Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in the SAMD12 gene.

Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy is a non-progressive disorder characterized by distal tremors. Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported globally with different genetic predispositions of autosomal dominant inheritance with a high degree of penetrance. In south India, Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported in a large cohort of 48 families, in which the genetic defect was not identified. This report pertains to the whole-genome analysis of four individuals followed by repeat-primed PCR for 102 patients from a familial cohort of 325 individuals. All the patients underwent extensive clinical evaluation including neuropsychological examinations. The whole-genome sequencing was done for two affected and two unaffected individuals, belonging to two different families. The whole-genome sequencing analysis revealed the repeat expansion of TTTTA and TTTCA in intron 4 of the SAMD12 gene located on chromosome 8 in the patients affected with Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy, whereas the unaffected family members were negative for the similar expansion. Further, the repeat-primed PCR analysis of 102 patients showed the expansion of the TTTCA repeats in the intron 4 of SAMD12 gene. All patients registered for this study belong to a single community called "Nadar" whose nativity is confined to the southern districts of India, with reported unique genetic characteristics. This is the largest and most comprehensive single report on clinically and genetically characterized Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy patients belonging to a unique ethnic group worldwide.

Altered mucins and aquaporins indicate dry eye outcome in patients undergoing Vitreo-retinal surgery.

Vitreo-retinal (VR) surgeries induce conjunctival changes. However, there are no study reports regarding prevalence and severity of dry eye after these surgeries. This study evaluated dry eye outcome after VR surgery. Patients undergoing VR surgery classified as scleral buckle and microincision vitrectomy surgery (n = 44, mean age: 56.09±10.2 years) were recruited. Dry eye evaluation was done before and 8 weeks after surgery (2 weeks after omitting topical eye drops). Conjunctival imprint cytology for goblet cell count and tear Mucin 5AC (MUC5AC) protein estimation was done. Gene expressions of MUC5AC, MUC4, MUC16, Aquaporin 4 (AQP4) and AQP5 were analyzed in the conjunctival imprint cells by qPCR. None of the patients exhibited clinical signs of dry eye after VR surgery. But the conjunctival goblet cell density (GCD) was significantly lowered post-VR surgery (63% cases, **p = 0.012) with no alterations in the tear MUC5AC protein. Post-VR surgery, the conjunctival cell gene expression of MUC4, MUC16 and AQP4 were significantly increased (*p = 0.025, *p = 0.05 and *p = 0.02 respectively) and AQP5 was significantly lowered (*p = 0.037), with no change in MUC5AC expression. Tear cytokines were significantly increased post-VR surgery (anti-inflammatory: IL1RA, IL4, IL5, IL9, FGF; PDGFbb and pro-inflammatory: IL2, IL6, IL15, GMCSF and IFNg). Though clinical signs of dry eye were not observed after VR surgery, ocular surface changes in the form of reduced GCD, altered MUC5AC, MUC4, MUC16, AQP4, AQP5 and cytokines are suggestive of dry eye outcome at the molecular level especially inpatients aged above 51 years, especially female gender and those who are diabetic.

Prospective analysis of the predictors of glaucoma following surgery for congenital and infantile cataract.

PURPOSE: A prospective longitudinal cohort study was performed to assess the incidence of and risk factors for the development of glaucoma following surgery for congenital/infantile cataract. METHODS: One hundred and one eyes of one hundred and one children, ≤12 years of age who had follow-up of ≥24 months were included. Group I included those who underwent surgery using an anterior approach, group II included those who underwent surgery using a posterior approach, and group III included those who underwent surgery using an anterior approach along with foldable intraocular lens implantation. Standard definitions for glaucoma and glaucoma suspect were used. The Cox proportional hazard model was used to analyze risk factors for glaucoma. RESULTS: Group I: 30 eyes (29.7%); group II: 11 eyes (10.9%); group III 60 eyes (59.4%). The incidence of glaucoma + glaucoma suspect was 7.9% (95% CL: 2.6, 13.2%) in the entire group. The incidence in group I was 16.7% (95% CL 3%, 30%), in group II was 18.2% (95% CL: 0, 41%) and in group III was 1.7% (95% CL: 0, 4.9%). Gonioscopy revealed high iris insertion with grade I (modified Shaffer grading) in one eye each in the glaucoma and glaucoma suspect group and open angles in the rest. Age at surgery of ≤3 months (HR: 6.6, 95% CL: 1.4, 30.6, p = 0.01) was found to be a significant risk factor within the aphakic group. CONCLUSIONS: Younger age at the time of surgery was the only identifiable risk factor for glaucoma.

