RESUMO
The BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3'-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colestase Intra-Hepática/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/mortalidade , Adrenoleucodistrofia/patologia , Adulto , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/mortalidade , Encefalopatias Metabólicas Congênitas/patologia , Criança , Pré-Escolar , Colestase Intra-Hepática/mortalidade , Colestase Intra-Hepática/patologia , Creatina/deficiência , Creatina/genética , Deleção de Genes , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/mortalidade , Deficiência Intelectual/patologia , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/mortalidade , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiênciaRESUMO
With the expansion of newborn screening to include many organic acidurias and fatty acid oxidation defects, effective therapies of these disorders will be needed. Currently severe disorders such as methylmalonic and propionic aciduria. conventional therapy with diet and oral L-camitine often prove ineffective in preventing failure to thrive and recurrent metabolic decompensations. L-carnitine provides a natural pathway for removal of the toxic metabolites in these disorders and is life saving therapy but, with poor oral absorption (25%), it is difficult to supply adequate carnitine to meet the metabolic needs of these patients. Long term intravenous L-carnitine therapy, administered through a subcutaneous venous access port in 5 patients with organic acidurias [propionic aciduria (2), methylmalonic aciduria (2), 3 methylglutaconic aciduria(1)] resulted in improved growth, lower frequency of metabolic decompensations and increased tolerance of natural protein in the diet. An added benefit was the ability to initiate fluid. electrolytes, and antibiotics during metabolic decompensations at home thus averting hospitalizations.
