Materiały źródłowe

• #1 Recent advances in understanding ichthyosis pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4926734/

  The ichthyoses, also known as disorders of keratinization (DOK), encompass a heterogeneous group of skin diseases linked by the common finding of abnormal barrier function, which initiates a default compensatory pathway of hyperproliferation, resulting in the characteristic clinical manifestation of localized and/or generalized scaling. […] Advances in next-generation sequencing technology have allowed for more rapid and cost-effective genetic analysis, leading to the identification of novel, rare mutations that cause DOK, many of which represent phenotypic expansion. This review focuses on new findings in syndromic and nonsyndromic ichthyoses, with emphasis on novel genetic discoveries that provide insight into disease pathogenesis. […] Mutations in over 50 genes have been reported to cause ichthyoses, and these affect a host of cellular functions including DNA repair, lipid biosynthesis, adhesion, and desquamation as well as other pathways. Despite myriad pathways for pathogenesis, each features disrupted barrier function.

• #2

  https://link.springer.com/article/10.1007/s40257-017-0313-x

  Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. […] Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. […] On the basis of new knowledge about the pathophysiology of different types of ichthyoses, novel and more individualized treatment options will hopefully soon become available. […] Virtually all types of ichthyosis show abnormal properties of the two outermost skin layers, the stratum granulosum and the stratum corneum, causing impairments of the skin barrier function. […] In principle, hyperkeratosis is a combined or isolated result of three mechanisms: (1) epidermal hyperproliferation, (2) increased cohesion of corneocytes, and (3) decreased desquamation from the skin surface.

• #3 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-are-Ichthyoses.aspx

  Ichthyoses involve a group of genetic disorders, caused by the inheritance of a fault or defective gene. Several mutations linked to different types of ichthyoses have been discovered over the years. Ichthyoses have been linked to mutations in more than 50 genes. […] Although the Online Mendelian Inheritance in Man (OMIM) database lists 11 genetic subgroups for ARCI. […] Loss-of-function mutations in the ABCA12 gene, which genes for an ATP-binding cassette (ABC) transporter, induce harlequin. This gene is required for lipid transport into lamellar granules and is essential for cornification and the creation of lipid barriers. […] The majority of ichthyosis treatments work to increase the skin’s barrier function. […] Furthermore, the development of gene therapy holds enormous potential for treating patients with these illnesses and should be pursued.

• #4 UPDATED MOLECULAR GENETICS AND PATHOGENESIS OF ICHTHYOSES

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4831217/

  Transglutaminase 1 plays a role in cornified cell envelope formation. […] Most ichthyosis phenotypes mentioned above exhibit a primary abnormality associated with a barrier function in the stratum corneum as their underlying pathogenetic mechanisms. […] The skin barrier of the stratum corneum has three major components, i.e., intercellular lipid layers, a cornified cell envelope and keratin/filaggrin degradation products. […] The formation of the intercellular lipid layers is essential for epidermal barrier function, and the defective formation of those layers is thought to result in a serious loss of barrier function, and to lead to extensive hyperkeratosis. […] ABCA12 has been highlighted, because it was recognized as a key molecule in keratinocytes lipid transport. […] Mutations in the lipid transporter protein ABCA12 cause defective lipid accumulations into lamellar granules, resulting in malformation of the intercellular lipid layers of the stratum corneum.

• #5 New developments in the molecular treatment of ichthyosis: review of the literature | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02430-6

  Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. […] Promising developments have been made in pathogenesis-based therapies, such as enzyme replacement therapy and gene therapy, and recent findings concerning the immune profile of ichthyosis patients have given new ground to repurpose biologicals. […] Mutations in over 50 genes are known to cause an ichthyosis phenotype. Four processes in skin cornification can be involved in the pathophysiology, i.e., the process of desquamation, impairment in the keratin synthesis, impairment in the synthesis of the cornified envelope or impairment in the organization of the stratum corneum extracellular lipid matrix. This leads to an altered epidermal differentiation, a defective epidermal barrier and increased transepidermal water loss (TEWL).

