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Neurological manifestations of autoinflammatory diseases in Chinese adult patients
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Neurological manifestations of autoinflammatory diseases in Chinese adult patients Wenyi Qin , Di Wu , Yi Luo , Mengzhu Zhao , Yi Wang , Xiaochun Shi , Lixin Zhou , Weihong Yu , Yang Sun , Rongrong Wang , Wen Zhang , Mengqi Liu , Min Shen PII: DOI: Reference:
S0049-0172(20)30012-3 https://doi.org/10.1016/j.semarthrit.2019.12.003 YSARH 51583
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Seminars in Arthritis & Rheumatism
Please cite this article as: Wenyi Qin , Di Wu , Yi Luo , Mengzhu Zhao , Yi Wang , Xiaochun Shi , Lixin Zhou , Weihong Yu , Yang Sun , Rongrong Wang , Wen Zhang , Mengqi Liu , Min Shen , Neurological manifestations of autoinflammatory diseases in Chinese adult patients, Seminars in Arthritis & Rheumatism (2020), doi: https://doi.org/10.1016/j.semarthrit.2019.12.003
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Highlights Neurological manifestations of systemic autoinflammatory diseases (AIDs) are diverse. Critical neurological damage is mainly seen in NLRP3-AID. Early treatment is essential to avoid irreversible neurological complications.
1
Neurological manifestations of autoinflammatory diseases in Chinese adult patients Wenyi Qin1,2, Di Wu1, Yi Luo1, Mengzhu Zhao1, Yi Wang3, Xiaochun Shi4, Lixin Zhou5, Weihong Yu6, Yang Sun7, Rongrong Wang7, Wen Zhang1, Mengqi Liu8, Min Shen1* 1
Department of Rheumatology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China 2
The Integrated Traditional Chinese and Western Medicine Department, the First
Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 3
Department of Otolaryngology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 4
Department of Infectious Disease, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 5
Department of Neurology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 6
Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences,
Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, 2
China 7
McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical
Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, China 8
Department of Radiology, the First Affiliated Hospital of Chongqing Medical
University, Chongqing 400016, China Email address: Wenyi
Qin
[email protected],
Di
Wu
[email protected],
Mengzhu
Zhao
[email protected],
Xiaochun
Shi
[email protected],
Weihong
[email protected],
[email protected], [email protected],
Yu
[email protected],
Yi
Luo
Yi
Wang
Lixin
Zhou
Yang
Sun
[email protected], Rongrong Wang [email protected], Wen Zhang [email protected], Mengqi Liu [email protected] *Correspondence to: Min Shen, MD, Department of Rheumatology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.
E-mail: [email protected]
ABSTRACT Objective: Systemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult
3
patients with SAIDs. Methods: Eighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. Results: Totally 31 out of 80 (38.8%) patients had neurological manifestations, including
14
familial
Mediterranean
fever
(45.2%),
6
NLRP3-associated
autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5-50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. Conclusion: Neurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible 4
neurological complications. Keywords: Nervous system; Autoinflammatory diseases; NLRP3-associated autoinflammatory disease; Familial Mediterranean fever; Sensorineural hearing loss; Chronic aseptic meningitis
Introduction Systemic autoinflammatory diseases (SAIDs) are a distinct group of disorders characterized by dysregulation of the innate immune system leading to a sterile multi-systemic inflammation [1]. It consists mainly of monogenic diseases, such as familial Mediterranean fever (FMF), NLRP3-associated autoinflammatory disease (NLRP3-AID) (formerly called cryopyrin-associated periodic syndrome, CAPS), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), NLRP12-associated autoinflammatory disease (NLRP12-AID), and Blau syndrome (BS) [2-4]. The common manifestations of SAIDs include recurrent fever associated with elevation of acute phase reactants, rash, serositis, arthritis, and lymphadenopathy [3]. The clinical manifestation of SAIDs is extremely variable and many systems can be involved, including the nervous system. Neurological involvements are commonly seen in NLRP3-AID, for example, headache observed in the mild phenotype (formerly called familial cold autoinflammatory syndrome, FCAS) [5,6], sensorineural hearing loss developed in the moderate phenotype (formerly called Muckle-Wells syndrome) [7], and the critical 5
neurologic complications of the severe phenotype (formerly called chronic infantile neurologic, cutaneous and articular syndrome, CINCA) [8]. In addition, severe encephalopathy
with
brain
calcification,
mental
retardation,
ischemic
and
hemorrhagic strokes can be seen in type I interferonopathy [1,9,10]. The neurological manifestation of this type of SAIDs is becoming more and more prominent. Neurological damage may be the initial or dominant feature of SAIDs, no matter in child-onset or adult-onset patients [11]. Therefore, it is very important to improve the understanding of the neurological manifestations of SAIDs to avoid diagnosis delay and improve the prognosis. However, the awareness of neurological manifestations in the monogenic SAIDs except NLRP3-AID is still very low among physicians. Our tertiary medical center has the only adult SAIDs center in China. We have recently reported Chinese adult patients with SAIDs which showed different phenotypes and genotypes from Caucasians and children with SAIDs [12-15]. Herein, we summarized the neurological manifestations of adult SAIDs patients in the Chinese population to provide new perspectives for the understanding of SAIDs. Patients and methods A total of 80 adult patients (≥16 years of age) were diagnosed as SAIDs at the Department of Rheumatology, Peking Union Medical College Hospital, from April 2015 to June 2019. Monogenic SAIDs were diagnosed according to the clinical features, along with the gene variants and response to conventional/biologic treatments [12,16]. The diagnosis of Yao syndrome (YAOS) was made according to the diagnostic criteria proposed by Yao and Shen [17]. Demographic data, clinical 6
characteristics, and laboratory tests were collected. All SAIDs patients underwent neurologic, ophthalmologic and otolaryngologic evaluation by a neurologist, an ophthalmologist and an otolaryngologist at least once at baseline or follow-up. Clinical history and nervous system manifestations of the patients were further assessed by a rheumatologist and a neurologist. Audiogram was used to document presence of any sensorineural deafness. Neurologic assessment was reinforced by a cranial magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis (cells > 5/mm3, proteins >0.4 g/dl, and CSF pressure > 200 mm H2O were considered abnormal) [18,19]. Optic nerve damage was evaluated by fundus examination and fundus angiography. Whole exome sequencing by Next Generation Sequencing was performed in each patient (Joy Orient Translational Medicine Research Centre Co., Ltd, Beijing, China). This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and performed according to the Declaration of Helsinki. Informed consents were obtained from all participants. In this research, the neurological manifestations were defined as headache, dizziness, chronic aseptic meningitis, intracranial hypertension, hydrocephalus, papilledema,
