Clinical Features, Imaging Characteristics, and Long-term Outcome of Dogs with Cranial Meningocele or Meningoencephalocele.

BACKGROUND: The term meningoencephalocele (MEC) describes a herniation of cerebral tissue and meninges through a defect in the cranium, whereas a meningocele (MC) is a herniation of the meninges alone. HYPOTHESIS/OBJECTIVES: To describe the clinical features, magnetic resonance imaging (MRI) characteristics, and outcomes of dogs with cranial MC and MEC. ANIMALS: Twenty-two client-owned dogs diagnosed with cranial MC or MEC. METHODS: Multicentric retrospective descriptive study. Clinical records of 13 institutions were reviewed. Signalment, clinical history, neurologic findings and MRI characteristics as well as treatment and outcome were recorded and evaluated. RESULTS: Most affected dogs were presented at a young age (median, 6.5 months; range, 1 month - 8 years). The most common presenting complaints were seizures and behavioral abnormalities. Intranasal MEC was more common than parietal MC. Magnetic resonance imaging identified meningeal enhancement of the protruded tissue in 77% of the cases. Porencephaly was seen in all cases with parietal MC. Cerebrospinal fluid (CSF) analysis identified mild abnormalities in 4 of 11 cases. Surgery was not performed in any affected dog. Seventeen patients were treated medically, and seizures were adequately controlled with anti-epileptic drugs in 10 dogs. Dogs with intranasal MEC and mild neurologic signs had a fair prognosis with medical treatment. CONCLUSION AND CLINICAL IMPORTANCE: Although uncommon, MC and MEC should be considered as a differential diagnosis in young dogs presenting with seizures or alterations in behavior. Medical treatment is a valid option with a fair prognosis when the neurologic signs are mild.

Mutations at codon 974 of the DPYD gene are a rare event.

A mutation at codon 974 of the dihydropyrimidine dehydrogenase (DPD) gene was previously described in a cancer patient with undetectable DPD enzyme activity who experienced severe toxicity when treated with 5-fluorouracil. We have studied the frequency of this mutation in 29 Scottish subjects with low DPD enzyme activity and in 274 American subjects. We detected no mutations in the 606 alleles studied and conclude that mutations at codon 974 are a rare event.

Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.

Dihydropyrimidine dehydrogenase (DPD) deficiency constitutes an inborn error in pyrimidine metabolism associated with thymine-uraciluria in pediatric patients and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) treatment. The molecular basis for DPD deficiency in a British family having a cancer patient that exhibited grade IV toxicity 10 d after 5-FU treatment was analyzed. A 165-bp deletion spanning a complete exon of the DPYD gene was found in some members of the pedigree having low DPD catalytic activity. Direct sequencing of lymphocyte DNA from these subjects revealed the presence of a G to A point mutation at the 5'-splicing site consensus sequence (GT to AT) that leads to skipping of the entire exon preceding the mutation during pre-RNA transcription and processing. A PCR-based diagnostic method was developed to determine that the mutation is found in Caucasian and Asian populations. This mutation was also detected in a Dutch patient with thymine-uraciluria and completely lacking DPD activity. A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects.

Analysis of the dihydropyrimidine dehydrogenase polymorphism in a British population.

Subjects with low or absent dihydropyrimidine dehydrogenase activity (DPD) are at risk of excessive toxicity or death when undergoing fluoropyrimidine chemotherapy. The DPD polymorphism has not been well characterized in the general population and the frequency of the enzyme deficiency is not known. In preparation for a population multicentre analysis of DPD activity, a comparison of sample preparation methods and a pilot study in normal volunteer subjects was performed. The stability of peripheral blood mononuclear cell DPD activity at -70 degrees C was determined in 35 mM sodium phosphate buffer with 10% glycerol, 100% fetal calf serum (FCS) or as a dry pellet. DPD activity declined in FCS and increased in glycerol buffer, both reaching a plateau value 14 days after blood sampling. The glycerol buffer method was then used to study DPD activity in 50 British subjects (36 M: 14F; 20-56 years). A 8.4-fold range in DPD activity was observed (30.4-256 pmol min-1 mg-1 protein). DPD activity was not influenced by age or cigarette smoking. This information will facilitate analysis of the DPD polymorphism in populations from different countries and ethnic groups.