الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 120 |  |  |
| | | from | 120 | | |
Abstract
FMF is an autosomal recessive hereditary disease and occurs as a result of point mutations (Single substitutions) in the Mediterranean Fever (MEFV) gene on the short arm of chromosome
16. This gene encodes a protein called pyrin, which is essentially responsible for the regulation of apoptosis, inflammation, and cytokines, and is mainly expressed in neutrophils, eosinophils, dendritic cells, and fibroblasts. It is presumed that the mutated pyrin molecule is theoretically not able to suppress, and thus the inflammatory response develops.
To date, more than 310 MEFV sequence variants have been reported. Most are located in exon 10, including the most common M694V, V726A, M680I and M694I mutations. The wide clinical variability in FMF is partly explained by genetic heterogeneity.
A cross-sectional study on forty patients who were diagnosed primarily on clinical basis to have FMF then to be genetically tested for the most common 12 mutations in the MEFV gene in the Genetic Research Unit, Ain Shams University(GRU-ASUH). They were 21 male and 19 female with an age ranging from 3 years to 25 years, their median age was 13.0 years.
Each and every patient was subjected to full history taking, clinical examination and investigations:
• A blood sample was withdrawn from each FMF patient for Molecular genetics study using DNA isolation followed by PCR amplification followed by hybridization (This assay covers 12 mutations in the MEFV gene: E148Q, P369S, F479L, M680I (G/C), M680I (G/A), I692deI, M694V, M691V, K695R, V726A, A744S, R761H).
• Erythrocyte Sedimentation Rate (ESR) of patients’ blood samples.
• C-Reactive Protein
• Fibrinogen
• Amyloid A
• Leukocyte count(TLC)
• Interleukin levels of (IL-10) and (IL-1b)
Results were collected, statistically analyzed and depicted as follows:
1. The minimum age of FMF patient is three years old, meanwhile the maximum is twenty- five years with a median age of 13.0 years. The mean duration level of the disease is 9.45±
3.76 years.
2. Among 40 FMF patients there were 70.0% with single mutation, followed by 27.5% with double mutation, and 2.5% with triple mutation.
3. Mutations were classified into 72.5% of the FMF patients were heterozygous which is the majority, followed by 27.5% were homozygous and 30.0% were compound heterozygous.
4. M694I, E148Q, V726A, M680I and M694V are the most common mutations of MEFV gene and that R761H, F479L and I692deI mutations did not appear in our study population.
5. The common heterozygous mutations observed in this study were E148Q and M694I. Meanwhile, the common homozygous mutations were M694I and M680I. The common compound mutations were M694I / V726A and M680I / V726A.
6. The percentage frequency of family history among the common FMF mutations was 57.5%.
7. The most common presenting symptoms among FMF patients were fever, abdominal pain, and Arthritis/Arthralgia (95.0%, 82.5% and 75.0% respectively). Meanwhile, erysipelas like erythema was the least common (5.0%).
8. Abdominal pain, arthralgia and combined presentations are significantly higher in heterozygous than in compound. On the other hand, chest pain was significantly higher in compound than heterozygous of E148Q mutation.
9. The combined and abdominal pain phenotyping were significantly high (100% and 100% respectively) in M694I mutation in comparison to the other mutations
10. The most sensitive independent variables (symptomatology) that predict the dependent variable (mutations) are vomiting for V726A, Weakness, fatigue & Myalgia for M680I, Arthralgia & Vomiting for E148Q and Vomiting for M694I.
11. According to the severity of FMF, our results showed that moderate class represents that intermediate is the commonest group 50.0% followed by mild class which represents 35.0% and severe class which represents 15.0%.
12. The ESR results in the majority of FMF patients represented higher than the range 20mm/hr with the highest percentage 72.0% followed by 20.0% and the minority was representing 7.5% with less than 6mm/hr.
13. Regarding to the TLC count, Majority of patients TLC count 11-≤50 represents 87.0% and only 12.5% count >50 with severe inflammation.
14. FMF patients were found to be +ve (>6 up to 96 mg/l) with CRP represent 77.5% and –ve for 22.5% which is highly significant difference.
15. According to the level of fibrinogen (mg/dl), Majority of patients value 77.5% with very high level ≥400mg/dl with significant difference followed by eight patients represent (20.0%) into value (100≥ 400mg/dl). While only 1 patient represents 2.5% (<100mg/dl).
16. Our study showed that 65.0% of FMF patients with Serum Amyloid A protein level from 30≥200 mg/L followed by 35.0% with protein level more than 200mg/L which little significant different is observed.
17. A highly significant differences were noted between the FMF patients and non-FMF groups regarding the CRP levels (mg/dl), Fibrinogen (mg/L), Amyloid A protein (mg/L) as well as ESR (mm/hrs.) measurements at baseline (p<0.001*) by the values 633.64%, 303.82%, 1258.78%, and 500.2% postoperatively. While no significant difference was noted between the two groups regarding the total leukocytes count (cells/L) measurements (p=0.093) by 7.9%.
18. The results revealed that serum (IL-10) levels for FMF group compared with control group showed no significant change by 17%, while serum (IL-1b) levels for FMF group compared with control group showed highly significant increase by 100.1% (p<0.001).
19. TLC, CRP, and Fibrinogen were not significantly changed between M694I and E148Q mutations, on the other hand, Amyloid A protein was moderate significantly increase (P<0.01) in E184Q mutation compared with M694I mutation with 27.7% while a high significant increase in ESR in M694I mutation (P<0.001) compared with E184Q mutation with 172.8%.
20. There is no obvious correlation as a whole was detected but through studying with particular mutation, the correlation was recorded in both major mutations but there is a positive correlation between IL-10 and IL-1b in M1964I and positive correlation between CRP and Fibrinogen in E184Q.
21. It is clear that Amyloid A protein is more sensitive for M694 Mutation, On the other side, E184Q mutation showed that ESR was more sensitive for this kind of mutation.
Conclusion and recommendations
Conclusion & Recommendations
from the course of this study we concluded that:
1. FMF is not an uncommon disease in the Egyptian population and unfortunately there is lack of awareness from the two sides, doctors, and patients.
2. FMF in our study population did show great diversity in terms of age of onset, presentation, severity, and response to treatment. This could be attributed to the heterogeneity of the
disease; multiplicity of the mutations and that every mutation could present as heterozygous, homozygous, and compound heterozygous.
3. Periodicity is the mainstay for diagnosing FMF even in mono-symptomatic presentation.
Our recommendations:
1. Follow-up of FMF patients to assess the course and progression of the disease.
2. Colchicine is the corner stone treatment for almost all patients with FMF to guard against the development of amyloidosis.
3. 24-hour urine testing for Amyloidosis for early diagnosis of renal affection and follow-up of treatment response.
4. Larger scale population screening and sequencing of the whole MEFV gene searching for new and uncommon mutations.
5. Larger scale evaluation of more clinical and serological biomarkers such as Cytokines.
6. We need to raise awareness and educate among doctors and general population for early diagnosis and proper management.