Ipsenbuus4312

OBJECTIVE To assess magnetic resonance spectroscopy (MRS) bone marrow fat fractions' ability to discern between untreated Gaucher disease patients and healthy controls based on assessment of bone marrow infiltration and evaluate response to enzyme replacement therapy (ERT) on serial imaging. METHODS This retrospective case-controlled study compared conventional MRI and bone marrow MRS findings in six pediatric and young adult Gaucher disease patients with age- and sex-matched controls, examining femoral neck and lumbar spine bone marrow fat fractions and bone marrow burden (BMB) scores. Separate analysis of six patients with serial imaging on ERT was performed with analysis of fat fractions, BMB scores, organ volumes, and serum chitotriosidase. RESULTS Untreated patients had significantly lower femoral and lumbar spine fat fractions than controls (0.32 versus 0.67, p = 0.041 and 0.17 versus 0.34, p = 0.041, respectively). Total BMB scores were significantly higher in patients (8.0 versus 3.5, p = 0.015). In patients on ERT with average follow-up of 3.5 years, femoral neck fat fraction was the sole significant predictor of treatment duration (R square 0.804, p  less then  0.001) when adjusted for age. Femoral neck fat fraction also correlated with lumbar spine fat fraction, liver volume and chitotriosidase (p  less then  0.05). MRS test-retest reliability was excellent (Pearson correlations 0.96, 0.99; p-values less then 0.001). BMB inter-rater reliability was good overall with an intra-class correlation coefficient of 0.79 for total score, although lumbar spine score reliability was poor at 0.45. CONCLUSION MRS-derived bone marrow fat fractions appear capable of detecting Gaucher disease severity and monitoring treatment-related changes as a predictor of ERT duration in pediatric and young adult patients. In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD. The goal of the current study was to evaluate the impact of Tubulin Polymerization Promoting Protein (TPPP) methylation on structural and fractional anisotropy (FA) corpus callosum (CC) measures. TPPP is involved in the development of white matter tracts in the brain and was implicated in stress-related psychiatric disorders in an unbiased whole epigenome methylation study. The cohort included 63 participants (11.73 y/o ±1.91) from a larger study investigating risk and resilience in maltreated children. Voxel-based morphometry (VBM) was used to process the structural data, fractional anisotropy (FA) was determined using an atlas-based approach, and DNA specimens were derived from saliva in two batches using the 450 K (N = 39) and 850 K (N = 24) Illumina arrays, with the data from each batch analyzed separately. After controlling for multiple comparisons and relevant covariates (e.g., demographics, brain volume, cell composition, 3 PCs), 850 K derived TPPP methylation values, in interaction with a dimensional measure of children's trauma experiences, predicted left and right CC body volumes and genu, body and splenium FA (p  less then  .007, all comparisons). The findings in the splenium replicated in subjects with the 450 K data. The results extend prior investigations and suggest a role for TPPP in brain changes associated with stress-related psychiatric disorders. PY-60 cell line V.OBJECTIVE To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants. METHODS A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes. RESULTS WES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function. CONCLUSION Our findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.