RARE DISEASE
X-linked ichthyosis syndrome
X-linked ichthyosis syndrome
X-linked ichthyosis syndrome
Drug discovery
0
drugs
With orphan designations
Overview
X-linked ichthyosis (XLI), caused by deletions or mutations in the STS gene (Xp22.3), results in steroid sulfatase deficiency and cholesterol sulfate accumulation, impairing desquamation. Clinical features include dark, polygonal scales on the trunk/extremities, delayed birth onset, corneal opacities, cryptorchidism, and elevated risks of neurodevelopmental disorders (e.g., ADHD) and cardiac arrhythmias [1][5][12].
Burden
Chronic scaling impacts quality of life, with psychosocial stress from visible skin lesions [8][12].
Associated cardiac, gastrointestinal, and neurodevelopmental conditions increase healthcare utilization [1][8].
Lifelong management required, with ~40% of cases undiagnosed/misdiagnosed due to mild presentation [1][5].
Therapies
Topical emollients (urea, lactic acid) and keratolytics (propylene glycol) to hydrate and reduce scale buildup [3][7][13].
Oral retinoids (acitretin, isotretinoin) for severe cases, though rarely required for XLI [3][7].
Genetic counseling for carriers (obstetric risks) and multidisciplinary monitoring for comorbidities [5][12].
Categories: rare genetic diseases, rare skin diseases
Research Papers
44 drug discovery papers about X-linked ichthyosis syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
44 drug discovery papers about X-linked ichthyosis syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-04-04 | Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy.
Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing for consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages, and predominantly palmoplantar skin involvement (nonsyndromic and syndromic). sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counselling and the initiation of therapy. All sEDDs are rare; the most common are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise and variable clinical features of sEDDs, the natural history of the diseases with advancing age and genotype-phenotype relationships are poorly defined. Of the 51 sEDDs, associated neurological (n = 36; 71%) and/or ophthalmological (n = 25; 49%) findings are most common, and 39% (n = 20) have associated hair abnormalities. The widespread use of topical lovastatin for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with the pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment of SPINK5-sEDD with kallikrein inhibitors. Many sEDDs may be amenable to gene editing or the introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryological development.
2023-11-24 | Molecular genetics and pathogenesis of ichthyosis
Ichthyosis encompasses a group of rare and heterogeneous genetic skin disorders characterized by defective epidermal barrier function, resulting in various clinical presentations of hyperkeratosis and scaling. In recent years, significant advances have been made in understanding the molecular genetics and pathogenesis of ichthyosis. The pathogenesis of ichthyosis is complex and varies depending on the underlying genetic defect. Over 20 genes have been identified as causing ichthyosis, and many more are likely to be discovered in the future. Recent research has unveiled the complex pathogenic mechanisms contributing to ichthyosis, from defects in epidermal barrier function to immune system involvement. This increased understanding is driving the pursuit of innovative treatment modalities, including biologics, small molecular inhibitors, and gene therapy, potentially revolutionizing ichthyosis management. This review provides a comprehensive understanding of the molecular genetics and pathogenesis of ichthyosis, a group of rare skin diseases characterized by abnormal skin barrier function and a range of clinical manifestations. It underscores the importance of recent genetic discoveries in shedding light on the underlying causes of various forms of ichthyosis and the potential for nanotechnology-based formulations to enhance therapeutic efficacy in managing these challenging conditions.
2022-11-18 | 305 Overlaps between inflammatory dermatoses and ichthyoses: need for novel therapeutic approaches
Ichthyoses form a heterogeneous group of well-defined inherited skin diseases. However, the comorbidity of these cornification disorders needs to be further investigated, as psoriasiform skin lesions and/or atopic manifestations may be observed in many affected individuals. We recruited 64 patients with ichthyoses, 29 psoriasis and 37 atopic dermatitis (AD) patients, assessed the disease severity by the Ichthyosis Area Severity Index (IASI; 0-48) and pruritus characteristics by the Neuroderm Questionnaire. Further, we performed immunohistochemical stainings of CCL27, Nos2, filaggrin, β-defensin-2 and CD1a on 15 skin samples of ichthyoses and compared them to psoriasis and AD. In ichthyosis the median disease severity was 8 with highest scores in Netherton syndrome (NTS). Generalized pruritus occurred in 84% of patients with a median intensity of 3 on the numeric rating scale (0-10). 13% described neuropathic itch qualities and 15 patients showed an impaired quality of life due to itch. Of note, almost 50% with systemic therapy still described moderate pruritus. In AD pruritus was significantly higher than in the group of psoriasis and ichthyosis (p ≤ 0,01). Staining of CCL27 and Nos2 revealed a psoriasis-like phenotype in more than 50% of ichthyosis patients. Filaggrin deficiency was not only observed in ichthyosis vulgaris (IV), but also in congenital ichthyoses and X-linked ichthyosis. ß-defensin-2 was present in some samples, and there were two patients (IV and XLI) with high levels of CD1a. Atopic diathesis was not only prevalent in IV and NTS, but among all subtypes. We conclude that immunological characterization of ichthyoses according to a psoriasiform or atopic diathese pattern could improve treatment of the disease. Novel targeted therapies may be subject of future clinical studies in ichthyosis to improve itch, skin inflammation and probably scaling.