optic
neuritis,
sensorineural
hearing
loss,
epilepsy,
cerebral
infarction/hemorrhage, brain atrophy, and other atypical symptoms of nervous system. Among them, brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis were considered as severe neurological injury [8,19-21]. Results Demographic data 7
In these 80 patients, there were 37 FMF (46.3%), 16 NLRP12-AID (20%), 9 NLRP3-AID (11.3%), 9 TRAPS (11.3%), 6 YAOS (7.5%) and 3 BS (3.8%). Among them, 31 patients (38.8%) had neurological manifestations, including 14 FMF (45.2%), 6 NLRP3-AID (19.4%), 5 TRAPS (16.1%), 5 NLRP12-AID (16.1%), and 1 YAOS (3.2%) (Table 1). Although 2 out of 3 patients with BS had blindness, it was not included in our data, since it was caused by uveitis instead of optic neuritis. All 31 patients were of Chinese Han ethnicity. There were 21 men and 10 women. Eleven patients (35.5%) were child-onset, while 20 (64.5%) had their disease onset after 16 years old. The mean time of disease onset was 20.0±16.1 years, and the median time of diagnosis delay was 11.7 (0.5-50) years. Six patients (19.4%) had family histories of SAIDs. The neurological features of these 31 SAIDs patients were summarized in Table 1. The most common characteristic was headache, which developed in 28 patients (90.3%). Other neurological manifestations included sensorineural hearing loss (6 patients, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), papilledema (3, 9.7%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). There were also patients suffered from epilepsy and other atypical symptoms. In these 31 patients, severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. Severe neurological damage happened mainly in NLRP3-AID patients (4, 50%), FMF (2, 25%) and NLRP12-AID (2, 25%). 8
FMF In our center, 14 out of 37 FMF patients (37.8%) presented with neurological manifestations, including 9 men and 5 women. The mean age at disease onset was 20.0±12.1 years, and the mean age at diagnosis was 34.5±10.0 years. Four patients had family histories of periodic fever. All patients had recurrent fever. During episodes, seven patients had generalized abdominal pain, three experienced chest pain, three had pericarditis, nine developed arthralgia/arthritis and four reported rashes. No patient had evidence of AA amyloidosis. All patients had good response to colchicine. In these 14 FMF patients, homozygous MEFV gene variants (NM_000243.2) were seen in 2 (14.3%), and heterozygous variants were identified in 12 (85.7%) (Table 1). The common variants of MEFV were p.E148Q, p.P369S, p.R408Q, p.R202Q and p.G304R. Headache occurred in all these 14 FMF patients (100%). Two patients (14.3%) complained of dizziness. Most of the symptoms (13 patients, 92.9%) were periodically occurred during the febrile episodes, and relieved after colchicine treatment. Chronic aseptic meningitis was diagnosed in one patient (7.1%) who manifested as continuous headache and dizziness with elevated protein in CSF, and headache aggravated with vomiting during the attacks. Colchicine had a poor effect on this patient. Another individual (7.1%) had periodic headache and lumbar puncture showed intracranial hypertension but without evidence of chronic aseptic meningitis. An atypical manifestation, falx cerebri calcification, was showed on MRI of one patient (Table 1). 9
NLRP3-AID For the 6 NLRP3-AID patients, neurological manifestations were the most complex and diverse among the Chinese adult SAIDs patients. The gender ratio of men and women was 5 to 1. The median age of disease onset was 8.5 (1.5-27.3) years, and the mean age at diagnosis was 25.0±10.0 years (Table 1). Only one patient had a family history of NLRP3-AID. All these patients had intermittent episodes of fever. The common clinical features except the nervous system included urticarial-like rash or erythema (4 patients), arthritis (4), conjunctivitis (4) and myalgia (3). Neurological manifestations were the initial symptoms of all these 6 NLRP3-AID patients. Four patients (66.7%) had headache, and one of them (16.7%) experienced dizziness. Among them, two patients (33.3%) experienced periodic headache. Chronic aseptic meningitis and intracranial hypertension were found in 2 patients (33.3%) who had persistent headache, manifesting as pleocytosis with neutrophil predominance and elevated protein in CSF. Both patients were once misdiagnosed as Lyme disease for chronic aseptic meningitis of unknown cause, yet anti-infective therapy was ineffective. Papilledema was observed in 3 patients (50%) (Figure 1), and optic neuritis diagnosed in 2 (33.3%). Another prominent symptom was sensorineural hearing loss, which developed in 4 patients (66.7%). Two patients (3.3%) had cerebrovascular diseases. Epilepsy, hydrocephalus and brain atrophy (Figure 2A) occurred in one patient respectively (16.7% separately). Some rare neurological damage was also seen in our cohort, such as hypertrophic tentorium cerebellum (Figure 2B, C and D), empty sella and cyst. Among the NLRP3-AID group, 4 patients 10
(66.7%) had severe neurological damage including chronic aseptic meningitis, sensorineural hearing loss, and optic neuritis. Interestingly, two of them had the same gene variant of NLRP3 p.T348M (NM_001243133.1) (Table 1). Since IL-1 inhibitors were not available in China, TNFα blockers were given to these four patients with severe neurological damage. Although the manifestations such as fever, rash and arthritis were recovered, the neurological symptoms were not obviously improved. TRAPS In our study, 5 out of 9 TRAPS patients (55.6%) suffered from nervous system damage. They were all men. The median age of disease onset was 11.0 (0.9-29.8) years, and the mean age at diagnosis was 25.5±14.1 years. One patient had a family history of TRAPS. The frequent symptoms were fever (5 patients), myalgia (4), arthralgia/arthritis (4), abdominal pain (4), rash (3), and conjunctivitis (3). Only two patients had periorbital edema. The most common neurological symptom of these 5 TRAPS patients was also periodic headache (100%). One patient (20%) had dizziness during the episodes, and one (20%) had cerebrovascular disease which happened during the interval. Other atypical symptoms included intermittent somnolence, neck pain and diplopia. These symptoms were ameliorated after therapy, except the cerebrovascular disease. NLRP12-AID Among 16 NLRP12-AID patients, 5 cases (31.3%) presented with neurological damage. There were 2 men and 3 women. The mean age of disease onset was 31.5±15.1 years, and the mean age at diagnosis was 33.0±13.5 years. All these five 11
