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John A Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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Chapter 23 - Lipoid Proteinosis
Handbook of clinical neurology, 2015Co-Authors: John A McgrathAbstract:Lipoid Proteinosis is a rare autosomal recessive disorder caused by mutations in ECM1, encoding extracellular matrix protein 1, a glycoprotein expressed in many organs and which has important protein–protein interactions in tissue homeostasis. Although the disease usually presents clinically with warty infiltration of the skin and mucous membranes and a hoarse voice, neuropsychological and neuropsychiatric abnormalities are often prominent features. There may be bean- or comma-shaped intracranial calcifications, often selectively affecting the amygdala. Patients with Lipoid Proteinosis therefore have been used as models for demonstrating physiologic and pathologic abnormalities of the amygdala with respect to fear processing, affect and cognition, anxiety and memory. Clinically, patients may also have epilepsy, especially involving the temporal lobes. Less common or rare disease associations are headache (including migraine), ataxia, dizziness, schizophrenia, generalized dystonia, transient brachiofacial paralysis, and intracerebral hemorrhage. Beyond the foci of calcification, the cause of the neurologic abnormalities in Lipoid Proteinosis is unknown, although the ECM1 protein can normally bind to various extracellular matrix proteins and glycosaminoglycans as well as certain enzymes, including matrix metalloproteinase 9. Loss of key protein–protein interactions may underscore some of the disease pathophysiology. There is currently no effective treatment for Lipoid Proteinosis and clinical care is largely supportive.
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molecular and neurological characterizations of three saudi families with Lipoid Proteinosis
BMC Medical Genetics, 2011Co-Authors: Mustafa A Salih, John A Mcgrath, Khaled K Abuamero, Saleh Alrasheed, Ibrahim A Alorainy, L Liu, Lionel Van Maldergem, Yasser H Alfaky, Adel H Alsuhaibani, Darren T OystreckAbstract:Background: Lipoid Proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with Lipoid Proteinosis (LP) from three unrelated consanguineous families. Methods: Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene. Results: All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8. Conclusions: These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.
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the molecular basis of Lipoid Proteinosis mutations in extracellular matrix protein 1
Experimental Dermatology, 2007Co-Authors: I. Chan, Lu Liu, Takahiro Hamada, Gomathy Sethuraman, John A McgrathAbstract:Lipoid Proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in Lipoid Proteinosis. In this article, we provide an update on the molecular pathology of Lipoid Proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.
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three dimensional imaging reveals major changes in skin microvasculature in Lipoid Proteinosis and lichen sclerosus
Journal of Dermatological Science, 2005Co-Authors: Cezary Kowalewski, Ien Chan, Anna Kozlowska, Marta Gorska, Katarzyna Woźniak, Stefania Jablonska, John A McgrathAbstract:Summary Background: Lipoid Proteinosis is a rare autosomal recessive disorder characterized by deposition of hyaline-like material in several organs, including skin. Pathogenic mutations have been found in the extracellular matrix protein 1 gene ( ECM1 ). Recent studies have disclosed that ECM1 is also a target antigen for autoantibodies in patients with the acquired disease, lichen sclerosus. Both conditions have been reported to show abnormalities in dermal blood vessels but these changes have not been fully assessed. Objective: The purpose of this study was to investigate the architecture of the cutaneous microvasculature in Lipoid Proteinosis and lichen sclerosus to better determine the role of ECM1 in the skin pathology observed in these disorders. Methods: Labeling of skin biopsies (Lipoid Proteinosis, lichen sclerosus and control skin) with antibodies to type IV collagen and laminin-1 and reconstruction of the dermal blood vessels using laser confocal microscopy and computer imaging. Results: In both Lipoid Proteinosis and lichen sclerosus there was reduplication of the basement membranes surrounding blood vessel walls. There were enlarged vessels in the mid and deep dermis that were orientated parallel to the dermal-epidermal junction. In addition, the normal capillary loop network in the dermal papillae, as well as the subcutaneous plexus and transverse connecting vessels were lacking in both disorders. Conclusion: This study demonstrates that skin microvasculature is grossly altered when ECM1 is targeted by inherited mutations (Lipoid Proteinosis) or acquired autoantibodies (lichen sclerosus) and that this glycoprotein appears to have an important role in regulating blood vessel physiology and anatomy in the skin.
