Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings.

Disorders of intracellular trafficking are a group of inherited disorders, which often display multisystem phenotypes. Vacuolar protein sorting (VPS) subunit C, composed of VPS11, VPS18, VPS16, and VPS33A proteins, is involved in tethering of endosomes, lysosomes, and autophagosomes. Our group and others have previously described patients with a specific homozygous missense VPS33A variant, exhibiting a storage disease phenotype resembling mucopolysaccharidosis (MPS), termed "MPS-plus syndrome." Here, we report two siblings from a consanguineous Turkish-Arabic family, who have overlapping features of MPS and intracellular trafficking disorders, including short stature, coarse facies, developmental delay, peripheral neuropathy, splenomegaly, spondylar dysplasia, congenital neutropenia, and high-normal glycosaminoglycan excretion. Whole exome sequencing and familial segregation analyses led to the homozygous NM_022575.3:c.540G>T; p.Trp180Cys variant in VPS16 in both siblings. Multiple bioinformatic methods supported the pathogenicity of this variant. Different monoallelic null VPS16 variants and a homozygous missense VPS16 variant had been previously associated with dystonia. A biallelic intronic, probably splice-altering variant in VPS16, causing an MPS-plus syndrome-like disease has been very recently reported in two individuals. The siblings presented herein display no dystonia, but have features of a multisystem storage disorder, representing a novel MPS-plus syndrome-like disease, associated for the first time with VPS16 missense variants.

How the occupational balance of healthcare professionals changed in the COVID-19 pandemic: A mixed design study.

BACKGROUND: Although it has been possible for many people to make a gradual transition to normal life or routine activities, the same seems far off for healthcare professionals. The current study examines in depth how the occupational balance of healthcare professionals has changed in the COVID-19 pandemic. METHODS: The current study has a mixed design, which involves collecting both qualitative and quantitative data. In the first stage of the study, which is the quantitative one, Turkish Occupational Balance Questionnaire (OBQ11-T) was used to collect data, whereas the second stage of the study, which is the qualitative one, was designed to explore occupational balance and the related issues via using semi-structured interviews. The Mann-Whitney U test was used to compare parameters between the groups (working in active-passive contact with COVID patients). On the other hand, qualitative data were evaluated via consensual qualitative data analysis. RESULTS: The level of occupational balance of healthcare professionals included in the study group was found to be significantly lower than the level of occupational balance of healthcare professionals included in the control group (P = .005). Although there was no clear problem in self-care activities of healthcare professionals, the balance between productivity and leisure time activities was disrupted. CONCLUSIONS: Occupational balance and leisure time use of healthcare professionals, especially those who have active contact with COVID patients, have been affected. A further investigation can be carried out according to gender, age, and other demographic qualities.

An investigation of different intracellular parameters for Inborn Errors of Metabolism: Cellular stress, antioxidant response and autophagy.

Oxidative stress is associated with various disease pathologies including Inborn Errors of Metabolism (IEMs), among the most important causes of childhood morbidity and mortality. At least as much as oxidative stress in cells, reductive stress poses a danger to the disruption of cell homeostasis. p62/SQSTM1, protects cells from stress by activation of Nrf2/Keap1 and autophagy pathways. In this study, we tested the role of cellular stress, mitochondrial dysfunction and autophagy via Nrf2/Keap1/p62 pathway in the pathophysiology of three main groups of IEMs. Our results showed that antioxidant and oxidant capacity alone would not be sufficient to reflect the true clinical picture of these diseases. ATP, ROS and mitochondrial membrane potantial (MMP) measurements demonstrated increased cellular stress and bioenergetic imbalance in methylmalonic acidemia (MMA), indicating mild mitochondrial dysfunction. In isovaleric acidemia (IVA), no major change was detected in ATP, ROS and MMP values. Propionic acidemia (PA), mitochondrial diseases (MIT) and mucopolysaccharidosis IV (MPS IV) might point out mitohormesis to cope with chronic reductive stress. Induction of Nrf2/Keap1/p62 pathway and increased expression of HMOX1 were detected in all IEMs. LC3B-II and p62 expression results indicated an impaired autophagic flux in MIT and MPS IV and an induction of autophagic flux in MMA, PA and IVA, but also partial expression of Beclin1, enables autophagy activation, was detected in all IEMs. We conclude that individual diagnosis and treatments are of great importance in IEMs. In addition, we assume that the application of therapeutic antioxidant or preventive treatments without determining the cellular stress status in IEMs may disrupt the sensitive oxidant-antioxidant balance in the cell, leading to the potential to further disrupt the clinical picture, especially in patients with reductive stress. To the best of our knowledge, this is the first study to simultaneously relate IEMs with cellular stress, mitochondrial dysfunction, and autophagy.