysis, erythrocyte hydroxymethylbilane synthase activity, and por-
centration of ALA low in the brain [8]. phyrin analysis [11]. Seizures were classified as generalized, focal, or
Recently, many patients with neuropsychiatric manifestations and unknown [12]. Systemic arterial hypertension was defined as blood
neuroimaging suggestive of PRES during porphyric attacks have been pressure ≥ 95th percentile (< 13 years), ≥130/80 (13–16 years),
identified. It is unknown whether these two phenomena always occur and ≥ 140/90 (≥17 years) [13,14]. Mean arterial pressure (MAP) was
together, but cerebral edema and vasoconstriction related to PRES are calculated as 1/3 systolic blood pressure + 2/3 diastolic blood pres-
plausible explanations for CNS dysfunction during porphyric attacks. sure. It was graded as normal (≤105 mmHg), slightly elevated
Nevertheless, this relationship has not been systematically studied. (106–115), and significant hypertension (≥116) [15]. Hyponatremia
Here, we present a systematic review of published case reports and was categorized as mild (Na ≤ 135), moderate (Na = 125–130), and
series to characterize the clinical-radiological features of PRES during profound/severe (Na < 125) [16]. Brain lesions distribution was ca-
porphyric attacks and discuss possible pathogenic mechanisms to ex- tegorized as lobar (frontal, parietal, occipital, temporal), cerebellum,
plain this relationship. brain stem, basal ganglia, cortical, and subcortical. Topographic pat-
terns were classified as dominant parieto-occipital, holo-hemispheric
watershed, and superior frontal sulcus [15].
2. Methods
2.7. Data analyses
2.1. Eligibility criteria
Continuous variables were summarized as medians/interquartile
We included any study describing patients with AHPs who devel-
ranges (IQR) and categorical variables as counts/percentages. One
oped PRES during porphyric attacks and that provided data at the
sample proportion Z-test was used to compare relative frequencies of
single-subject level. To be included, patients had to have 1) convincing
seizures, mental changes, hypertension, and hyponatremia in this re-
clinical evidence of an AHP, 2) confirmed porphyric attacks, and 3) a
view against theoretical relative frequencies of the same manifestation
description of PRES in head MRI or CT scans. Articles were excluded if
during porphyric attacks derived from published series [17–19]. As
alternative etiologies of PRES were identified [1] or double report a
~30% of asymptomatic AHPs mutation carriers have a high UPBG (up
patient.
to 15-fold ULN), we compared demographic and clinical features of
patients with UPBG≥15-fold and patients with UPBG < 15-fold or
2.2. Information sources and search positive qualitative tests to evaluate the impact of a possible mis-
classification. The median age was compared using the Wilcoxon rank-
PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched sum test and categorical variables using the chi-squared test or Fisher's
through July 30, 2019. No restrictions were applied. Reference lists of exact test. Two-sided p-values < .05 were considered statistically sig-
included studies were reviewed manually (Search strategy in supple- nificant. Analyses were performed in Stata Statistical Software, V.14
ments). (College Station, TX: StataCorp LP.).

2
 Table 1
A detailed summary of the included articles. Demographic, clinical, biochemical, and neuroimaging features of patients with PRES during porphyric attacks (n = 46).
Set Sex/Age Country Type UPBG (n-fold BP (MAP) Na Neurological manifestations Neuroimaging findings Ref.
ULN)

A F/21 NZ HCP High (15) 171 / 125* 125 Seizures, delirium MRI = Edema. Non-enhancing (RP, LP, RO, LO). Reversible (6 w) [32]
F/23 Spain AIP High (86) NR 114 Seizures, unconscious MRI = ↑ T2 Cortical and Subcortical. Non-enhancing. ↑ ADC (LF, RF). Reversible (2 m) [54]
D.A. Jaramillo-Calle, et al.

F/36 Russia AIP High 180/100 (127) 137 Seizures, paresis, mental changes CT = Hypodense lesions (LF, RF, LT, RT). Reversible (1.5 m) [58] (#1)
F/24 India AIP High (34) NR 129 Seizures, lethargy MRI = ↑ T2. ↑ DWI / ↓ ADC (RF, LF, RT, LT, RP, LP, RO, LO). Reversible (1.5 m). MRA = Normal [58]
(#14)
F/28 China AIP High NR 120 Seizures, paresis, dysarthria, unconscious MRI = ↑ FLAIR Cortical and Subcortical. Non-enhancing. (RP, LP, RO, LO). Reversible (6 m) [60]
F/38 Japon AIP High (52) 183/114 (137) NR Seizures, impaired consciousness MRI = ↑ FLAIR Subcortical ↑DWI (RO, LO) Reversible (21 d). MRA = Normal [61]
F/18 USA AIP High (626) 160/115 (130) NR Seizures, confusion, hallucinations, somnolence, MRI = ↑ T2 subcortical. Enhancing. (RF, LF, RT, LT). Reversible (5 w). CA = Vasoconstriction [62]
disorientation, headache
F/57 USA VP High (11) 193/103 (133) 120 Seizures, paresis, confusion MRI = ↑ T2 cortical and subcortical. ↑DWI / ↑ ADC. (RT, LT, RP, LP, RO, LO). [22]
F/39 Taiwan AIP High (17) NR NR Paresis, headache MRI = ↑ FLAIR subcortical (RF, LF, RP, LP, RO, LO). Reversible (1 y) [23]
F/9 China AIP High (37) 175/110 (132) NR Seizures, confusion, visual disturbances MRI = ↑ T2 (RP, LP, RO, LO). Reversible (5 d) [24]
F/20 USA AIP High (21) 170/120 (137) 128 Seizures, paresis, lethargy, hallucinations MRI = ↑ T2 (RF, LF, RP, LP). Reversible (10 d) [28]
F/24 SK AIP High (39) 160/100 (120) NR Seizures, paresis, visual disturbances MRI = ↑ T2/FLAIR cortical and subcortical. Non-enhancing. [31]
↓ DWI / ↑ ADC (RF, RO, LO, pons, midbrain, thalamus, basal ganglia, left corona radiata).
Reversible (2 w)
F/20 USA AIP High (201) 148/118 (128) NR Seizures, lethargy MRI = ↑ T2/FLAIR (RF, LF, LT, RT, RP, LP, RO, LO). Reversible (1 m) [33]
F/18 China AHP High 136/101 (113) 104 Seizures, hallucinations MRI = ↑ T2/FLAIR Cortical and Subcortical, ↓ DWI / ↑ ADC (RF, LF, RP, LP, RO, LO) Reversible [34] (#2)
(2 w). MRA = Normal
F/18 Colombia AHP High (4) 150/71 (97) 137 Seizures, paresis, disorientation, somnolence, MRI = ↑ FLAIR Cortical/Subcortical. Enhancing. No restricted diffusion. (LF, RF, LP, RP, LO, [46]
blindness RO). Reversible (19 d)
F/22 India AHP High 190/110 (137) NR Seizures, disorientation, blindness MRI = ↑ Cortical and Subcortical (RF, LF, LT, RT, RP, LP) No restricted diffusion. Reversible (14 [50]
d)
F/21 Canada AHP High (184) NR NR Seizures MRI = ↑ FLAIR cortical and subcortical [51]

3
(RF, LF, RP, LP, RO, LO). Reversible (3 w)
M/60 Taiwan AHP High (70) 164/98 (120) NR Seizures, paresis, psychosis, impaired MRI = ↑ T2/FLAIR cortical and subcortical. Non-enhancing. (RF, LF, RP, LP, RO, LO). Reversible [52]
consciousness, disorientation, confusion (6 w)
B F/22 USA AIP High (12) 220/NR NR Seizures, diplopia, headache MRI = ↑ T2. Non-enhancing. (RO, LO). Partially reversible (5 d). CTA = Normal [25]
F/29 Japon AIP High (41) 135/75 (95) 94 Seizures, paresis, unconscious MRI = ↑ T2. Enhancing. (Caudate nucleus, putamen, pons, and thalamus). Cortical necrosis. [26]
Partially reversible (10 m)
F/35 Switzerland AIP High (168) NR NR Seizures, paresis, blindness MRI = ↑ T2 (RO, LO, calcarine). Partially reversible (6 m) – Ischemic lesions [27] (#1)
F/32 Switzerland AHP High (87) 170/100 (123) NR Seizures, paresis, blindness MRI = ↑ T2 Subcortical. Enhancing. (RF, RO, LO). Not reversible (4 w) – Ischemic lesions [27] (#2)
M/20 Pakistan AHP High (11) 140/100 (113) NR Seizures, impaired consciousness MRI = ↑ T2/FLAIR. Non-enhancing. Restricted diffusion. (RO, LO, parasagittal). Partially [53]
reversible (1 w) – Ischemic lesions. MRA = Normal
F/20 Germany AHP High 170/100 (123) NR Seizures, paresis, visual disturbances MRI = ↑ T2 (LF, RO, LO). Not reversible (10 d). MRA/CA = Normal [55]
F/25 Turkey AHP High 180/120 (140) Seizures, paresis, blindness, unconscious MRI = ↑ T2/FLAIR cortical and subcortical ↑DWI / ↓ ADC (RF, LF, RP, LP, RO, LO, LF, RCb, LCb, [56]
corpus callosum). Not reversible (6 m). Ischemic lesions
C F/43 Belgium AIP High 200/NR 132 Confusion, blindness, vertigo MRI = ↑ T2 (RO, LO). Not reversible (36 m) – Ischemic lesions. MRA/CA = Vasoconstriction [57]
F/39 France AHP High Normal 125 Paresis, blurred vision, headache, mental MRI = ↑ T2 (RP, LP, RO, LO, Cb). ↓ ADC. MRA/CA = Vasoconstriction / thrombosis. [35]
changes CT = Subarachnoid hemorrhage. Partially reversible (6 d)
F/33 USA AHP High NR 121 Seizures, paresis, confusion, apraxia MRI = ↑ T2 cortical. Non-enhancing. (RP, LP). Partially reversible/Ischemic lesions (4 d). [36]
MRA/CA = Vasoconstriction
F/20 Japon AHP High (98) 176/93 (121) 123 Seizures, paresis, emotional lability MRI = ↑ FLAIR. ↑ DWI / ↑ADC (RP, LP, RO, LO, RF LF, RCb, LCb). Partially reversible (51 d) – [57]
Ischemic lesions. MRA = Vasoconstriction
(continued on next page)
Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx
 Table 1 (continued)

Set Sex/Age Country Type UPBG (n-fold BP (MAP) Na Neurological manifestations Neuroimaging findings Ref.
ULN)

D F/62 France AIP High (39.3) 170/80 (110) NR Seizures, hallucinations, unconscious MRI = ↑ FLAIR cortical and subcortical. ↑ DWI / ↑ADC. (RF, LF, RO, LO) [20]
High (> 10) 177/103 (128) NR Seizures, blindness
F/29 Spain AIP High Hypertension 128 Confusion, blindness MRI = ↑ FLAIR cortical and subcortical. ↑ DWI (RF, LF, RP, LP, RT, LT, RO, LO, LF, RCb, LCb) [21]
D.A. Jaramillo-Calle, et al.

