RESUMEN

BACKGROUND AND OBJECTIVES: To describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod. METHODS: The Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period. RESULTS: A total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data. DISCUSSION: The causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.

Asunto(s)

Clorhidrato de Fingolimod , Meningitis Criptocócica , Bases de Datos Factuales , Femenino , Clorhidrato de Fingolimod/efectos adversos , Humanos , Incidencia , Masculino , Meningitis Criptocócica/inducido químicamente , Meningitis Criptocócica/tratamiento farmacológico , Persona de Mediana Edad , Estados Unidos

RESUMEN

PURPOSE: To understand the involvement of the CYP1B1 gene in cases of primary open-angle (POAG) and primary angle-closure (PACG) glaucomas and obtain the haplotype background of these mutations. METHODS: The entire coding region of CYP1B1 was screened by resequencing in 224 unrelated cases of POAG (n = 134) and PACG (n = 90) and 200 ethnically matched normal control subjects from Indian populations. Six intragenic single nucleotide polymorphisms (SNPs) in CYP1B1 (-13T>C, R48G, A119S, V432L, D449D, and N453S) were used to generate haplotype data for the cases and controls and linkage disequilibrium (LD) and haplotype analysis were performed with Haploview software, which uses the EM (expectation-maximization) algorithm. RESULTS: The frequency of CYP1B1 mutations was higher among POAG (18.6%; 95% CI, 12.9-26.1) than PACG (11.1%; 95% CI, 6.1-19.3) cases. There was a marked allelic heterogeneity, and the Arg368His was the most prevalent mutation across both the phenotypes. The spectrum of CYP1B1 mutations was largely similar across different POAG populations. Haplotypes generated with intragenic SNPs indicated the C-C-G-G-T-A to be a risk haplotype associated with CYP1B1 mutations in POAG (P = 0.006) and PACG (P = 0.043), similar to that observed in cases of primary congenital glaucoma worldwide. CONCLUSIONS: The results demonstrate an involvement of CYP1B1 in a proportion of POAG and PACG cases that should be explored further. The similar haplotype background of these mutations is indicative of their common origin across multiple glaucoma phenotypes.

Asunto(s)

Hidrocarburo de Aril Hidroxilasas/genética , Glaucoma de Ángulo Cerrado/genética , Glaucoma de Ángulo Abierto/genética , Haplotipos/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Citocromo P-450 CYP1B1 , Análisis Mutacional de ADN , Humanos , Desequilibrio de Ligamiento , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple

RESUMEN

PURPOSE: To evaluate the role of the optineurin gene (OPTN) in Indian primary open angle glaucoma (POAG) patients from different parts of the country. METHODS: Two hundred patients with POAG and 200 ethnically matched normal controls were recruited from various parts of India for the study. The entire coding region of OPTN along with the intron-exon boundaries were screened by PCR and single strand conformation polymorphism (SSCP) followed by direct sequencing. A rapid screening method was developed for some of the observed variants by denaturing high performance liquid chromatography (dHPLC). Four variants were also confirmed by digesting the amplicon with appropriate restriction enzymes. RESULTS: Seven nucleotide changes were observed in OPTN of which one was a putative mutation in exon 16 (Arg545Gln) that was observed in six POAG patients and not in the controls (p<0.05). The remaining variants comprised four single nucleotide polymorphisms (SNPs) in the coding region (Thr34Thr, Met98Lys, Arg149Arg, and Asn303Lys) and two in intron 6 (879-10G>A and 879-5C>T). But frequencies of the minor allele were not significantly different among the patients and controls. The Met98Lys variant that was identified to be a potential risk factor for NTG and POAG in some Asian populations and also for modulating IOP in Caucasian populations, did not exhibit any significant association to the disease phenotype. CONCLUSIONS: Despite a putative mutation (Arg545Gln) in some patients, the present study does not suggest a significant involvement of OPTN in POAG patients of Indian origin.

Asunto(s)

Glaucoma de Ángulo Abierto/genética , Mutación , Factor de Transcripción TFIIIA/genética , Proteínas de Ciclo Celular , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Exones/genética , Glaucoma de Ángulo Abierto/etnología , Humanos , India , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Factores de Riesgo