2022-10-27 | Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes
Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.
2022-05-10 | Use of Two Combination Creams for the Treatment of Ichthyosis and Ichthyosiform Disorders
Abstract Background. Treatment options for Ichthyosis and Ichthyosiform disorders are limited and often unsatisfactory. Topical cholesterol and statin have been previously used with good results. Objective. To assess the change in the disease severity score after a therapeutic regimen consisting of two combination creams: 2% cholesterol with 2% lovastatin, and 10% glycolic acid with 0.025% tretinoin and 2% ketoconazole. Methods. This study was conducted at the American University of Beirut Medical Center between March 2019 and March 2020. Pregnant women were excluded. The combination creams were used daily or as tolerated by the patients. Results. 24 patients completed the study. The median age was 7.5 years. The average percent reductions in the severity scores were 40% at 1 month (n=20), 44.8% at 2 months (n=18), and 60.3% at 3 months (n=10). Side effects consisted mainly of mild irritation which resolved upon altering the frequency of application. Limitations. Limitations of our study include the relatively small number of participants (due to the rarity of such diseases), the subjective nature of some of the scoring criteria, and the inconsistent follow-up times. Conclusion. These findings suggest a benefit from these two combination creams in the treatment of Ichthyosis and Ichthyosiform disorders.
proteins
2022-08-22 | Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis
Tight junction (TJ) formation is vital for epidermal barrier function. We aimed to specifically manipulate TJ barriers in the reconstructed human epidermis (RHE) by claudin-1 and -4 knockdown (KD) and by claudin-binding fusion proteins of glutathione S-transferase and modified C-terminal fragments of Clostridium perfringens enterotoxin (GST-cCPE). Impedance spectroscopy and tracer permeability imaging were employed for functional barrier assessment and investigation of claudin contribution. KD of claudin-1, but not claudin-4, impaired the paracellular barrier in vitro. Similarly, claudin-binding GST-cCPE variants weakened the paracellular but not the stratum corneum barrier. Combining both TJ targeting methods, we found that claudin-1 targeting by GST-cCPE after claudin-4 KD led to a marked decrease in paracellular barrier properties. Conversely, after claudin-1 KD, GST-cCPE did not further impair the barrier. Comparison of GST-cCPE variants with different claudin-1/claudin-4 affinities, NHS-fluorescein tracer detection, and immunostaining of RHE paraffin sections showed that GST-cCPE variants bind to extrajunctional claudin-1 and -4, which are differentially distributed along the stratum basale-stratum granulosum axis. GST-cCPE binding blocks these claudins, thereby specifically opening the paracellular barrier of RHE. The data indicate a critical role for claudin-1 in regulating paracellular permeability for ions and small molecules in the viable epidermis. Claudin targeting is presented as a proof-of-concept for precise barrier modulation.
2020-12-23 | Ichthyoses in everyday practice: management of a rare group of diseases.
Ichthyoses comprise a heterogeneous group of hereditary disorders of keratinization characterized by a highly varied clinical picture. A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life, and rare, sometimes severe congenital ichthyoses. Patients with very mild symptoms often do not even realize they have ichthyosis. The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis. Mapping a family tree is also diagnostically useful. Besides skin manifestations, important aspects of the clinical examination and history include disease onset, presence of a collodion membrane at birth as well as the presence of hair anomalies and extracutaneous signs and symptoms. Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment. For patients with severe disease, systemic acitretin treatment should be considered on a case-by-case basis. While ichthyoses are generally limited to the skin, there are syndromic forms that may affect other organs and that require interdisciplinarity cooperation. Although ichthyoses remain incurable, they can be managed well with symptomatic treatment. However, such treatment is frequently time consuming and expensive. In the future, novel therapeutic approaches might include enzyme replacement and gene therapies as well as antiinflammatory drugs.