F/20 Spain HCP High (907) 166/111 (129) 126 Paresis, blurred vision, headache MRI = PRES Subcortical (RO, LO) [59]
F/35 Taiwan AIP High NR 127 Seizures, paresis MRI = ↑ T2/FLAIR. ↓ DWI. (RF, RP, LP, RO, LO) [29]
M/17 India AIP High (175) 170/110 (130) 128 Seizures, unconscious MRI = ↑ (RF, LF, RP, LP, RO, LO) [30]
M/27 China AHP High 159/101 (120) 130 Seizures, paresis MRI = ↑ T2/FLAIR. Enhancing. ↓DWI / ↑ADC (RF, LF, RP, LP, RO, LO) [34] (#1)
F/26 India AHP High 160/100 (120) 130 Seizures, hallucinations, mental changes MRI = ↑ T2/FLAIR (RP, LP, RO, LO, LF, RCb, LCb) [37]
F/16 Nepal AHP High NR 126 Seizures, unconscious MRI = PRES [38]
F/26 UK AHP High NR 138 Seizures, nystagmus MRI = ↑ T2. Non-enhancing. (Diffuse bilateral) [39]
F/5 India AHP High 100/70 (80) 113 Seizures, paresis, somnolence MRI = ↑ T2 (RF, RO, LO, parafalcine) [40]
CT = Hypodensity (RF, LF, RP, LP, RO, LO)
F/26 France AHP High NR 120 Seizures, anxiety, blurred vision, headache ↑ T2/FLAIR. ↑DWI / ↑ADC. (LF, RP, LP). CTA = Normal [41]
M/17 India AHP High (23) 140/110 (120) 120 Seizures, paresis, impaired consciousness MRI = ↑ T2/FLAIR. Isointense DWI / ↑ADC (RP, LP, RO, LO) [42]
F/24 Colombia AHP High NR NR Paresis MRI = PRES [44]
F/75 SK AHP High 130/80 (97) 118 Seizures, paresis, somnolence, mental changes MRI = “lesions in bilateral post central gyrus, medial thalami, periventricular, periaqueductal [45]
and hypothalamus”
F/12 SA AHP High (9) 166/115 (132) 131 Seizures, obtunded, paresis, blindness ↑ T2/FLAIR cortical and subcortical (RP, LP, RO, LO) [47]
M/12 India AHP High 170/110 (130) 126 Impaired consciousness, hallucinations, CT = Hypodense lesions (RO, LO) [48]
confusion, disorientation, blindness
M/19 India AHP High 140/100 (113) 144 Seizures, paresis, unconscious, blindness MRI = ↑ T2 (RO, LO) [49]

Set A, Reversible lesions; Set B, Non-reversible lesions; Set C, Non-reversible lesions + cerebral vasoconstriction; Set D, Unreported follow-up neuroimaging. ADC, Apparent diffusion coefficient; AHP, Acute hepatic
porphyria (unspecified); AIP, Acute intermittent porphyria; CA, Catheter angiography; CT, Computerized tomography; CTA, Computerized tomography angiography; DWI, Diffusion-weighted imaging; F, Female; FLAIR,

4
Fluid attenuation inversion recovery; GM, Grey matter; HCP, Hereditary coproporphyria; LCb, Left cerebellum; LF, Left frontal lobe; LO, Left occipital lobe; LP, Left parietal lobe; LT, Left temporal lobe; M, Male; MRA,
Magnetic resonance angiography; MRI, Magnetic resonance imaging; NR, Not reported; NZ, New Zealand; PRES, Posterior reversible encephalopathy syndrome; RCb, Right cerebellum; Ref, Reference; RF, Right frontal
lobe; RO, Right occipital lobe; RP, Right parietal lobe; RT, Right temporal lobe; SA, South Afrika; SK, South Korea; UK, United Kingdom; ULN, Upper limit of normal; UPBG, Urinary porphobilinogen; USA, United States of
America; VP, Variegate porphyria. *Maximum systolic and diastolic blood pressure separately.
Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx
D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

Table 2 and alcohol consumption (4.8%, 1/21).

Demographic and clinical features of patients with PRES during 47 attacks.
All UPBG UPBG P-value 3.4. Clinical and biochemical features
patients ≥15-fold < 15-fold a

Seizures occurred in 85.1% (40/47) of attacks [generalized: 62.5%

n (%) 46 (100) 19 (41.3) 27 (58.7)
(25/40), focal: 17.5% (7/40), unknown: 20% (8/40)]. 70.2% (33/47)
Attacks, n (%) 47 (100) 19 (40.4) 28 (59.6)
Demographics
had hypertension. Mean arterial blood pressure could be estimated for
Female, n (%) 39 (84.8) 23 (85.2) 16 (84.2) 1b 30 attacks (median MAP: 123.3, IQR: 17.1 mmHg, range: 80–140), of
c
Age, years, median ± IQR 24 ± 13.8 23 ± 15 25 ± 14 0.92 which 13.3% (4/30) was normal, 13.3% (4/30) slightly elevated, and
Severe attacks 46 (97.9) 19 (100) 26 (96.3) 1b 73.3% (22/30) significant hypertension. Chronic hypertension was
CNS manifestations, n (%)
b described only in two patients [20,22]. 55.3% (26/47) had hypona-
Seizures 40 (85.1) 17 (89.5) 23 (82.1) 0.68
Mental changes 34 (72.3) 13 (68.4) 21 (75) 0.62 tremia. Serum sodium values were available for 25 patients (median
Paresis 25 (53.2) 10 (52.6) 15 (53.6) 0.95 Na: 125, IQR: 8 mEq/L, range: 94–132), of which 8% (2/25) had mild
Visual disturbances 18 (38.3) 5 (26.3) 13 (46.4) 0.16 hyponatremia, 48% (12/25) moderate, and 44% (11/25) profound/
b
Headaches 6 (12.8) 3 (15.8) 3 (10.7) 0.67
severe. Acute kidney injury was described in two patients [31,41].
Other manifestations, n (%)
Abdominal pain 39 (83) 14 (73.7) 25 (89.3) 0.24 b 19.1% (9/47) required mechanical ventilation. CSF analysis was per-
Hypertension 33 (70.2) 13 (68.4) 20 (71.4) 0.82 formed in 6 patients; normal results were found in 5 and high glucose
Tachycardia 26 (55.3) 12 (63.2) 14 (50) 0.37 levels (98 mg/dL) in 1. One sample proportion Z-test indicated that
Vomiting 15 (31.9) 7 (36.8) 8 (28.6) 0.55 relative frequencies of seizures, mental changes, hypertension, and
Dark urine 13 (27.7) 4 (21.1) 9 (32.1) 0.40
hyponatremia in this review were higher than in series of patients with
Constipation 13 (27.7) 5 (26.3) 8 (28.6) 0.86
Hyponatremia 26 (55.3) 8 (42.1) 18 (64.3) 0.13 porphyric attacks (Fig. 1).
Treatment, n (%)
Hemin 28 (59.6) 12 (63.2) 16 (57.1) 0.68 3.5. Neuroimaging findings and prognosis
Mortality d, n (%) 4 (8.5) 1 (5.3) 3 (12.0) 0.62 b

Table 4 summarizes neuroimaging findings. Forty-four patients had

IQR, Interquartile range; MAP, Mean arterial pressure; PRES, Posterior re-
versible encephalopathy syndrome; ULN, Upper limit of normal; UPBG, Urinary head MRI and two head CT. Diffusion-weighted images were reported
porphobilinogen. a Between 4- to 15-fold or positive qualitative test. b p-values in 13 patients, 10 had non-restricted diffusion, and three restricted
for Fisher's Exact tests (Expected counts < 5). c p-values for Wilcoxon rank-sum diffusion. Follow-up neuroimaging was obtained in 28 patients (median
tests. d Data available for 45 cases. p-values without superscript correspond to time to follow-up images = 30 days, range: 4–1080 days). Ischemic le-
Pearson's chi-squared tests. sions were detected in 19.6% (9/46) of the patients and were the most
common reason for no reversibility in follow-up images [81.8% (9/
3. Results 11)]. Two patients had long-term neurological sequelae. The mortality
rate was 9.1% (4/44).
3.1. Study selection and characteristics
4. Discussion
Searches provided 269 citations. Sixty-two articles were selected for
full-text review, of which 19 articles were excluded (References of ex- 4.1. Pathogenesis of PRES during porphyric attacks
cluded articles and PRISMA flow chart in supplements). Reasons for
exclusion included unmeasured or low UPBG (n = 17), alternative The pathogenesis of PRES is not entirely understood. Endothelial
etiology of PRES (n = 3), and case duplication (n = 1). Forty-three dysfunction leading to BBB compromise and capillary leakage is con-
articles were included [39 case reports and 4 case series] [20–62], sidered the central pathogenic process. Given the heterogeneous nature
which reported 46 patients. Patients were from 20 countries in Africa, of PRES, various mechanisms may lead to endothelial dysfunction in
Asia, Europe, Latin America, North America, and Oceania. A detailed different clinical scenarios. For example, failed cerebral autoregulation
summary of included patients is presented in Table 1. Methodological could be caused by severe hypertension, immunological activation, and
quality assessment in supplements. direct endothelial toxicity [63]. These alterations may occur during
porphyric attacks and increase the vulnerability of some patients to
3.2. Demographic characteristics develop PRES and CNS dysfunction (Fig. 2) [4,64,65]. Dysfunction of
hemoproteins due to heme deficiency, increased oxidative stress, mi-
Table 2 summarizes demographic and clinical features. 84.8% (39/ tochondrial bioenergetic failure, and hyponatremia are mechanisms
46) of the patients were women and 15.2% (7/46) men (Ratio of ~5:1), that may contribute to the development of PRES during porphyric at-
with a median age of 24 and IQR = 13.8 years (Range: 5–75 years). tacks.

3.3. Porphyria diagnosis and precipitating factors 4.2. Hypertension and failed cerebral autoregulation

Porphyria type was confirmed by DNA analysis in 23.9% (11/46) Systemic arterial hypertension occurs in 30–55% of porphyric at-
(Table 3), reduced erythrocyte hydroxymethylbilane synthase activity tacks. It may be the result of sympathetic overactivity, autonomic
in 17.4% (8/46), and porphyrin analysis in 6.5% (3/46). 52.2% (24/46) neuropathy, or higher response to adrenergic agonists in the mesenteric
of patients had unspecified AHP, 41.3% (19/46) AIP, 4.3% (2/46) circulation during attacks [10,66,67]. A leading theory of the patho-
hereditary coproporphyria, and 2.2% (1/46) variegate porphyria. physiology of PRES indicates that abrupt and severe elevations of blood
Forty-seven porphyric attacks were described, 40.4% (19/47) were pressure above the upper limit of cerebral autoregulation
confirmed by UPBG ≥ 15-fold and 59.6% (28/47) by UPBG < 15-fold (MAP~150 mmHg) lead to vasodilation, hyperperfusion, and compro-
(n = 7) or positive qualitative tests (n = 21). Precipitating factors were mise of the BBB, resulting in interstitial extravasation of plasma and
identified for 44.7% (21/47) of porphyric attacks, a single precipitant cerebral vasogenic edema [1]. Therefore, acute systemic arterial and
in 71.4% (15/21), and multiple in 28.6% (6/21). They included in- intracranial hypertension and sudden changes in blood pressure might
fections (47.6%, 10/21), caloric deprivation (33.3%, 7/21), medica- be involved in the pathogenesis of PRES during porphyric attacks.
tions (14.3%, 3/21), surgery (14.3%, 3/21), acute illness (9.5%, 2/21), However, only 45.6% of the patients included in this review had

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D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

Table 3
Genetic mutations reported in patients with PRES during porphyric attacks (n = 11).
Type Gene Nucleotide change Amino acid change Ref

Missense CPOX c.863 T > G p.Leu288Trp [32]

HMBS c.517C > T p.Arg173Trp [43]
HMBS c.83G > T p.Ser28Ile [54]
HMBS c.77G > A p.Arg26His [58] (#1)
Nonsense HMBS c.849G > A p.Trp283* [20]
CPOX c.289C > T p.Gln97Xaa [59]
Deletion HMBS c.652-2del p.Gly218_Leu257del [58] (#14)
HMBS c.875_876delAA p.Gln292Argfs*14 [60]
HMBS c.651 + 2delT [61]
Splice site PPOX IVS11 + G → C [22]
Complex Rearrangement HMBS c.88–16.-4delAAGTCTCTACCCGinsCA [23]

CPOX, Coproporphyrinogen oxidase; HMBS, Hydroxymethylbilane synthase; PPOX, Protoporphyrinogen oxidase; PRES, Posterior reversible encephalopathy syn-
drome; Ref, Reference.

Fig. 1. Seizures, mental changes, hypertension, and hyponatremia during porphyric attacks with PRES compared to porphyric attacks in general [17–19]. *p < .001
for one sample proportion Z-test.

significant hypertension, and MAP was within the limits of cerebral ALA movement through BBB is mainly by passive diffusion with a
autoregulation in all of them. Besides, there were two patients with meager influx rate (~0.2 mg per min), which leads to cerebral levels
chronic hypertension, which causes adaptive vascular changes that that are ~1% of plasma levels [73]. Studies in AIP mice and patients
adjust the range of cerebral autoregulation to higher blood pressures. with porphyric attacks have shown no accumulation of ALA in the brain
These findings suggest that there likely are other additional con- and cerebrospinal fluid (CSF) despite significant elevations in plasma
tributing factors involved in the pathogenesis of PRES during porphyric [71,72,74–76]. Unlike BBB, there is a saturable transport mechanism
attacks [68]. Nevertheless, it is important to consider that blood pres- for ALA in the blood-CSF barrier via peptide transporter 2 (PEPT2).
sure may not have been measured when it was at maximal values. Also, PEPT2 catalyzes ALA transport by coupling its translocation with a
pronounced and rapid fluctuations of blood pressure over baseline va- transmembrane electrochemical proton gradient generating the driving
lues may be more important than the absolute increment [69]. Finally, force. It keeps ALA CSF levels low compared to plasma and exerts a
in some susceptible patients, acute hypertension can lead to endothelial neuroprotective effect against ALA toxicity [73]. In this regard, a
dysfunction even when the increment in blood pressure does not exceed functional polymorphism in PEPT2, which affects the tightness of
the limits of cerebral autoregulation. binding of ALA to the transporter, and which has been shown to in-
An alternative theory proposes that PRES is a consequence of brain fluence the likelihood of progressive renal disease in AHP, may be re-
hypoperfusion and ischemia caused by endothelial dysfunction from levant. PEPT2 has two major variants designated PEPT2*1 (higher ALA
diverse systemic toxic insults (e.g., cytotoxins, immunogens, and neu- affinity) and PEPT2*2 (lower ALA affinity) [77]. PEPT2*2 carriers may
ropeptides) [68]. These toxic insults may occur during porphyric at- have lower ALA brain efflux, which results in more significant neuro-
tacks, which may account for PRES in normotensive patients and hy- toxicity. For instance, children with the PEPT2*2 variant and lead
pertensive patients with blood pressure within the limits of cerebral poisoning have poorer motor dexterity and working memory, pre-
autoregulation. sumably because of reduced ALA brain clearance [78]. In a recent study
of 122 patients with genetically confirmed AIP and PEPT2 genotyping,
26% of the patients were PEPT2*2 carriers [79]. cis-Acting poly-
4.3. Central nervous system and porphyrin precursors toxicity morphisms can impair PEPT2 expression [77]. After exogenous ad-
ministration of ALA, PEPT2-deficient mice exhibit ~30-fold higher ALA
The BBB is virtually impermeable to porphyrin precursors [70–73].

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Table 4 CSF levels, lower survivability, and a worse neuromuscular function

Neuroimaging findings in patients with PRES during porphyric compared to wild-type mice [73]. Therefore, patients carrying these
attacks (n = 43). polymorphisms may have a greater susceptibility to develop PRES and
N (%) CNS dysfunction during porphyric attacks. To date, however, studies of
PEPT2 variants have not been reported in patients with AHP and PRES.
Brain lesion distribution 43 (91.5) Porphyrin precursors are probably not involved in the initial brain
Occipital lobes 35 (81.4)
injury during porphyric attacks given that BBB impermeability and
Parietal lobes 28 (65.1)
Frontal lobes 26 (60.5) PEPT2 limits brain exposure to them. One patient with variegate por-
Temporal lobes 7 (16.3) phyria developed encephalopathy and seizures during an attack despite
Cerebellum 5 (11.6) low concentrations of ALA and PBG in the CSF [76], which suggests
Basal ganglia 2 (4.6)
that either porphyrin precursors are very potent neurotoxins or that
Brainstem 2 (4.6)
Subcortical 19 (44.2)
other factors were involved. However, after BBB compromise or PEPT2
Cortical 16 (37.2) dysfunction, porphyrin precursors might secondarily accumulate in the
Topographic patterns 40 (85.1) brain and cause direct injury. Studies in mice have shown that direct
Dominant parieto-occipital 22 (55) administration of ALA and PBG into the lateral ventricle of the brain
Holohemispheric watershed 14 (35)
(i.e., avoiding the BBB) causes seizures in a dose-dependent manner
Superior frontal sulcus 4 (10)
Contrast medium 13 (27.6) [7]. ALA molecular structure resembles that of the neurotransmitters
Enhancement 5 (38.5) gamma-aminobutyric acid and L-glutamate, which allow it to interact
Non-enhancement 8 (61.5) with their receptors [6]. These alterations might explain the higher
Follow-up images 28 (59.6)
incidence of seizures in this review compared to previous reports of
Reversible findings 17 (60.7)
Partially reversible 7 (25)
PRES (60–75%) or porphyric attacks (20–30%) [1,19,80]. However,
Non-reversible 4 (14.3) unprovoked seizures outside attacks are rare in patients with AHPs, as
Angiographic studies 12 (25.5) well as in those who have recovered from PRES [81].
Normal caliber arteries 7 (58.3) The defective function of the BBB may occur as porphyric attacks
Signs of vasoconstriction 5 (41.7)
progress due to ALA vascular toxicity, endothelial dysfunction, systemic
PRES, Posterior reversible encephalopathy syndrome. inflammation, and mitochondrial bioenergetic failure. Likewise, the

