Impact of multiple MEFV variants of unknown significance on the diagnosis and clinical presentation of familial Mediterranean fever.

The detection of variants of unknown significance (VUS) in familial Mediterranean fever (FMF) is common; however, their diagnostic value remains elusive, and the interpretation of multiple VUS remains difficult. Therefore, we examined FMF diagnosis-associated factors 1-year post-genetic testing in patients with only VUS and assessed the impact of multiple VUS on diagnosis and clinical features. A 1-year follow-up was conducted on patients clinically suspected of having FMF without confirmatory diagnosis owing to the presence of only VUS. Clinical features were compared between patients with a single VUS and those with multiple VUS among patients diagnosed with FMF. Among 261 patients followed up, 202 were diagnosed with FMF based on clinical judgment. No specific clinical symptoms or variant patterns at genetic testing were associated with diagnosis at 1 year. Multiple VUS was significantly and independently associated with a lower response to colchicine than single VUS among patients diagnosed with FMF. However, clinical symptoms showed no correlation with the number of VUS. In conclusion, predicting FMF diagnosis 1-year post-genetic testing in patients with only VUS remains challenging. Moreover, the impact of multiple VUS on FMF may be limited owing to the lack of correlation with clinical features, except colchicine response.

Variables for differential diagnosis of familial Mediterranean fever: multiple correspondence analysis of a large Japanese cohort.

OBJECTIVES: We investigated differential diagnoses that should be noted with familial Mediterranean fever (FMF) and useful variables for differentiation in a large Japanese cohort. METHODS: Patients aged ≥13 years who were clinically suspected of having FMF by Livneh criteria were studied 1 year after MEFV genetic testing. Patients ultimately diagnosed with other diseases were studied, and the association among each disease, patient characteristics, and clinical variables were analyzed using multiple correspondence analysis. RESULTS: In total, 504 patients were included in this study; 34 (6.7%) were diagnosed with a disease other than FMF. The most common diagnosis was Behçet's disease, followed by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, inflammatory bowel disease, myelodysplastic syndromes (MDS), and infectious diseases. Although none of the non-FMF patients had exon 10 variants, some responded to colchicine treatment. Multiple correspondence analysis suggested that atypical symptoms such as stomatitis were associated with Behçet's disease and PFAPA syndrome, whereas characteristic situations such as disease onset ≥40 years were associated with MDS and infectious diseases. CONCLUSION: Careful follow-ups and reanalysis of the diagnosis should be performed for patients with atypical findings and no exon 10 variants, even if their symptoms meet the clinical criteria for FMF.

Triggering factors for febrile attacks in Japanese patients with familial Mediterranean fever.

OBJECTIVES: We occasionally encounter patients with familial Mediterranean fever (FMF) whose attacks are triggered by specific factors; however, information regarding these factors is limited. Our purpose was to identify the factors that trigger febrile attacks in Japanese patients with FMF. METHODS: Our retrospective study included 372 patients (229 women, 143 men) with FMF, who were diagnosed between April 2007 and June 2018. We retrospectively investigated clinical features, genetic variants, and the factors that the patients perceived to have triggered their attacks. Patients completed a questionnaire that included the following triggering factors, anxiety, psychological stress, tiredness, excitement, environmental change, and menstruation. RESULTS: Of 372 patients, 180 (49.4%) reported some triggering factors. Psychological stress and tiredness were commonly reported factors regardless of sex; however, menstruation (39.7%, n=91) was the most commonly reported triggering factor in female patients with FMF. Menstrual-related patients had a younger age of onset and diagnosis, a higher frequency of peritonitis, and a higher rate of patients with endometriosis compared with the non-menstrual-related patients. CONCLUSIONS: Gaining an understanding of these triggering factors could help to reduce attacks and educate the patients. Clinicians may need to consider FMF for patients who have fever and serositis that occurs with every menstrual period.

Late-onset familial Mediterranean fever in Japan.

