Inherited CD59 deficiency, where neurology and genetics intertwine.

OBJECTIVES: To describe the clinical phenotype of eight children diagnosed with CD59 deficiency and their ultimate neurological outcome. METHODS: The data of our cases were extensively reviewed both clinical and ancillary tests; investigations included: neuroimaging, neurophysiological studies, and laboratory tests. RESULTS: All patients presented during early infancy with Guillain-Barre syndrome later they suffered repeated relapses leading to the diagnosis of chronic axonal neuropathy. Recurrent stroke and acute necrotizing encephalopathy were described, 2 patients in each group. One girl developed acute disseminated encephalomyelitis while one boy developed acute transverse myelitis. Overt hemolytic anemia requiring blood transfusion reported in six patients. CONCLUSION: Inherited CD59 deficiency is an autosomal recessive disorder which can have devastating neurological consequences. First line immunotherapy including intravenous immunoglobin, corticosteroids, and plasma exchange may have transient beneficial effect. Reports of targeted therapy with eculizumab might be lifesaving. Genetic counseling is crucial.

Is there a role for HLA-G in the induction of regulatory T cells during the maintenance of a healthy pregnancy?

PROBLEM: Pregnancy remains an immune challenge for the uterus that has to adapt to a semi-allogeneic fetus using various regulatory mechanisms. Both HLA-G and regulatory T cells (CD4+  CD25+  FOXP3+  Tregs ) are upregulated in successful pregnancy, but not in abortion. It is unclear if HLA-G plays a role in the upregulation of regulatory cells. METHOD OF STUDY: We measured the level of both sHLA-G and Treg  cells in the blood of healthy pregnant multigravida, unexplained recurrent spontaneous abortions (URSA) and healthy non-pregnant and nulliparous females. We cultured peripheral blood lymphocytes of healthy non-pregnant multigravida females who never had an abortion with lymphocytes of their partners at ratio of 1:1, with and without sHLA-G to detect changes in number of Treg  cells, or relevant cytokines. RESULTS: Soluble HLA-G concentrations and Treg  cells percentage were significantly lower in women with URSA as compared to healthy pregnant multigravida women and were comparable to healthy non-pregnant nulliparous women. Percentage of Tregs  increased between zero time and mixed lymphocyte cultures (MLC) in both cultures with and without recombinant sHLA-G but no significant difference between the two cultures. When stimulated with sHLA-G the mean extracellular IL-10 concentration was unchanged, while the mean INF-γ concentration was slightly higher with no significant difference. Intracellular TGF-ß was higher in CD4+  cells after incubation with sHLA-G. CONCLUSION: The results of this study are consistent with previous studies on the role of sHLA-G and Treg  cells in inducing immune-tolerance in pregnancy. The results also suggest a possible role for HLA-G in the enrichment of Treg  cells.

Genetic combination of angiotensin-converting enzyme with methylene tetrahydrofolate reductase polymorphisms and the risk of type 2 diabetes mellitus in Bahrain.

INTRODUCTION: Bahrain has a high prevalence of type 2 diabetes mellitus (T2DM). Previously, Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM in Bahrainis. The relationship between the disease progression in Bahraini T2DM population and the genetic polymorphism of methylene-tetrahydrofolate-reductase (MTHFR) C677T is still under investigation. AIM: The current study investigated the distribution of MTHFR C677T gene polymorphism among Bahraini T2DM patients and examined the interaction between ACE I/D and MTHFR C677T polymorphisms on the risk of developing T2DM and its long-term complications. MATERIALS AND METHODS: Polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) were used to test for the presence of ACE I/D and MTHFR C677T polymorphisms in 171 patients with T2DM compared to 188 healthy (non-diabetic) age-matched control subjects from Bahrain. RESULTS: The incidence of the DD genotype and D allele of the ACE gene was high among Bahraini T2DM patients. MTHFR allele and genotype frequencies did not differ between patients and controls. No significant relationship was identified between the combinations of ACE I/D and MTHFR C677T polymorphisms with T2DM. CONCLUSIONS: The results clearly showed an association of the ACE I/D polymorphism with the progression of T2DM, but when it interacts with MTHFR polymorphism no influence was detected on the increased risk of T2DM.

