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Background Monogenic neurodegenerative diseases represent a heterogeneous group of disorders caused by mutations in genes involved in various cellular functions including autophagy, which mediates degradation of cytoplasmic contents by their transport into lysosomes. Abnormal autophagy is associated with hereditary ataxia and spastic paraplegia, amyotrophic lateral sclerosis and frontal dementia, characterised by intracellular accumulation of non-degraded proteins. We investigated the genetic basis of complex HSP in a consanguineous family of Arab-Muslim origin, consistent with autosomal recessive inheritance. Methods Exome sequencing was followed by variant filtering and Sanger sequencing for validation and familial segregation. Studies for mRNA and protein expression used real-time PCR and immunoblots. Patients' primary fibroblasts were analysed using electron microscopy, immunofluorescence, western blot analysis and ectopic plasmid expression for its impact on autophagy. Results We identified a homozygous missense variant in CHMP3 (Chr2:86507484 GRCh38 (NM_016079.4): c.518C>T, p.Thr173Ile), which encodes CHMP3 protein. Segregation analysis validated the presence of the homozygous variant in five affected individuals, while healthy family members were found either heterozygous or wild type for this variant. Primary patient's fibroblasts showed significantly reduced levels of CHMP3. Electron microscopy disclosed accumulation of endosomes, autophagosomes and autolysosomes in patient's fibroblasts, which correlated with higher levels of autophagy markers, p62 and LC3-II. Ectopic expression of wild-type CHMP3 in primary patient fibroblasts led to reduction of the p62 particles accumulation and number of endosomes and autophagosomes compared with control. Conclusions Reduced level of CHMP3 is associated with complex spastic paraplegia phenotype, through aberrant autophagy mechanisms. [ABSTRACT FROM AUTHOR]

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life‐threatening plexiform neurofibroma in a 9‐month‐old female infant with NF1. Germline mutations in two RASopathy‐associated genes were identified using whole‐exome sequencing—a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein‐coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild‐type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non‐NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy. [ABSTRACT FROM AUTHOR]

Ichthyosis and deafness syndrome is a group of devastating genodermatoses caused by heterozygous mutations in GJB2, encoding the gap junction protein connexin 26. These syndromes are characterized by severe skin disease, hearing loss, recurrent infections, and cutaneous neoplasms. Cutaneous somatic mutations in the same gene are associated with porokeratotic eccrine ostial dermal duct nevus. Here we report a family in which a parent presented with localized epidermal nevus and his child suffered with hystrix‐like ichthyosis with deafness. Histologic examination of the parent's cutaneous lesion revealed verrucous epidermal nevus without features of porokeratotic eccrine ostial dermal duct nevus. Genetic analysis identified the same pathogenic variant, GJB2 c.148G>A (p.D50N), in DNA extracted from the parent's cutaneous lesion and the child's leukocytes, but not in the parent's leukocytes. This study expands the phenotypic heterogeneity of GJB2 mosaic variants in addition to porokeratotic eccrine ostial dermal duct nevus, and emphasizes the importance of molecular diagnosis of mosaic skin diseases considering the risk of severe inherited diseases in the offspring. [ABSTRACT FROM AUTHOR]

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo‐plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis‐localization, leading to enhanced epidermal desquamation. We investigated two Arab‐Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo‐plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis‐localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age‐ and gender‐matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling. [ABSTRACT FROM AUTHOR]

The article presents a case study of 10-year-old girl who was presented with hypotrichosis and follicular keratinization abnormality. It notes the treatment of hair follicle disorder with keratosis pilaris atrophicans (KPA), presence of desmosomal cadherin DSG4 in hair follicle and autosomal recessive (AR) inheritance in KPA caused by mutation in DSG4.

It is unclear whether patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) continue to harbor the same genotype during hospital readmissions. We characterized 140 MRSA strains isolated from 33 persistent MRSA carriers with hospital readmissions. Nearly half of the patients continued to harbor the same genotype, and the rest acquired different genotypes. Among 25 patients who received eradication therapy, 16 (64%) were colonized with MRSA strains exhibiting different genotypes from the preexisting one.