Mutations in the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), the lysosomal storage disorder (LSD), and are the most common genetic risk factor of Parkinson’s disease (PD). Lysosome functionality plays a critical role for secretion of extracellular vesicles (EVs) and their content. Here we compared EVs from the blood plasma of 8 GD patients and 8 controls in terms of amounts, size distribution, and composition of their protein cargo. EVs were isolated via sequential centrifugation and characterized by сryo-electron microscopy (cryo-EM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS). The presence of exosomal markers HSP70 and tetrasponins were analyzed by Western blot and flow cytometry. Protein profiling was performed by mass-spectrometry (shotgun analysis). Here, for the first time we reported an increased size and altered morphology in exosomes derived from blood plasma of GD patients. An increased size of plasma exosomes from GD patients compared to controls was demonstrated by cryo-EM and DLS (р less then 0.0001, p less then 0.001, respectively) and confirmed by mode size detected by NTA (p less then 0.02). Cryo-EM demonstrated an increased number of double and multilayer vesicles in plasma EVs from GD patients. We found that the EVs were enriched with the surface exosomal markers (CD9, СD63, CD81) and an exosome-associated protein HSP70 in case of the patients with the disease. Proteomic profiling of exosomal proteins did not reveal any proteins associated with PD pathogenesis. Thus, we showed that lysosomal dysfunction in GD patients lead to a striking alteration of plasma exosomes in size and morphology.FLVCR1 encodes for a transmembrane heme exporter protein and it is known to cause a rare form of syndromic retinitis pigmentosa posterior column ataxia with retinitis pigmentosa. Recently, the FLVCR1-associated phenotype has been expanded with sporadic reports of hereditary sensory-autonomic neuropathy or non-syndromic retinitis pigmentosa. Here, we report a 23-year- old female with early onset hypomyelinating sensory-autonomic neuropathy and retinitis pigmentosa. Both features were present since childhood. The patient developed signs of advanced retinitis pigmentosa by the age of 10 years leading to legal blindness after the age of 18. Following candidate gene panel testing, which was negative, whole exome sequencing revealed compound heterozygous pathogenic FLVCR1 variants NM_014053.3 c.3G > T; p.(Met1?) and NM_014053.3 c.730G > A; p.(Gly244Ser), the latter variant is novel. In this report we highlight the association of retinitis pigmentosa with hypomyelinating sensory-autonomic neuropathy, which could be underdiagnosed due to variable severity. To summarize, the phenotypic heterogeneity of FLVCR1 variants is broad and should include retinitis pigmentosa along with range of neurological features.Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2). However, the prevalence of NF2 in individuals with PMS and a r (22) is unknown. Individuals with PMS and a r (22) chromosome evaluated at the Greenwood Genetic Center (GGC) or by international collaborators, or identified through the PMS International Registry (PMSIR) were contacted and participated in a clinical questionnaire. Forty-four families completed the questionnaire and consented for the study. Of the individuals with a r (22), 7 (16%) carried a diagnosis of NF2. The average age of diagnosis of r (22) was 18 years old in individuals with NF2 and three years old in individuals without NF2 (p-value less then 0.001). Clinical findings were similar among all individuals in our sample with the exception of hearing loss, present in 57% of individuals with NF2 and 8% of individuals without NF2 (p-value less then 0.01). This is the largest clinical report of individuals with PMS and a r (22) chromosome. We show a diagnosis of NF2 in individuals with r (22) is not uncommon and may be under ascertained. Moreover, the presentation of NF2 in this cohort is variable and lifelong routine screening for features of NF2 in this population should be considered.

Vertebral fracture assessment (VFA)-detected abdominal aortic calcification (AAC) has been validated as an indicator of increased risk of vertebral fractures (VFs) in other populations but this relationship in rheumatoid arthritis (RA) is unclear. We assess the prevalence of AAC on VFA scans and its potential relationship with prevalent VFs in a cohort of RA women.

We enrolled 250 women with RA. VFA images, and scans of the lumbar spine and proximal femur were obtained using dual-energy x-ray absorptiometry. The presence/severity of VFs and AAC were carried out using validated approaches.

AAC was detected in 95 of 250 (38%) eligible subjects and 83 (33.2%) had at least one VF. Significantly subjects with VFs had a higher AAC score (3.4±3.8 versus 0.7±1.4; p˂0.001) and higher prevalence of AAC than those without VFs (65% versus 26%; P˂0.001). The group with VFs tended to be older, had more menopausal women, and lower lumbar spine and total hip BMD than those without VF. Trolox molecular weight They also had a long-standing disease and high DAS 28-CRP, a great steroid cumulative dose, and a high prevalence of rheumatoid factor (RF). In multivariate analyses, a significant association was noted between prevalent VFs and age of patients, RA disease activity, presence of densitometric osteoporosis, RF, and VFA-detected AAC, whereas there was no significant association with steroid cumulative dose and disease duration.

VFA is a convenient tool for the diagnosis of VFs and AAC. In this cohort, VFA-detected AAC was independently associated with prevalent VFs.

VFA is a convenient tool for the diagnosis of VFs and AAC. In this cohort, VFA-detected AAC was independently associated with prevalent VFs.Syndromic craniosynostoses are defined by the premature fusion of one or more cranial and facial sutures, leading to skull vault deformation, and midfacial retrusion. More recently, mandibular shape modifications have been described in FGFR-related craniosynostoses, which represent almost 75% of the syndromic craniosynostoses. Here, further characterisation of the mandibular phenotype in FGFR-related craniosynostoses is provided in order to confirm mandibular shape modifications, as this could contribute to a better understanding of the involvement of the FGFR pathway in craniofacial development. The aim of our study was to analyse early mandibular morphology in a cohort of patients with FGFR2- (Crouzon and Apert) and FGFR3- (Muenke and Crouzonodermoskeletal) related syndromic craniosynostoses. We used a comparative geometric morphometric approach based on 3D imaging. Thirty-one anatomical landmarks and eleven curves with sliding semi-landmarks were defined to model the shape of the mandible. In total, 40 patients (12 with Crouzon, 12 with Apert, 12 with Muenke and 4 with Crouzonodermoskeletal syndromes) and 40 age and sex-matched controls were included (mean age 13.