RESUMO
Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Antígenos de Neoplasias/genética , Testes Genéticos , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/patologia , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transporte Vesicular , Adolescente , Adulto , Bélgica , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Análise Mutacional de DNA/métodos , Perfilação da Expressão Gênica , Genótipo , Humanos , Lactente , Amaurose Congênita de Leber/diagnóstico , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fenótipo , Proteínas/genética , Degeneração Retiniana/genética , Distrofias Retinianas/genética , Distrofias Retinianas/patologia , Adulto JovemRESUMO
In 15 Belgian subjects with prelingual sensorineural hearing impairment, the connexin 26 (GJB2) gene and the connexin 30 (GJB6) gene were analyzed for the presence of the 35delG mutation and the delta(GJB6-D13S1830) deletion first described by del Castillo et al in 2002. Seven patients were found to be homozygous for the 35delG mutation; 7 were combined heterozygotes for the 35delG mutation and the GJB6 deletion. In 11 subjects, phenotype and genotype were correlated. Significant, transient progression, in the range of 1.7 to 2.7 dB/y, was only found in 2 patients in the first part of the second decade of life. Hearing impairment was otherwise stable, with mean thresholds of 75, 90, and 100 dB at 0.125, 0.25, and 0.5 kHz, respectively, and 100 dB or higher at 1 to 4 kHz. There was no significant difference in hearing impairment between the patients with the homozygous 35delG mutation in GJB2 and those who are heterozygous for both the 35delG mutation and the deletion encompassing part of GJB6.
Assuntos
Conexinas/genética , Perda Auditiva Neurossensorial/genética , Mutação Puntual/genética , Adolescente , Adulto , Audiometria de Tons Puros , Limiar Auditivo/fisiologia , Criança , Conexina 26 , Conexina 30 , Fragmentação do DNA , Análise Mutacional de DNA , Seguimentos , Deleção de Genes , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The objective of this study is to look for evidence based or scientific guidelines for selection of newborns with congenital cytomegalovirus (CMV) infection that might benefit from treatment with ganciclovir. MATERIALS AND METHODS: A literature search was conducted involving the MEDLINE database and the Cochrane Collaboration Library. Abstracts were reviewed to select pertinent articles dealing with ganciclovir therapy in neonates. References from selected articles as well as from reviews were screened for additional relevant articles. In total, 13 case reports (16 patients in all), three descriptive uncontrolled studies (20 patients in all), two randomized dose-comparative studies (54 patients in all) and one randomized controlled study (42 patients) were identified. OBSERVATIONS: All reported patients presented with central nervous system manifestation of CMV infection. Only the randomized controlled study showed a reduction of hearing deterioration in the treated group. Published predictors of hearing loss in congenitally CMV infected children allow identification of candidates that might benefit from treatment. Studies so far are promising but of insufficient number to make evidence based recommendations about indications for treatment of congenital CMV. As such, studies are very difficult to conduct and treatment of infants at high risk of hearing loss may appear justified. There is scientific data to help clinicians in selecting a subgroup of infants that is at higher risk of hearing deterioration and therefore might benefit the most from ganciclovir therapy.