Fig. 2. Proposed pathogenic model for brain edema and CNS dysfunction during porphyric attacks. Initiating event: Exposure to factors that increase the demand or
degradation of heme upregulates ALAS1, leading to the excessive synthesis of toxic porphyrin precursors (ALA and PBG). Inflammation: ALA pro-oxidative effect
might cause organ damage and the release of inflammatory mediators. Cytokines induce the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin, P-
selectin), which interact with leukocytes and potentiate ROS production. ROS, ALA, and PTX3 might cause direct endothelial cell injuries, increasing the expression
of VEGF and vascular permeability. Mitochondrial bioenergetic failure: Increased heme utilization might cause a relative deficiency that reduces activities of respiratory
chain complexes. Besides, upregulated ALAS1 might increase the demand for succinyl-CoA for ALA synthesis, causing cataplerosis of the TCAC with a low supply of
reduced cofactors. These alterations might cause mitochondrial bioenergetic failure and enhance ROS production. A low ATP supply impairs energy-dependent
processes, such as PEPT2 and NA+/K+ ATPase function. ADH excess: ALA neurotoxicity and the effect of IL-6 in the hypothalamus might lead to an increment in
ADH secretion. ADH inhibits NA+/K+ ATPase and induces NKCC2 and AQP4 in astrocytes, leading to increase ion/water influx and swelling. ADH excess may also
lead to hyponatremia. NO deficiency: PTX3, heme deficiency and ROS might impair NOS function, thus decreasing NO synthesis and causing endothelial
dysfunction. PEPT2 dysfunction: The PEPT2*2 variant has a lower affinity for ALA than PEPT2*1, which might cause a diminished ALA efflux in choroid plexus and a
more significant ALA neurotoxicity in the brain. Hyponatremia, low CSF pH, and lack of ATP might also reduce PEPT2 function. These pathological processes do not
necessarily occur in the order described, nor are all present in each patient. Besides, their individual impact is probably small and differs between them. The
vulnerability to BBB compromise probably increases progressively as more abnormalities occur and act synergistically. The concurrence of multiple factors related to
the porphyria, the patient, and certain precipitants is probably necessary to cause PRES and CNS dysfunction. ADH, Antidiuretic hormone; ALA, 5-Aminolevulinic
acid; ALAS1, 5-Aminolevulinic acid synthase-1; AQP4, Aquaporin-4; BBB, Blood-brain barrier; ICAM1, Intracellular adhesion molecule-1; IL, Interleukin; NKCC1,
Na+ K+ 2Cl− Cotransporter 1; NO, Nitric oxide; NOS, Nitric oxide synthase; PBG, Porphobilinogen; PEPT2, Peptide transporter-2; PTX3, Pentraxin-3; ROS, Reactive
oxygen species; SON, Supraoptic nucleus; SPV, Supraventricular nucleus; TCA, Tricarboxylic acid cycle; TNF, Tumor necrosis factor; VCAM1, Vascular cell adhesion
protein-1; VEGF, Vascular endothelial growth factor.

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PEPT2 transport rate may be impaired by conditions that change CSF mitochondrial DNA [86]. Bioenergetic failure might increase the sus-
pH and electrochemical gradient generated by the Na+/H+ exchanger ceptibility to develop brain edema and ALA neurotoxicity by impairing
(e.g., respiratory acidosis or hyponatremia) [82,83]. Remarkably, energy-dependent processes, such as PEPT2 function and sodium
60.8% of the patients in this review either required mechanical venti- transport in glial cells. Mitochondrial dysfunction also modifies Ca++
lation or had hyponatremia. homeostasis, intensifies ROS production, and induces apoptosis [99],
factors that can lead to endothelial dysfunction and PRES.
4.4. Immunological activation and endothelial dysfunction
4.6. Reversible cerebral vasoconstriction
PRES is observed almost exclusively in conditions that cause sys-
temic inflammation (e.g., autoimmune disorders, preeclampsia/ Reversible cerebral vasoconstriction was found in 41.7% of patients
eclampsia, and sepsis), so another pathogenic theory suggests that a with PRES during porphyric attacks who underwent angiography,
primary inflammatory insult involving T-cell activation, cytokine re- which is higher than previously reported in most series of PRES [1].
lease, and leukocyte adhesion lead to endothelial dysfunction and BBB Ischemic lesions were identified in 19.6% of all patients and were the
compromise [63]. A recent case-control study showed that symptomatic most common reason for incomplete radiologic recovery, as described
AIP patients have higher levels of several pro-inflammatory cytokines in other studies [1]. This finding supports that porphyric attacks may
(e.g., IL-1b, IL-2, IL-6, IL-17, TNF, INF-γ) and vascular endothelial lead to permanent brain damage with long-term consequences (e.g.,
growth factor (VEGF) compared to matched healthy controls, which cognitive impairment and focal neurological deficits), mainly explained
was partly attributed to porphyria-induced organ damage (e.g., the by ischemic lesions, which reinforces the importance of early treatment
liver, kidney, nervous system, pancreas). These findings suggest that on the chronic consequences of AHPs.
inflammation might have a role in the pathophysiology of AHP [84]. PRES and porphyric attacks have been independently associated
IL-17 and IL-2 stimulate macrophages to secrete TNF, IL-1b, and IL- with arterial and arteriolar vasoconstriction, but the pathogenic me-
6, which along with INF-γ, induce the expression of adhesion molecules chanisms remain unclear. In both cases, they may include endothelial
(e.g., intracellular adhesion molecule-1, vascular cell adhesion protein- dysfunction, oxidative stress, and low nitric oxide levels [1,100]. Ex-
1, E-selectin, P-selectin). Adhesion molecules interact with leukocytes perimental studies have shown that ALA induces arteriolar vasocon-
and stimulate reactive oxygen species (ROS) production. ALA and striction [101]. Increased adrenergic vasoconstriction and reduced
porphyrins also induce oxidative stress [85,86]. ROS and ALA may cholinergic vasodilation responses have been demonstrated in mesen-
cause direct endothelial cell injuries [87]. TNF, IL-1b, and IL-6 promote teric arteries of AIP mice, which are resolved after the administration of
the expression of VEGF, which weakens endothelial cell tight junctions hemin [67]. Heme deficiency, high PTX3 levels, and ROS production
and activates the vesiculo-vacuolar organelle, thus increasing vascular during porphyric attacks may also contribute to vasoconstriction by
permeability. VEGF plasma levels in symptomatic AIP patients are up to impairing nitric oxide synthase function and nitric oxide bioavailability
8.3-fold higher compared to matched healthy controls [84]. Ad- [91,102,103]. Furthermore, mitochondrial bioenergetic failure may
ditionally, pentraxin-3 (PTX3) plasma levels correlate positively with contribute to vasoconstriction by increasing ROS formation and altering
the biochemical activity of AIP after controlling for potential con- Ca++ homeostasis [93,104]. Finally, high levels of antidiuretic hor-
founders and other inflammatory markers [84]. Similarly, PTX3 levels mone (ADH) may stimulate vasoconstriction in patients with hypona-
positively correlate with the severity of endothelial dysfunction in tremia during porphyric attacks [105].
several diseases associated with PRES (e.g., preeclampsia, chronic
kidney disease, and systemic lupus erythematosus) [88–90]. Experi- 4.7. Hyponatremia, antidiuretic hormone, and brain edema
mental models in C57BL6 and FCγ receptor/P-selectin knockout mice
have shown that PTX3 induces dysfunction and morphological changes Although the incidence of hyponatremia in patients with PRES is
in endothelial cells through several mechanisms [91]. Therefore, en- unclear [2,80,106], numerous case reports have described an associa-
dothelial dysfunction due to immunological activation might be in- tion between these conditions [107–109]. Hyponatremia is also found
volved in the pathogenesis of PRES during porphyric attacks [92]. in 20–30% of patients with porphyric attacks, but it occurred about 2-
fold more frequently in AIP patients with PRES, suggesting a role for
4.5. Mitochondrial dysfunction hyponatremia in the pathogenesis of cerebral edema during porphyric
attacks. Hyponatremia produces an abnormal osmotic pressure gradient
Mitochondrial bioenergetic failure may lead to neuromuscular al- between the blood and interstitial fluid and cellular elements of the
terations given the high energy demand of the nervous system and brain, which drive water into brain cells. Thus, it can contribute to
muscles [93]. A wide range of brain lesions is observed in MRI scans of cerebral edema and encephalopathy in the presence of factors that
patients affected by mitochondrial diseases, which sometimes re- hinder brain adaptation capacity [e.g., acute starvation (< 48 h), es-
sembles those of PRES [94,95]. In vitro and in vivo studies have shown trogen, hypoxia, and/or increased ADH] [105]. 76.9% of patients with
that mitochondrial dysfunction is a frequent abnormality of AHP. Stu- hyponatremia in this review were women in premenopausal ages.
dies in cultured skin fibroblasts from AIP subjects with half-normal Porphyric attacks are more common in this population due in part to
hydroxymethylbilane synthase revealed impaired mitochondrial NADH the inducing effect of estrogen and progesterone on ALAS1 [4]. PRES is
oxidation [96]. Altered mitochondrial oxidative phosphorylation and also more common in women, even when patients with eclampsia are
ATP production have also been demonstrated in the liver, muscle, and not considered, but to a lesser extent than porphyric attacks. Hypona-
brain of AIP mice compared to wild-type mice [64,65]. In AHP subjects tremia is usually acute during porphyric attacks. Cerebral hypoxia may
compared to matched healthy controls, mitochondrial stress tests have also occur in patients with respiratory failure during porphyric attacks.
shown a decreased mitochondrial bioenergetic capacity, glycolytic Estrogens, ADH, hypoxia, mitochondrial bioenergetic failure, and ALA
function, and oxidative burst [97]. A significant inverse correlation inhibit Na+/K+ ATPase, which impairs the capacity of glial cells to
between UPBG excretion and mitochondrial oxygen consumption has extract solutes and water from the brain and prevent cerebral edema
been observed as well [98]. Several mechanisms might explain the [105,110]. Finally, the PEPT2 function can be reduced up to 59% at low
mitochondrial dysfunction during porphyric attacks. Heme deficiency sodium concentrations [83], which further decreases ALA brain efflux.
can reduce enzymatic activities of respiratory chain complexes [64,65]. Thus, patients with significant hyponatremia during porphyric attacks
Also, cataplerosis of the tricarboxylic acid cycle with a low supply of might have an increased risk of cerebral edema and encephalopathy.
reduced cofactors can occur due to the increased demand for succinyl- Hyponatremia is also a clearly defined cause of seizures, which em-
CoA for ALA synthesis by ALAS1 [64,65]. ALA can also directly damage phasizes the importance of evaluating and managing this factor in

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D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

Fig. 3. Concurrence of factors in the pathogenesis of PRES and CNS dysfunction during porphyric attacks.