patients had recurrent fever, four complained of urticarial-like rash, four developed arthralgia/arthritis, and three had abdominal pain. Similar to NLRP3-AID, the most prominent neurological presentations of NLRP12-AID patients were recurrent headache (5, 100%) and sensorineural hearing loss (2, 40%) accompanied with fever. Hearing loss was transient in both patients. YAOS Only one out of six patients with YAOS had neurological manifestations during the course of disease. She manifested as recurrent fever with arthralgia, abdominal pain and fatigue. Cerebral infarction happened in this patient during a fever attack and fortunately, no nervous system sequelae were observed. Discussion This study reported the neurological manifestations in a large cohort of Chinese adult patients for the first time. Our study showed that the neurological damage was prominent and diverse in SAIDs patients. The results indicate that neurological damage should be considered an important part of the SAIDs diagnosis and treatment. It is already established that NLRP3-AID is one of SAIDs which has the most complex and diverse neurological manifestations, especially in the early stage [21-23]. In addition, we found several distinctions in our patients. First, there were no patients suffering from mental retardation in the Chinese adult NLRP3-AID patients. Indeed, it has been demonstrated that mental retardation is most frequently seen in the severe type of NLRP3-AID [24,25], which was not included in our cohort. Second, two NLRP3-AID patients who presented with salient neurological injury had the same 12
genotype, a heterozygous p.T348M of NLRP3 gene. According to some case reports, p.T348M was related to recurrent skin rash without fever episodes or intracranial hypertension with papilledema [26]. Meanwhile, p.T348M might be associated with sensorineural hearing loss [27,28]. Notably, in our patients, p.T348M was related to sensorineural hearing loss, chronic aseptic meningitis, hydrocephalus and brain atrophy as well with an early onset. We suggest that physicians should be aware of this genotype-phenotype correlation. Third, optic neuritis was a significant symptom with high morbidity in the moderate phenotype of NLRP3-AID in our center. It has been mentioned that optic neuritis is less frequent in NLRP3-AID in Caucasian population, except for the severe phenotype (CINCA) [1,27]. This difference between Chinese and Caucasian patients might be due to the genotype diversity. Therefore, optic neuritis should be suspected when NLRP3-AID patients complain of blurred vision. In regard to the neurological damage in FMF, headache has been occasionally reported [28-32]. The pathogenic mechanism of headache in FMF is complex and multifactorial.
Intracranial
hypertension,
chronic
aseptic
meningitis,
and
FMF-induced vasculitis which might lead to stroke, may be responsible for the development of headache. Similar to the literature, headache was the most common neurological symptom in our patients with FMF. Some studies showed that the neurological manifestations of FMF were related to a higher rate of homozygous p.M694V variant in the MEFV gene [30,31]. However, we found the common variants of the MEFV gene in our patients were p.E148Q, p.P369S, p.R408Q, p.R202Q and 13
p.G304R, instead of p.M694V. On the other hand, although the incidence of headache was as high as 37.8% in FMF patients in our study, intracranial hypertension and chronic aseptic meningitis were only identified in two of them. This could probably be due to the mild severity of headache in these patients, which made CSF analysis, fundus and imaging examination unindicated in most patients. Hence, the findings reinforce that we should pay more attention to the neurological damage of FMF in the future. It was observed in our study and literature that the neurological manifestations of NLRP12-AID were similar to those of NLRP3-AID, but less frequent and severe [32]. For example, we found that hearing loss in most of NLRP12-AID patients was temporary and could be relieved shortly after effective treatments. Moreover, there were no NLRP12-AID patients suffering from severe neurological manifestations such as chronic aseptic meningitis, optic neuritis, hydrocephalus and brain atrophy. For other SAIDs like TRAPS, YAOS, and BS, the neurological manifestations were seldom seen. It’s worth mentioning that we had identified three unique TNFRSF1A gene variants in TRAPS patients 1, 3 and 4, besides two pathological variants in this gene (TRAPS patients 2 and 5) which were reported by the Infevers website. TRAPS patient 3 in our study had typical manifestation of periodic fever and colchicine was ineffective. In fact, we didn’t find any variants of periodic fever syndrome genes except homozygous c.769-23 (IVS8) T>C, which was previously classified as likely benign. Thus, we consider c.769-23 (IVS8) T>C might be related to the phenotype of this patient. In addition, since the minor allele frequency (MAF) of c.*64T>C in 14
non-coding region was only 0.0012 in Asian population, and it is predicted to be probably damaging when using an in silico analysis algorithm, we think it might play a role in the clinical manifestation of TRAPS patient 4. We consider S290I as a novel variant in TRAPS, since the typical phenotype of patient 1, and a MAF of less than 0.00052 in the Asian population. Although headache was a common symptom of FMF and TRAPS, unlike NLRP3-AID, patients with FMF or TRAPS often present with nonspecific headaches but do not present with more specific neurological findings. In our patients, 25% had severe neurological damage and serious sequelae. According to the literature, sensorineural hearing loss in NLRP3-AID was characteristically worst at higher frequencies. Despite optimal treatment, almost 20% of patients evolved to hearing loss [1,33]. Low awareness and delayed diagnosis may be the major reasons for the irreversible organ injury. Currently, there have been several kinds of biological agents which are effective in many SAIDs. Therefore, we advance that early recognition and treatment of neurological symptoms, per se, is critical to avoid organ damage and improve prognosis. Conclusion Neurological damage was prominent and diverse in SAIDs patients. Physicians should fully realize neurological symptoms, in not only pediatric but also adult patients with SAIDs, and promptly perform CSF analysis and brain imaging. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications. 15
Conflict of Interest: None. Acknowledgements The authors would like to acknowledge the patients for their consents to participate in the study. Funding This work was supported by the National Natural Science Foundation of China (grant number 81501405); Natural Science Foundation of Beijing (grant number 7192170); the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (grant number 2017-I2M-3-001); and the National Key Research and Development Program of China (grant number 2016YFC0901500, 2016YFC0901501).