Objectives: Most patients with familial Mediterranean fever (FMF) have their first attack at age < 20 years. Information about late-onset (age ≥40 years) FMF is limited. We aimed to evaluate the demographic, clinical, and genetic characteristics of late-onset FMF patients in the Japanese population.Methods: We retrospectively analyzed 292 patients with FMF. Patients were divided into three groups according to age of disease onset: Group I, ≤19 years; Group II, 20-39 years; and Group III, ≥40 years.Results: Of 292 patients, 44 (15.1%) experienced their first attack at age ≥40 years. While high fever (97.7%) and arthritis (45.5%) were common symptoms in Group III patients, peritonitis (40.9%) and pleuritis (25.0%) were significantly lower than in other groups. The frequency of patients carrying p.M694I (18.2%), which is the most representative mutation in Japan, was significantly lower in Group III than in Group I. The response to colchicine therapy was good (95.1%) and similar in all groups.Conclusions: In Japan, more patients than expected had late-onset FMF. They had a milder form of disease, with less frequent peritonitis and pleuritis. The response to colchicine treatment was good. Clinicians should consider FMF for patients with unexplained recurrent febrile episodes, regardless of age.

Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis.

In order to elucidate the pathomechanism of ocular amyloid formation in a liver-transplanted patient with hereditary ATTR amyloidosis, we investigated detailed biochemical features of ocular amyloid. The patient was a 49-year-old woman with V30M transthyretin (TTR) variant (p.TTRV50M), who underwent ophthalmectomy due to corneal rupture 10 years after liver transplantation (LT). The amyloid was selectively isolated from several portions in intra- and extraocular tissues using a laser microdissection (LMD) system and analyzed by liquid chromatography-tandem mass spectrometry to determine the composition percentage of wild-type and variant TTR in the isolated amyloid. Biochemical analysis revealed that the amyloid consisted mainly of variant TTR in intraocular tissues with a percentage > 80%. On the contrary in the extraocular muscles, wild-type TTR was the main component of the amyloid with a percentage of ∼70%. Our data indicate that intraocular amyloid formation strongly depends on locally synthesized variant TTR and the contribution of wild-type TTR to amyloid formation is quite limited.

Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations.

INTRODUCTION: Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent self-limiting fever and serositis that mainly affects Mediterranean populations. Many patients with FMF have been reported in Japan due to increasing recognition of this condition and the availability of genetic analysis for the gene responsible, MEFV. The present study was performed to elucidate the clinical characteristics of Japanese FMF patients and to examine the precise genotype-phenotype correlation in a large cohort of Japanese FMF patients. METHODS: We analyzed the MEFV genotypes and clinical manifestations in 116 patients clinically diagnosed as having FMF and with at least one mutation. RESULTS: The most frequent mutation in Japanese patients was E148Q (40.2%), followed by M694I (21.0%), L110P (18.8%), P369S (5.4%), and R408Q (5.4%). In contrast, common mutations seen in Mediterranean patients, such as M694V, V726A, and M680I, were not detected in this population. The clinical features with M694I were associated with more severe clinical course compared to those seen with E148Q. P369S/R408Q showed variable phenotypes with regard to both clinical manifestations and severity. Patients with M694I showed a very favorable response to colchicine therapy, while those with P369S and R408Q did not. CONCLUSIONS: Clinical features and efficacy of treatment in Japanese FMF patients vary widely according to the specific MEFV gene mutation, and therefore genetic analysis should be performed for diagnosis in cases of Japanese FMF.

Steady turnover of amyloid fibril proteins in gastric mucosa after liver transplantation in familial amyloid polyneuropathy.

INTRODUCTION: Our previous study demonstrated marked regression of amyloid deposits in abdominal fat tissues of familial amyloid polyneuropathy (FAP) patients treated with liver transplantation (LT). To determine whether similar changes in deposited amyloid can also occur in other organs, we examined gastric mucosal amyloid before and after LT in FAP patients with ATTRV30M. METHODS: We histopathologically and biochemically investigated gastric mucosal amyloid before and after LT in six FAP patients with ATTRV30M.The amounts of amyloid deposits in biopsied gastric mucosa were determined by microscopy, and the proportion of wild-type transthyretin (TTR) in extracted amyloid fibril proteins was assayed by liquid chromatography-ion trap mass spectrometry. Similar examinations were also performed in 21 untreated FAP patients and 13 transplanted patients with ATTRV30M. RESULTS: The amount of deposited amyloid was not markedly different before and after LT in six patients. However, the composition ratios of wild-type TTR in gastric mucosal amyloid increased markedly from 20.0% ± 11.4% before LT to 43.2% ± 13.8% after LT. In addition, the ratio of wild-type TTR in all transplanted patients was significantly higher than that in untransplanted patients (72.7% ± 25.5%, 23.8% ± 14.3%, respectively). CONCLUSIONS: Our results showed that the components of amyloid fibril proteins in gastric mucosa of transplanted FAP patients are different from those in untreated patients: a significant portion of preexisting ATTRV30M-derived amyloid seemed to be replaced by wild-type TTR-derived amyloid postoperatively, indicating that continuous turnover of amyloid deposits can occur in all organs in transplanted FAP patients. It was also confirmed that wild-type TTR plays an important role in the pathogenesis of postoperative amyloid deposition in transplanted FAP patients.