• #6 Ichthyosis: A Road Model for Skin Research | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3433

  The understanding of monogenetic disorders of cornification, including the group of diseases called ichthyoses, has expanded greatly in recent years. Studies of the aetiology of more than 50 types of ichthyosis have almost invariably uncovered errors in the biosynthesis of epidermal lipids or structural proteins essential for normal skin barrier function. The barrier abnormality per se may elicit epidermal inflammation, hyperproliferation and hyperkeratosis, potentially contributing to the patients skin symptoms. […] This overview exemplifies a wide range of approaches used to elucidate the aetiopathogenesis of various types of ichthyosis, research that concurently results in a better understanding of normal human skin biology and yields new ideas about dermatotherapy. […] Despite a thick stratum corneum (SC), patients with ichthyosis usually have variably increased transepidermal water loss (TEWL). This is due to various defects in the biosynthesis of proteins and lipids essential for normal barrier formation, specific for each of the 4 main types of non-syndromic ichthyosis.

• #7 Ichthyosis vulgaris

  https://dermnetnz.org/topics/ichthyosis-vulgaris

  Ichthyosis vulgaris results from loss-of-function mutations in the gene encoding the protein filaggrin (FLG), which is mapped on the epidermal differentiation complex on chromosome 1q21. The mutations lead to defective production of filaggrin. […] Filaggrin is a filament-associated epidermal protein required for the binding of keratin fibres in epidermal cells, to form an effective skin barrier. It helps maintain the skin pH, retain moisture in the stratum corneum, and reduce trans-epidermal water loss (TEWL). […] Xerosis or dryness results from the reduced skin hydration associated with defective filaggrin. Excessive scale results from the inability of the squames (skin cells) to remain hydrated as they move upward through the stratum corneum. Hyperkeratosis results from compensatory repair mechanisms increasing cell proliferation.

• #8 Hereditary and Acquired Ichthyosis Vulgaris: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1112753-overview

  Hereditary ichthyosis vulgaris is an autosomal dominant genetic disorder first evident in early childhood. It is the most common form of ichthyosis, accounting for more than 95% of ichthyosis cases. Mutations in genes relating to skin barrier formation produce it. […] It is often caused by altered profilaggrin expression leading to scaling and desquamation. […] The protein filaggrin is important in maintaining effective skin barrier function. Loss-of-function mutations in the profilaggrin gene (FLG) are evident in up to 10% of the population, causing ichthyosis vulgaris and representing a major risk factor for the development of atopic dermatitis. […] This discovery, in 2006, represented a marked a breakthrough in the understanding of these disorders. […] Ichthyosis vulgaris is classified as a retention hyperkeratosis. The only known molecular marker affected by hereditary ichthyosis vulgaris is profilaggrin, a high molecular weight filaggrin precursor.

• #9 Hereditary and Acquired Ichthyosis Vulgaris: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1112753-overview

  Profilaggrin, synthesized in the granular layer of the epidermis, is a major component of keratohyalin granules. Through various posttranslational modifications, profilaggrin is converted to filaggrin, which aggregates keratin intermediate filaments in the lower stratum corneum. […] Normal expression of the profilaggrin gene can be first detected in the granular layer. In ichthyosis vulgaris, the expression of profilaggrin is absent or reduced in the epidermis. This biochemical abnormality correlates with the decreased numbers of keratohyalin granules and the clinical severity of the condition. […] The profilaggrin gene is part of a cluster of genes on 1q21 that encodes for structural proteins expressed in terminally differentiating epidermis. […] An association exists between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis.

• #10 Hereditary and Acquired Ichthyosis Vulgaris: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1112753-overview

  Two common filaggrin (FLG) null mutations cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. […] Comprehensive analysis of the gene encoding filaggrin uncovered prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. […] Filaggrin mutations p.R501X and c.2282del4 were analyzed in patients with ichthyosis vulgaris. […] Homozygotes and compound heterozygotes may be severely affected, whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. […] The presence of FLG mutations in 15 of 21 ichthyosis vulgaris patients were studied with a marked generalized scaling phenotype, including 8 affected members of a 4-generation family. […] Filaggrin mutation c.3321delA was identified in a Korean patient with ichthyosis vulgaris and atopic dermatitis.

