Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.

Transmantle dysplasia in tuberous sclerosis: clinical features and surgical outcome in four children.

In the literature, several malformations of cortical development have been described as additional lesions in tuberous sclerosis complex. Among these lesions, a very large focal cortical dysplasia has peculiar magnetic resonance imaging features: a signal abnormality that extends radially inward toward the lateral ventricle from the pachygyric cortical surface plus a homogeneous clinical picture. Affected patients have early-onset drug-resistant epilepsy and severe developmental delay. We describe the clinical, genetic, neurophysiologic, and neuroradiologic characteristics of four patients affected by tuberous sclerosis and this type of cortical dysplasia these patients are of special interest because they have been operated on for their dysplastic lesions. Total control of seizures has been achieved in the three children who underwent a complete lesionectomy. This result cannot be permanent, however, because of the presence of other cortical tubers which could become epileptogenic. All things considered, our choice was to give these children at least temporary relief from severe epilepsy and possibly support for developmental progression.