RESUMEN

PURPOSE: Myocilin gene defects have been originally implicated in primary open angle glaucoma (POAG). Based on multiple reports for the occurrence of Gln48His mutation (c.144G>T; HGMD accession number CM023962) among Indian POAG patients, we wanted to estimate the prevalence of this mutation in primary open angle and primary congenital glaucoma (PCG) in India and assess its role in the causation of the disease. METHODS: Two hundred cases each of POAG and PCG were screened for the Gln48His mutation by RFLP (AccI) analysis of the PCR amplicons followed by confirmation of the c.144G>T change by direct sequencing. RESULTS: The Gln48His mutation was detected in 9 different glaucoma patients (four POAG and five PCG). While all four POAG cases were heterozygous, among PCG cases, four were heterozygous and one exhibited homozygous genotype for the mutation. One each of POAG and PCG patients was detected to be heterozygous for CYP1B1 mutation (c.1656C>T, Pro437Leu) and (c.1449G>A, Arg368His), respectively. None of the 300 ethnically matched normal controls contained either the MYOC or CYP1B1 mutation(s). CONCLUSIONS: The myocilin mutation, Gln48His, represents an allelic condition involving a spectrum of glaucoma phenotypes in Indian populations, and could be a potential risk factor towards disease predisposition among patients of Indian origin. The study also highlights the role of MYOC as a candidate in different glaucoma subtypes that needs to be investigated further.

Asunto(s)

Proteínas del Citoesqueleto/genética , Proteínas del Ojo/genética , Glaucoma de Ángulo Abierto/congénito , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Mutación Puntual , Adulto , Hidrocarburo de Aril Hidroxilasas/genética , Pueblo Asiatico/genética , Citocromo P-450 CYP1B1 , Análisis Mutacional de ADN , Glaucoma de Ángulo Abierto/etnología , Humanos , India , Lactante , Recién Nacido , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Prevalencia

RESUMEN

We describe a consanguineous Indian family having spinocerebellar ataxia type 2 (SCA2) expansions with complex phenotypes (early-onset, dopa-responsive parkinsonism, ataxia and retinitis pigmentosa). The two probands having homozygous SCA2 mutations presenting with early-onset dopa-responsive parkinsonism without ataxia develop dyskinesias within a year of starting levodopa. Their siblings, heterozygous for SCA2 mutations, had retinitis pigmentosa with or without ataxia. Approximately 38% of family members with SCA2 mutations were asymptomatic.

Asunto(s)

Expansión de las Repeticiones de ADN , Fenotipo , Proteínas/genética , Adulto , Anciano , Ataxia/genética , Ataxinas , Análisis Mutacional de ADN , Homocigoto , Humanos , India , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso , Trastornos Parkinsonianos/genética , Linaje , Retinitis Pigmentosa/genética

Asunto(s)

Hidrocarburo de Aril Hidroxilasas/genética , Glaucoma/genética , Terminología como Asunto , Sustitución de Aminoácidos , Citocromo P-450 CYP1B1 , Humanos , Mutación Puntual

Asunto(s)

Proteínas del Ojo/genética , Glaucoma/genética , Glicoproteínas/genética , Terminología como Asunto , Codón sin Sentido , Proteínas del Citoesqueleto , Humanos , Mutación Puntual

RESUMEN

PURPOSE: Axenfeld-Rieger anomaly (ARA) is a form of anterior segment dysgenesis of the eye, mainly caused by mutations in the FOXC1 gene. We had earlier reported a novel mutation in the wing region of FOXC1 in an autosomal dominant family. The present study was aimed to identify the spectrum of mutations in the FOXC1 gene in a cohort of Indian ARA patients from different ethnic backgrounds, and to understand its role in the disease pathogenesis. METHODS: Two new autosomal dominant families and seven sporadic cases of ARA from different ethnic backgrounds were screened for mutations by direct sequencing of the coding region of the FOXC1 gene. Another autosomal dominant ARA family that was previously reported by us was also included for comparative analysis of clinical genetic parameters. The segregation of the mutations in the autosomal dominant families was analyzed by haplotype and restriction analysis. Genotype-phenotype correlation were also undertaken to study the role of FOXC1 in phenotypic manifestation in the patient cohort. RESULTS: Three of the nine ARA cases harbored mutations in FOXC1, of which two novel nonsense mutations Q2X and Q123X, resulted in haploinsufficiency of the gene product. The missense mutation (M161K) that we previously reported in an autosomal dominant family was also found in another family. Haplotype analysis of these two families suggested multiple founders in the same ethnic group. The mutations resulted in variable expressions of phenotype among the patients as assessed from their prognosis based on visual outcomes. CONCLUSIONS: Significant genetic heterogeneity of FOXC1 was observed in a multi-ethnic population studied in this region of India resulting in variable ARA phenotypes. The different visual outcome seen in the patients suggest a variable expression of FOXC1 and also provide some insight for understanding the gene functions in this population.

Asunto(s)

Segmento Anterior del Ojo/anomalías , Proteínas de Unión al ADN , Anomalías del Ojo/genética , Heterogeneidad Genética , Iris/anomalías , Mutación , Factores de Transcripción/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Córnea/anomalías , Análisis Mutacional de ADN , Anomalías del Ojo/etnología , Femenino , Factores de Transcripción Forkhead , Genotipo , Haplotipos , Humanos , India , Lactante , Recién Nacido , Presión Intraocular/genética , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa