Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15

• Published in: Journal of inherited metabolic disease 2009-12, Vol.32 (Suppl 1), p.349-353
• Main Authors: Ferrer-Bolufer, Irene, Dalmau, Jaime, Quiroga, Ramiro, Oltra, Silvestre, Orellana, Carmen, Monfort, Sandra, Roselló, Mónica, De La Osa, Alberto, Martinez, Francisco
• Format: Article
• Language: English
• Subjects: Adult; Angelman Syndrome - complications; Angelman Syndrome - genetics; Base Sequence; Biochemistry; Case Report; Child, Preschool; Chromosomes, Human, Pair 15; DNA Mutational Analysis; Fathers; Female; Genomic Imprinting; Human Genetics; Humans; Infant; Infant, Newborn; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Pediatrics; Pedigree; Tyrosinemias - complications; Tyrosinemias - genetics; Uniparental Disomy
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-009-9014-9

Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence risk in the family is negligible. On the other hand, the lack of maternal contribution causes Angelman syndrome, a neurodevelopmental disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13, and more specifically, of the UBE3A gene. This gene shows a tissue-specific imprinting, and only the maternally derived allele is expressed in certain areas of the brain. We observed through a literature review that uniparental disomy probably occurs more frequently than suspected, although it is more usually detected when the uniparental disomy implies the appearance of a disease because of the gene imprinting or by reduction to homozygosity of a recessive mutation. The conclusion is that uniparental disomy should always be considered when more than one genetic disease mapping to the same chromosome is present in a patient.