• #11

  https://www.jci.org/articles/view/111552

  The pathological scaling in recessive x-linked ichthyosis is associated with accumulation of abnormal quantities of cholesterol sulfate in stratum corneum. […] To determine whether or not cholesterol sulfate accumulates in recessive x-linked ichthyosis as a direct result of the missing enzyme, steroid sulfatase, we quantitated both steroid sulfatase and its substrate, cholesterol sulfate, in different epidermal strata, as well as within stratum corneum subcellular fractions obtained from normal human and neonatal mouse epidermis and from patients with recessive x-linked ichthyosis. […] In contrast, in recessive x-linked ichthyosis epidermis, enzyme levels were virtually undetectable at all levels. […] In both normal and in recessive x-linked ichthyosis stratum corneum, cholesterol sulfate appeared primarily within membrane domains, paralleling the pattern of steroid sulfatase localization.

• #12

  https://www.jci.org/articles/view/111552

  Finally, the role of excess cholesterol sulfate in the pathogenesis of recessive x-linked ichthyosis was directly tested by topical applications of this substance, which produced visible scaling in hairless mice in parallel to an increased cholesterol sulfate content of the stratum corneum. […] In contrast, in recessive x-linked ichthyosis, degradation of cholesterol sulfate does not occur and cholesterol sulfate accumulates specifically in the stratum corneum, where it produces visible scale.

• #13 Ichthyosis – Wikipedia

  https://en.wikipedia.org/wiki/Ichthyosis

  Ichthyosis is a family of genetic skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cause and mode of inheritance (e.g., dominant, recessive, autosomal or X-linked). Ichthyosis comes from Greek (ichthys)’fish’, since dry, scaly skin is the defining feature of all forms of ichthyosis. […] Ichthyosis has been found to be more common in Native American, Asian, Mongolian groups. There is no way to prevent ichthyosis. […] Ichthyosis is a genetically and phenotypically heterogeneous disease that can be isolated and restricted to the skin manifestations or associated with extracutaneous symptoms, one of which is limb reduction defect known as CHILD syndrome, a rare inborn error of metabolism of cholesterol biosynthesis that is usually restricted to one side of the body.

• #14 X linked recessive ichthyosis: Current concepts

  https://www.wjgnet.com/2218-6190/full/v4/i3/129.htm

  The STS protein has 583 amino acids with a molecular weight of 62 kDa. The first 22 amino acids correspond to the leader peptide, which is cleaved post-translationally to give rise to the mature enzyme. […] The STS enzyme is attached to the rough endoplasmic reticulum and hydrolyzes the sulfate groups of the sulfated 3-hydroxysteroids such as dehydroepiandrosterone sulfate (DHEAS), cholesterol sulfate, pregnenolone sulfate and androstenediol 3 sulfate, metabolites that serve as precursors for estrogens, androgens, and cholesterol. […] More than 90% of XLI patients present a complete STS gene deletion and flanked sequences, the remainders have showed 7 intragenic deletions whereas 14 point mutations with a complete loss of the STS activity have been reported. […] One explanation for the deletion of the STS gene and flanking sequences on the short arm of the X chromosome is the presence of families of repeated sequences in low copy number on both sides of the STS gene.

• #15 X linked recessive ichthyosis: Current concepts

  https://www.wjgnet.com/2218-6190/full/v4/i3/129.htm

  The increase of CS induces the expression of the skin barrier protein filaggrin and plays a role in the differentiation of normal keratinocyte. […] Rupture of CS cycle by STS defect produces an increase of CS from 1% to 10%-12% in the stratum corneum of the epidermis; this results in: (1) a decrease barrier function with a failure of the normal liquid-crystalline transition phase of intercellular lipids; and (2) an abnormal corneocyte retention stimulating the hyperplasia epidermal-inflammation and a thickened stratum corneum. […] The increase of CS is in relation with the decrease of the activity serine protease and the increase of Ca2+, producing corneodesmosomal retention.