patients with porphyria attacks. data may have been described in the reports. Two articles only reported
Hyponatremia during porphyric attacks is sometimes the result of the diagnosis of PRES in head MRI scans without providing pictures or a
inappropriate secretion of ADH (SIADH). The hypersecretion of ADH detailed description of the main findings, so it was not possible to re-
may be due to ALA neurotoxicity in the hypothalamus, which is not assess the veracity of the diagnosis [38,44]. The same radiological
protected by BBB [111]. Growing evidence indicates that IL-6 is a techniques were not performed in all patients, so it is difficult to
crucial regulator of ADH secretion by acting as an effector in areas of compare them and draw more general conclusions about neuroimaging
the brain that are involved in its release [112]. IL-6 activates the sub- during porphyric attacks. Besides, as PRES is a dynamic process, radi-
fornical organ and the organum vasculosum of the lamina terminalis, ological findings may vary depending on when the study is done during
thus leading to thirst and increased vasopressin secretion by neurons the evolution of the syndrome. As ~30% of asymptomatic AHPs mu-
from the supraoptic nucleus and paraventricular nucleus. IL-6 serum tation carriers have a high UPBG (up to 15-fold ULN), misclassification
levels also reflect disease activity in some autoimmune disorders that may have occurred in patients in whom porphyric attacks were con-
cause PRES, such as SLE [113]. In the case of SLE, serum IL-6 levels are firmed by UPBG < 15-fold or positive qualitative tests. However,
significantly higher in patients with PRES than in those without PRES characteristics of patients with UPBG≥15-fold and patients with
and healthy controls [114]. Similarly, IL-6 plasma levels in AIP patients UPBG < 15-fold or positive qualitative tests did not differ significantly.
have been found to be 2.5-fold higher than in controls [84]. However, Finally, the proposed pathogenic model for PRES and CNS during
the association between IL-6, ADH, and PRES during porphyric attacks porphyric attacks was constructed based on the comparison of ab-
still needs to be investigated. High ADH serum levels in AIP patients normalities found in AHPs and other diseases frequently related to
may also be an appropriate physiological response since decreased PRES and brain edema. Therefore, it is still necessary to performed
blood volumes have been demonstrated even without porphyric attacks studies directly in AHP patients or specific in vitro models of porphyria
[115]. Interestingly, when ADH monitoring was performed in an AIP to reach definitive conclusions. Nevertheless, this model serves as a
patient with PRES during a porphyric attack, high ADH plasma levels rational framework for those future investigations.
were detected [57]. Similarly, high ADH levels have been described in
other conditions associated with PRES (e.g., preeclampsia/eclampsia,
6. Conclusions
chronic kidney disease, and anticancer drugs). Moreover, there is a
significant overlap between some anticancer drugs associated with
This systematic review shows that brain edema, vasoconstriction,
PRES and with SIADH. The use of desmopressin, a synthetic ADH
and ischemia can explain the clinical manifestations of CNS dysfunction
analog, has also been associated with PRES [116].
in some patients with porphyric attacks. Seizures, hyponatremia, and
ADH facilitates brain cells swelling through several mechanisms. It
vasoconstriction seem to be more frequent in these patients than ex-
increases intracellular osmolarity by increasing the influx of Na+, K+,
pected for either PRES or porphyric attacks, perhaps due to synergy
2Cl- and reducing Na+ efflux. ADH also increases the free water influx
between both conditions. Several porphyria-related abnormalities may
through astrocytic aquaporin 4. Besides, the stimulation of V1a re-
lead to PRES or increase the risk of cerebral edema (e.g., systemic in-
ceptors leads to platelet aggregation, cerebral vasoconstriction and
flammation, ALA toxicity, mitochondrial dysfunction, hyponatremia,
augmented sympathetic tone, producing endothelial dysfunction and
and antidiuretic hormone excess). However, the individual impact of
cerebral ischemia. Cerebral ischemia stimulates overexpression of VEGF
each abnormality is probably small, since they are also observed in
and increases endothelial permeability, which leads to vasogenic cer-
patients without central involvement, and differ among different ab-
ebral edema. In the periphery, stimulation of ADH receptors could
normalities. The vulnerability to BBB compromise probably increases
contribute to some symptoms generally reported in PRES and porphyric
progressively as more abnormalities occur and begin to act synergisti-
attacks such as acute systemic arterial hypertension and renal failure
cally. Therefore, the concurrence of multiple factors related to the
[105,116].
porphyria, the patient, and certain precipitants is probably necessary
(Fig. 3). Furthermore, patients with CNS dysfunction during attacks
5. Limitations may develop long-term sequelae, such as cognitive decline and focal
neurological deficits, which may likely be explained by ischemic le-
This review has some limitations. Selection and publication bias is sions. A clearer definition of these pathophysiological phenomena will
possible because reports of unusual forms of diseases are more likely to have a great impact on the management of patients with porphyria
be published. Information bias is also possible as not all the essential attacks. The next step for future research would be to assess the

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D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