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18
Table 1 Clinical and genetic features of 31 SAIDs patients with neurological manifestations Patients
FMF-1
Sex
M
Age at
Delay of
onset,
diagnosis
years
, years
16
8
Genotype
Family
Headache
Dizziness
IH
CAM
SHL
ON
Papilledema
Seizure
-
+
-
-
-
-
-
-
-
history
MEFV(R408Q,E148Q,P369S, R202Q)
FMF-2
F
0.5
20
MEFV(G304R)
-
+
-
-
-
-
-
-
-
FMF-3
M
26
13
MEFV(I591T,R202Q)
-
+
-
+
-
-
-
-
-
FMF-4
F
17
0.5
MEFV(E148Q)
-
+
-
-
-
-
-
-
-
FMF-5
M
22
7
MEFV(P369S)
-
+
-
-
-
-
-
-
-
FMF-6
F
7
30
MEFV(E148Q)
+
+
+
-
-
-
-
-
-
FMF-7
M
18
6
MEFV(E148Q,R408Q,P369S)
+
+
-
-
-
-
-
-
-
FMF-8
M
36
0.6
MEFV(G304R,E148Q,L110P)
+
+
-
-
-
-
-
-
-
#
FMF-9
M
26
28
MEFV(E148Q ,P369S)
-
+
-
-
-
-
-
-
-
FMF-10
M
0.1
22
MEFV(E128Q)
-
+
-
-
-
-
-
-
-
FMF-11
F
35
4
MEFV(E148Q,R408Q,P369S)
-
+
-
-
-
-
-
-
-
FMF-12
M
29
4
MEFV(E148Q)
-
+
+
-
+
-
-
-
-
FMF-13
M
12
25
MEFV(R202Q#)
+
+
-
-
-
-
-
-
-
FMF-14
F
35
3
MEFV(R408Q,G304R,P369S)
-
+
-
-
-
-
-
-
-
NLRP3-AID-1
M
46
1
NLRP3(Q705K)
-
-
-
-
-
-
-
-
-
NLRP3-AID-2
M
21
2
NLRP3(V72M)
-
+
-
-
-
-
-
-
+
NLRP3-AID-3
M
2
29
NLRP3(T348M)
-
+
-
+
+
+
+
+
-
NLRP3-AID-4
F
0
20
NLRP3(D303G)
+
-
-
-
-
+
-
+
-
NLRP3-AID-5
M
10
12
NLRP3(T348M)
-
+
+
+
+
+
+
+
-
NLRP3-AID-6
M
7
20
NLRP3(M116I)
-
+
-
-
-
+
-
-
-
TRAPS-1
M
20
4
TNFRSF1A(S290I)
-
+
-
-
-
-
-
-
-
TRAPS-2
M
1
15
TNFRSF1A(V202D)
-
+
-
-
-
-
-
-
-
TRAPS-3
M
38
1.5
TNFRSF1A(c.769-23(IVS8)T
+
+
-
-
-
-
-
-
-
TNFRSF1A(c.*64T>C)
-
+
+
-
-
-
-
-
-
>C#) TRAPS-4
M
0.5
16.5
TRAPS-5
M
2
50
TNFSF1A(V202G)
-
+
-
-
-
-
-
-
-
NLRP12-AID-1
M
18
10
NLRP12(p.R1030X,32)
-
+
-
-
-
-
-
-
-
NLRP12-AID-2
F
36
0.5
NLRP12(F402L)
-
+
-
-
-
+
-
-
-
NLRP12-AID-3
F
26
4
NLRP12(G39V)
-
+
-
-
-
+
-
-
-
NLRP12-AID-4
F
40
0.5
NLRP12(F402L)
-
+
-
-
-
-
-
-
-
NLRP12-AID-5
M
61
2
NLRP12(E24A)
-
+
-
-
-
-
-
-
-
YAOS-1
F
42
3
NOD2(Y514H)
-
-
-
-
-
-
-
-
-
19
FMF:
familial
Mediterranean
fever;
NLRP3-AID:
NLRP3-associated
autoinflammatory disease; TRAPS: tumor necrosis factor receptor-associated periodic syndrome; NLRP12-AID: NLRP12-associated autoinflammatory disease; YAOS: Yao syndrome; IH: intracranial hypertension; CAM: chronic aseptic meningitis; SHL: sensorineural hearing loss; ON: optic neuritis; CI/CH: cerebral infarction/hemorrhage; BA: brain atrophy; #: homozygous.
Figure legend Fig. 1. The fundus color photography and fluorescein angiography. A1 and A2: The fundus photography and fluorescein angiography of the left eye in a healthy control. B1 and B2: The left eye fundus photography and fluorescein angiography showed papilledema and optic atrophy in an NLRP3-AID patient.
20
Fig. 2. The cranial MRI of an NLRP3-AID patient. T2 FLAIR of cranial MRI showed ventricular
dilatation,
widening
sulcus
and
obvious
brain
atrophy
(A).
Contrast-enhanced T1-weighted images showed hypertrophic tentorium cerebellum on coronal (B), axial (C), and sagittal (D) planes, respectively (red arrows).
