Neurological Manifestations and Neuroimaging Findings of Acute Intermittent Porphyria Patients

DOI: https://doi.org/10.21203/rs.3.rs-77039/v1

Abstract

Background: Acute intermittent porphyria (AIP) is an inherited disorder of heme biosynthesis, a porphyric attack can affect the autonomic, peripheral, and central nervous systems. The neurological clinical manifestations of which are incompletely understood. The neuroimaging findings of AIP could be reversible.

Methods: In this report, we describe 29 cases of AIP, focusing on neurological clinical features and neuro-imaging. Results: In this study, we showed two cases of PRES, two cases of ODS, two cases of porphyric encephalopathy (cortical laminar necrosis), one case of RESLES. We divided 29 cases into 2 groups ,the blood sodium levels of who with MRI/CT abnormality were significantly lower than which with normal MRI/CT(110±43.15mmol/L and 117±57.02mmol/L, p=0.01).

Conclusions: To the best of our knowledge, these are the biggest series of MRI in AIP in China, and the only published cases of ODS associated with AIP in China. Hyponatremia may be an important mechanism in porphyric encephalopathy.

Background

Acute intermittent porphyria (AIP) is a rare autosomal dominant inherited disorder characterized by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthetic pathway. Most AIP patients are no symptoms except for acute intermittent attacks. Such attacks are characterized by diverse symptoms including abdomen pain, tachycardia, hypertension, unawareness, seizures and psychiatric symptoms[1, 2]. There are just a few reports of the neuroimaging findings in AIP patients with acute neurologic manifestations including seizures. The performance of brain MRI of AIP is diverse. Posterior reversible encephalopathy syndrome (PRES) is associated with potentially reversible neuroradiological abnormalities predominantly in the parieto-occipital lobes. Osmotic demyelination syndrome (ODS) refers to central pontine myelinolysis and extrapontine myelinolysis. Reversible splenial lesion syndrome (RESLES) is a clinico-radiological syndrome characterized by the presence of reversible lesions specifically involving the splenium of the corpus callosum (SCC). Many of these studies have suggested that MRI changes were related to PRES[35]. The relationship of the neurological manifestations and neuroimaging findings of AIP is not well understood. Here, we describe 29 cases of neuroimaging findings of AIP with neurological symptoms.

Patients And Methods

From January 2013 to July 2019, a total of 69 patients were diagnosed with AIP in the emergency center of our hospital. The following diagnostic criteria were used: 1) acute attack symptoms and 2) positive for urine porphobilinogen (PBG). We conducted a retrospective analysis of these patients. 29 of 69 had neurological symptoms (convulsion, confusion, difficulty swallowing etc). We collected information about ethnicity, past medical history, clinical features, neuro-imaging, medications, treatment, investigations and outcome of these 29 patients. Among 29 patients 26 agreed to have genetic testing for porphobilinogen deaminase (PBGD) gene mutations. We did the genetic screening tests of AIP in these families.

Qualitative screening tests of urinary PBG (Watson-Schwartz method)

Urine porphobilinogen (PBG) was quantitatively screened using the Watson-Schwartz method. Briefly, urine was added to Ehrlich's reagent (0.7 g dimethylamine broane dissolved in 150 mL concentrated hydrochloric acid and 100 mL water). After 1–2 min, a saturated sodium acetate solution was added, and the non-specific colors were removed by extraction with chloroform and n-butanol. A positive PBG result was indicated by a distinct pink color in the lower layer[6].

CNS Studies

During porphyric attack, brain CT and/or MRI was performed on most (25/29) patients with CNS symptoms or headache, while electroencephalography (EEG) was performed on some (5/29) patients, CSF test was performed on (7/29) patients.

