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2.
Ital J Pediatr ; 50(1): 76, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38637879

ABSTRACT

BACKGROUND: Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of skin fragility disorders characterized by blister formation following minor trauma. Four major types are distinguished based on the level of cleavage within the skin. Most EB forms present severely disabling cutaneous and systemic signs and symptoms. Management relies on daily time-consuming and distressing topical medications, and symptomatic treatment of systemic findings. Disease manifestations, symptoms, and daily care strongly affect patient and caregiver quality of life (QoL). To date, there are two validated EB-specific questionnaires, the "Quality of Life in Epidermolysis Bullosa" (QOLEB) and the "Epidermolysis Bullosa Burden of Disease" (EB-BoD) for the evaluation of patient and family disease burden, respectively. The aim of our study was to develop an Italian translation of the two questionnaires and to pilot-test them. METHODS: The guidelines for translation and cross-cultural adaptation of health-related QoL measures were followed. Initially, two separate translations were generated for each questionnaire, and subsequently reconciled by an expert committee. This was followed by a back-translation process. The original texts and all translations underwent revision by the expert committee, resulting in definitive versions. The final versions were then tested in a pilot study involving cognitive debriefing in a group of 17 families, representative of all EB major types. RESULTS: The translation and reconciliation process led to minor changes to obtain semantic/idiomatic/cultural equivalence of the Italian versions with the original ones and to reconcile the questions with the answer options. The cognitive debriefing process showed a good understanding and did not require text modifications. CONCLUSIONS: The Italian versions of the QOLEB and EB-BoD provide valuable tools in everyday clinical practice of reference centers, and they allow the participation in multicenter international real-life observational studies as well as in controlled clinical trials. They enable the identification of disease-specific psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.


Subject(s)
Epidermolysis Bullosa , Quality of Life , Humans , Quality of Life/psychology , Pilot Projects , Epidermolysis Bullosa/diagnosis , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/psychology , Cost of Illness , Surveys and Questionnaires , Italy
4.
Mol Ther ; 32(5): 1497-1509, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38429928

ABSTRACT

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.


Subject(s)
Cell Adhesion , Epidermolysis Bullosa , Laminin , Lentivirus , Humans , Laminin/metabolism , Laminin/genetics , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/metabolism , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/pathology , Child , Lentivirus/genetics , Male , Female , Child, Preschool , Genetic Therapy/methods , Genetic Vectors/genetics , Epithelial Cells/metabolism , Cells, Cultured , Gene Expression , Adolescent , Infant
5.
Exp Dermatol ; 33(3): e15042, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38459626

ABSTRACT

In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)-exemplary for this group of diseases-describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo-epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non-curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes-non-aminoglycoside antibiotics and non-aminoglycoside compounds-are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.


Subject(s)
Codon, Nonsense , Epidermolysis Bullosa , Humans , Codon, Terminator , Gentamicins/pharmacology , Gentamicins/therapeutic use , Aminoglycosides/pharmacology , Aminoglycosides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/therapy
6.
Int J Mol Sci ; 25(4)2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38396920

ABSTRACT

The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient's skin upon minimal mechanical stress. Causal for this severe condition are genetic mutations in genes, leading to the functional impairment, reduction, or absence of the encoded protein within the skin's basement membrane zone connecting the epidermis to the underlying dermis. The major burden of affected families justifies the development of long-lasting and curative therapies operating at the genomic level. The landscape of causal therapies for EB is steadily expanding due to recent breakthroughs in the gene therapy field, providing promising outcomes for patients suffering from this severe disease. Currently, two gene therapeutic approaches show promise for EB. The clinically more advanced gene replacement strategy was successfully applied in severe EB forms, leading to a ground-breaking in vivo gene therapy product named beremagene geperpavec (B-VEC) recently approved from the US Food and Drug Administration (FDA). In addition, the continuous innovations in both designer nucleases and gene editing technologies enable the efficient and potentially safe repair of mutations in EB in a potentially permanent manner, inspiring researchers in the field to define and reach new milestones in the therapy of EB.