21
Neurological manifestations of autoinflammatory diseases in Chinese adult patients Wenyi Qin , Di Wu , Yi Luo , Mengzhu Zhao , Yi Wang , Xiaochun Shi , Lixin Zhou , Weihong Yu , Yang Sun , Rongrong Wang , Wen Zhang , Mengqi Liu , Min Shen PII: DOI: Reference:
S0049-0172(20)30012-3 https://doi.org/10.1016/j.semarthrit.2019.12.003 YSARH 51583
To appear in:
Seminars in Arthritis & Rheumatism
Please cite this article as: Wenyi Qin , Di Wu , Yi Luo , Mengzhu Zhao , Yi Wang , Xiaochun Shi , Lixin Zhou , Weihong Yu , Yang Sun , Rongrong Wang , Wen Zhang , Mengqi Liu , Min Shen , Neurological manifestations of autoinflammatory diseases in Chinese adult patients, Seminars in Arthritis & Rheumatism (2020), doi: https://doi.org/10.1016/j.semarthrit.2019.12.003
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Highlights Neurological manifestations of systemic autoinflammatory diseases (AIDs) are diverse. Critical neurological damage is mainly seen in NLRP3-AID. Early treatment is essential to avoid irreversible neurological complications.
1
Neurological manifestations of autoinflammatory diseases in Chinese adult patients Wenyi Qin1,2, Di Wu1, Yi Luo1, Mengzhu Zhao1, Yi Wang3, Xiaochun Shi4, Lixin Zhou5, Weihong Yu6, Yang Sun7, Rongrong Wang7, Wen Zhang1, Mengqi Liu8, Min Shen1* 1
Department of Rheumatology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China 2
The Integrated Traditional Chinese and Western Medicine Department, the First
Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 3
Department of Otolaryngology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 4
Department of Infectious Disease, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 5
Department of Neurology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China 6
Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences,
Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, 2
China 7
McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical
Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, China 8
Department of Radiology, the First Affiliated Hospital of Chongqing Medical
University, Chongqing 400016, China Email address: Wenyi
Qin
[email protected],
Di
Wu
[email protected],
Mengzhu
Zhao
[email protected],
Xiaochun
Shi
[email protected],
Weihong
[email protected],
[email protected], [email protected],
Yu
[email protected],
Yi
Luo
Yi
Wang
Lixin
Zhou
Yang
Sun
[email protected], Rongrong Wang [email protected], Wen Zhang [email protected], Mengqi Liu [email protected] *Correspondence to: Min Shen, MD, Department of Rheumatology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.
E-mail: [email protected]
ABSTRACT Objective: Systemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult
3
patients with SAIDs. Methods: Eighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. Results: Totally 31 out of 80 (38.8%) patients had neurological manifestations, including
14
familial
Mediterranean
fever
(45.2%),
6
NLRP3-associated
autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5-50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. Conclusion: Neurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible 4
neurological complications. Keywords: Nervous system; Autoinflammatory diseases; NLRP3-associated autoinflammatory disease; Familial Mediterranean fever; Sensorineural hearing loss; Chronic aseptic meningitis
Introduction Systemic autoinflammatory diseases (SAIDs) are a distinct group of disorders characterized by dysregulation of the innate immune system leading to a sterile multi-systemic inflammation [1]. It consists mainly of monogenic diseases, such as familial Mediterranean fever (FMF), NLRP3-associated autoinflammatory disease (NLRP3-AID) (formerly called cryopyrin-associated periodic syndrome, CAPS), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), NLRP12-associated autoinflammatory disease (NLRP12-AID), and Blau syndrome (BS) [2-4]. The common manifestations of SAIDs include recurrent fever associated with elevation of acute phase reactants, rash, serositis, arthritis, and lymphadenopathy [3]. The clinical manifestation of SAIDs is extremely variable and many systems can be involved, including the nervous system. Neurological involvements are commonly seen in NLRP3-AID, for example, headache observed in the mild phenotype (formerly called familial cold autoinflammatory syndrome, FCAS) [5,6], sensorineural hearing loss developed in the moderate phenotype (formerly called Muckle-Wells syndrome) [7], and the critical 5
neurologic complications of the severe phenotype (formerly called chronic infantile neurologic, cutaneous and articular syndrome, CINCA) [8]. In addition, severe encephalopathy
with
brain
calcification,
mental
retardation,
ischemic
and
hemorrhagic strokes can be seen in type I interferonopathy [1,9,10]. The neurological manifestation of this type of SAIDs is becoming more and more prominent. Neurological damage may be the initial or dominant feature of SAIDs, no matter in child-onset or adult-onset patients [11]. Therefore, it is very important to improve the understanding of the neurological manifestations of SAIDs to avoid diagnosis delay and improve the prognosis. However, the awareness of neurological manifestations in the monogenic SAIDs except NLRP3-AID is still very low among physicians. Our tertiary medical center has the only adult SAIDs center in China. We have recently reported Chinese adult patients with SAIDs which showed different phenotypes and genotypes from Caucasians and children with SAIDs [12-15]. Herein, we summarized the neurological manifestations of adult SAIDs patients in the Chinese population to provide new perspectives for the understanding of SAIDs. Patients and methods A total of 80 adult patients (≥16 years of age) were diagnosed as SAIDs at the Department of Rheumatology, Peking Union Medical College Hospital, from April 2015 to June 2019. Monogenic SAIDs were diagnosed according to the clinical features, along with the gene variants and response to conventional/biologic treatments [12,16]. The diagnosis of Yao syndrome (YAOS) was made according to the diagnostic criteria proposed by Yao and Shen [17]. Demographic data, clinical 6
characteristics, and laboratory tests were collected. All SAIDs patients underwent neurologic, ophthalmologic and otolaryngologic evaluation by a neurologist, an ophthalmologist and an otolaryngologist at least once at baseline or follow-up. Clinical history and nervous system manifestations of the patients were further assessed by a rheumatologist and a neurologist. Audiogram was used to document presence of any sensorineural deafness. Neurologic assessment was reinforced by a cranial magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis (cells > 5/mm3, proteins >0.4 g/dl, and CSF pressure > 200 mm H2O were considered abnormal) [18,19]. Optic nerve damage was evaluated by fundus examination and fundus angiography. Whole exome sequencing by Next Generation Sequencing was performed in each patient (Joy Orient Translational Medicine Research Centre Co., Ltd, Beijing, China). This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and performed according to the Declaration of Helsinki. Informed consents were obtained from all participants. In this research, the neurological manifestations were defined as headache, dizziness, chronic aseptic meningitis, intracranial hypertension, hydrocephalus, papilledema,