• #16 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Types-of-Ichthyosis.aspx

  Ichthyosis is an inherited group of skin disorders characterized by xerosis and scaling. […] The Ichthyosis Consensus Conference produced a consensus classification for ichthyosis in 2009 based on pathophysiology, clinical symptoms, and manner of inheritance. […] Ichthyosis Vulgaris and X-linked recessive ichthyosis are the most frequent, both caused by well-known genetic abnormalities. […] IV is caused by autosomal dominant mutations in the filaggrin gene (FLG), which is required for epidermal development and skin barrier formation. […] Loss-of-function mutations in ABCA12, which encodes an ATP-binding cassette (ABC) transporter, induce HI. […] ABCA12 is required for lipid transport into lamellar granules and is important in cornification and lipid barrier formation. […] Mutations in the keratin family genes KRT1, KRT2, and KRT10 cause all kinds of keratinopathic ichthyosis. […] Histological findings include epidermal thickening in ichthyotic skin and keratinocyte differentiation disruption with parakeratosis.

• #17 Harlequin-type ichthyosis – Wikipedia

  https://en.wikipedia.org/wiki/Harlequin-type_ichthyosis

  Harlequin-type ichthyosis is caused by mutations in the ABCA12 gene. This gene codes for a protein necessary for transporting lipids out of cells in the outermost layer of skin. The disorder is autosomal recessive and inherited from parents who are carriers. […] Harlequin-type ichthyosis is caused by a loss-of-function mutation in the ABCA12 gene. This gene is important in regulating protein synthesis for the development of the skin layer. Mutations in the gene cause impaired transport of lipids in the skin layer and may also lead to shrunken versions of the proteins responsible for skin development. […] ABCA12 is thought to be a lipid transporter in keratinocytes necessary for lipid transport into lamellar granules during the formation of the lipid barrier in the skin.

• #18 Harlequin Ichthyosis (Pathogenesis, Morphology, and Diagnosis)

  https://repository.limu.edu.ly/handle/123456789/2016

  Ichthyosis are a family of 20 congenital diseases that produce a dense hyperkeratotic Epidermis Harlequin ichthyosis is the most serious and often lethal form of recessive congenital ichthyosis. […] Severe ABCA12 deficiency results in malformation of intercellular lipid layers in the cornified layers and leads to epidermal lipid barrier disruption. […] In HI patients, at least one mutation on each allele must be a truncation or deletion mutation to cause serious loss of ABCA12 function. […] This report was undertaken with an objectives to review the mutation in (ABAC12) underline the severe congenital skin disease and to know the prenatal diagnosis of harlequin ichthyosis and to describe the pathomechanism of harlequin ichthyosis and the characteristic morphologic abnormality of harlequin ichthyosis detected in amniotic fluid cells.

• #19 UPDATED MOLECULAR GENETICS AND PATHOGENESIS OF ICHTHYOSES

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4831217/

  Research into the molecular genetics and pathomechanisms of ichthyoses have advanced considerably, resulting in the identification of several causative genes and molecules underlying the disease. […] Skin barrier defects are involved in the pathogenesis of various types of ichthyosis. […] The known causative molecules underlying ichthyosis include ABCA12, lipoxygenase-3, 12R-lipoxygenase, CYP4F22, ichthyin and steroid sulfatase, all of which are thought to be related to the intercellular lipid layers. […] ABCA12 is a known keratinocyte lipid transporter associated with lipid transport in lamellar granules and a loss of ABCA12 function leads to defective lipid transport in the keratinocytes, resulting in the most severe, harlequin ichthyosis phenotype. […] Other causative molecules for ichthyoses are transglutaminase 1, keratins and filaggrin.

• #20 UPDATED MOLECULAR GENETICS AND PATHOGENESIS OF ICHTHYOSES

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4831217/

  The fact that ABCA3 (a member of the same protein superfamily as ABCA12) functions in pulmonary surfactant lipid secretion via the production of similar lamellar-type granules within lung alveolar type II cells further supports this concept. […] There is little doubt that the defective formation of the stratum corneum intercellular lipid layers is caused by abnormal keratinocyte lipid metabolism, transport, and/or secretion, constituting one of the major pathogenetic mechanisms underlying congenital ichthyosis. […] Several critical molecules causing ichthyosis are thought to be involved in the formation of the stratum corneum intercellular lipid layers.