Familial Mediterranean fever in Japan.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is prevalent in Mediterranean populations. While it is considered a rare disease in the rest of world, a significant number of FMF patients have been reported in East Asia, including Japan. Our aim was to determine the prevalence of FMF in Japan and elucidate the clinical and genetic features of Japanese patients. A primary nationwide survey of FMF was conducted between January and December 2009. Hospitals specializing in pediatrics and hospitals with pediatric, internal medicine, and rheumatology/allergy departments were asked to report all patients with FMF during the survey year. The estimated total number of Japanese FMF patients was 292 (95% confidence interval, 187-398 people). We evaluated the clinical and genetic profiles of Japanese patients from the data obtained in a secondary survey of 134 FMF patients. High-grade fever was observed in 95.5%, chest pain (pleuritis symptoms) in 36.9%, abdominal pain (peritonitis symptoms) in 62.7%, and arthritis in 31.3%. Of the patients profiled, 25.4% of patients experienced their first attack before 10 years of age, 37.3% in their teens, and 37.3% after age 20 years. Colchicine was effective in 91.8% of patients at a relatively low dose (mean dose, 0.89 ± 0.45 mg/d). AA amyloidosis was confirmed in 5 patients (3.7%). Of the 126 patients studied, 109 (86.5%) were positive for 1 or more genetic mutations and 17 (13.5%) had no mutation detected. Common Mediterranean fever gene (MEFV) mutations were E148Q/M694I (19.8%) and M694I/normal (12.7%). The differences in the prevalence of peritonitis, pleuritis, and a family history of FMF were statistically significant between FMF patients with MEFV exon 10 mutations compared with those without exon 10 mutations.In conclusion, a significant number of patients with FMF exist in Japan. Although Japanese patients with FMF are clinically or genetically different from Mediterranean patients, the delay in diagnosis is an issue that should be resolved.

Postmortem findings in a patient with cerebral amyloid angiopathy actively treated with corticosteroid.

We examined histopathological changes in cerebrovascular amyloid deposition in a patient with cerebral amyloid angiopathy receiving corticosteroid therapy. A 69-year-old female developed subacute onset cognitive decline, and magnetic resonance image (MRI) showed subarachnoid hemorrhage with leptomeningeal enhancement. She entered in an apathetic state due to communicating hydrocephalus and a ventricle-peritoneal (V-P) shunt operation was performed. Brain biopsy disclosed multiple cortical microhemorrhages and severe Congophilic angiopathy with positive Aß-immunoreactivity in most vessels. Inflammatory mononuclear cells surrounded a few severe amyloid-laden leptomeningeal vessels. She received high-dose corticosteroid, which was slowly tapered. She gradually recovered but finally died 1.5 years later with no recurrence of CAA-related hemorrhages. Postmortem examination of the brain showed multiple old microhemorrhages in the cortex and extensive degeneration of cerebral white matter. The cortical and leptomeningeal vascular walls showed a few Congophilic amyloid deposits, but small deposits with Aß-immunoreactivity were frequently seen. There was no infiltration of inflammatory cells in either leptomeninges or vascular walls. Electron microscopy revealed sparse aggregation of amyloid fibrils in significant numbers of vascular walls. Biochemical analysis disclosed that Aß1-40-immunoreactive amyloid protein fractions obtained from the patient's leptomeninges were very small in amount. Comparing the previous biopsy findings with those at autopsy, the total disappearance of the inflammatory cell infiltration and diminishing of the cerebrovascular amyloid deposits were noted.

