RESUMEN
Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD-deficient patients presented with unusual clinical phenotypes including pregnancy-induced symptoms, transient visual impairment, severe developmental delay, cortical blindness, and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G>A mutation and a novel missense variant c.1700G>A (p.G567E). The recombinantly expressed p.G567E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein. Genome sequencing of the affected son established compound heterozygosity for the c.1700G>A and an imperfect 115,731 bp inversion with breakpoints at chr1: 98,113,121 (intron 8) and chr1: 97,997,390 (intron 12) of the DPYD associated with a 4 bp deletion (chr1: 97,997,386_97,997,389del). Whole exome and mitochondrial DNA analyses for the mother and daughter did not reveal additional mutated genes of significance. Thus, an inversion in DPYD should be considered in patients with an inconclusive genotype or unusual clinical phenotype.
Asunto(s)
Deficiencia de Dihidropirimidina Deshidrogenasa/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Mutación Missense/genética , Paraparesia Espástica/genética , Adolescente , Adulto , Preescolar , Mapeo Cromosómico , Deficiencia de Dihidropirimidina Deshidrogenasa/fisiopatología , Exones/genética , Femenino , Genotipo , Heterocigoto , Humanos , Lactante , Intrones/genética , Masculino , Paraparesia Espástica/fisiopatología , Fenotipo , Eliminación de Secuencia/genética , Secuenciación Completa del GenomaRESUMEN
Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare defect of the first step of the pyrimidine catabolic pathway. Patients with a complete enzyme deficiency may be clinically asymptomatic or suffer from neurological abnormalities of various severity. We report a case of an 8-year-old girl with psychomotor retardation and mild course of the disease. Analysis of urine showed strongly elevated levels of uracil and thymine, and no DPD activity could be detected in peripheral blood mononuclear cells. Sequence analysis of the DPD gene (DPYD) revealed that our patient was homozygous for the common splice-site mutation IVS14+1G > A, which suggest that the carrier status for this mutation may be not rare in the Polish population.