• #21 New developments in the molecular treatment of ichthyosis: review of the literature | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02430-6

  The genetic defect in ARCI is based on mutations in numerous genes. The most common form of ARCI is caused by mutations in the transglutaminase-1 (TGM1) gene, which encodes for the transglutaminase-1 (TG1) protein. TG1 mediates crosslinking of cytoplasmic proteins onto the plasma membrane to form the cornified envelope. […] In NS, there is a LEKTI deficiency resulting in unrestrained KLK activation in the epidermis. This obstructs stratum corneum cohesion and therefore leads to detachment of the stratum corneum, causing a severe permeability barrier defect. […] The mutations may also interfere with lamellar body secretion and therefore the lipid membrane formation, causing impaired barrier function. […] Gene therapy is aiming to restore the wild type gene function. In another genodermatosis, epidermolysis bullosa (EB), gene therapy has led to promising results.

• #22 Lamelar Ichthyosis – Athenaeum Scientific Publishers

  https://athenaeumpub.com/lamelar-ichthyosis/

  Lamellar ichthyosis is a genetic autosomal recessive skin disease that appears at birth in the form of collodion membrane that covers all over body of the baby. Lamellar ichthyosis is generated by gene mutation which is located in chromosome 14q11 that serves to code Transglutaminase 1 (TGM-1) enzyme synthesis. […] The mutated gene in LI is TGM-1 gene locus that serves in the formation of lipid and protein component in corneum stratum. TGM-1 gene is located in chromosome 14q11. TGM-1 gene serves to catalyze the cellular protein bond, including involucrin, loricrin, small protein that is rich with proline, keratin, and filaggrin during the formation of corneum stratum. The protein complex will deposed into plasm membrane creating cornification sheath. Transglutaminase 1 also functions in ceramide adhesion in lamellar body, therefore the role is essential in the formation of protein and lipid component of corneum stratum.

• #23 A shared Th17-dominant immune profile across the ichthyosis spectrum – Research Day 2017

  https://www.feinberg.northwestern.edu/researchday/2017/showItem.php?id=104348

  Expression of these markers was highly correlated with overall ichthyosis severity (total IASI), erythema (IASI-E), and TEWL, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. […] Overall, the data shows that all ichthyoses share impressive TH17/IL-23 skewing in skin with strong expression of IL-17/TNF-synergistic/additive markers similar to that seen in psoriasis. […] These new findings suggest that the highly effective IL-17 antagonist medications used in psoriasis might be applicable to patients with ichthyosis, leading to a new treatment paradigm for ichthyosis. […] We anticipate that this trial (4 month double-blind/8 month open-label) will determine whether the Th17 skewing is merely an antimicrobial response to the barrier deficit or is a critical factor in driving inflammation and scaling.

• #24

  https://link.springer.com/article/10.1007/s40257-022-00718-8

  The term inherited ichthyosis refers to a heterogeneous group of mendelian disorders of cornification that involve the integument with varying degrees of scaling. […] Despite the therapeutic impasse imposed by the options above, the emergence of pathogenesis-based treatments along with novel gene therapies appear promising and hold the potential to halt or even revert disorders that arise from single genetic mutations, although research is still quite lacking in this domain. […] Hence, this review aims to highlight the various treatment modalities available for the management of the cutaneous manifestations of non-syndromic inherited ichthyosis, with an added emphasis on pathogenesis-targeted therapies. […] Understanding immune profiles in ichthyosis may lead to novel therapeutic targets.

