Genotype-Phenotype Correlations in CYP1B1-Associated Primary Congenital Glaucoma Patients Representing Two Large Cohorts from India and Brazil.

BACKGROUND: Primary congenital glaucoma (PCG), occurs due to the developmental defects in the trabecular meshwork and anterior chamber angle in children. PCG exhibits genetic heterogeneity and the CYP1B1 gene has been widely implicated worldwide. Despite the diverse mutation spectra, the clinical implications of these mutations are yet unclear. The present study attempted to delineate the clinical profile of PCG in the background of CYP1B1 mutations from a large cohort of 901 subjects from India (n=601) and Brazil (n=300). METHODS: Genotype-phenotype correlations was undertaken on clinically well characterized PCG cases from India (n=301) and Brazil (n=150) to assess the contributions of CYP1B1 mutation on a set of demographic and clinical parameters. The demographic (gender, and history of consanguinity) and quantitative clinical (presenting intraocular pressure [IOP] and corneal diameter [CD]) parameters were considered as binary and continuous variables, respectively, for PCG patients in the background of the overall mutation spectra and also with respect to the prevalent mutations in India (R368H) and Brazil (4340delG). All these variables were fitted in a multivariate logistic regression model using the Akaike Information Criterion (AIC) to estimate the adjusted odds ratio (OR) using the R software (version 2.14.1). RESULTS: The overall mutation spectrum were similar across the Indian and Brazilian PCG cases, despite significantly higher number of homozygous mutations in the former (p=0.024) and compound heterozygous mutations in the later (p=0.012). A wide allelic heterogeneity was observed and only 6 mutations were infrequently shared between these two populations. The adjusted ORs for the binary (demographic) and continuous (clinical) variables did not indicate any susceptibility to the observed mutations (p>0.05). CONCLUSIONS: The present study demonstrated a lack of genotype-phenotype correlation of the demographic and clinical traits to CYP1B1 mutations in PCG at presentation. However, the susceptibility of these mutations to the long-term progression of these traits are yet to be deciphered.

Combined 12-month WHO/MDT MB regimen and Mycobacterium w. vaccine in multibacillary leprosy: a follow-up of 136 patients

A total of 136 patients with BI > or = 2 having been followed up for at least 2 years or more were included in the analyses. Seventy-seven out of 136 patients had completed three years follow up. All patients were given WHO/MDT MB regimen for 12 months and additionally 4 doses of Mycobacterium w. vaccine at 3-month intervals. The age of the patients varied from 6 to 77 years (mean 34 +/- 11.3 years) and they had the disease varying from 3 months to 7 years (mean = 1.9 +/- 1.4 years). The mean of the BI before starting treatment was 3.6 +/- 1.3. At the end of 2 years follow-up, a total of 54 patients out of the 136 (39.7%) had become smear-negative. A larger proportion of patients, 39/46 (84.8%) with BI of 4 had become smear-negative at the end of 2 years. Out of the 77 patients who were available for follow up at 3 years, 30/33 (90.9%) patients with BI of 4, respectively, had attained smear negativity. Reactions occurred more frequently after 6 months of therapy and over a period of time their frequency gradually decreased, however, they continued to occur even two years after RFT. During the course of MDT and thereafter in follow up 4.6% and 1.3% of the patients developed new deformities or an increase in the existing grade of deformities, respectively. Three relapses (2 in LL and 1 in BL) occurred in patients having initial BI of > 4. One patient relapsed in the second year and the other two relapsed in the third year of follow up and were successfully treated with reintroduction of the same MDT MB regimen. Local ulceration healing with scar formation and regional lymphadenopathy were the only local reactions to the vaccine seen in 47/136 (34.5%) patients. All the patients showed histopathological improvement in the form of a gradual reduction of granuloma fraction. Although the results of this limited period follow up are satisfactory, a long-term follow-up in larger number of patients will settle the issue of safety and efficacy of shortened MDT MB regimen and the place of immunotherapy with M. w. vaccine in multibacillary patients.

Impact of combined Mycobacterium w vaccine and 1 year of MDT on multibacillary leprosy patients

A total of 20 bacteriologically positive multibacillary (MB) leprosy patients older than 18 years of age with a bacterial index (BI) of 2+ or greater were given standard World Health Organization multiple drug therapy (MDT-MB) for 12 consecutive months plus four intradermal doses of Mycobacterium w vaccine at 3 monthly intervals (Study group). Twenty age-matched MB patients were given WHO/MDT alone (Control group). The patients of both groups were followed up for 1 year. Improvements in the patients were periodically monitored by clinical (Ramu's score), bacteriological (SSS), histopathological (skin biopsy) and immunological (lepromin conversion) parameters. Study group patients showed more significant improvements in all parameters except for lepromin conversion compared to patients in the Control group. The incidence of type 1 reaction was more in the Study group (30% vs 10%), while the incidence of type 2 reaction was more in the Control group (25% vs 15%). Neuritis associated with reactions was seen more often in the Control group compared to the Study group (20% vs 10%). The addition of Mycobacterium w vaccine as an adjunct to the 1-year WHO/MDT regimen appears to be significantly more beneficial in MB leprosy patients with a high initial BI compared to WHO/MDT given alone. Studies on larger numbers of patients with extended follow up will be in order.

Computed tomographic study of paranasal sinuses in lepromatopus leprosy

Twenty patients (18 males, 2 females) with lepromatous leprosy and 10 age- and sex-matched controls were subjected to computed tomographic (CT) scans of the paranasal sinuses (PNS). The mean bacterial (BI) and morphological indexes were 3.4+ and 1%, respectively. Nasal symptoms were present in nine (45%) patients; 15 (75%) out of 20 patients showed significant abnormalities on CT scans of the PNS compared to none of the 10 controls. The maxillary and ethmoid sinuses were affected in 11 (55%) patients each, followed by the sphenoid sinus in four (20%) patients. Frontal sinus involvement was least frequent, only one (5%) patient showed CT changes. Mucosal thickening was the most common finding followed by soft-tissue densities and, rarely, a fluid level was seen in the PNS. Involvement of the PNS correlated with a high BI of 4+ or more (75% vs 37.5%). Paranasal sinus involvement is an integral part of lepromatous leprosy since histological involvement was present even when the CT scan was apparently normal.