RESUMO
OBJECTIVE: Monogenic congenital cataract is one of the most genetically heterogeneous ocular conditions with almost 30 different genes involved in its etiology. In adult patients, genotype-phenotype correlations are troubled by eye surgery during infancy and/or long-term ocular complications. Here, we describe the molecular diagnosis of GALK1 deficiency as the cause of autosomal recessive congenital cataract in a family from Costa Rica. METHODS: Four affected siblings were included in the study. All of them underwent eye surgery during the first decade but medical records were not available. Congenital cataract was diagnosed by report. Molecular analysis included genome wide homozygosity mapping using a 250K SNP Affymetrix microarray followed by PCR amplification and direct nucleotide sequencing of candidate gene. RESULTS: Genome wide homozygosity mapping revealed a 6Mb region of homozygosity shared by two affected siblings at 17q25. The GALK1 gene was included in this interval and direct sequencing of this gene revealed a homozygous c.1144C>T mutation (p.Q382) in all four affected subjects. CONCLUSIONS: This work demonstrates the utility of homozygosity mapping in the retrospective diagnosis of a family with congenital cataracts in which ocular surgery at early age, the lack of medical records, and the presence of long term eye complications, impeded a clear clinical diagnosis during the initial phases of evaluation.
Assuntos
Catarata/congênito , Catarata/genética , Galactoquinase/genética , Genes Recessivos , Mutação , Idoso , Mapeamento Cromossômico/métodos , Análise Mutacional de DNA/métodos , Olho , Feminino , Galactoquinase/deficiência , Ligação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Molecular/métodos , Linhagem , Estudos Retrospectivos , IrmãosRESUMO
133 patients with congenital or idiopathic cataracts were studied (94 patients had ages between 1 month and 14 years; 10 patients had ages between 16 and 50 years and 29 patients did not have an age registry) along with 18 patients with a clinical diagnosis of classic galactosemia. The activity of galactokinase (GALAK) and that of erythrocyte galactose-1-phosphate uridyl transferase (GALT) was measured. There were no individuals with a total deficiency of GALK or GALT. The cataract patients of ages between 1 monthly and 14 years, 3 (3.19%) and 4 (4.25%) showed GALK and GALT levels in the range corresponding to the respective heterozygotes. As compared with the expected incidence of heterozygotes in the general population (0.2% for GALK and 0.8% for GALT) we found a significant rise of individuals with low levels of enzymes for the metabolism of galactose. The possibility that heterozygote galactosemic states contribute a risk factor in the development of cataracts and its therapeutic implications are discussed.
Assuntos
Catarata/etiologia , Galactoquinase/deficiência , Galactose/metabolismo , Galactosemias/diagnóstico , UTP-Hexose-1-Fosfato Uridililtransferase/deficiência , Adolescente , Adulto , Catarata/congênito , Catarata/enzimologia , Catarata/genética , Criança , Pré-Escolar , Galactoquinase/sangue , Galactosemias/complicações , Galactosemias/epidemiologia , Galactosemias/genética , Frequência do Gene , Triagem de Portadores Genéticos , Humanos , Incidência , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Fatores de Risco , UTP-Hexose-1-Fosfato Uridililtransferase/sangueRESUMO
Galactose is a major nutrient in normal newborn infants and serves as a substrate for energy production and fuel storage and a regulator of carbohydrate assimilation. Inborn errors of galactose metabolism have contributed to our understanding of the potential toxicity of this carbohydrate. In addition to the classic acute manifestations of neonatal galactosemia, long-term follow-up of surviving patients have revealed unusual neurodevelopmental and reproductive problems. Many investigators have suggested that the newborn infant can utilize galactose better than adults and that neonatal galactose assimilation exceeds that of glucose. Galactose may be an excellent substitute for glucose among hyperinsulinemic infants of diabetic mothers or premature infants with glucose intolerance. However, until further investigations are performed to define the role of galactose in newborn nutrition and to determine its potential toxicity, galactose should not be used as the primary carbohydrate in sick newborn infants.