Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to nonconsanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p. Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature

“…Case 2 carried the polymorphism c.1601G>A p.(Ser534Asn), also known as DPYD*4 is a rare mutation identified previously and linked to clinical DPD deficiency [14][15][16]. This case represents an intermediate metabolizer despite being homozygous for DPYD*4.…”

“…Case 3 was heterozygous for the very rare c.257C>T (p. Pro86Leu) variant which was also reported prior to associate with clinical DPD deficiency. His Oncologist elected not to proceed with capecitabine after discovering this variant [15][16][17][18].…”

Focal Neurotoxicity Associated With Topical 5-Fluorouracil

“…Individuals with these genetic abnormalities are usually asymptomatic and are not aware of their deficiency until they are exposed to capecitabine or 5-FU. It is rare to have symptomatic DPD deficiency, but some patients with more severe degrees of deficiency may experience neurological issues such as delayed cognitive and motor development, leading to intellectual disabilities [ 7 ]. Patients with partial loss of DPD function are at an increased risk for adverse effects following the administration of 5-FU, while those with a complete loss of function are at much higher risk and often experience fatal outcomes [ 8 ].…”

DPD status and fluoropyrimidines-based treatment: high activity matters too

“…Population studies [2,3] on lymphocyte DPD distribution indicate a Gaussian curve of DPD activity distribution including both low and high values. The elucidation of genetic mechanisms underlining DPD variability is increasingly being appreciated [4]. Loss of DPD activity evidenced by phenotypic and/or genotype screening has proven its predictive clinical value in identifying patients at risk for toxicity [1,3,[5][6][7][8][9].…”