• #25

  https://link.springer.com/article/10.1007/s40257-017-0313-x

  Importantly, the barrier defects in nonsyndromic ichthyosis may per se have systemic consequences. […] For a more complete update on the pathophysiology of the various types of ichthyosis, the reader is referred to excellent reviews by Schmuth et al. […] ARCI is caused by mutations in more than a dozen different genes, including TGM1, ABCA12, CYP4F22, ALOXE3/ALOX12B, NIPAL4, CERS3, SDR9C7, PNPLA1, SLC27A4, and LIPN. […] The disease-causing keratin mutations often occur in certain hotspot regions, changing the protein structure so that its hetero-dimerization is altered, thus resulting in cytoskeletal fragility. […] In addition to causing epidermolysis, the keratin mutations may perturb the skin barrier function by interfering with the secretion of lamellar bodies and affecting the extracellular lipid membrane formation.

• #26 Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195792

  Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis. […] While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain. […] Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration. […] At the histological level, there is a great similarity between the IH-CM and Ichthyosis hystrix Lambert types since these types both exhibit thick hyperkeratosis, papillomatous proliferation, and cellular vacuolisation.

• #27 Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195792

  The c1609_16010delGGinsA mutation was shown to produce an aberrant and truncated protein tail of 77 residues, which lacks seven out of ten glycine loops. […] Mutations within different domains of distinct keratins therefore result in diverse pathological phenotypes. […] Our results demonstrate that IH-CM is a clinical entity caused by mutations in KRT10 or KRT1, that modify the three-dimensional structure of the C-terminal domain formed by this specific keratin dimer. […] This change disturbs the pairing of all subsequent amino acids, leading to the impairment of the correct interaction between the K1-V2/K10-V2 domains and resembling the effects of the deletion mutations previously described in KRT1. […] Indeed, our data highly suggest a fundamental role of the KRT1/10 V2 domain in IH-CM pathogenesis, indicating that the clinical phenotype of a specific keratin disease is not only dependent on the affected keratin or on a specific amino acid change but also relies on changes in defined conformational domains that are responsible for specific functions.

• #28 Congenital Ichthyosis: An Overview of Current and Emerging Therapies | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0415

  Congenital ichthyosis is a collective name for a group of monogenetic disorders of cornification, sometimes associated with systemic symptoms. There may be an abnormal quality or quantity of scale produced, abnormal thickness of stratum corneum or abnormal keratinocyte kinetics, often associated with skin inflammation. […] Over the last decade, many new aetiologies have been elucidated, making it easier to identify correctly various subtypes of ichthyosis and to provide proper genetic counselling to the patients and/or their parents. However, therapy of ichthyosis remains mainly symptomatic and is empirically based on the use of topical emollients, various keratolytic agents and, in more severe cases, oral retinoids (vitamin A analogues). […] The leading causes of LI are truncating or missense mutations in the gene encoding keratinocyte transglutaminase type 1 (TGM1), which inactivate the enzyme and result in a deficient cross-linking of cornified cell envelope proteins. The second most common cause of ARCI, at least in Europe, appears to be ichthyin mutations. Ichthyin is a transmembrane protein presumably involved in the lipid transport and function of lamellar granules; its deficiency leads to an accumulation of membrane-like structures in granular cells and corneocytes recognized on electron microscopy as EM type III.

• #29 New developments in the molecular treatment of ichthyosis: review of the literature | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02430-6

  Gene therapy can be achieved by different approaches. A classical approach is introduction of the wild type gene copy into cells, using a viral vector. However, there are safety concerns regarding insertional mutagenesis that comes with the use of a viral vector. […] Another technique is gene editing. With gene editing, sequence specific nucleases are used to induct artificial double strand DNA breaks. This will activate the natural DNA repair system, without the risk of random integration of the transgene as with the use of a viral vector.

• #30

  https://link.springer.com/article/10.1007/s40257-022-00718-8

  Pathogenesis-based therapy with repurposed biologics for monogenic inflammatory skin disorders. […] Biologic therapy targeting IL-17 ameliorates a case of congenital ichthyosiform cornification disorder. […] Pathogenesis-based therapies in ichthyoses. […] Correction of steroid sulfatase deficiency by gene transfer into basal cells of tissue-cultured epidermis from patients with recessive X-linked ichthyosis. […] Long-term faithful recapitulation of transglutaminase 1-deficient lamellar ichthyosis in a skin-humanized mouse model, and insights from proteomic studies. […] Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. […] Transglutaminase 1 replacement therapy successfully mitigates the autosomal recessive congenital ichthyosis phenotype in full-thickness skin disease equivalents.