Subject(s)
Epidermolysis Bullosa , Humans , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/pathology , Skin/metabolism , Epidermis/metabolism , Blister , Mutation
9.
Orphanet J Rare Dis ; 18(1): 268, 2023 09 04.
Article in English | MEDLINE | ID: mdl-37667330

ABSTRACT

BACKGROUND: Inherited epidermolysis bullosa (EB) is a cluster of rare, genetic skin and mucosal fragility disorders with multi-system and secondary effects, in which blistering and erosions occur in response to friction/mechanical trauma. Considering the incurable and potentially life-limiting nature of the condition and the challenges posed by its symptoms, a palliative approach to EB-related care is necessary. However, knowledge and experience related to the provision of EB palliative care is minimal. Evidence-based, best care guidelines are needed to establish a base of knowledge for practitioners to prevent or ease suffering while improving comfort at all stages of the illness, not just the end of life. METHODS: This consensus guideline (CG) was begun at the request of DEBRA International, an international organization dedicated to improvement of care, research, and dissemination of knowledge for EB patients, and represents the work of an international panel of medical experts in palliative care and EB, people living with EB, and people who provide care for individuals living with EB. Following a rigorous, evidence-based guideline development process, the author panel identified six clinical outcomes based on the results of a survey of people living with EB, carers, and medical experts in the field, as well as an exhaustive and systematic evaluation of literature. Recommendations for the best clinical provision of palliative care for people living with EB for each of the outcomes were reached through panel consensus of the available literature. RESULTS: This article presents evidence-based recommendations for the provision of palliative healthcare services that establishes a base of knowledge and practice for an interdisciplinary team approach to ease suffering and improve the quality of life for all people living with EB. Any specific differences in the provision of care between EB subtypes are noted. CONCLUSIONS: Because there is yet no cure for EB, this evidence-based CG is a means of optimizing and standardizing the IDT care needed to reduce suffering while improving comfort and overall quality of life for people living with this rare and often devastating condition.


Subject(s)
Epidermolysis Bullosa , Palliative Care , Terminal Care , Epidermolysis Bullosa/therapy , Humans
11.
Clin Exp Dermatol ; 48(8): 920-925, 2023 Jul 21.
Article in English | MEDLINE | ID: mdl-37192348

ABSTRACT

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.


Subject(s)
Epidermolysis Bullosa , Glomerulonephritis, IGA , Adult , Humans , Epidermolysis Bullosa/blood , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa Simplex , Epidermolysis Bullosa, Junctional , Glomerulonephritis, IGA/blood , Glomerulonephritis, IGA/etiology , Glomerulonephritis, IGA/genetics , Glomerulonephritis, IGA/therapy
12.
Hemodial Int ; 27(3): E37-E40, 2023 07.
Article in English | MEDLINE | ID: mdl-37056043

ABSTRACT

Epidermolysis bullosa (EB) is a genetic disease characterized by skin fragility presenting with blistering and skin erosions. Recurrent skin infections are noted to be associated with the pathogenesis of IgA nephropathy. End stage kidney disease (ESKD) is a rare complication in patients with EB (Ducret F., et al., Nephrol Ther, 2008). Kidney replacement therapy is very challenging in this vulnerable patient population (Fine JD. et al., Am J Kidney Dis, 2004). Herein, we describe the adaptations to our home nocturnal hemodialysis training and operations to facilitate a patient with EB and ESKD to undergo personalized home nocturnal hemodialysis therapy.


Subject(s)
Epidermolysis Bullosa , Kidney Failure, Chronic , Humans , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/pathology , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/etiology , Renal Dialysis
13.
Adv Skin Wound Care ; 36(9): 486-494, 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37098819