Genetic testing

The molecular genetic analysis of the HMBS gene was performed by direct sequencing of peripheral blood sample. All 14 exons of the PBGD gene and a minimum of 20 base pairs of flanking intronic DNA for each exon were amplified by polymerase chain reaction (PCR) (Tiangen Biotech, Beijing, China) and subsequently sequenced using the BigDye Terminator Cycle sequencing kit version 3.1 (ABI Biosystems) on an ABI PRISM 3730 Sequence Analyzer according to the manufacturer’s instructions. We aligned the sequences by Chromas software and ncbi website (http://blast.ncbi.nlm.nih.gov/Blast.cgi) to identify variations. We also annotated the filtered variants as “known” or “novel”, depending on whether they had been previously reported in the 1000 Genomes Project (http://www.1000genomes.org/data)

All methods were performed in accordance with the relevant guidelines and regulations.

Results

The demographics, disease course, clinical features and of these 29 AIP patients are summarized in table I. The patients had a disease history ranging from 4 days to 6 years. Acute attacks were accompanied by gastrointestinal symptoms in 28 patients. 29 patients all exhibited neurological manifestations, including consciousness disturbance (n = 25), convulsion or seizure (n = 21), and muscle weakness (n = 7). 3 of the 29 patients exhibited impairment of bulbar and respiratory function. 29 patients all had a documented history of hyponatremia (97–127 mmol/l). 12 patients had MRI/CT abnormality.

Results for electrophysiology and radiological studies, and molecular genetic analysis are summarized in table II.

We divided 29 patients into 2 groups, group 1(MRI/CT abnormality), group 2(MRI/CT normal), there are significant differences in blood sodium levels between the two groups ,[Na]of group 1(110 ± 43.15 mmol/L) lower than group 2(117 ± 57.02 mmol/L, p = 0.01).

MRI scans of Case 8 (14th day after onset) showed abnormal signals in the cerebral cortex, which were isointensity on T1W1 images, hyper-intensity on T2W2. (Fig. 1A and B). The cranial MRI performed 11 days later revealed that the lesions determined on the first MRI were enhanced on contrast-enhanced axial T1-weighted MRI (Fig. 1C, D and E), repeated brain MRI at 10 months showing that the gyriform cortical lesions larger than before (Fig. 1F and G). Case 6 also had the same abnormal signals located in the cerebral cortex as case 3, but case 6 wasn’t followed up.

The initial brain MRI of Case 20 revealed hyperintense gyriform lesions on fluid-attenuated inversion recovery (FLAIR) images (Fig. 3A and B). The cranial MRI performed 40 days later revealed that the lesions determined on the first MRI were significantly regressed (Fig. 3C and D, respectively). MRI findings of Case 9 just like Case 6.

Brain MRI of Case 16 revealed central pontine and extra pontine myelinolysis on FLAIR images (Fig. 2A and B). The cranial MRI five months later revealed that the lesions determined on the first MRI were significantly regressed (Fig. 2C and D, respectively). MRI findings of case 2,16 and 27 all diagnoses as ODS, but case 2 wasn’t followed up, case 27 aggravated after 18 days .

Due to the lack of hemin in China, only supportive treatments could be administered, including high carbohydrate intake (250–300 g of glucose per day), fluid restriction (< 2000 ml per day), and avoiding suspicious drugs.

Sequence analysis of the PBGD gene identified 25 mutations in 25 patients are summarized in table 2 (3 patient didn’t make detection). There were nine missense, four nonsense, seven splicing mutations, two aberrant splice site mutations.

More details of case 9 and case 28 have been previously published.

Discussion

Porphyria is a collective name of seven different diseases that are caused by an enzyme deficiency that inhibits the synthesis of heme. AIP is one of four forms of acute porphyria, which is caused by an inherited deficiency of PBGD. Symptoms of AIP occur during intermittent attacks are caused by the excess production of porphyrin precursors in the visceral, peripheral, autonomic, and central nervous systems, and may be life threatening.