Serum Paraoxonase activity in relation to lipid profile in Age-related Macular Degeneration patients.

Age-related Macular Degeneration (AMD) is a multifactorial disease causing visual impairment in old age. Oxidative stress is one of the main contributors for the disease progression. Paraoxonase (PON), a HDL-resident antioxidant enzyme which removes oxidized low density lipoprotein (oxLDL), which is not studied much in AMD. This study assesses the PON activities in relation to the lipid status and genetic variants in AMD patients. In this prospective case-control study, a total of 48 AMD patients and 30 unrelated healthy controls were recruited. The serum oxLDL and Plasma Homocysteine (Hcy) levels were estimated by ELISA. Plasma Homocysteine thiolactone (HCTL) was estimated by HPLC. Serum PON activities were estimated by spectrophotometry. PON gene expression was assessed by qPCR and protein expression by western blot, immunofluorescence and FACS analysis. Two known single nucleotide polymorphisms (SNPs) in the coding region of PON1, Q192R and L55M variants were checked in the AMD patients and controls and their association with PON activity and lipid levels were determined. Serum paraoxonase (PONase) and thiolactonase (PON-HCTLase) activities were significantly elevated in AMD patients than in controls apart from elevated serum levels of total cholesterol (TC), triglycerides (TG), oxLDL. While serum LDL levels in AMD patients correlate positively with PON HCTLase activity, the serum high density lipoprotein (HDL) correlates with both PONase and PON-HCTLase activities. However, multiple regression analysis showed that, amongst the parameters, only serum TG was a significant risk factor for AMD, after adjusting for demographic parameters as well as cataract. PON2 was significantly increased at the level of gene expression (p = 0.03) as seen in circulating peripheral blood mononuclear cells (PBMC) of AMD patients possibly mediated by the transcription factor SP1, that showed 2-fold increase. PON1 and 2 protein expressions also showed significant increase in the PBMC of AMD patients. At serum level, PON1 protein was significantly increased in AMD patients. Cholesterol transporters such as CD36, SR-B1 and ABCA1 gene expressions were also found to be higher (1.5, 1.9 and 2.4-fold respectively) in AMD, though not statistically significant. While the wet AMD (CNV) was found to be associated with increase in oxLDL and serum PONase activity, the dry AMD was associated with increased HDL and serum PON-HCTLase activity. The genotype and allele frequencies of Q192R & L55M were not significantly different between AMD patients and controls. However, altered lipid status and PON activities were associated with the genotype in AMD patients. A higher enzyme activity was observed for the RR genotype of Q192R in the cohort, irrespective of case and control. Thus the PON genotype and phenotype seem to play a role in the pathogenesis of AMD.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) in a unique south Indian community.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME)/familial adult onset myoclonic epilepsy (FAME) is a nonprogressive disorder characterized by (1) distal tremors that are usually precipitated by posture and action; (2) stimulus-sensitive myoclonus that is predominantly seen in the upper limb and is precipitated by photic stimuli, fatigue, emotional stress, and sleep deprivation; (3) seizures that were predominantly of the generalized tonic-clonic type that showed significant response to antiepileptic drugs (AEDs). ADCME has been reported worldwide with different genetic loci in Japanese families (8q23.3-q24.1), Italian families (2p11.1-q12.2), a French family (5p15.3.1-p15.1), and a Thai family (3q26.32-q28). ADCME has not been reported in South India and is still not recognized as an independent entity under the International League Against Epilepsy (ILAE). We report 241 patients with ADCME identified belonging to 48 families. The 48 families are domiciled in two southern districts of Tamilnadu in India, belonging to a community called "Nadar" whose nativity is confined to these southern districts, with reported unique genetic characteristics. This study is reported for the presentation of this rare disease in a unique ethnic group, and is the largest single report on ADCME worldwide.