ABSTRACT

OBJECTIVE: To identify cases and summarize outcomes of cutaneous malignancies in patients with epidermolysis bullosa (EB). DATA SOURCES: MEDLINE and EMBASE databases were searched on February 8, 2022. STUDY SELECTION: Original observational or experimental studies with cases of cutaneous malignancy in patients with inherited EB were included. DATA EXTRACTION: Data were extracted by two reviewers in duplicate. DATA SYNTHESIS: A total of 87 articles with 367 patients were included in this systematic review. Squamous cell carcinomas were the most common malignancy (94.3%) with a median survival of 60 months. The presence of metastasis was investigated at diagnosis in 77 patients; 18.8% of patients had detectable metastasis. Patients with squamous cell carcinoma with metastasis at diagnosis had significantly shorter median survival (16.8 months) than those without (72 months; P = .027). The remission rate was 47.6%. At the end of follow-up, 15.1% were alive with disease, and 41.6% were deceased. Other malignancies included malignant melanoma and basal cell carcinoma. The most common initial modes of management were excisions (71.9%) and amputations (17.6%). Other modes included chemotherapy (4.6%), radiation (3.9%), and no treatment (2.6%). The overall rate of recurrence or new lesions was 38.8%, with a median time of 16 months to recurrence or new lesions. Immediate recurrence was lowest following amputation (4.3%). There were no statistically significant differences in median survival among initial excision, amputation, and all other modes combined ( P = .30). CONCLUSIONS: Squamous cell carcinomas in patients with EB have a high likelihood of metastasis and mortality. Surgical excision is the most common intervention. There are no significant differences in survival among different initial management options. There is a need for research that documents and monitors outcomes of the treatment options.


Subject(s)
Carcinoma, Basal Cell , Carcinoma, Squamous Cell , Epidermolysis Bullosa , Melanoma , Skin Neoplasms , Humans , Skin Neoplasms/therapy , Skin Neoplasms/pathology , Carcinoma, Squamous Cell/therapy , Carcinoma, Squamous Cell/pathology , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/pathology
15.
Br J Dermatol ; 189(1): 80-90, 2023 07 07.
Article in English | MEDLINE | ID: mdl-37098154

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is a rare, genetically and clinically heterogeneous group of skin fragility disorders. No cure is currently available, but many novel and repurposed treatments are upcoming. For adequate evaluation and comparison of clinical studies in EB, well-defined and consistent consensus-endorsed outcomes and outcome measurement instruments are necessary. OBJECTIVES: To identify previously reported outcomes in EB clinical research, group these outcomes by outcome domains and areas and summarize respective outcome measurement instruments. METHODS: A systematic literature search was performed in the databases MEDLINE, Embase, Scopus, Cochrane CENTRAL, CINAHL, PsycINFO and trial registries covering the period between January 1991 and September 2021. Studies were included if they evaluated a treatment in a minimum of three patients with EB. Two reviewers independently performed the study selection and data extraction. All identified outcomes and their respective instruments were mapped onto overarching outcome domains. The outcome domains were stratified according to subgroups of EB type, age group, intervention, decade and phase of clinical trial. RESULTS: The included studies (n = 207) covered a range of study designs and geographical settings. A total of 1280 outcomes were extracted verbatim and inductively mapped onto 80 outcome domains and 14 outcome areas. We found a steady increase in the number of published clinical trials and outcomes reported over the past 30 years. The included studies mainly focused on recessive dystrophic EB (43%). Wound healing was reported most frequently across all studies and referred to as a primary outcome in 31% of trials. Great heterogeneity of reported outcomes was observed within all stratified subgroups. Moreover, a diverse range of outcome measurement instruments (n = 200) was identified. CONCLUSIONS: We show substantial heterogeneity in reported outcomes and outcome measurement instruments in EB clinical research over the past 30 years. This review is the first step towards harmonization of outcomes in EB, which is necessary to expedite the clinical translation of novel treatments for patients with EB.


Subject(s)
Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa , Humans , Epidermolysis Bullosa/therapy , Wound Healing , Registries , Patient Reported Outcome Measures
16.
Int J Mol Sci ; 24(7)2023 Mar 23.
Article in English | MEDLINE | ID: mdl-37047074

ABSTRACT

Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.


Subject(s)
Codon, Nonsense , Genetic Diseases, Inborn , Peptide Chain Elongation, Translational , Precision Medicine , Rare Diseases , Suppression, Genetic , Animals , Humans , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Codon, Nonsense/genetics , Cystic Fibrosis/genetics , Cystic Fibrosis/therapy , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/therapy , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/therapy , Nephritis, Hereditary/genetics , Nephritis, Hereditary/therapy , Nonsense Mediated mRNA Decay , Peptide Chain Elongation, Translational/drug effects , Precision Medicine/methods , Precision Medicine/trends , Rare Diseases/genetics , Rare Diseases/therapy , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/therapy , Shwachman-Diamond Syndrome/genetics , Shwachman-Diamond Syndrome/therapy , Suppression, Genetic/drug effects , Suppression, Genetic/genetics , Peptide Chain Termination, Translational/drug effects , Aminoglycosides/pharmacology
17.
J Palliat Med ; 26(8): 1159-1164, 2023 08.
Article in English | MEDLINE | ID: mdl-36888536