2013-02-15 | Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58
Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL. Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.
gene therapies
2025-12-24 | PROBLEMS OF ADAPTATION OF POST-BIRTH CHILDREN AT BIRTH AND IN THE EARLY NEONATAL PERIOD
Cause of post-term pregnancy is usually unknown, but a previous post-term pregnancy increases the risk by 2-3 times. Post-term pregnancy can be caused by disorders affecting the fetal pituitary-adrenal system (e.g., anencephaly, adrenal hypoplasia, congenital adrenal hyperplasia) and X-linked ichthyosis associated with placental sulfatase deficiency. In most cases, fetal growth continues until birth. However, in some cases, placental involution (as pregnancy progresses) and multiple infarcts are observed, as well as villous degeneration, leading to placental insufficiency syndrome. As a result, the fetus receives inadequate nutrients and oxygen from the mother, resulting in a thin (due to soft tissue depletion), malnourished infant with depleted glycogen stores and reduced amniotic fluid volume. Such infants are considered premature and, depending on the onset of placental insufficiency and the severity of the condition, may be small for gestational age. Although, placental insufficiency with impaired maturation can occur at any gestational age, it most often occurs after 41-42 weeks of pregnancy.
small molecules
2025-04-04 | Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy.
Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing for consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages, and predominantly palmoplantar skin involvement (nonsyndromic and syndromic). sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counselling and the initiation of therapy. All sEDDs are rare; the most common are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise and variable clinical features of sEDDs, the natural history of the diseases with advancing age and genotype-phenotype relationships are poorly defined. Of the 51 sEDDs, associated neurological (n = 36; 71%) and/or ophthalmological (n = 25; 49%) findings are most common, and 39% (n = 20) have associated hair abnormalities. The widespread use of topical lovastatin for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with the pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment of SPINK5-sEDD with kallikrein inhibitors. Many sEDDs may be amenable to gene editing or the introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryological development.
2023-11-24 | Molecular genetics and pathogenesis of ichthyosis
Ichthyosis encompasses a group of rare and heterogeneous genetic skin disorders characterized by defective epidermal barrier function, resulting in various clinical presentations of hyperkeratosis and scaling. In recent years, significant advances have been made in understanding the molecular genetics and pathogenesis of ichthyosis. The pathogenesis of ichthyosis is complex and varies depending on the underlying genetic defect. Over 20 genes have been identified as causing ichthyosis, and many more are likely to be discovered in the future. Recent research has unveiled the complex pathogenic mechanisms contributing to ichthyosis, from defects in epidermal barrier function to immune system involvement. This increased understanding is driving the pursuit of innovative treatment modalities, including biologics, small molecular inhibitors, and gene therapy, potentially revolutionizing ichthyosis management. This review provides a comprehensive understanding of the molecular genetics and pathogenesis of ichthyosis, a group of rare skin diseases characterized by abnormal skin barrier function and a range of clinical manifestations. It underscores the importance of recent genetic discoveries in shedding light on the underlying causes of various forms of ichthyosis and the potential for nanotechnology-based formulations to enhance therapeutic efficacy in managing these challenging conditions.
2022-11-18 | 305 Overlaps between inflammatory dermatoses and ichthyoses: need for novel therapeutic approaches
Ichthyoses form a heterogeneous group of well-defined inherited skin diseases. However, the comorbidity of these cornification disorders needs to be further investigated, as psoriasiform skin lesions and/or atopic manifestations may be observed in many affected individuals. We recruited 64 patients with ichthyoses, 29 psoriasis and 37 atopic dermatitis (AD) patients, assessed the disease severity by the Ichthyosis Area Severity Index (IASI; 0-48) and pruritus characteristics by the Neuroderm Questionnaire. Further, we performed immunohistochemical stainings of CCL27, Nos2, filaggrin, β-defensin-2 and CD1a on 15 skin samples of ichthyoses and compared them to psoriasis and AD. In ichthyosis the median disease severity was 8 with highest scores in Netherton syndrome (NTS). Generalized pruritus occurred in 84% of patients with a median intensity of 3 on the numeric rating scale (0-10). 13% described neuropathic itch qualities and 15 patients showed an impaired quality of life due to itch. Of note, almost 50% with systemic therapy still described moderate pruritus. In AD pruritus was significantly higher than in the group of psoriasis and ichthyosis (p ≤ 0,01). Staining of CCL27 and Nos2 revealed a psoriasis-like phenotype in more than 50% of ichthyosis patients. Filaggrin deficiency was not only observed in ichthyosis vulgaris (IV), but also in congenital ichthyoses and X-linked ichthyosis. ß-defensin-2 was present in some samples, and there were two patients (IV and XLI) with high levels of CD1a. Atopic diathesis was not only prevalent in IV and NTS, but among all subtypes. We conclude that immunological characterization of ichthyoses according to a psoriasiform or atopic diathese pattern could improve treatment of the disease. Novel targeted therapies may be subject of future clinical studies in ichthyosis to improve itch, skin inflammation and probably scaling.
2022-10-27 | Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes
Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.
