Mutation update: The spectra of PLEC sequence variants and related plectinopathies.

Plectin, encoded by PLEC, is a cytoskeletal linker of intermediate filaments expressed in many cell types. Plectin consists of three main domains that determine its functionality: the N-terminal domain, the Rod domain, and the C-terminal domain. Molecular defects of PLEC correlating with the functional aspects lead to a group of rare heritable disorders, plectinopathies. These multisystem disorders include an autosomal dominant form of epidermolysis bullosa simplex (EBS-Ogna), limb-girdle muscular dystrophy (LGMD), aplasia cutis congenita (ACC), and an autosomal recessive form of EBS, which may associate with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and/or congenital myasthenic syndrome (EBS-MyS). In this study, genotyping of over 600 Iranian patients with epidermolysis bullosa by next-generation sequencing identified 15 patients with disease-causing PLEC variants. This mutation update analyzes the clinical spectrum of PLEC in our cohort and in the literature and demonstrates the relationship between PLEC genotype and phenotypic manifestations. This study has integrated our seven novel PLEC variants and phenotypic findings with previously published data totaling 116 variants to provide the most complete overview of pathogenic PLEC variants and related disorders.

Pathomechanisms of epidermolysis bullosa: Beyond structural proteins.

Epidermolysis bullosa (EB), a phenotypically and genetically heterogeneous disorder, has been linked to mutations in the genes encoding structural proteins that reinforce skin integrity via dermal-epidermal adhesion. Breakdowns in these adhesion mechanisms result in four different subtypes of EB classified on the basis of the level of tissue separation within the cutaneous basement membrane zone (BMZ). Mutations in as many as 17 distinct genes that encode structural proteins in the BMZ have been linked to EB. Despite the clinical and histopathological confirmation of EB, many cases remain genetically unsolved. Technical advancements in next-generation sequencing have paved the way for the identification of genes involved in the pathophysiology of EB. Structural proteins have long been identified as the candidate molecules altered in EB, however, recently non-structural proteins, encoded for example by PLOD3, USB1, EXPH5, and KLHL24, involved in enzymatic modification or migration of structural proteins have been implicated. In this overview, we discuss recent work regarding these proteins vis-à-vis their function, associated clinical manifestations, and involvement in the pathogenesis of EB.

Pathogenic DST sequence variants result in either epidermolysis bullosa simplex (EBS) or hereditary sensory and autonomic neuropathy type 6 (HSAN-VI).

DST encodes bullous pemphigoid antigen-1 (BPAG1), a protein with eight tissue-specific isoforms expressed in the skin, muscle, brain and nerves. Accordingly, mutations in this gene are associated with epidermolysis bullosa simplex (EBS) and hereditary sensory and autonomic neuropathy type 6 (HSAN-VI). The genotypic spectrum is attested to by 19 distinct mutations but genotype-phenotype correlation for both disorders is not well established. In this study, we performed next-generation sequencing (NGS) on two families with different phenotypic presentations, one foetus (P1) with musculoskeletal and neurological malformations established by prenatal ultrasound and family history, and a 15-year-old female patient (P2) with skin blistering. P1 had a novel homozygous nonsense mutation, DST: NM_001144769, c.3805C>T, p.R1269* within a region of genetic homozygosity (ROH). This mutation resides within the plakin domain of BPAG1 and ablates all isoforms of this protein, leading to novel extracutaneous phenotypes consistent with HSAN-VI in P1. P2 had a recurrent homozygous mutation DST: NM_001723.7, c.3370C>T, p.Gln1124* that presented with giant, trauma-induced skin blisters without extracutaneous involvement. This mutation is located within the coiled-coil domain present in the skin isoform of DST, BPGA1-e, associated with EBS. In summary, we report two families with pathogenic DST variants and expand the spectrum of DST genotype and phenotypes.

The Impact of COVID-19 on Teledermatology: A Review.

The accelerated implementation and use of teledermatology during the coronavirus disease 2019 pandemic has met with successes and challenges. This review explores how telemedicine was used in dermatology before the pandemic, the regulatory adaptions made in response to the pandemic, and the effectiveness of the rapid implementation of teledermatology during the coronavirus disease 2019 pandemic, and, finally, how teledermatology has expanded in response to the pandemic. This review examines lessons learned and how teledermatology's reliance on digital technologies might paradoxically exacerbate health care disparities, and finally, considers the future outlook.

The Use of Clozapine in the Serious Mental Illness Patients Enrolled in an Assertive Community Treatment Program.

