Prediction of long-term outcome in glycine encephalopathy: a clinical survey

OBJECTIVE: Glycine encephalopathy (GE) is a rare autosomal recessive inborn error of glycine degradation resulting in severe encephalopathy with ensuing poor outcome. Attenuated variants with a significantly better outcome have been reported. Early prediction of long-term outcome is not yet possible. METHODS: We compared the clinical and biochemical features of 45 children, each with a different course of the disease, to help determine predictors of long-term outcome. RESULTS: The most common presenting symptoms were hypotonia, seizures, and coma. In this study, 85% of the patients presented within the first week of life, and 15% presented after the neonatal period up to the age of 12 months. Developmental progress was made by 19% of those children presenting during the neonatal period and by 50% of those presenting in infancy. Initial CSF and plasma glycine concentrations were not useful in differentiating severe and attenuated outcome. A severe outcome was significantly associated with early onset of spasticity, frequent hiccupping, EEG burst-suppression or hypsarrhythmia patterns, microcephaly, and congenital or cerebral malformations, e.g. corpus callosum hypoplasia. An attenuated outcome was significantly associated with hyperactivity and choreiform movement disorders. We describe a severity score which facilitates the prediction of the outcome in patients with GE. CONCLUSION: Prediction of the outcome of GE may be facilitated by recognizing selected clinical parameters and early neuroimaging findings

Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3)

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considere

Management of phenylketonuria in Europe: Survey results from 19 countries

To gain better insight in the most current diagnosis and treatment practices for phenylketonuria (PKU) from a broad group of experts, a European PKU survey was performed. The questionnaire. consisting of 33 questions, was sent to 243 PKU professionals in 165 PKU centers in 23 European countries. The responses were compiled and descriptive analyses were performed. One hundred and one questionnaires were returned by 93/165 centers (56%) from 19/23 European countries (83%). The majority of respondents (77%) managed patients of all age groups and more than 90% of PKU teams included physicians or dieticians/nutritionists. The greatest variability existed especially in the definition of PKU phenotypes, therapeutic blood phenylalanine (Phe) target concentrations, and follow-up practices for PKU patients. The tetrahydrobiopterin (BH4: sapropterin) loading test was performed by 54% of respondents, of which 61% applied a single dose test (20 mg/kg over 24 h). BH4 was reported as a treatment option by 34%. This survey documents differences in diagnostic and treatment practices for PKU patients in European centers. In particular, recommendations for the treatment decision varied greatly between different European countries. There is an urgent need to pool long-term data in PKU registries in order to generate an evidence-based international guideline