Genotype-phenotype correlation in FMF patients: A “non classic” recessive autosomal or “atypical” dominant autosomal inheritance?

Procopio, V.; Manti, Sara; Bianco, Giovanna; Conti, Giovanni; Romeo, Andrea; Maimone, Francesco; Arrigo, Teresa; Cutrupi, Maria Concetta; Salpietro, Carmelo; Cuppari, Caterina

doi:10.1016/j.gene.2017.10.068

Cited by 37 publications

(25 citation statements)

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“…However, it is still unknown whether any other genetic, epigenetic, or environmental factors are present in patients with FMF with heterozygote MEFV mutations. [15][16][17] Our patient did not fulfill the Yalçinkaya et al 18 Amyloidosis is the most devastating complication of FMF. The appropriate colchicine treatment was suggested to decrease the rate of amyloidosis to 8.6% in a large cohort from Turkey.…”

Section: Figurementioning

confidence: 63%

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Renal Amyloidosis in Deficiency of Adenosine Deaminase 2: Successful Experience With Canakinumab

et al. 2018

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Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease that was firstly described in patients with early-onset strokes, livedo reticularis, and periodic fever resembling polyarteritis nodosa. In reported case series, researchers described highly variable manifestations, including autoimmunity, immunodeficiency, hepatosplenomegaly, pancytopenia, ichthyosiform rash, and arthritis, in patients with DADA2. A thirteen-year-old female patient who was born to consanguineous parents was admitted to our hospital with generalized edema and leg pain. A physical examination revealed splenomegaly and left knee arthritis. Nephrotic-range proteinuria and hypoalbuminemia were present, and a renal biopsy revealed amyloidosis. Despite the absence of periodic fever and livedo reticularis, our patient had suggestive features of DADA2, including low serum immunoglobulin G and immunoglobulin M levels, hepatosplenomegaly, and renal amyloidosis. We found a heterozygote Met694Val mutation in the Mediterranean fever gene and a novel homozygote Thr317Argfs*25 (c.950-950delCys) mutation in the cat eye chromosome region 1 gene. A functional analysis revealed absent plasma adenosine deaminase 2 activity. Canakinumab was administered because of unresponsive proteinuria despite 2 months of treatment with colchicine and methylprednisolone. Proteinuria improved after 7 doses of canakinumab. In conclusion, DADA2 should be considered in the differential diagnosis of renal amyloidosis, particularly in the absence of homozygote Mediterranean fever mutations. Although anti–tumor necrosis factor agents are widely offered in DADA2 treatment, we speculate that canakinumab may be an appropriate treatment of renal amyloidosis in DADA2.

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Section: Figurementioning

confidence: 63%

“…Patients with heterozygote MEFV mutations usually present with mild disease. 15,16 Heterozygote MEFV mutations lead to a 6.3 to 8.1 times elevated risk of FMF symptoms compared with nonmutations. Therefore, it was suggested that heterozygosity may PEDIATRICS Volume 142, number 5, November 2018 3…”

Section: Discussionmentioning

confidence: 99%

Renal Amyloidosis in Deficiency of Adenosine Deaminase 2: Successful Experience With Canakinumab

et al. 2018

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“…22,25,26 Moreover, the complicated genotype-phenotype correlation is further compounded by several doubts on mode of inheritance of the disease. 27 Because of the autosomal recessive nature, subjects with clinical FMF should have 2 mutations in both alleles. 8,9 However, a second allele has not been detected in almost 30% of the individuals affected by FMF, probably as result of a loss-or gain-of-function or of gene-dosage effect.…”

Section: Discussionmentioning

confidence: 99%

Lack of clear and univocal genotype‐phenotype correlation in familial Mediterranean fever patients: A systematic review

et al. 2018

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Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated; however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyze the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF.

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“…Moreover, with regards to genotypephenotype correlation, some data reported that patients carrying heterozygous mutations showed a more severe disease when compared both to subjects carrying homozygous and compound heterozygous mutations. 8 Patients carrying MEFV mutations can also display aspecific clinical manifestations as well as significant changes in disease behavior over time.…”

Section: Introductionmentioning

confidence: 99%

<p>Neurological Manifestations in Familial Mediterranean Fever: a Genotype-Phenotype Correlation Study</p>

Salehzadeh

Ahad

Motezarre

et al. 2020

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Background and Aims: Familial Mediterranean Fever (FMF) is a periodic autoinflammatory disease with an autosomal recessive hereditary pattern. The aim of this study is to explain the spectrum of possible neurological manifestations and its genotypephenotype correlation in patients with familial Mediterranean fever. Methods: In this case series study, data of 311 FMF patients at the FMF Registration Center in Iran (http://www.fmfiran.ir/) was studied. Patient's information was entered into a researcher designed questionnaire. Data were analyzed by SPSS software. Results: The mean age of the 181 male and 130 female patients was 23.01 years, ranging from 3-78 years old. Twelve common MEFV gene analyses were performed in 311 patients, with mutated results in 187 (60.1%) patients. The most common neurological manifestations were headache in 47.26%; 64.1% of those were persistent and 35.9% had a recurrent nature. Other neurological manifestations were vertigo (83 patients, 26.7%), paresthesia (72 patients, 23.2%), tremor (53 patients, 17%), disorientation (40 patients, 12.9%), breath-holding (23 patients, 7.4%), migraine (19 patients, 6.1%), syncope (8 patients, 2.6%), epilepsy (7 patients, 2.3%), febrile seizure (4 patients, 1%), and ataxia (5 patients, 1.6%). There were no cases of stroke or metabolic disorders among these patients. Conclusion: The prevalence of epilepsy among FMF patients was significantly higher than the general population. FMF patients with negative results for MEFV gene mutations had significant frequency of headache, paresthesia, breath-holding, and ataxia.

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Genotype-phenotype correlation in FMF patients: A “non classic” recessive autosomal or “atypical” dominant autosomal inheritance?

Cited by 37 publications

References 30 publications

Renal Amyloidosis in Deficiency of Adenosine Deaminase 2: Successful Experience With Canakinumab

Renal Amyloidosis in Deficiency of Adenosine Deaminase 2: Successful Experience With Canakinumab

Lack of clear and univocal genotype‐phenotype correlation in familial Mediterranean fever patients: A systematic review

<p>Neurological Manifestations in Familial Mediterranean Fever: a Genotype-Phenotype Correlation Study</p>

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