Immunological aspects of biopsy-proven lupus nephritis in Bahraini patients with systemic lupus erythematosus.

Lupus nephritis (LN) is a frequent and potentially serious complication of systemic lupus erythematosus (SLE) that may influence morbidity and mortality. Immunological investigations are aiding tools to the kidney biopsy findings in early diagnosis, in addition to monitoring the effect of therapy. The aim of the present study is to highlight the role of these investigations in a group of Bahraini patients and to determine whether there is any positive association between these findings and the outcome of LN. The current study is a retrospective case-control study of randomly selected 88 SLE patients, 44 with biopsy-proven LN and 44 without, acting as controls. All renal biopsies performed during the period from 1996 to 2012 were classified according to the World Health Organization classification. Immunological investigations analyzed are: Antinuclear antibodies (ANA), anti-ds DNA, anti-ENA, anti-cardiolipin antibodies (abs) and complement components C3, C4. Human leukocyte antigen (HLA) typing class II was performed on selected cases. All patients had positive ANA (100%). A significantly high frequency of anti-Smith abs among the non-LN group (43.18%) compared with the LN group (18.18%) was found (P <0.001). On the other hand, the anti-Ro/SSA abs in the non-LN group was also found at a statistically higher frequency (20.45%) compared with that in the LN group (4.54%) (P <0.01). Anti-ds-DNA abs were found to be higher in the LN group (84.09%) compared with the non-LN group (70.45%), but the difference was not statistically significant (P = 0.082). There was a positive association of ANA positivity and low C3 and or C4 in the studied group. In our study, 88.2% of the HLA typed patients had HLADR2, DR3 or both. In conclusion, in our Arabic Bahraini SLE patients, the presence of anti-Smith, anti-Ro/SSA and anti-RNP antibodies and the absence of anti-dsDNA antibodies are independent predictive markers for renal involvement. However, more prospective studies with a larger number of patients are essential to ascertain those findings.

Genotypes and allele frequencies of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism among Bahraini population with type 2 diabetes mellitus and related diseases.

Insertion/deletion (I/D) polymorphism, of a 287-bp Alu repetitive sequence in intron 16 of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with different types of diseases and has been widely investigated in different populations with different ethnic origins. Various reports were published suggesting inter-ethnic variations in the frequency of allelic forms of the ACE gene. The goal of this study was to test the distribution of alleles and the different genotypes of ACE (I/D) polymorphism in Bahraini subjects and compare the results with those obtained from other population studies. The Bahraini population is an Arabic peninsula population with a high prevalence of T2DM and hypertension. A total of 560 unrelated Bahraini individuals were recruited in this study and the presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was done by PCR-based assays and the presence or absence of the genotypes were analyzed by the gel electrophoresis. The distribution of II, ID, and DD genotypes showed differences among Bahraini subjects, and the frequency of the D allele was significantly (P < 0.05) higher in the studied group. The results obtained for the D allele are consistent with those obtained from previous studies among Arabs, Africans, and Caucasians, but differs significantly (P < 0.05) from those in Japanese and Chinese, thus proving the ethnic variation in the distribution of the ACE alleles in different populations.

Angiotensin-converting enzyme gene polymorphisms and T2DM in a case-control association study of the Bahraini population.