incidence of PRES in patients with CNS dysfunction during porphyric [19] D.A. Jaramillo-Calle, D.C. Acevedo, Acute hepatic porphyrias in Colombia: an
attacks. Furthermore, comparing the prevalence of PEPT2 variants and analysis of 101 patients, JIMD Rep. 44 (2019) 65–72, https://doi.org/10.1007/
8904.
levels of PTX3, IL6, nitric oxide metabolites, and ADH/copeptin in these [20] M. Fourgeaud, T. Vidal, C. Schmitt, J.M. Blouin, C. Ged, E. Richard, Posterior
patients versus those without CNS dysfunction or PRES during por- reversible encephalopathy syndrome in a patient with acute intermittent por-
phyric attacks. phyria, Rev. Neurol. (Paris) (2019), https://doi.org/10.1007/s00415-009-5415-9
pii: S0035–3787(18)30965–2.
[21] R.A. Losno, A. Combalia, P. Aguilera, Reversible encephalopathy syndrome in
Acknowledgments acute porphyria attack, Med. Clin. (Barc.) (2019), https://doi.org/10.1016/j.
medcli.2019.01.022 pii: S0025–7753(19)30116–2.
[22] H.L. Bonkovsky, P. Siao, Z. Roig, E.T. Hedley-White, T.J. Flotte, Case records of the
We thank Dr. Florence Chateau and Dr. Ricardo Losno for providing Massachusetts General Hospital. Case 20-2008: abdominal pain and weakness
information about their case reports, and Ms. Jesenia Avendaño and after gastric bypass surgery, N. Engl. J. Med. 358 (2008) 2813–2825, https://doi.
Mr. Luis Carlos Hoyos for their excellent library support. org/10.1056/NEJMc081545.
[23] H.C. Kuo, C.C. Huang, C.C. Chu, M.J. Lee, W.L. Chuang, C.L. Wu, T. Wu, H.C. Ning,
C.Y. Liu, Neurological complications of acute intermittent porphyria, Eur. Neurol.
References 66 (2011) 247–252, https://doi.org/10.1159/000330683.
[24] B. Zhao, Q. Wei, Y. Wang, Y. Chen, H. Shang, Posterior reversible encephalopathy
[1] J.E. Fugate, A.A. Rabinstein, Posterior reversible encephalopathy syndrome: syndrome in acute intermittent porphyria, Pediatr. Neurol. 51 (2014) 457–460,
clinical and radiological manifestations, pathophysiology, and outstanding ques- https://doi.org/10.1016/j.pediatrneurol.2014.05.016.
tions, Lancet Neurol. 14 (2015) 914–925, https://doi.org/10.1016/S1474- [25] M. Dahlgren, A. Khosroshahi, J.H. Stone, A 22-year-old woman with severe
4422(15)00111-8. headaches, vomiting, and tonic-clonic seizures, Arthritis Care Res. 63 (2011)
[2] J. Hinchey, C. Chaves, B. Appignani, J. Breen, L. Pao, A. Wang, M.S. Pessin, 165–171, https://doi.org/10.1002/acr.20249.
C. Lamy, J.-L. Mas, L.R. Caplan, A reversible posterior leukoencephalopathy syn- [26] S. Susa, M. Daimon, Y. Morita, M. Kitagawa, A. Hirata, H. Manaka, H. Sasaki,
drome, N. Engl. J. Med. 334 (1996) 494–500, https://doi.org/10.1056/ T. Kato, Acute intermittent porphyria with central pontine myelinolysis and cor-
NEJM199602223340803. tical laminar necrosis, Neuroradiology. 41 (1999) 835–839, https://doi.org/10.
[3] K.E. Anderson, Acute hepatic porphyrias: current diagnosis &amp; management, 1007/s002340050852.
Mol. Genet. Metab. (2019), https://doi.org/10.1016/j.ymgme.2019.07.002. [27] H. Kupferschmidt, A. Bont, H. Schnorf, T. Landis, E. Walter, J. Peter,
[4] H.L. Bonkovsky, N. Dixon, S. Rudnick, Pathogenesis and clinical features of the S. Krähenbühl, P.J. Meier, Transient cortical blindness and bioccipital brain le-
acute hepatic porphyrias (AHPs), Mol. Genet. Metab. (2019), https://doi.org/10. sions in two patients with acute intermittent porphyria, Ann. Intern. Med. 123
1016/j.ymgme.2019.03.002 pii: S1096–7192(19)30084–8. (1995) 598–600, https://doi.org/10.7326/0003-4819-123-8-199510150-00006.
[5] D.M. Bissell, J.C. Lai, R.K. Meister, P.D. Blanc, Role of delta-aminolevulinic acid in [28] P.H. King, A.C. Bragdon, MRI reveals multiple reversible cerebral lesions in an
the symptoms of acute porphyria, Am. J. Med. 128 (2015) 313–317, https://doi. attack of acute intermittent porphyria, Neurology. 41 (1991) 1300–1302, https://
org/10.1016/j.amjmed.2014.10.026. doi.org/10.1212/wnl.41.8.1300.
[6] M.J. Brennan, R.C. Cantrill, Delta-Aminolaevulinc acid is a potent agonist for [29] G.H. New, P.Y. Hsu, M.H. Wu, Acute intermittent porphyria exacerbation fol-
GABA autoreceptors, Nature. 280 (1979) 514–515, https://doi.org/10.1038/ lowing in vitro fertilization treatment, Taiwan. J. Obstet. Gynecol. 55 (2016)
280514a0. 281–284, https://doi.org/10.1016/j.tjog.2015.08.025.
[7] C.A. Pierach, P.S. Edwards, Neurotoxicity of aminolevulinic acid and porphobili- [30] J.S. Somana, T. Uma, Acute intermittent Porphyria, J. Evol. Res. Med. Biochem. 3
nogen, Exp. Neurol. 62 (1978) 810–814, https://doi.org/10.1016/0014-4886(78) (2017) 5–6.
90287-x. [31] S.Y. Kang, J.H. Kang, J.C. Choi, J.S. Lee, Posterior reversible encephalopathy
[8] U.A. Meyer, M.M. Schuurmans, R.L. Lindberg, Acute porphyrias: pathogenesis of syndrome in a patient with acute intermittent porphyria, J. Neurol. 257 (2010)
neurological manifestations, Semin. Liver Dis. 18 (1998) 43–52, https://doi.org/ 663–664, https://doi.org/10.1007/s00415-009-5415-9.
10.1055/s-2007-1007139. [32] D. Lambie, C. Florkowski, C. Sies, A. Raizis, W.K. Siu, C. Towns, A case of her-
[9] M.H. Murad, S. Sultan, S. Haffar, F. Bazerbachi, Methodological quality and editary coproporphyria with posterior reversible encephalopathy and novel co-
synthesis of case series and case reports, BMJ Evid. Based Med. 23 (2018) 60–63, proporphyrinogen oxidase gene mutation c.863T > G (p.Leu288Trp), Ann. Clin.
https://doi.org/10.1136/bmjebm-2017-110853. Biochem. 55 (2018) 616–619, https://doi.org/10.1177/0004563218774597.
[10] B. Wang, S. Rudnick, B. Cengia, H.L. Bonkovsky, Acute hepatic porphyrias: review [33] D.C. Silveira, M. Bashir, J. Daniel, M.H. Lucena, F. Bonpietro, Acute intermittent
and recent progress, Hepatol. Commun. 3 (2018) 193–206, https://doi.org/10. porphyria presenting with posterior reversible encephalopathy syndrome and la-
1002/hep4.1297. teralized periodic discharges plus fast activity on EEG, Epilepsy. Behav. Case Rep.
[11] H.L. Bonkovsky, V.C. Maddukuri, C. Yazici, K.E. Anderson, D.M. Bissell, 6 (2016) 58–60, https://doi.org/10.1016/j.ebcr.2016.08.004.
J.R. Bloomer, J.D. Phillips, H. Naik, I. Peter, G. Baillargeon, K. Bossi, L. Gandolfo, [34] X. Zheng, X. Liu, Y. Wang, R. Zhao, L. Qu, H. Pei, M. Tuo, Y. Zhang, Y. Song, X. Ji,
C. Light, D. Bishop, R.J. Desnick, Acute porphyrias in the USA: features of 108 H. Li, L. Tang, X. Yin, Acute intermittent porphyria presenting with seizures and
subjects from porphyrias consortium, Am. J. Med. 127 (2014) 1233–1241, https:// posterior reversible encephalopathy syndrome: two case reports and a literature
doi.org/10.1016/j.amjmed.2014.06.036. review, Medicine (Baltimore) 97 (2018) e11665, , https://doi.org/10.1097/MD.
[12] R.S. Fisher, J.H. Cross, J.A. French, N. Higurashi, E. Hirsch, F.E. Jansen, L. Lagae, 0000000000011665.
S.L. Moshé, J. Peltola, E. Roulet Perez, I.E. Scheffer, S.M. Zuberi, Operational [35] F. Chateau, R. Mohamedi, F.G. Barral, Reversible cerebrovascular event during an
classification of seizure types by the international league against epilepsy: position acute porphyric crisis. A case report, J. Radiol. 90 (2009) 1863–1867.
paper of the ILAE commission for classification and terminology, Epilepsia. 58 [36] K.S. Black, P. Mirsky, P. Kalina, R.W. Greenberg, K.E. Drehobl, M. Sapan,
(2017) 522–530, https://doi.org/10.1007/s10309-018-0216-8. E. Meikle, Angiographic demonstration of reversible cerebral vasospasm in por-
[13] J.T. Flynn, D.C. Kaelber, C.M. Baker-Smith, D. Blowey, A.E. Carroll, S.R. Daniels, phyric encephalopathy, AJNR Am. J. Neuroradiol. 16 (1995) 1650–1652.
S.D. de Ferranti, J.M. Dionne, B. Falkner, S.K. Flinn, S.S. Gidding, C. Goodwin, [37] H. Arora, G. Baheti, A. Jain, M. Bhalsod, V. Mehta, Acute intermittent porphyria
M.G. Leu, M.E. Powers, C. Rea, J. Samuels, M. Simasek, V.V. Thaker, E.M. Urbina, with posterior reversible encephalopathy syndrome in pregnancy: a case report, J.
Clinical Practice Guideline for screening and management of high blood pressure Med. Res. Innov 3 (2019), https://doi.org/10.15419/jmri.142 e000142.
in children and adolescents, Pediatrics 140 (2017), https://doi.org/10.1542/peds. [38] A. Dutta, B. Rajbhandari, P. Thapa, B. Shrestha, M. Yadav, S. Joshi, Acute inter-
2017-1904 pii: e20171904. mittent porphyria- perplexed by the purple, Nepal Med J. 01 (2018) 73–77.
[14] B. Williams, G. Mancia, W. Spiering, E. Agabiti Rosei, M. Azizi, M. Burnier, [39] A. Dagens, M.J. Gilhooley, Acute intermittent porphyria leading to posterior re-
D. Clement, A. Coca, G. De Simone, A. Dominiczak, T. Kahan, F. Mahfoud, versible encephalopathy syndrome (PRES): a rare cause of abdominal pain and
J. Redon, L. Ruilope, A. Zanchetti, M. Kerins, S. Kjeldsen, R. Kreutz, S. Laurent, seizures, BMJ Case Rep 8 (2016), https://doi.org/10.1136/bcr-2016-215350
G.Y.H. Lip, R. McManus, K. Narkiewicz, F. Ruschitzka, R. Schmieder, E. Shlyakhto, pii:bcr2016215350.
K. Tsioufis, V. Aboyans, I. Desormais, 2018 practice guidelines for the manage- [40] C. Divecha, M.S. Tullu, A. Gandhi, C.T. Deshmukh, Acute intermittent porphyria: a
ment of arterial hypertension of the European Society of Hypertension and the critical diagnosis for favorable outcome, Indian J. Crit. Care Med. 20 (2016)
European Society of Cardiology: ESH/ESC task force for the management of ar- 428–431.
terial hypertension, J. Hypertens. 36 (2018) 2284–2309, https://doi.org/10. [41] J. Guéniat, B. Delpont, L. Garnier, M. Aidan, M. Giroud, Y. Béjot, Posterior re-
1097/HJH.0000000000001940. versible encephalopathy syndrome revealing acute intermittent porphyria, Rev.
[15] W.S. Bartynski, J.F. Boardman, Distinct imaging patterns and lesion distribution in Neurol. (Paris) 172 (2016) 402–403, https://doi.org/10.1016/j.neurol.2016.06.
posterior reversible encephalopathy syndrome, AJNR Am. J. Neuroradiol. 28 002.
(2007) 1320–1327, https://doi.org/10.3174/ajnr.A0549. [42] K.R. Radhakrishnan, A rare metabolic disorder porphyrias neurological manifes-
[16] E.J. Hoorn, R. Zietse, Diagnosis and treatment of hyponatremia: compilation of the tations, Univ. J. Med. Med. Sci. 2 (2016).
guidelines, J. Am. Soc. Nephrol. 28 (2017) 1340–1349, https://doi.org/10.1681/ [43] P. Olivier, D. Van Melkebeke, P.J. Honoré, L. Defreyne, D. Hemelsoet, Cerebral
asn.2016101139. vasospasm in acute porphyria, Eur. J. Neurol. 24 (2017) 1183–1187, https://doi.
[17] R.J. Hift, P.N. Meissner, An analysis of 112 acute porphyric attacks in Cape Town, org/10.1111/ene.13347.
South Africa, Medicine (Baltimore) 84 (2005) 48–60, https://doi.org/10.1097/01. [44] C. Adams, P. Amaya, Quadriparesis and rhabdomyolysis due to acute intermittent
md.0000152454.56435.f3. porphyria: Case report, XXIII Congreso Colombiano de Medicina Interna, Acta
[18] J.A. Stein, D.P. Tschudy, Acute intermittent porphyria. A clinical and biochemical Médica Colombiana, 2014, p. 28.
study of 46 patients, Medicine(Baltimore). 49 (1970) 1–16. [45] E.Y. Park, Y.S. Kim, K.J. Lim, H.K. Lee, S.K. Lee, H. Choi, M.H. Kang, Severe
neurologic manifestations in acute intermittent porphyria developed after spine