optic
neuritis,
sensorineural
hearing
loss,
epilepsy,
cerebral
infarction/hemorrhage, brain atrophy, and other atypical symptoms of nervous system. Among them, brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis were considered as severe neurological injury [8,19-21]. Results Demographic data 7
In these 80 patients, there were 37 FMF (46.3%), 16 NLRP12-AID (20%), 9 NLRP3-AID (11.3%), 9 TRAPS (11.3%), 6 YAOS (7.5%) and 3 BS (3.8%). Among them, 31 patients (38.8%) had neurological manifestations, including 14 FMF (45.2%), 6 NLRP3-AID (19.4%), 5 TRAPS (16.1%), 5 NLRP12-AID (16.1%), and 1 YAOS (3.2%) (Table 1). Although 2 out of 3 patients with BS had blindness, it was not included in our data, since it was caused by uveitis instead of optic neuritis. All 31 patients were of Chinese Han ethnicity. There were 21 men and 10 women. Eleven patients (35.5%) were child-onset, while 20 (64.5%) had their disease onset after 16 years old. The mean time of disease onset was 20.0±16.1 years, and the median time of diagnosis delay was 11.7 (0.5-50) years. Six patients (19.4%) had family histories of SAIDs. The neurological features of these 31 SAIDs patients were summarized in Table 1. The most common characteristic was headache, which developed in 28 patients (90.3%). Other neurological manifestations included sensorineural hearing loss (6 patients, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), papilledema (3, 9.7%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). There were also patients suffered from epilepsy and other atypical symptoms. In these 31 patients, severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. Severe neurological damage happened mainly in NLRP3-AID patients (4, 50%), FMF (2, 25%) and NLRP12-AID (2, 25%). 8
FMF In our center, 14 out of 37 FMF patients (37.8%) presented with neurological manifestations, including 9 men and 5 women. The mean age at disease onset was 20.0±12.1 years, and the mean age at diagnosis was 34.5±10.0 years. Four patients had family histories of periodic fever. All patients had recurrent fever. During episodes, seven patients had generalized abdominal pain, three experienced chest pain, three had pericarditis, nine developed arthralgia/arthritis and four reported rashes. No patient had evidence of AA amyloidosis. All patients had good response to colchicine. In these 14 FMF patients, homozygous MEFV gene variants (NM_000243.2) were seen in 2 (14.3%), and heterozygous variants were identified in 12 (85.7%) (Table 1). The common variants of MEFV were p.E148Q, p.P369S, p.R408Q, p.R202Q and p.G304R. Headache occurred in all these 14 FMF patients (100%). Two patients (14.3%) complained of dizziness. Most of the symptoms (13 patients, 92.9%) were periodically occurred during the febrile episodes, and relieved after colchicine treatment. Chronic aseptic meningitis was diagnosed in one patient (7.1%) who manifested as continuous headache and dizziness with elevated protein in CSF, and headache aggravated with vomiting during the attacks. Colchicine had a poor effect on this patient. Another individual (7.1%) had periodic headache and lumbar puncture showed intracranial hypertension but without evidence of chronic aseptic meningitis. An atypical manifestation, falx cerebri calcification, was showed on MRI of one patient (Table 1). 9
NLRP3-AID For the 6 NLRP3-AID patients, neurological manifestations were the most complex and diverse among the Chinese adult SAIDs patients. The gender ratio of men and women was 5 to 1. The median age of disease onset was 8.5 (1.5-27.3) years, and the mean age at diagnosis was 25.0±10.0 years (Table 1). Only one patient had a family history of NLRP3-AID. All these patients had intermittent episodes of fever. The common clinical features except the nervous system included urticarial-like rash or erythema (4 patients), arthritis (4), conjunctivitis (4) and myalgia (3). Neurological manifestations were the initial symptoms of all these 6 NLRP3-AID patients. Four patients (66.7%) had headache, and one of them (16.7%) experienced dizziness. Among them, two patients (33.3%) experienced periodic headache. Chronic aseptic meningitis and intracranial hypertension were found in 2 patients (33.3%) who had persistent headache, manifesting as pleocytosis with neutrophil predominance and elevated protein in CSF. Both patients were once misdiagnosed as Lyme disease for chronic aseptic meningitis of unknown cause, yet anti-infective therapy was ineffective. Papilledema was observed in 3 patients (50%) (Figure 1), and optic neuritis diagnosed in 2 (33.3%). Another prominent symptom was sensorineural hearing loss, which developed in 4 patients (66.7%). Two patients (3.3%) had cerebrovascular diseases. Epilepsy, hydrocephalus and brain atrophy (Figure 2A) occurred in one patient respectively (16.7% separately). Some rare neurological damage was also seen in our cohort, such as hypertrophic tentorium cerebellum (Figure 2B, C and D), empty sella and cyst. Among the NLRP3-AID group, 4 patients 10
(66.7%) had severe neurological damage including chronic aseptic meningitis, sensorineural hearing loss, and optic neuritis. Interestingly, two of them had the same gene variant of NLRP3 p.T348M (NM_001243133.1) (Table 1). Since IL-1 inhibitors were not available in China, TNFα blockers were given to these four patients with severe neurological damage. Although the manifestations such as fever, rash and arthritis were recovered, the neurological symptoms were not obviously improved. TRAPS In our study, 5 out of 9 TRAPS patients (55.6%) suffered from nervous system damage. They were all men. The median age of disease onset was 11.0 (0.9-29.8) years, and the mean age at diagnosis was 25.5±14.1 years. One patient had a family history of TRAPS. The frequent symptoms were fever (5 patients), myalgia (4), arthralgia/arthritis (4), abdominal pain (4), rash (3), and conjunctivitis (3). Only two patients had periorbital edema. The most common neurological symptom of these 5 TRAPS patients was also periodic headache (100%). One patient (20%) had dizziness during the episodes, and one (20%) had cerebrovascular disease which happened during the interval. Other atypical symptoms included intermittent somnolence, neck pain and diplopia. These symptoms were ameliorated after therapy, except the cerebrovascular disease. NLRP12-AID Among 16 NLRP12-AID patients, 5 cases (31.3%) presented with neurological damage. There were 2 men and 3 women. The mean age of disease onset was 31.5±15.1 years, and the mean age at diagnosis was 33.0±13.5 years. All these five 11