Neurological manifestations of AIP include epileptic seizures, impaired consciousness, behavioral changes and hyponatremia maybe caused by inappropriate antidiuretic hormone syndrome [7, 8]. Peking union medical college hospital reported the characteristics of 36 Chinese patients with acute porphyria in 2016; 12 patients experienced neurological symptoms involving the CNS (12/36 confusion, 10/36 convulsion, 2/36 rapid progression to acute respiratory insufficiency)[7]. The prodromal symptoms in these cases included abdominal pain, muscle weakness. The weakness in case 9 and 15 progressed rapidly to quadriparesis and acute respiratory insufficiency, resulting in the delayed diagnosis.

The pathophysiology of the nervous system involvement of AIP patients is not very clear. Most reports of the neurological manifestations and brain imaging findings of AIP have been restricted to a single or small number of cases[810]. In vivo studies in mice have suggested that multiple mechanisms leading to the varied symptoms, including interactions between 5-Aminolevulinic acid (ALA) and gamma-Aminobutyric acid (GABA) receptors and possibly heme depletion in nerve cells[9]. However, some findings in AIP patients have suggested that the relationship between the severity of neurological manifestations and the ALA/PBG levels is little[10]. In mainland China, tests of ALA and PBG levels are unavailable, it had been found that the serum sodium concentration was significantly negatively correlated with convulsion in our clinical studies[7]. These findings may reveal many factors contributing to the neurological manifestations of AIP. In 2011, the Chang Gung Memorial Hospital in Taiwan reported 12 cases of AIP; 9 patients experienced neurological symptoms involving the CNS (8 consciousness disturbance, 4 convulsion/seizure, 1 behavioral change). Among 4 patients who underwent brain MRI, 3 showed normal results, and 1 showed PRES, and this lesion recovered after 1 year[10]. In our study, 29 patients experienced CNS neurological symptoms, among 20 patients who underwent MRI, 9 showed MRI abnormality (2 PRES,4 ODS, 3 porphyric encephalopathy,1 RESLES).

The porphynic encephalopathy are believed to be most likely due to transient ischemic cerebral changes, although specific mechanism is unknown[11, 12]. These porphynic encephalopathy showed cortical and subcortical increased signal and gyriform diffuse enhancement[1113].Our case 6 and 8 (Fig. 1) had similar cerebral abnormalities, case 8 had been followed by 3 MRI though 10 mons, showed consistent cerebral abnormalities, case 6 wasn’t followed up.

Even though there are only a handful of PRES has been reported in AIP patients, it is by far the most common MRI abnormalities in AIP[3, 4, 9, 10]. In these cases, transient changes were observed in the cerebral cortex on MRI. Usually, these lesions are partially or completely reversible, symmetrical cortical and subcortical involvements of the occipital and parietal lobes, without or with mild enhancement, as observed in case 20 (Fig. 3). The most widely accepted hypothesis of the pathophysiology of PRES is the hyperperfusion theory[14]. The mechanism of PRES in AIP has been suggested to be mediated by hypertension due to autonomic dysfunction[5]. Case 20 progressed to dysphoria, confusion and severe hyponatremia after being diagnosed with “pregnancy-induced hypertension.” However, our first patient with PRES in AIP (case 9) remained normotensive throughout, but she also had severe hyponatremia. Cases of PRES secondary to hyponatremia are rare in the literature[5, 15], little is known about the influence of hyponatremia on cerebrovascular regulation.

ODS refers to central pontine myelinolysis and extrapontine myelinolysis. These disorders are characterized by insults to regions of the brain with anatomical features predisposing white matter tracts to myelin injury in the setting of osmotic disturbances and their attempted correction[16]. Although many AIP patients have hyponatremia[7], ODS in AIP has been rarely previously reported[13]. Case 2,5,16 and 27 are first reported cases of AIP with ODS in China. These two patients had severe hyponatremia, which was quickly corrected before she experienced confusion or frequent convulsion. After three weeks, MRI of case 5 showed typical central pontine myelinolysis and extrapontine myelinolysis, as shown in Fig. 2. The clinical outcome of ODS was thought to be universally devastating[16], but case 5 completely recovered, and the MRI lesions regressed (Fig. 2). The MRI lesions of case 2 after 2 weeks no changed to the first time.

