RESUMO
Maple syrup urine disease (MSUD) is an intoxication-type inherited metabolic disorder in which hyperleucinemia leads to brain swelling and death without treatment. MSUD is caused by branched-chain alpha-ketoacid dehydrogenase deficiency due to biallelic loss of the protein products from the genes BCKDHA, BCKDHB, or DBT, while a distinct but related condition is caused by loss of DLD. In this case series, eleven individuals with MSUD caused by two pathogenic variants in DBT are presented. All eleven individuals have a deletion of exon 2 (delEx2, NM_001918.3:c.48_171del); six individuals are homozygous and five individuals are compound heterozygous with a novel missense variant (NM_001918.5:c.916 T > C [p.Ser306Pro]) confirmed to be in trans. Western Blot indicates decreased amount of protein product in delEx2;c.916 T > C liver cells and absence of protein product in delEx2 homozygous hepatocytes. Ultrahigh performance liquid chromatography-tandem mass spectrometry demonstrates an accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes. Individuals with these variants have a neonatal-onset, non-thiamine-responsive, classical form of MSUD. Strikingly, the entire cohort is derived from families who immigrated to the Washington, DC, metro area from Honduras or El Salvador suggesting the possibility of a founder effect.
Assuntos
Doença da Urina de Xarope de Bordo , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , América Central , Genômica , Humanos , Recém-Nascido , Doença da Urina de Xarope de Bordo/genética , MutaçãoRESUMO
Congenital disorders of glycosylation (CDG) are a heterogeneous group of inborn errors of metabolism mostly causing multisystem disease. In 2013, biallelic mutations in the GMPPA gene were described in association with one such CDG known as alacrima, achalasia, and mental retardation syndrome (AAMR). To date, 18 patients have been reported, nearly all displaying the same pathognomonic triad of symptoms described in the name. This condition shares considerable phenotypic overlap with Triple-A syndrome caused by biallelic mutations in the AAAS gene; however, AAMR lacks the characteristic adrenocortical findings associated with Triple-A syndrome. We report three patients from two unrelated families with the same homozygous GMPPA mutation (c.265dup, p.L89fs). Notably, both families reported indigenous Maya-Mam heritage and originated from the town of Concepción Chiquirichapa in Quezaltenango, Guatemala. Our cases help to expand the AAMR phenotype by outlining dysmorphic features not well described in the prior cases. Additionally, we encourage all providers with patients presenting with this unique triad of symptoms to consider sequencing of the GMPPA gene. Special consideration should be given to families of Guatemalan Maya-Mam ancestry who may also have this identified founder mutation. Finally, this condition may indeed be underdiagnosed based on a review of the literature.
Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Glicosilação , Deficiência Intelectual/genética , Nucleotidiltransferases/genética , Adolescente , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/patologia , Criança , Consanguinidade , Acalasia Esofágica/epidemiologia , Acalasia Esofágica/patologia , Éxons/genética , Feminino , Homozigoto , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Proteínas do Tecido Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Linhagem , FenótipoRESUMO
El síndrome de Pallister-Killian es un cuadro poco común, de ocurrencia esporádica, que se caracteriza por retardo mental severo, anomalías congénitas variadas y zonas hipo o hiperpigmentadas en piel que siguen las líneas de Blaschko. Se debe a una anomalía cromosómica:, la tetrasomía del brazo corto del cromosoma 12 en algunas líneas celulares. En este artículo se discuten tres casos con diagnóstico de síndrome de Pallister Killian, cada uno con características citogenéticas diferentes, que involucran todo o parte del brazo corto del cromosoma 12
Pallister-Killian syndrome is a rare sporadic condition, characterized by severe mental retardation, various congenital anomalies and hyper and hypopigmented skin areas that follow lines of Blaschko. It is caused by a chromosomal alteration: tetrasomy of the short arm of chromosome 12 in some cell lines. In this article we discuss three cases of Pallister Killian syndrome, each with a different cytogenetic description involving all or part of the short arm of chromosome 12