10
D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

surgery under general anesthesia: a case report, Korean J Anesth. 67 (2014) [71] L. Terr, L.P. Weiner, An autoradiographic study of δ-aminolevulinic acid uptake by
217–220, https://doi.org/10.4097/kjae.2014.67.3.217. mouse brain, Exp. Neurol. 79 (1983) 564–568, https://doi.org/10.1016/0014-
[46] A. Enríquez-Marulanda, M. Shinchi, A.M. Granados, J.L. Orozco, Acute inter- 4886(83)90234-0.
mittent porphyria and its relationship with posterior reversible encephalopathy [72] M. Yasuda, L. Gan, B. Chen, C. Yu, J. Zhang, M.A. Gama-Sosa, D.D. Pollak,
syndrome: case report, Acta Neurológica Colomb. 32 (2016) 155–160. S. Berger, J.D. Philips, W. Edelmann, R.J. Desnick, Homozygous hydro-
[47] A.K. Mutyaba, E.C. Gardiner, S. Murphy, A case of blinding abdominal pain, S. Afr. xymethylbilane synthase knock-in mice provide pathogenic insights into the se-
Med. J. 101 (2011) 454–455. vere neurological impairments present in human homozygous dominant acute
[48] J.I. Bhat, U.A. Qureeshi, M.A. Bhat, Acute intermittent porphyria with transient intermittent porphyria, Hum. Mol. Genet. 28 (2019) 1755–1767, https://doi.org/
cortical blindness, Indian Pediatr. 47 (2010) 977–978, https://doi.org/10.1007/ 10.1093/hmg/ddz003.
s13312-010-0152-9. [73] S.R. Ennis, A. Novotny, J. Xiang, P. Shakui, T. Masada, W. Stummer, D.E. Smith,
[49] M.K. Garg, A.K. Mohapatro, J.S. Dugal, A.P. Singh, Cortical blindness in acute R.F. Keep, Transport of 5-aminolevulinic acid between blood and brain, Brain Res.
intermittent porphyria, J. Assoc. Physicians India 47 (1999) 727–729. 959 (2003) 226–234, https://doi.org/10.1016/S0006-8993(02)03749-6.
[50] S. Bhuyan, A.K. Sharma, R.K. Sureka, V. Gupta, P.K. Singh, Sudden bilateral re- [74] A. Gorchein, R. Webber, Delta-Aminolevulinic acid in plasma, cerebroespinal
versible vision loss: a rare presentation of acute intermittent porphyria, J. Assoc. fluid, saliva, and erythrocytes: studies in normal, uraemic and porphyrica subjects,
Physicians India 62 (2014) 432–434. Clin. Sci. (Lond.) 72 (1987) 103–112, https://doi.org/10.1042/cs0720103.
[51] S.G. Bicknell, J.D. Stewart, Neuroimaging findings in acute intermittent porphyria, [75] H.L. Bonkowsky, D.P. Tschudy, A. Collins, J. Doherty, I. Bossenmaier, R. Cardinal,
Can J Neurol Sci. 38 (2011) 656–658, https://doi.org/10.1017/ C.J. Watson, Repression of the overproduction of porphyrin precursors in acute
s0317167100012221. intermittent porphyria by intravenous infusions of hematin, Proc. Natl. Acad. Sci.
[52] F.C. Shen, C.H. Hsieh, C.R. Huang, C.C. Lui, W.C. Tai, Y.C. Chuang, Acute inter- U. S. A. 68 (1971) 2725–2729, https://doi.org/10.1073/pnas.68.11.2725.
mittent porphyria presenting as acute pancreatitis and posterior reversible en- [76] V.A. Percy, B.C. Shanley, Prophyrin precursors in blood, urine and cerebrospinal
cephalopathy syndrome, Acta Neurol. Taiwanica 17 (2008) 177–183. fluid in acute porphyria, S. Afr. Med. J. 52 (1977) 219–222.
[53] R. Shahid, N. Ahmed, Posterior reversible leukoencephalopathy (PRES) in acute [77] J. Pinsonneault, C.U. Nielsen, W. Sadée, Genetic variants of the human H+/di-
intermittent porphyria (AIP): a rare neurological complication, Pakistan, J. Radiol. peptide transporter PEPT2: analysis of haplotype functions, J. Pharmacol. Exp.
23 (2016) 73–75. Ther. 311 (2004) 1088–1096, https://doi.org/10.1124/jpet.104.073098.small.
[54] E. Rivero Sanz, J.L. Camacho Velasquez, S. Santos Lasaosa, C. Tejero Juste, [78] C. Sobin, M.G. Flores-Montoya, M. Gutierrez, N. Parisi, T. Schaub, δ-
Neuroimaging abnormalities in a patient with posterior reversible encephalopathy Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and
syndrome due to acute intermittent porphyria, Neurologia. 31 (2016) 580–583, peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobeha-
https://doi.org/10.1016/j.nrl.2014.11.003. vior in low-level lead exposed children, Neurotoxicol. Teratol. 47 (2015) 137–145,
[55] T. Wessels, F. Blaes, C. Röttger, M. Hügens, S. Hüge, M. Jauss, Cortical amaurosis https://doi.org/10.1016/j.ntt.2014.12.001.
and status epilepticus with acute porphyria, Nervenarzt 76 (2005), https://doi. [79] D. Tchernitchko, Q. Tavernier, J. Lamoril, C. Schmitt, N. Talbi, S. Lyoumi,
org/10.1007/s00115-004-1871-8 992–995,997–998. A.M. Robreau, Z. Karim, L. Gouya, E. Thervet, A. Karras, H. Puy, N. Pallet, A
[56] C. Gürses, A. Durukan, S. Sencer, Ş. Akça, B. Baykan, A. Gökyiğit, A severe neu- variant of peptide transporter 2 predicts the severity of porphyria-associated
rological sequela in acute intermittent porphyria: presentation of a case from kidney disease, J. Am. Soc. Nephrol. 28 (2017) 1924–1932, https://doi.org/10.
encephalopathy to quadriparesis, Br. J. Radiol. 81 (2008) e135–e140, https://doi. 1681/asn.2016080918.
org/10.1259/bjr/39757649. [80] J.E. Fugate, D.O. Claassen, H.J. Cloft, D.F. Kallmes, O.S. Kozak, A.A. Rabinstein,
[57] T. Takata, K. Kume, Y. Kokudo, K. Ikeda, M. Kamada, T. Touge, K. Deguchi, Posterior reversible encephalopathy syndrome: associated clinical and radiologic
T. Masaki, Acute intermittent porphyria presenting with posterior reversible en- findings, Mayo Clin. Proc. 85 (2010) 427–432, https://doi.org/10.4065/mcp.
cephalopathy syndrome, accompanied by prolonged vasoconstriction, Intern. 2009.0590.
Med. 56 (2017) 713–717, https://doi.org/10.2169/internalmedicine.56.7654. [81] S. Datar, T. Singh, A.A. Rabinstein, J.E. Fugate, S. Hocker, Long-term risk of sei-
[58] E. Pischik, Neurological Manifestations and Molecular Genetics of Acute zures and epilepsy in patients with posterior reversible encephalopathy syndrome,
Intermittent Porphyria in North Western Russia, University of Helsinki, 2006. Epilepsia. 56 (2015) 564–568, https://doi.org/10.1111/epi.12933.
[59] G. Pichler, F. Martinez, C. Fernandez, J. Redon, Unusual case of severe hy- [82] Y. Hu, H. Shen, R.F. Keep, D.E. Smith, Peptide transporter 2 (PEPT2) expression in
pertension in a 20-year-old woman, Hypertension. 66 (2015) 1093–1097, https:// brain protects against 5-aminolevulinic acid neurotoxicity, J. Neurochem. 103
doi.org/10.1161/HYPERTENSIONAHA.115.06271. (2007) 2058–2065, https://doi.org/10.1111/j.1471-4159.2007.04905.x.
[60] J. Yang, H. Yang, Q. Chen, B. Hua, T. Zhu, Y. Zhao, X. Yu, H. Zhu, Z. Zhou, [83] S.M. Ocheltree, H. Shen, Y. Hu, J. Xiang, R.F. Keep, D.E. Smith, Role of PEPT2 in
Reversible MRI findings in a case of acute intermittent porphyria with a novel the choroid plexus uptake of glycylsarcosine and 5-aminolevulinic acid: studies in
mutation in the porphobilinogen deaminase gene, Blood Cells Mol. Dis. 63 (2017) wild-type and null mice, Pharm. Res. 21 (2004) 1680–1685, https://doi.org/10.
21–24, https://doi.org/10.1016/j.bcmd.2016.12.005. 1023/b:pham.0000041465.89254.05.
[61] Y. Sakashita, T. Hamada, T. Machiya, M. Yamada, Acute intermittent porphyria [84] E. Storjord, J.A. Dahl, A. Landsem, H. Fure, J.K. Ludviksen, S. Goldbeck-Wood,
presenting as posterior reversible encephalopathy syndrome with hyperperfusion B.O. Karlsen, K.S. Berg, T.E. Mollnes, E. Nielsen, O.L. Brekke, Systemic in-
in bilateral occipital lobes: a case report, J. Neurol. Sci. 377 (2017) 47–49, https:// flammation in acute intermittent porphyria: a case–control study, Clin. Exp.
doi.org/10.1016/j.jns.2017.03.052. Immunol. 187 (2017) 466–479, https://doi.org/10.1111/cei.12899.
[62] B.V. Maramattom, R.A. Zaldivar, S.M. Glynn, S.D. Eggers, E.F. Wijdicks, Acute [85] H.P. Monteiro, E.J. Bechara, D.S. Abdalla, Free radicals involvement in neurolo-
intermittent porphyria presenting as a diffuse encephalopathy, Ann. Neurol. 57 gical porphyrias and lead poisoning, Mol. Cell. Biochem. 103 (1991) 73–83,
(2005) 581–584, https://doi.org/10.1002/ana.20432. https://doi.org/10.1007/BF00229595.
[63] Z. Chen, G.Q. Shen, A. Lerner, B. Gao, Immune system activation in the patho- [86] J. Onuki, Y. Chen, P.C. Teixeira, R.I. Schumacher, M.H. Medeiros, B. Van Houten,
genesis of posterior reversible encephalopathy syndrome, Brain Res. Bull. 131 P. Di Mascio, Mitochondrial and nuclear DNA damage induced by 5-aminolevu-
(2017) 93–99, https://doi.org/10.1016/j.brainresbull.2017.03.012. linic acid, Arch. Biochem. Biophys. 432 (2004) 178–187, https://doi.org/10.
[64] C. Homedan, J. Laafi, C. Schmitt, N. Gueguen, T. Lefebvre, Z. Karim, V. Desquiret- 1016/j.abb.2004.09.030.
Dumas, C. Wetterwald, J.C. Deybach, L. Gouya, H. Puy, P. Reynier, Y. Malthièry, [87] C.J. Chang, Y.H. Lee, J.Y. Yang, C.J. Weng, F.C. Wei, Pilot in vitro toxicity study of
Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a 5-ALA and photofrin in microvascular endothelial cell cultures hemangioma, J.
mouse model, Int. J. Biochem. Cell Biol. 51 (2014) 93–101, https://doi.org/10. Clin. Laser Med. Surg. 15 (1997) 83–87, https://doi.org/10.1089/clm.1997.15.83.
1016/j.biocel.2014.03.032. [88] R.R. Hamad, M.J. Eriksson, E. Berg, A. Larsson, K. Bremme, Impaired endothelial
[65] C. Homedan, C. Schmitt, J. Laafi, N. Gueguen, V. Desquiret-Dumas, H. Lenglet, function and elevated levels of pentraxin 3 in early-onset preeclampsia, Acta
Z. Karim, L. Gouya, J. Deybach, G. Simard, H. Puy, Y. Malthièry, P. Reynier, Obstet. Gynecol. Scand. 91 (2012) 50–56, https://doi.org/10.1111/j.1600-0412.
Mitochondrial energetic defects in muscle and brain of a hmbs−/−mouse model 2011.01238.x.
of acute intermittent porphyria, Hum. Mol. Genet. 24 (2015) 5015–5023, https:// [89] A. Witasp, M. Rydén, J.J. Carrero, A.R. Qureshi, L. Nordfors, E. Näslund,
doi.org/10.1093/hmg/ddv222. F. Hammarqvist, S. Arefin, K. Kublickiene, P. Stenvinkel, Elevated circulating le-
[66] K.E. Anderson, S. Sassa, D.F. Bishop, R.J. Desnick, Chapter 124: disorders of heme vels and tissue expression of pentraxin 3 in uremia: a reflection of endothelial
biosynthesis: X-linked sideroblastic anemia and the porphyrias, Online Metab. dysfunction, PLoS One 8 (2013) e63493, , https://doi.org/10.1371/journal.pone.
Mol. Bases Inherit. Dis. (2014) 1–255, https://doi.org/10.1036/ommbid.153. 0063493.
[67] V.M. Pulgar, M. Yasuda, L. Gan, R.J. Desnick, H.L. Bonkovsky, Sex differences in [90] R. Assandri, M. Monari, A. Colombo, A. Dossi, A. Montanelli, Pentraxin 3 plasma
vascular reactivity in mesenteric arteries from a mouse model of acute intermittent levels and disease activity in systemic lupus erythematosus, Autoimmune Dis.
porphyria, Mol. Genet. Metab. (2019), https://doi.org/10.1016/j.ymgme.2019. 2015 (2015) 354014, https://doi.org/10.1155/2015/354014.
01.005 pii: S1096–7192(18)30583–3. [91] A. Carrizzo, P. Lenzi, C. Procaccini, A. Damato, F. Biagioni, M. Ambrosio,
[68] B. Gao, C. Lyu, A. Lerner, A.M. McKinney, Controversy of posterior reversible G. Amodio, P. Remondelli, C. Del Giudice, R. Izzo, A. Malovini, L. Formisano,
encephalopathy syndrome: what have we learnt in the last 20 years? J. Neurol. V. Gigantino, M. Madonna, A.A. Puca, B. Trimarco, G. Matarese, F. Fornai,
Neurosurg. Psychiatry 89 (2018) 14–20, https://doi.org/10.1136/jnnp-2017- C. Vecchione, Pentraxin 3 induces vascular endothelial dysfunction through a p-
316225. selectin/matrix metalloproteinase-1 pathway, Circulation. 131 (2015) 1495–1505,
[69] A.A. Rabinstein, J. Mandrekar, R. Merrell, O.S. Kozak, O. Durosaro, J.E. Fugate, https://doi.org/10.1161/circulationaha.114.014822.
Blood pressure fluctuations in posterior reversible encephalopathy syndrome, J. [92] D. Konukoglu, H. Uzun, Endothelial dysfunction and hypertension, Adv. Exp. Med.
Stroke Cerebrovasc. Dis. 21 (2012) 254–258, https://doi.org/10.1016/j. Biol. 956 (2017) 511–540, https://doi.org/10.1007/5584.
jstrokecerebrovasdis.2011.03.011. [93] C. Tzoulis, L.A. Bindoff, Acute mitochondrial encephalopathy reflects neuronal
[70] S.C. García, M.B. Moretti, M.V. Garay, A. Batlle, δ-Aminolevulinic acid transport energy failure irrespective of which genome the genetic defect affects, Brain. 135
through blood-brain barrier, Gen. Pharmacol. 31 (1998) 579–582, https://doi. (2012) 3627–3634, https://doi.org/10.1093/brain/aws223.
org/10.1016/S0306-3623(98)00038-X. [94] M. Mascalchi, M. Montomoli, R. Guerrini, Neuroimaging in mitochondrial