patients had recurrent fever, four complained of urticarial-like rash, four developed arthralgia/arthritis, and three had abdominal pain. Similar to NLRP3-AID, the most prominent neurological presentations of NLRP12-AID patients were recurrent headache (5, 100%) and sensorineural hearing loss (2, 40%) accompanied with fever. Hearing loss was transient in both patients. YAOS Only one out of six patients with YAOS had neurological manifestations during the course of disease. She manifested as recurrent fever with arthralgia, abdominal pain and fatigue. Cerebral infarction happened in this patient during a fever attack and fortunately, no nervous system sequelae were observed. Discussion This study reported the neurological manifestations in a large cohort of Chinese adult patients for the first time. Our study showed that the neurological damage was prominent and diverse in SAIDs patients. The results indicate that neurological damage should be considered an important part of the SAIDs diagnosis and treatment. It is already established that NLRP3-AID is one of SAIDs which has the most complex and diverse neurological manifestations, especially in the early stage [21-23]. In addition, we found several distinctions in our patients. First, there were no patients suffering from mental retardation in the Chinese adult NLRP3-AID patients. Indeed, it has been demonstrated that mental retardation is most frequently seen in the severe type of NLRP3-AID [24,25], which was not included in our cohort. Second, two NLRP3-AID patients who presented with salient neurological injury had the same 12
genotype, a heterozygous p.T348M of NLRP3 gene. According to some case reports, p.T348M was related to recurrent skin rash without fever episodes or intracranial hypertension with papilledema [26]. Meanwhile, p.T348M might be associated with sensorineural hearing loss [27,28]. Notably, in our patients, p.T348M was related to sensorineural hearing loss, chronic aseptic meningitis, hydrocephalus and brain atrophy as well with an early onset. We suggest that physicians should be aware of this genotype-phenotype correlation. Third, optic neuritis was a significant symptom with high morbidity in the moderate phenotype of NLRP3-AID in our center. It has been mentioned that optic neuritis is less frequent in NLRP3-AID in Caucasian population, except for the severe phenotype (CINCA) [1,27]. This difference between Chinese and Caucasian patients might be due to the genotype diversity. Therefore, optic neuritis should be suspected when NLRP3-AID patients complain of blurred vision. In regard to the neurological damage in FMF, headache has been occasionally reported [28-32]. The pathogenic mechanism of headache in FMF is complex and multifactorial.
Intracranial
hypertension,
chronic
aseptic
meningitis,
and
FMF-induced vasculitis which might lead to stroke, may be responsible for the development of headache. Similar to the literature, headache was the most common neurological symptom in our patients with FMF. Some studies showed that the neurological manifestations of FMF were related to a higher rate of homozygous p.M694V variant in the MEFV gene [30,31]. However, we found the common variants of the MEFV gene in our patients were p.E148Q, p.P369S, p.R408Q, p.R202Q and 13
p.G304R, instead of p.M694V. On the other hand, although the incidence of headache was as high as 37.8% in FMF patients in our study, intracranial hypertension and chronic aseptic meningitis were only identified in two of them. This could probably be due to the mild severity of headache in these patients, which made CSF analysis, fundus and imaging examination unindicated in most patients. Hence, the findings reinforce that we should pay more attention to the neurological damage of FMF in the future. It was observed in our study and literature that the neurological manifestations of NLRP12-AID were similar to those of NLRP3-AID, but less frequent and severe [32]. For example, we found that hearing loss in most of NLRP12-AID patients was temporary and could be relieved shortly after effective treatments. Moreover, there were no NLRP12-AID patients suffering from severe neurological manifestations such as chronic aseptic meningitis, optic neuritis, hydrocephalus and brain atrophy. For other SAIDs like TRAPS, YAOS, and BS, the neurological manifestations were seldom seen. It’s worth mentioning that we had identified three unique TNFRSF1A gene variants in TRAPS patients 1, 3 and 4, besides two pathological variants in this gene (TRAPS patients 2 and 5) which were reported by the Infevers website. TRAPS patient 3 in our study had typical manifestation of periodic fever and colchicine was ineffective. In fact, we didn’t find any variants of periodic fever syndrome genes except homozygous c.769-23 (IVS8) T>C, which was previously classified as likely benign. Thus, we consider c.769-23 (IVS8) T>C might be related to the phenotype of this patient. In addition, since the minor allele frequency (MAF) of c.*64T>C in 14
non-coding region was only 0.0012 in Asian population, and it is predicted to be probably damaging when using an in silico analysis algorithm, we think it might play a role in the clinical manifestation of TRAPS patient 4. We consider S290I as a novel variant in TRAPS, since the typical phenotype of patient 1, and a MAF of less than 0.00052 in the Asian population. Although headache was a common symptom of FMF and TRAPS, unlike NLRP3-AID, patients with FMF or TRAPS often present with nonspecific headaches but do not present with more specific neurological findings. In our patients, 25% had severe neurological damage and serious sequelae. According to the literature, sensorineural hearing loss in NLRP3-AID was characteristically worst at higher frequencies. Despite optimal treatment, almost 20% of patients evolved to hearing loss [1,33]. Low awareness and delayed diagnosis may be the major reasons for the irreversible organ injury. Currently, there have been several kinds of biological agents which are effective in many SAIDs. Therefore, we advance that early recognition and treatment of neurological symptoms, per se, is critical to avoid organ damage and improve prognosis. Conclusion Neurological damage was prominent and diverse in SAIDs patients. Physicians should fully realize neurological symptoms, in not only pediatric but also adult patients with SAIDs, and promptly perform CSF analysis and brain imaging. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications. 15
Conflict of Interest: None. Acknowledgements The authors would like to acknowledge the patients for their consents to participate in the study. Funding This work was supported by the National Natural Science Foundation of China (grant number 81501405); Natural Science Foundation of Beijing (grant number 7192170); the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (grant number 2017-I2M-3-001); and the National Key Research and Development Program of China (grant number 2016YFC0901500, 2016YFC0901501).