ABSTRACT

Background: Epidermolysis bullosa (EB) comprises a group of rare genetic conditions that are characterized by fragility of the skin and mucous membranes and formation of blisters with minor trauma. Severe forms can be life limiting. The palliative care needs of children with severe EB are poorly described. Aim: The aim of this case series was to examine the contribution of a pediatric palliative care service to the complex health care needs of children with severe EB. Methods: We present a case series of five children with severe forms of EB who were known to the state-wide Victorian Paediatric Palliative Care Service, with a discussion of our learnings in caring for these children and their families. Results: Medical treatment decision making in EB provokes complex ethical, psychological, personal, and professional dilemmas. This case series highlights the diversity of management approaches that may be considered, each tailored to the unique context of the child and family.


Subject(s)
Epidermolysis Bullosa , Hospice and Palliative Care Nursing , Child , Humans , Palliative Care , Epidermolysis Bullosa/therapy , Rare Diseases , Clinical Decision-Making
18.
Orphanet J Rare Dis ; 18(1): 38, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36823529

ABSTRACT

BACKGROUND: Anemia is a common complication of severe forms of epidermolysis bullosa (EB). To date, there are no guidelines outlining best clinical practices to manage anemia in the EB population. The objective of this manuscript is to present the first consensus guidelines for the diagnosis and management of anemia in EB. RESULTS: Due to the lack of high-quality evidence, a consensus methodology was followed. An initial survey exploring patient preferences, concerns and symptoms related to anemia was sent to EB patients and their family members. A second survey was distributed to EB experts and focused on screening, diagnosis, monitoring and management of anemia in the different types of EB. Information from these surveys was collated and used by the panel to generate 26 consensus statements. Consensus statements were sent to healthcare providers that care for EB patients through EB-Clinet. Statements that received more than 70% approval (completely agree/agree) were adopted. CONCLUSIONS: The end result was a series of 6 recommendations which include 20 statements that will help guide management of anemia in EB patients. In patients with moderate to severe forms of EB, the minimum desirable level of Hb is 100 g/L. Treatment should be individualized. Dietary measures should be offered as part of management of anemia in all EB patients, oral iron supplementation should be used for mild anemia; while iron infusion is reserved for moderate to severe anemia, if Hb levels of > 80-100 g/L (8-10 g/dL) and symptomatic; and transfusion should be administered if Hb is < 80 g/L (8 g/dL) in adults and < 60 g/L (6 g/dL) in children.


Subject(s)
Anemia , Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa , Child , Adult , Humans , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/diagnosis , Epidermolysis Bullosa/therapy , Anemia/diagnosis , Anemia/drug therapy , Anemia/etiology , Consensus , Health Personnel , Iron
19.
Int J Dermatol ; 62(4): 459-475, 2023 Apr.
Article in English | MEDLINE | ID: mdl-35524482

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is an inherited genodermatosis that results in mucocutaneous fragility. There is a lack of data on the impact of this disease on parents. There are no studies on the impact on siblings and few on healthcare professionals in dealing with this devastating disease. METHODS: A scoping review was performed using the Arksey and O'Malley and PRISMA-ScR framework. Twenty-seven articles were reviewed, and a data-charting sheet was formulated. RESULTS: Parents make great sacrifices and are resilient in caring for their sick children but are at risk of depression. Siblings play a vital role in caring for their siblings, but their needs may be overlooked because the main focus is on the sibling with EB. Healthcare professionals may suffer burnout and compassion fatigue in caring for patients and their families with EB. CONCLUSION: Comprehensive care of the family and the awareness of the challenges experienced by healthcare professionals is essential to the holistic care of a patient with EB.


Subject(s)
Epidermolysis Bullosa , Child , Humans , Epidermolysis Bullosa/therapy , Siblings , Health Personnel , Delivery of Health Care
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