RESUMO
Adrenal hypoplasia congenita (AHC) can occur due to deletions or mutations in the DAX 1 (NR0B1) gene on the X chromosome (OMIM 300200). This form of AHC is therefore predominantly seen in boys. Deletion of the DAX 1 gene can also be part of a larger contiguous deletion including the centromeric dystrophin and glycerol kinase (GK) genes. We report a girl with a de novo deletion at Xp21.2 on the maternal chromosome, including DAX1, the GK gene and 3' end of the dystrophin gene, who presented with salt losing adrenal insufficiency and moderate developmental delay, but relatively mild features of muscular dystrophy. Investigation using the androgen receptor as a marker gene identified skewed inactivation of the X chromosome. In the patient's leucocytes, the paternal X chromosome was completely inactive, but in muscle 20% of the active chromosomes were of paternal origin. Thus skewed X inactivation (deletion on the active maternal X chromosome with an inactive paternal X chromosome) is associated with AHC in a female. Variability in X inactivation between tissues may account for the pronounced salt loss and adrenal insufficiency but mild muscular dystrophy.
Assuntos
Insuficiência Adrenal/congênito , Insuficiência Adrenal/genética , Inativação do Cromossomo X , Insuficiência Adrenal/diagnóstico , Receptor Nuclear Órfão DAX-1 , Proteínas de Ligação a DNA/genética , Distrofina/genética , Feminino , Deleção de Genes , Ligação Genética , Glicerol Quinase/genética , Glicerol Quinase/metabolismo , Humanos , Recém-Nascido , Fenótipo , Receptores do Ácido Retinoico/genética , Proteínas Repressoras/genéticaAssuntos
Cromossomos Humanos X , Glicerol Quinase/deficiência , Glicerol/urina , Doenças do Sistema Nervoso/genética , Aberrações dos Cromossomos Sexuais , Pré-Escolar , Dieta com Restrição de Gorduras , Humanos , Hiperlipoproteinemia Tipo IV/dietoterapia , Hiperlipoproteinemia Tipo IV/genética , Lactente , Recém-Nascido , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/dietoterapia , Fenótipo , Fatores de Risco , Morte Súbita do Lactente/genéticaRESUMO
AIM: To follow two children with isolated glycerol kinase deficiency (GKD) with severe symptoms into adulthood. METHODS: The patients were followed during approximately 20 y and interviewed about symptoms, diet and physical activity. Fasting provocations, bicycle ergometer tests, dietary registrations, enzyme and mutation analysis were performed by standard protocols. RESULTS: The activity of glycerol kinase (GK) in fibroblasts was <10% of reference. One case had a deletion of exon 17, the other a mutation in exon 7 of the GK gene (601 A-->G). Both mothers were heterozygotes. Two maternal male cousins in one of the families were hemizygotes without symptoms. Tests performed in childhood documented pronounced sensitivity to fasting and physical exercise, whereas such tests at 23 and 31 y of age were essentially normal but with pronounced ketonaemia. After puberty, the boys had no hypoglycaemic symptoms and now report no problems with their condition; thus, their phenotype has changed over time. CONCLUSION: The greater importance of glycerol as a gluconeogenetic substrate in children than in adults may explain the episodes in young patients with GKD, often elicited by catabolic stress. With meals at frequent intervals, access to glucose and avoidance of strenuous sports, the prognosis is good for a normal adult life of a young child with isolated GKD and symptoms of hypoglycaemia.
Assuntos
Glicerol Quinase/deficiência , Glicerol/urina , Mutação , Acetoacetatos/urina , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Seguimentos , Genótipo , Glicerol/sangue , Glicerol Quinase/genética , Glicerol Quinase/metabolismo , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , PrognósticoRESUMO
We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.
Assuntos
Anormalidades Múltiplas/enzimologia , Glicerol Quinase/deficiência , Glicerol Quinase/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Criança , Feminino , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Exame Neurológico , Oftalmologia , Linhagem , Gravidez , Diagnóstico Pré-NatalRESUMO
Amniocentesis was performed in a woman who previously had given birth to a boy who died at 12 months of age with a diagnosis of glyceroluria and adrenal insufficiency. A high amount of glycerol (9.0 standard deviations above mean for controls) was found in the amniotic fluid. Enzyme activity of glycerol-kinase (ATP:glycerol-3-phosphotransferase, EC 2.7.1.30) in the cultured amniotic fluid cells was very low. The pregnancy was terminated and a male fetus was aborted. Examinations of DNA isolated from the fetus did demonstrate deletions of two out of 16 DNA probes mapping to the short arm of the X-chromosome. The probes failing to hybridize to DNA from the fetus were C7 (DXS28) and L1.4 (DXS68), both mapping to Xp21.3 and located terminal to the Duchenne locus.