All 29 cases we reported showed severe hyponatremia, and it was found that the serum sodium concentration was significantly negatively correlated with convulsion before[7]. Blood sodium levels of who with MRI/CT abnormality were significantly lower than which with normal MRI/CT(110 ± 43.15 mmol/L and 117 ± 57.02 mmol/L, p = 0.01).We suggest that hyponatremia may be not only a clinical feature of AIP but also an important mechanism in porphyric encephalopathy. An increase in vasopressin levels occurs in hyponatremia[5]. Vasopressin facilitates the movement of water molecules into cerebral cells independently of hyponatremia by reducing the use of cerebral oxygen. Hyponatremia therefore plays an important role in cerebral edema. More research is needed in the future to prove this hypothesis. Because hyponatremia is a common feature in AIP, the rapid correction of hyponatremia should be avoided to prevent ODS.

Conclusion

In summary, the pathophysiology of the neurological manifestations in AIP patients is not well understood, cortical laminar necrosis, PRES, ODS and RESLES can all exhibit CNS involvement in AIP. Additionally, hyponatremia may be important mediators in the mechanism of porphyric encephalopathy.

Abbreviations

AIP

Acute Intermittent Porphyria

MRI

magnetic resonance imaging

PRES

Posterior reversible encephalopathy syndrome

ODS

Osmotic demyelination syndrome

RESLES

Reversible splenial lesion syndrome

SCC

splenium of the corpus callosum

PBGD

porphobilinogen deaminase gene

HMBS

hydroxymethylbilane synthase

FLAIR

fluid-attenuated inversion recovery images

T2WI

T2-weighted images

T1WI

T1-weighted images

ADC

apparent diffusion coefficient

CSF

cerebral spinal fluid

PCR

polymerase chain reaction

Declarations

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975 (revised in 2000). The study protocol was approved by the Ethics Committee of the Institutional Review Board at Peking Union Medical College Hospital (PUMCH). A written consent form, stating acceptance of genetic testing, was signed by the patients and their family members.

Conflict of Interest

The authors declare that they have no conflict of interest.

Contribution list:

Substantial contributions to conception, design and writing: JC and JY.MRI image analysis: FH, HY and JC. Gene mutation detection: QC. Drafting the article or revising it: TZ, YZ, XY, HZ.

Funding

This study was supported by Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program(2019Z).Manuscript writing were funded in this study. The funding bodies played no role in the design of the study, nor in the collection, analysis, or interpretation of the data.

Availability of data and materials

The data used and/or analysed to support the results of the current study are available from the corresponding author on reasonable request.