• #31 Bathing-suit ichthyosis: A rare but valuable entity for developing personalised pathogenesis-based therapies for autosomal recessive congenital ichthyosis – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/bathing-suit-ichthyosis-a-rare-but-valuable-entity-for-developing-personalised-pathogenesis-based-therapies-for-autosomal-recessive-congenital-ichthyosis/

  Bathing-suit ichthyosis (BSI) is a rare and mild form of autosomal recessive congenital ichthyosis (ARCI), clinically characterised by a restricted distribution of dark adherent skin scales. In-situ and in-vitro studies, complemented with digital thermal imaging, deduced that BSI is caused by pathogenic variants in the TGM1 (transglutaminase-1) gene that decrease the thermostability of the encoded enzyme, particularly at warmer regions of the body. […] Nevertheless, in the context of incurable diseases like ARCI, identifying naturally occurring mild phenotypes and delving deeper into their underlying molecular mechanisms might provide innovative leads for the development of affordable and indigenous therapeutics. […] Given that a majority of BSI-causing TGM1 variants involve arginine residues at CpG sites and/or NCG-GNN consensus motif, it is plausible that epigenetic regulatory mechanisms like methylation/demethylation processes might indeed be playing a dominant role in BSI pathogenesis, in addition to reduced thermostability. Rapid advances in genomic technologies are enabling us to address complex questions beyond the regular phenotype-genotype correlations, and making them accessible might benefit the development of indigenous pathogenesis-based therapies for incurable diseases like ARCI.

• #32 Pathogenesis‐based therapy for ichthyosis

  https://escholarship.org/uc/item/1qb746zt

  During the past 20 years, tremendous progress has been made in our understanding of the molecular basis of many genetic skin conditions. […] In this chapter, we provide an overview of the pathoetiology of the various types of ichthyoses and demonstrate how a pathogenesis-based approach can potentially lead to innovative treatments for these conditions. […] Notably, this strategy has been successfully validated for the treatment of the rare X-linked dominant condition, CHILD syndrome, in which topical applications of cholesterol and lovastatin together to affected skin resulted in marked improvement of the skin phenotype.

• #33 Congenital Ichthyosis: An Overview of Current and Emerging Therapies | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0415

  The abnormal keratins also interfere with the movement of lamellar bodies toward the cell periphery, resulting in defective intercorneocyte lipids, as in CIE. […] The most severe forms of ichthyosis represent a serious handicap, requiring life-long therapy and affecting the patients whole life situation. Associated complications, such as heat intolerance due to anhidrosis, eye disease, hearing problems due to debris in the external ear ducts, finger contractions, chronic skin infections, etc., add to the patients morbidity and often require medical attention. Thus both medical and ethical considerations support the attempt to develop more experimental treatments, including cutaneous gene transfer, to help this group of patients. […] Our understanding of how various genes are involved in causing ichthyosis has increased enormously over the last decade, revealing a spectrum of diverse pathogenic mechanisms that extend from abnormal structural proteins (keratins, filaggrin, loricrin, cornified cell envelope, etc.) to deficient enzymes or transport proteins essential for the lipid metabolism in the epidermis (cholesterol sulphatase, lipoxygenases, ABCA12, etc.).

• #34 Autosomal recessive congenital ichthyosis: CERS3 mutations identified by a next generation sequencing panel targeting ichthyosis genes | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2017137

  Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis. […] In this study, we report six previously unreported variants in CERS3 in six extended families among the 140 families tested (4.3%) affected by non-syndromic, autosomal recessive congenital ichthyosis (OMIM#615023). […] Our study now increases the total number of reported CERS3 mutations in ARCI from 2 to 8, scattered along the entire gene. […] In summary, application of a NGS array targeting 38 ichthyosis associated genes in a large cohort of ichthyosis patients from a consanguineous population allowed us to identify previously unreported mutations in CERS3 which brings the total number of mutations reported in this gene to eight.

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