Bahrain has one of the highest incidence rates of type 2 diabetes mellitus (T2DM). Development of diabetic nephropathy (DN) as a complication was noticed in some patients while absent in others. This interesting observation raises the role of certain genetic risk factors for the development of DN. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM. While some patients have predisposition to DN in the population, others have negative association. The present case-control association study was designed to investigate the association of ACE I/D polymorphism in T2DM patients in Bahrain especially in those who developed DN. A total of 360 T2DM patients (110 with DN and 250 without DN) and 360 healthy (non-diabetic) age-matched subjects were recruited for this study for comparison. The presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was investigated using PCR-gel electrophoresis. The results show that the distribution of the homozygote DD genotype of the ACE gene was high among Bahraini T2DM patients compared to the healthy non-diabetic subjects. In addition, the distribution of the deletion (D) allele was high among Bahraini T2DM patients with DN when compared to the healthy non-diabetic subjects. However, there was no significant difference in the distribution of ACE I/D allele and genotypes between DN patients when compared to those T2DM patients without DN. The results obtained in this study are in closely agreement with some previous reports which show a strong association of ACE polymorphism with T2DM patients, yet not a risk factor for development of DN.

Juvenile systemic lupus erythematosus in Bahrain. A tertiary referral center experience.

OBJECTIVE: To analyze the clinical and serological features of children with systemic lupus erythematosus (SLE) in a major referral center in Bahrain and to assess the comorbidity, its morbidity, and mortality. METHODS: We retrospectively reviewed the medical charts of children with SLE treated in the Pediatric Rheumatology Clinic at Salmaniya Medical Complex, Kingdom of Bahrain from 1998 to 2007. The ethical approval for the study was obtained from the Research Health Committee, Ministry of Health, Kingdom of Bahrain. RESULTS: Thirty-two children with SLE were identified. Thirty-one (96.8%) were Bahrainis. The mean age was 14 +/- 4 years, the mean age of disease onset was 9 +/- 4 years and the mean duration of illness was 7 +/- 5 years. The female to male ratio was 2.5:1. Twenty-five percent of the cases had relatives with SLE. Eight patients (25%) had sickle cell anemia (SCA). Systems involved were as follows: skin (93%), kidney (81%), musculoskeletal system (65%), blood (56%), gastrointestinal tract (31%), central nervous system (31%), lungs and cardiovascular system (21%). Serological tests showed: positive antinuclear antibody in 90.6%, and positive anti double-stranded DNA antibody in 65%. The morbidity rate was 21% (n=7) due to complication and 12.5% (n=4) died. CONCLUSION: Clinical and serological results were comparable with the international studies. Nephritis was the primary cause of morbidity and mortality. Coexistence of SLE with SCA was also reported in other studies and may need further investigation with genetic studies.

Microbiological infections in HIV positive Bahraini patients with low CD4+ T-lymphocyte count.

The correlation of CD4+ T-lymphocyte count and the distribution of pathogenic or opportunistic microbial infection most commonly found in HIV positive individuals differ from one area to the other. The present study reports such findings in 67 HIV positive Bahraini patients in the period May 1997 to Nov. 1998. CD4+ T-lymphocyte count was measured using flow cytometry. Bacterial and fungal cultures were performed. Serological diagnosis was performed when indicated. Viral study was done serologically. The distribution of CD4+ T-lymphocyte count in the studied group was: 21 patients (31.3%) less than 100 cells/microl, 5 patients (7.5%) 100-200 cells/microl, 25 patients (37.3%) 201-500 cells/microl and 16 patients (23.9%) with count more than 500 cells/microl. Among patients with low CD4 count (less than 100 cells/microl) (n=21), microbial infections varied from fungal infections 66%, bacterial infections 57% and viral infections 4.8%. Bacterial infections included Salmonellosis (14.3%), Staphylococcus epidermidis (14.3%), Pseudomonas aeruginosa (9.5%), H. influenzae (9.5%), Legionellosis (4.8%) and E. coli (4.8%). Fungal infection included Candida albicans (52.4%), Pneumocystis carinii (9.5%), Cryptococcus neoformans (4.8%). Viral infection included H. simplex to (4.8%). Fungal infections were the highest common infection in thus study. The most common microbial infection was Candida albicans. P. carinii and Cryptococcus neoformans were less common than found in other studies world wide.