References

  1. Floderus Y, Shoolingin-Jordan PM, Harper P. Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. Clin Genet. 2002;62(4):288–97.
  2. Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: A 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412–25.
  3. Kang SY, Kang JH, Choi JC, Lee JS. Posterior reversible encephalopathy syndrome in a patient with acute intermittent porphyria. J Neurol. 2010;257(4):663–4.
  4. Lakhotia M, Pahadiya HR, Singh J, Bhansali S, Choudhary S, Jangid H. Posterior reversible encephalopathy syndrome as a rare presenting feature of acute intermittent porphyria. Neurol India. 2015;63(4):607–9.
  5. Zhao B, Wei Q, Wang Y, Chen Y, Shang H. Posterior reversible encephalopathy syndrome in acute intermittent porphyria. Pediatr Neurol. 2014;51(3):457–60.
  6. Buttery JE, Carrera AM, Pannall PR. Analytical sensitivity and specificity of two screening methods for urinary porphobilinogen. Ann Clin Biochem. 1990;27(Pt 2):165–6.
  7. Yang J, Chen Q, Yang H, Hua B, Zhu T, Zhao Y, Zhu H, Yu X, Zhang L, Zhou Z. Clinical and Laboratory Features of Acute Porphyria: A Study of 36 Subjects in a Chinese Tertiary Referral Center. BioMed research international. 2016;2016:3927635.
  8. Yang J, Yang H, Chen Q, Hua B, Zhu T, Zhao Y, Yu X, Zhu H, Zhou Z. Reversible MRI findings in a case of acute intermittent porphyria with a novel mutation in the porphobilinogen deaminase gene. Blood Cells Mol Dis. 2017;63:21–4.
  9. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis. 1998;18(1):43–52.
  10. Kuo HC, Huang CC, Chu CC, Lee MJ, Chuang WL, Wu CL, Wu T, Ning HC, Liu CY. Neurological complications of acute intermittent porphyria. European neurology. 2011;66(5):247–52.
  11. Aggarwal A, Quint DJ, Lynch JP. 3rd: MR imaging of porphyric encephalopathy. AJR American journal of roentgenology. 1994;162(5):1218–20.
  12. King PH, Bragdon AC. MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria. Neurology. 1991;41(8):1300–2.
  13. Susa S, Daimon M, Morita Y, Kitagawa M, Hirata A, Manaka H, Sasaki H, Kato T. Acute intermittent porphyria with central pontine myelinolysis and cortical laminar necrosis. Neuroradiology. 1999;41(11):835–9.
  14. Maramattom BV, Zaldivar RA, Glynn SM, Eggers SD, Wijdicks EF. Acute intermittent porphyria presenting as a diffuse encephalopathy. Ann Neurol. 2005;57(4):581–4.
  15. Eroglu N, Bahadir A, Erduran E: A Case of ALL Developing Posterior Reversible Encephalopathy Secondary to Hyponatremia. Journal of pediatric hematology/oncology 2017, 39(8):e476-e478.
  16. Alleman AM. Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Semin Ultrasound CT MR. 2014;35(2):153–9.

Tables

Table 1 Clinical findings of these AIP patients with neurological symptoms

Patient

Age

Time to Dx (number of attacks)

 

Clinical features

serum Na (mEq/L)

Neuological symtom

Non-neuological symtom

1

F21

2 w

confusion, convulsion

Cyclical attacks, abdominal pain, constipation,

106

2

F22

6 m

confusion, convulsion

Cyclical attacks, abdominal pain,

110

3

F22

2m

Limb weakness

 

126

4

F24

2w

confusion, convulsion,limb weakness

Cyclical attacks, abdominal pain,

113

5

F22

6 mons (2)

Weakness of lower limbs,Involuntary activity,Urinary incontinence

Cyclical attacks, abdominal pain,

112

6

F24

1 year (5)

confusion, convulsion

Cyclical attacks, abdominal pain, constipation,

114

7

F24

 

confusion

Cyclical attacks, abdominal pain, abnormal liver dysfunction

117

8

F23

11mon(2)

Pains in the whole body, convulsion, urine retention

Cyclical attacks, abdominal pain,constipation

115

9

F28

1mon(1)

numbness of extremities, confusion, convulsion,dysphagia, dysarthria, respiratory failure needed invasive mechanical ventilation

Cyclical attacks, dark tea-colored urine

120

10

F34

 

confusion, convulsion

 

112

11

F34

 

confusion, convulsion

Cyclical attacks, abdominal pain,constipation

128

12

F21

5mon

confusion, convulsion and limb weakness

Cyclical attacks, abdominal pain,constipation

127

13

F23

2mon

confusion, convulsion

Cyclical attacks, abdominal pain,constipation

123

14

F21

4d

confusion

constipation

112

15

F27

 

Confusion,convulsion,dysphagiarespiratory failure needed invasive mechanical ventilation

Cyclical attacks, abdominal pain, constipation,

116

16

F17

6mons (2)