2022-05-10 | Use of Two Combination Creams for the Treatment of Ichthyosis and Ichthyosiform Disorders
Abstract Background. Treatment options for Ichthyosis and Ichthyosiform disorders are limited and often unsatisfactory. Topical cholesterol and statin have been previously used with good results. Objective. To assess the change in the disease severity score after a therapeutic regimen consisting of two combination creams: 2% cholesterol with 2% lovastatin, and 10% glycolic acid with 0.025% tretinoin and 2% ketoconazole. Methods. This study was conducted at the American University of Beirut Medical Center between March 2019 and March 2020. Pregnant women were excluded. The combination creams were used daily or as tolerated by the patients. Results. 24 patients completed the study. The median age was 7.5 years. The average percent reductions in the severity scores were 40% at 1 month (n=20), 44.8% at 2 months (n=18), and 60.3% at 3 months (n=10). Side effects consisted mainly of mild irritation which resolved upon altering the frequency of application. Limitations. Limitations of our study include the relatively small number of participants (due to the rarity of such diseases), the subjective nature of some of the scoring criteria, and the inconsistent follow-up times. Conclusion. These findings suggest a benefit from these two combination creams in the treatment of Ichthyosis and Ichthyosiform disorders.
proteins
2022-08-22 | Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis
Tight junction (TJ) formation is vital for epidermal barrier function. We aimed to specifically manipulate TJ barriers in the reconstructed human epidermis (RHE) by claudin-1 and -4 knockdown (KD) and by claudin-binding fusion proteins of glutathione S-transferase and modified C-terminal fragments of Clostridium perfringens enterotoxin (GST-cCPE). Impedance spectroscopy and tracer permeability imaging were employed for functional barrier assessment and investigation of claudin contribution. KD of claudin-1, but not claudin-4, impaired the paracellular barrier in vitro. Similarly, claudin-binding GST-cCPE variants weakened the paracellular but not the stratum corneum barrier. Combining both TJ targeting methods, we found that claudin-1 targeting by GST-cCPE after claudin-4 KD led to a marked decrease in paracellular barrier properties. Conversely, after claudin-1 KD, GST-cCPE did not further impair the barrier. Comparison of GST-cCPE variants with different claudin-1/claudin-4 affinities, NHS-fluorescein tracer detection, and immunostaining of RHE paraffin sections showed that GST-cCPE variants bind to extrajunctional claudin-1 and -4, which are differentially distributed along the stratum basale-stratum granulosum axis. GST-cCPE binding blocks these claudins, thereby specifically opening the paracellular barrier of RHE. The data indicate a critical role for claudin-1 in regulating paracellular permeability for ions and small molecules in the viable epidermis. Claudin targeting is presented as a proof-of-concept for precise barrier modulation.
2020-12-23 | Ichthyoses in everyday practice: management of a rare group of diseases.
Ichthyoses comprise a heterogeneous group of hereditary disorders of keratinization characterized by a highly varied clinical picture. A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life, and rare, sometimes severe congenital ichthyoses. Patients with very mild symptoms often do not even realize they have ichthyosis. The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis. Mapping a family tree is also diagnostically useful. Besides skin manifestations, important aspects of the clinical examination and history include disease onset, presence of a collodion membrane at birth as well as the presence of hair anomalies and extracutaneous signs and symptoms. Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment. For patients with severe disease, systemic acitretin treatment should be considered on a case-by-case basis. While ichthyoses are generally limited to the skin, there are syndromic forms that may affect other organs and that require interdisciplinarity cooperation. Although ichthyoses remain incurable, they can be managed well with symptomatic treatment. However, such treatment is frequently time consuming and expensive. In the future, novel therapeutic approaches might include enzyme replacement and gene therapies as well as antiinflammatory drugs.
2013-02-15 | Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58
Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL. Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.
gene therapies
2025-12-24 | PROBLEMS OF ADAPTATION OF POST-BIRTH CHILDREN AT BIRTH AND IN THE EARLY NEONATAL PERIOD
Cause of post-term pregnancy is usually unknown, but a previous post-term pregnancy increases the risk by 2-3 times. Post-term pregnancy can be caused by disorders affecting the fetal pituitary-adrenal system (e.g., anencephaly, adrenal hypoplasia, congenital adrenal hyperplasia) and X-linked ichthyosis associated with placental sulfatase deficiency. In most cases, fetal growth continues until birth. However, in some cases, placental involution (as pregnancy progresses) and multiple infarcts are observed, as well as villous degeneration, leading to placental insufficiency syndrome. As a result, the fetus receives inadequate nutrients and oxygen from the mother, resulting in a thin (due to soft tissue depletion), malnourished infant with depleted glycogen stores and reduced amniotic fluid volume. Such infants are considered premature and, depending on the onset of placental insufficiency and the severity of the condition, may be small for gestational age. Although, placental insufficiency with impaired maturation can occur at any gestational age, it most often occurs after 41-42 weeks of pregnancy.
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