Introduction Health care cost is projected to reach 20% of the nation's gross national product (GNP) by 2016. 6.2% of this is from mental health. The National Institute of Mental Health (NIMH) estimates the prevalence of serious mental illness (SMI) at 13.1 million or 5.2% of American adults age 18 or over. Hence, mental health care cost for this patient population is significant. Patients with SMI involved in an Assertive Community Treatment (ACT) program are individuals who experience the most intractable symptoms and the greatest level of dysfunction from their mental illness. These individuals typically are institutionalized in a long-term facility such as the state hospital. Clozapine has shown superior efficacy over first- and most second-generation antipsychotics in both treating treatment-resistant and non-treatment-resistant schizophrenia which has been supported by several large trials. There is also evidence of its efficacy in suicidality, aggression and substance misuse. In fact, clozapine has been approved by the FDA for use in refractory schizophrenia and suicidality in schizoaffective disorder. Due to the risk of agranulocytosis, clozapine is underutilized. The purpose of this study is to conduct a retrospective cohort study through chart review to analyze whether the addition of clozapine to ACT treatment of SMI patients in a community hospital from 2008 to 2018 led to decreased frequency of hospitalizations and increased clinical stability. Materials and methods A retrospective study using electronic medical record (EMR) of patients ages 20 and above who were enrolled in the ACT program at a community hospital from December 1, 2008 to December 31, 2018. Variables were collected from the EMR and de-identified during data collation. Analysis was performed using SPSS software package. Results A total of 179 patients enrolled in the ACT program and their data was extracted from the EMR. Twenty-five (62.5%) of these patient enrollments were on clozapine. They were made up of 53.6% male, 81.9% White/Asian, 18.1% Black; 44.1% ages between 36 to 50 years old, 30.2% were aged 18 to 35 years old, and 25.7% greater than 50 years old. There was no difference in age, sex, race, ethnicity, and insurance type in ACT program between those using clozapine and those not on clozapine. There was a higher proportion of psychiatric hospitalizations among clozapine users compared with the non-clozapine user group (62.5% vs 41.5%, p = 0.019). However, the two groups did not differ from one another in terms of psychiatric emergency visits (p = 0.128) or frequency of ACT visits (p = 0.002). Conclusion Effective treatment that will reduce hospitalizations and the burden of chronic disability in patients with SMI would greatly reduce mental health care cost. Clozapine remains the gold standard in the treatment of refractory schizophrenia. But due to the risk of agranulocytosis, clozapine is underutilized. It was hoped that this study will support the use of clozapine in SMI patients. Disappointingly, the use of clozapine did not prevent relapses and hospitalizations in this patient population and patients on clozapine seemed to have increased hospitalizations, compared to those who were not on clozapine. Perhaps, a different outcome would have occurred if the focus was limited to the patients themselves who were on Clozapine and ascertain what the rate of hospitalization was before the start of clozapine vs after the use of clozapine.

The Use of Long-Acting Injectable Antipsychotics (LAI) in the Serious Mental Illness (SMI) Patients Enrolled in an Assertive Community Treatment (ACT) Program.

Introduction Patients with serious mental illness (SMI) experience highly intractable symptoms and great levels of dysfunction from their mental illness. Relapse prevention is critical as psychopathology, social and occupational functioning worsen with repeated psychotic episodes. Poor medication adherence is a strong predictor of relapse. Use of long-acting injectable antipsychotics (LAI) is among the most effective treatment specially in the context of non-adherence and yet remains underutilized. This single center retrospective study conducted using the electronic medical record (EMR) of patients enrolled in an Assertive Community Treatment (ACT) program at a community hospital was analyzed as to whether use of LAI among these patients reduce the frequency of emergency room visits and hospitalizations. Materials and methods Single center retrospective study using EMR of patients ages 20 and above who were enrolled at the ACT program at a community hospital from December 1, 2008 to December 31, 2018. Variables were collected from the EMR and de-identified into an Excel spreadsheet for data collation. Analysis was performed using SPSS software package. Results A total of 179 patients enrolled in the ACT program and their hospitalizations were extracted from the EMR. Seventy-six (42.5%) of these hospitalizations had patients on LAI. The hospitalizations were made up of 53.6% male, 81.9% White/Asian, 18.1% Black; 44.1% ages between 36 and 50 years old, 30.2% ages between 18 and 35 years old, and 25.7% greater than 50 years old. There was no difference in age, sex, race, ethnicity, insurance type and time spent in ACT program between those using LAI and those not on LAI. There was a higher proportion of psychiatric hospitalizations among LAI users compared with the non-LAI user group (57.9% vs 37.4%, p = 0.007). However, the two groups did not differ from one another in terms of psychiatric emergency visits (p = 0.266) or frequency of ACT visits (p = 0.062). Conclusion To date, all of the new-generation antipsychotic LAI have demonstrated a statistically and clinically significant decrease of relapse rates over placebo. Despite this, LAIs are not widely prescribed for a variety of reasons, including the reservations of patients, clinicians and payers. It would seem, though, that our patient population at the ACT program do not seem to benefit from use of LAI in relapse prevention. These results are counterintuitive in that one would expect that patients with serious mental illness would benefit from use of LAI. Perhaps, individuals with SMI are a different subset of population and they do not respond as well to LAI.

Kindler epidermolysis bullosa-like skin phenotype and downregulated basement membrane zone gene expression in poikiloderma with neutropenia and a homozygous USB1 mutation.

Epidermolysis bullosa (EB) is a genotypically heterogeneous group of disorders characterized by cutaneous blistering and erosions with a tremendous spectrum of severity. One of the distinct forms of EB, Kindler EB (KEB), manifests with blistering and poikiloderma; this subtype of EB is caused by mutations in the FERMT1 gene encoding kindlin-1. In this study, we investigated a patient clinically diagnosed as KEB with reduced FERMT1 gene expression and intensity of immunostaining for kindlin-1. Transmission electron microscopy showed lamina densa reduplication, frequently observed in KEB. However, no mutations were identified in FERMT1 in this patient with consanguineous parents, and this gene resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous sequence variant at the +4 position of intron 2 in the USB1 gene, encoding an exoribonuclease required for processing of U6 snRNA, a critical component of spliceosomes. Examination of the patient's RNA by RNA-Seq confirmed the pathogenicity of this variant, causing aberrant splicing predicted to result in loss of function of USB1. Mutations in this gene have been reported in patients with poikiloderma and neutropenia, with a few reported cases in association with skin fragility, a condition distinct from the KEB phenotype. Transcriptome analysis revealed that several genes, expressed in the cutaneous basement membrane zone and previously associated with different subtypes of EB, were differentially downregulated at the mRNA level. EB-associated mRNA downregulation was confirmed at protein levels by skin immunofluorescence. These observations provide a novel mechanism for blistering and erosions in the skin as a result reduced presence of adhesion complexes critical for stable association of epidermis and dermis at the level of cutaneous basement membrane zone.