11
D.A. Jaramillo-Calle, et al. Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

disorders, Essays Biochem. 62 (2018) 409–421, https://doi.org/10.1042/ role of sex, age, vasopressin, and hypoxia, Am. J. Physiol. Physiol. 295 (2008)
EBC20170109. F619–F624, https://doi.org/10.1152/ajprenal.00502.2007.
[95] Y. Ng, G. Gorman, D. Turnbull, M. Martikainen, The diagnosis of posterior re- [106] T.G. Liman, G. Bohner, P.U. Heuschmann, M. Endres, E. Siebert, The clinical and
versible encephalopathy syndrome, Lancet Neurol. 14 (2015) 1073, https://doi. radiological spectrum of posterior reversible encephalopathy syndrome: the ret-
org/10.1016/S1474-4422(15)00256-2. rospective Berlin PRES study, J. Neurol. 259 (2012) 155–164, https://doi.org/10.
[96] H.L. Bonkowsky, D.P. Tschudy, E.C. Weinbach, P.S. Ebert, J.M. Doherty, 1007/s00415-011-6152-4.
Porphyrin synthesis and mitochondrial respiration in acute intermittent porphyria: [107] N. Eroglu, A. Bahadir, E. Erduran, A case of ALL developing posterior reversible
studies using cultured human fibroblasts, Transl. Res. 85 (1975) 93–102, https:// encephalopathy secondary to hyponatremia, J. Pediatr. Hematol. Oncol. 39 (2017)
doi.org/10.5555/uri:pii:0022214375904552. e476–e478, https://doi.org/10.1097/MPH.0000000000000827.
[97] B. Chacko, M.L. Culp, J. Bloomer, J. Phillips, Y.F. Kuo, V. Darley-Usmar, [108] J.S. Jeon, S.P. Park, J.G. Seo, Posterior reversible encephalopathy syndrome due to
A.K. Singal, Feasibility of cellular bioenergetics as a biomarker in porphyria pa- hyponatremia, J. Epilepsy Res. 4 (2014) 31–33, https://doi.org/10.14581/jer.
tients, Mol. Genet. Metab. Rep. 19 (2019) 100451, , https://doi.org/10.1016/j. 14008.
ymgmr.2019.100451. [109] P. Aulakh, E. Fatakhov, C.F. Koch Jr., S. Kapil, Posterior reversible encephalopathy
[98] N. Dixon, T. Li, B. Marion, D. Faust, S. Dozier, A. Molina, S. Rudnick, syndrome with documented hyponatraemia, BMJ Case Rep (2013), https://doi.
H.L. Bonkovsky, Pilot study of mitochondrial bioenergetics in subjects with acute org/10.1136/bcr-2013-009311 pii: bcr2013009311.
porphyrias, Mol. Genet. Metab. (2019), https://doi.org/10.1016/j.ymgme.2019. [110] V.A. Russell, M.C. Lamm, J.J. Taljaard, Inhibition of Na+, K+-ATPase activity by
05.010 pii: S1096–7192(19)30153–2. delta-aminolevulinic acid, Neurochem. Res. 8 (1983) 1407–1415, https://doi.org/
[99] X.Y. Zhao, M.H. Lu, D.J. Yuan, D.E. Xu, P.P. Yao, W.L. Ji, H. Chen, W.L. Liu, 10.1007/BF00964997.
C.X. Yan, Y.Y. Xia, S. Li, J. Tao, Q.H. Ma, Mitochondrial dysfunction in neural [111] N. Pallet, A. Karras, E. Thervet, L. Gouya, Z. Karim, H. Puy, Porphyria and kidney
injury, Front. Neurosci. 13 (2019) 30, https://doi.org/10.3389/fnins.2019.00030. diseases, Clin. Kidney J. 11 (2018) 191–197, https://doi.org/10.1093/ckj/sfx146.
[100] T.R. Miller, R. Shivashankar, M. Mossa-Basha, D. Gandhi, Reversible cerebral [112] R.M. Swart, E.J. Hoorn, M.G. Betjes, R. Zietse, Hyponatremia and inflammation:
vasoconstriction syndrome, part 1: epidemiology, pathogenesis, and clinical the emerging role of interleukin-6 in osmoregulation, Nephron Physiol. 118
course, Am. J. Neuroradiol. 36 (2015) 1392–1399, https://doi.org/10.3174/ajnr. (2011) 45–51, https://doi.org/10.1159/000322238.
a4214. [113] C. Thanadetsuntorn, P. Ngamjanyaporn, C. Setthaudom, K. Hodge, N. Saengpiya,
[101] T.A. Middelburg, H.S. De Bruijn, L. Tettero, A. Van Der Ploeg Van, H.A. Den P. Pisitkun, The model of circulating immune complexes and interleukin-6 im-
Heuvel, E.R. Neumann, D.J. Robinson De Haas, Topical hexylaminolevulinate and proves the prediction of disease activity in systemic lupus erythematosus, Sci. Rep.
aminolevulinic acid photodynamic therapy: complete arteriole vasoconstriction 8 (2018) 2620, https://doi.org/10.1038/s41598-018-20947-4.
occurs frequently and depends on protoporphyrin IX concentration in vessel wall, [114] J. Merayo-Chalico, A. Barrera-Vargas, G. Juárez-Vega, J. Alcocer-Varela, A. Arauz,
J. Photochem. Photobiol. B 126 (2013) 26–32, https://doi.org/10.1016/ D. Gómez-Martín, Differential serum cytokine profile in patients with systemic
jjphotobiol.2013.06.014. lupus erythematosus and posterior reversible encephalopathy syndrome, Clin.
[102] J. Thachil, Nitric oxide and the clinical manifestations of acute porphyria, Intern. Exp. Immunol. 192 (2018) 165–170, https://doi.org/10.1111/cei.13095.
Med. J. 38 (2008) 732–735, https://doi.org/10.1111/j.1445-5994.2008.01778.x. [115] J.R. Bloomer, P.D. Berk, H.L. Bonkowsky, J.A. Stein, N.I. Berlin, D.P. Tschudy,
[103] D. Pierini, N.S. Bryan, Nitric oxide availability as a marker of oxidative stress, Blood volume and bilirubin production in acute intermittent porphyria, N. Engl. J.
Methods Mol. Biol. 1208 (2015) 63–71, https://doi.org/10.1039/b009171p. Med. 284 (1971) 17–20, https://doi.org/10.1056/NEJM197101072840104.
[104] H. Shen, P. Liang, S. Qiu, B. Zhang, Y. Wang, P. Lv, The role of Na+, K+-ATPase [116] B. Largeau, O. Le Tilly, B. Sautenet, C. Salmon Gandonnière, C. Barin-Le Guellec,
in the hypoxic vasoconstriction in isolated rat basilar artery, Vasc. Pharmacol. 81 S. Ehrmann, Arginine vasopressin and posterior reversible encephalopathy syn-
(2016) 53–60, https://doi.org/10.1016/j.vph.2016.02.004. drome pathophysiology: the missing link? Mol. Neurobiol. 56 (2019) 6792–6806,
[106] J.C. Ayus, S.G. Achinger, A. Arieff, Brain cell volume regulation in hyponatremia: https://doi.org/10.1007/s12035-019-1553-y.

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