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18
Table 1 Clinical and genetic features of 31 SAIDs patients with neurological manifestations Patients
FMF-1
Sex
M
Age at
Delay of
onset,
diagnosis
years
, years
16
8
Genotype
Family
Headache
Dizziness
IH
CAM
SHL
ON
Papilledema
Seizure
-
+
-
-
-
-
-
-
-
history
MEFV(R408Q,E148Q,P369S, R202Q)
FMF-2
F
0.5
20
MEFV(G304R)
-
+
-
-
-
-
-
-
-
FMF-3
M
26
13
MEFV(I591T,R202Q)
-
+
-
+
-
-
-
-
-
FMF-4
F
17
0.5
MEFV(E148Q)
-
+
-
-
-
-
-
-
-
FMF-5
M
22
7
MEFV(P369S)
-
+
-
-
-
-
-
-
-
FMF-6
F
7
30
MEFV(E148Q)
+
+
+
-
-
-
-
-
-
FMF-7
M
18
6
MEFV(E148Q,R408Q,P369S)
+
+
-
-
-
-
-
-
-
FMF-8
M
36
0.6
MEFV(G304R,E148Q,L110P)
+
+
-
-
-
-
-
-
-
#
FMF-9
M
26
28
MEFV(E148Q ,P369S)
-
+
-
-
-
-
-
-
-
FMF-10
M
0.1
22
MEFV(E128Q)
-
+
-
-
-
-
-
-
-
FMF-11
F
35
4
MEFV(E148Q,R408Q,P369S)
-
+
-
-
-
-
-
-
-
FMF-12
M
29
4
MEFV(E148Q)
-
+
+
-
+
-
-
-
-
FMF-13
M
12
25
MEFV(R202Q#)
+
+
-
-
-
-
-
-
-
FMF-14
F
35
3
MEFV(R408Q,G304R,P369S)
-
+
-
-
-
-
-
-
-
NLRP3-AID-1
M
46
1
NLRP3(Q705K)
-
-
-
-
-
-
-
-
-
NLRP3-AID-2
M
21
2
NLRP3(V72M)
-
+
-
-
-
-
-
-
+
NLRP3-AID-3
M
2
29
NLRP3(T348M)
-
+
-
+
+
+
+
+
-
NLRP3-AID-4
F
0
20
NLRP3(D303G)
+
-
-
-
-
+
-
+
-
NLRP3-AID-5
M
10
12
NLRP3(T348M)
-
+
+
+
+
+
+
+
-
NLRP3-AID-6
M
7
20
NLRP3(M116I)
-
+
-
-
-
+
-
-
-
TRAPS-1
M
20
4
TNFRSF1A(S290I)
-
+
-
-
-
-
-
-
-
TRAPS-2
M
1
15
TNFRSF1A(V202D)
-
+
-
-
-
-
-
-
-
TRAPS-3
M
38
1.5
TNFRSF1A(c.769-23(IVS8)T
+
+
-
-
-
-
-
-
-
TNFRSF1A(c.*64T>C)
-
+
+
-
-
-
-
-
-
>C#) TRAPS-4
M
0.5
16.5
TRAPS-5
M
2
50
TNFSF1A(V202G)
-
+
-
-
-
-
-
-
-
NLRP12-AID-1
M
18
10
NLRP12(p.R1030X,32)
-
+
-
-
-
-
-
-
-
NLRP12-AID-2
F
36
0.5
NLRP12(F402L)
-
+
-
-
-
+
-
-
-
NLRP12-AID-3
F
26
4
NLRP12(G39V)
-
+
-
-
-
+
-
-
-
NLRP12-AID-4
F
40
0.5
NLRP12(F402L)
-
+
-
-
-
-
-
-
-
NLRP12-AID-5
M
61
2
NLRP12(E24A)
-
+
-
-
-
-
-
-
-
YAOS-1
F
42
3
NOD2(Y514H)
-
-
-
-
-
-
-
-
-
19
FMF:
familial
Mediterranean
fever;
NLRP3-AID:
NLRP3-associated
autoinflammatory disease; TRAPS: tumor necrosis factor receptor-associated periodic syndrome; NLRP12-AID: NLRP12-associated autoinflammatory disease; YAOS: Yao syndrome; IH: intracranial hypertension; CAM: chronic aseptic meningitis; SHL: sensorineural hearing loss; ON: optic neuritis; CI/CH: cerebral infarction/hemorrhage; BA: brain atrophy; #: homozygous.
Figure legend Fig. 1. The fundus color photography and fluorescein angiography. A1 and A2: The fundus photography and fluorescein angiography of the left eye in a healthy control. B1 and B2: The left eye fundus photography and fluorescein angiography showed papilledema and optic atrophy in an NLRP3-AID patient.
20
Fig. 2. The cranial MRI of an NLRP3-AID patient. T2 FLAIR of cranial MRI showed ventricular
dilatation,
widening
sulcus
and
obvious
brain
atrophy
(A).
Contrast-enhanced T1-weighted images showed hypertrophic tentorium cerebellum on coronal (B), axial (C), and sagittal (D) planes, respectively (red arrows).
21