Confusion,convulsion,dysphagiarespiratory failure needed invasive mechanical ventilation

Cyclical attacks, abdominal pain, constipation,vomiting

104

17

F22

6d

Confusion, convulsion,

abdominal pain, constipation,

106

18

F28

5 years(21)

Confusion, convulsion,

Cyclical attacks, abdominal pain, constipation,

108

19

F24

2mon

Confusion, convulsion,limb weakness

Cyclical attacks, abdominal pain, constipation,

119

20

F29

6mon

long lasting pain in the limbs and fatigue ,dysphoria and confusion

Cyclical attacks, abdominal pain

108

21

F24

5years

Confusion, convulsion

Cyclical attacks, abdominal pain, constipation,

100

22

F35

7mon

Confusion, convulsion

abdominal pain, constipation,

113

23

F27

7days

Confusion, convulsion

Cyclical attacks, abdominal pain, constipation,

120

24

F24

11mon

limb weakness

Cyclical attacks, abdominal pain, constipation,

122

25

F30

6years

Confusion and limb weakness

Cyclical attacks, abdominal pain,

124

26

F29

2years

Confusion, convulsion

Cyclical attacks, abdominal pain, constipation,hypertension

116

27

F19

1mon

Confusion, convulsion

Cyclical attacks, abdominal pain, constipation,

97

28

F20

7days(1)

sleepiness, confusion and then convulsion

abdominal pain, nausea, vomiting and dark tea-colored urine

119

 

 

Table II Summary of brain imaging findings, electrophysiological findings and molecular defects

Patient

EEG findings

CT findings

MRI findings

MRI follow-up

(Time to 1st MRI)

Csf

mutation in PBGD gene

1

Negtive

Brain edema

 

 

Normal

Ala330Pro

2

Moderate abnormal

 

central pontine and extra pontine myelinolysis on FLAIR images

 

Normal

Trp283Term

3

 

Normal

 

 

Normal

 

4

 

normal

 

 

 

 

5

 

 

central pontine and extra pontine myelinolysis on FLAIR images

No change (2 weeks)

 

NO

6

 

 

T2-weighted shows predominantly cortical increased signal

 

 

c.613-1 G>A

7

 

normal

 

 

normal

 

8

 

 

T2-weighted shows predominantly cortical increased signal

Aggravated(10days),lesions reduced to 1st MRI(10mons)

 

Trp283Term

9

 

 

hyper intense gyriform lesions on FLAIR images

regressed(6mons)

 

Gln292fs

10

 

 

Normal

 

 

Arg173Trp

11

 

Normal

 

 

 

GLU209term

12

 

 

Normal

 

 

c.211-2G>A

13

 

 

Normal

 

 

c.88-1G>C

14

 

 

Normal

 

 

Glu250Gln

15

 

 

Normal

 

 

Arg173Trp

16

 

 

central pontine and extra pontine myelinolysis on FLAIR

regressed(5mons)

 

Lys70ASN

17

 

Low density of parietal lobe

 

 

 

c.210G>A

18

 

 

Normal

 

 

Ala219Pro

19

 

 

Normal

 

 

c.87+5G>T

20

 

 

hyperintense gyriform lesions on FLAIR images

regressed(40 days)

 

Gly218Glu

21

 

normal

 

 

 

I336Hfs*23

22

 

Brain edema

 

 

normal

c.912+1G>C(splicing)

23

 

Normal

Normal

 

 

c.826-1G>C

24

 

 

Normal

 

 

Arg173Trp

25

 

 

Normal

 

 

c.88-1G>C

26

 

 

Normal

 

 

Arg173Trp

27

 

 

central pontine and extra pontine myelinolysis on FLAIR

Aggravated(18days)

 

 

28

 

 

isolated lesion of the SCC, with T2 and FLAIR hyperintensity, T1 hypointensity

regressed(15 days)

 

W198*