Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3–10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3–10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.
Mutations in the EIF2AK3 gene have been identified in patients with Wolcott-Rallison syndrome - a rare autosomal recessive disorder associated with permanent neonatal insulin-dependent diabetes. Despite the fact that different mutations have been observed in every single unrelated case reported so far, most patients presented with similar characteristics, such as osteopenia, epiphyseal dysplasia as well as hepatic and/or renal dysfunction. The EIF2AK3 gene was analyzed using a PCR-based sequencing approach in two Wolcott-Rallison patients and their parents. We report two cases from different families carrying the same and novel truncating nonsense mutation in the EIF2AK3 gene that encodes the pancreatic eukaryotic initiation factor 2alpha kinase 3. This mutation clearly displays different clinical characteristics in the two patients we examined. Remarkably, the onset of diabetes was different for the two patients, and there was also heterogeneity in other clinical manifestations. These cases illustrate the important role of alternative pathways that could, to some extent, take over or supplement a defective metabolic pathway. This supports the idea that there is no simple relationship among clinical manifestations and EIF2AK3 mutations.
This study aims to describe the feasibility of a nutritional intervention that promotes healthy eating habits early after cancer pediatric diagnosis in patients and their parents. Participants were recruited 4 to 12 weeks after cancer diagnosis as part of the VIE study. The one-year nutritional intervention included an initial evaluation and 6 follow-up visits every 2 months with a registered dietician. The feasibility assessment included rates of retention, participation, attendance, completion of study measures, and participants’ engagement. A preliminary evaluation of the intervention's impact on the participants’ dietary intakes was conducted. A total of 62 participants were included in the study (51.6% male, mean age = 8.5 years, mean time since diagnosis = 13.2 weeks). The retention and attendance rates were 72.6% and 71.3%, respectively. Attendance to follow-up visits declined over time, from 83.9% to 48.9%. A majority of participants had high participation (50.8%) and high engagement (56.4%). Measures of body-mass-index or weight-for-length ratio and dietary 24-h recalls were the procedures with the highest completion rates. Participants with refractory disease or relapse were less likely to complete the intervention. Post-intervention, participants (n = 21) had a lower sodium intake compared to the initial evaluation. These results suggest that a nutritional intervention that involves patients and parents early after a pediatric cancer diagnosis is feasible.
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