Wild-type transthyretin significantly contributes to the formation of amyloid fibrils in familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met.

Wild-type transthyretin is inherently an amyloidogenic protein, but its contribution to the formation of amyloid fibrils remains unclear in familial amyloid polyneuropathy patients. Our aim in this study was to elucidate the ratio of wild-type transthyretin in amyloid deposits in familial amyloid polyneuropathy patients. Abdominal fat amyloid fibrils in 44 familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met who had not undergone liver transplantation were examined. The amyloid fibrils were extracted from abdominal fat tissues and the composition ratios of wild-type and variant transthyretin were analyzed with liquid chromatography tandem mass spectrometry. The amyloid fibrils in abdominal fat tissues were composed of not only variant but also wild-type transthyretin in most patients (mean ratio, 40.7% ± 27.5%). The composition ratios of wild-type transthyretin in patients older than 50 years were significantly higher than those in patients younger than 50 (50.7% ± 26.9% versus 30.7 ± 24.8%). Our results indicate that wild-type transthyretin significantly contributes to the formation of amyloid fibrils in familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met, and its contribution tends to increase in older patients, suggesting that aging may play an important role in wild-type transthyretin-derived amyloid fibril formation in familial amyloid polyneuropathy patients. This is the first report showing the relationship between wild-type transthyretin deposition and aging in familial amyloid polyneuropathy patients. In addition, wild-type transthyretin may be more strongly amyloidogenic than previously considered because it is detectable even in amyloid fibrils isolated from young familial amyloid polyneuropathy patients.

Periodic peritonitis due to familial Mediterranean fever in a patient with systemic lupus erythematosus.

We report a patient with systemic lupus erythematosus (SLE) who showed periodic peritonitis with spontaneous remission. She showed compound heterozygous mutations in the MEFV gene, leading to the diagnosis of familial Mediterranean fever (FMF). Oral colchicine successfully reduced the severity and frequency of her peritonitis. SLE occasionally manifests abdominal symptoms, but in cases with periodic peritonitis, associated FMF should be considered as a possible cause.

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy.

We report here two patients with amyloidogenic transthyretin (ATTR) Val30Met familial amyloid polyneuropathy (FAP) who developed numbness in both hands and were diagnosed as having bilateral carpal tunnel syndrome (CTS). In both patients systemic TTR amyloidosis consisting of polyneuropathy affecting both upper and lower limbs and/or autonomic dysfunction gradually appeared after surgery for CTS. Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30Met FAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms. It is also notable that both patients had no genealogical relationship with two Japanese endemic foci of this disease.

Clinical and genetic features of familial Mediterranean fever in Japan.

OBJECTIVE: Familial Mediterranean fever (FMF) is thought to be a rare disorder in Japan, and the clinical features of Japanese patients with FMF remain unclear. Our aim was to elucidate the clinical characteristics of FMF in Japanese patients. METHODS: We analyzed clinical and genetic data of 80 patients based on the results of a nationwide questionnaire survey and review of the literature. RESULTS: From clinical findings of 80 Japanese patients, high-grade fever was observed in 98.8%, chest attacks (pleuritis symptoms) in 61.2%, abdominal attacks (peritonitis symptoms) in 55.0%, and arthritis in 27.5%. Twenty-four percent of patients experienced their first attacks before 10 years of age, 40% in their teens, and 36% after age 20 years. Colchicine was effective in many patients at a relatively low dose (< 1.0 mg/day). AA amyloidosis was seen in only 1 patient. Common MEFV mutation patterns were E148Q/M694I (25.0%), M694I alone (17.5%), and L110P/E148Q/M694I (17.5%), and no patient carried the M694V mutation, the most common mutation in Mediterranean patients with FMF. CONCLUSION: A larger than expected number of patients with FMF exist in Japan, and the clinical presentation of Japanese FMF patients seems to be relatively milder than those of Mediterranean FMF patients. AA amyloidosis rarely occurs in Japanese patients, probably due to difference in patterns of the MEFV genotype between Japanese and Mediterranean patients.