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Clinical and molecular abnormalities in Lipoid Proteinosis.
European journal of dermatology : EJD, 2005Co-Authors: S Desmet, Takahiro Hamada, John A Mcgrath, Stijn Devos, Ien Chan, Ingeborg Dhooge, Jean NaeyaertAbstract:Lipoid Proteinosis (hyalinosis cutis et mucosae) is a rare, autosomal recessive disease. The main clinicopathological features comprise skin and mucous membrane infiltration and scarring with deposition of hyaline material. In this report, we describe a 6-year-old boy in whom a diagnosis of Lipoid Proteinosis was first suspected when he presented with blisters and erosions at 4 years, a history of life-long dysphonia and a previous epileptic convulsion. The diagnosis was confirmed by histology and identification of a homozygous frameshift mutation, 501insC, in exon 6 of the gene encoding extracellular matrix protein 1, ECM1. Lipoid Proteinosis may show protean clinical features and be difficult to diagnose on clinical grounds alone. This case report illustrates that Lipoid Proteinosis may show protean clinical features and yet remain undiagnosed for many years. Although the gold standard for definite diagnosis remains histology, molecular characterisation of the gene mutation will add to our understanding of genotype-phenotype correlation and perhaps to the development of a rationale for future therapeutics.
Takahiro Hamada - One of the best experts on this subject based on the ideXlab platform.
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clinical and histopathological response to acitretin therapy in Lipoid Proteinosis
Journal of Dermatological Treatment, 2011Co-Authors: Gulsen Akoglu, Aysen Karaduman, Sibel Ergin, Gul Erkin, Ozay Gokoz, Omer Faruk Unal, Takahiro HamadaAbstract:Lipoid Proteinosis (LP) is a rare autosomal recessive genodermatosis associated with deposition of periodic acid-Shiff (PAS)-positive hyaline material in skin, mucosa, and other tissues. LP is caused by loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). No curative therapy is available. In this report, we describe the clinicopathological and genetic features of a Turkish LP family with four cases, and evaluate the response of acitretin therapy. Patients were presented with hoarseness and beaded eyelid papules, thickened frenulum, hyperkeratotic plaques and infiltrated warty papules and nodules. Skin biopsies revealed deposition of PAS-positive hyaline material in dermis. A homozygous nonsense mutation in exon 3 of the ECM1 gene, R53X, was detected in the family. Acitretin therapy was administered in two patients, in whom some regression and softening of skin lesions were achieved. However, no histopathological change in PAS-positive deposition could be detected. Although there is no current effective treatment for LP, acitretin may be helpful for patients, especially those who complain about hyperkeratosis.
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the molecular basis of Lipoid Proteinosis mutations in extracellular matrix protein 1
Experimental Dermatology, 2007Co-Authors: I. Chan, Lu Liu, Takahiro Hamada, Gomathy Sethuraman, John A McgrathAbstract:Lipoid Proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in Lipoid Proteinosis. In this article, we provide an update on the molecular pathology of Lipoid Proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.
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Clinical and molecular abnormalities in Lipoid Proteinosis.
European journal of dermatology : EJD, 2005Co-Authors: S Desmet, Takahiro Hamada, John A Mcgrath, Stijn Devos, Ien Chan, Ingeborg Dhooge, Jean NaeyaertAbstract:Lipoid Proteinosis (hyalinosis cutis et mucosae) is a rare, autosomal recessive disease. The main clinicopathological features comprise skin and mucous membrane infiltration and scarring with deposition of hyaline material. In this report, we describe a 6-year-old boy in whom a diagnosis of Lipoid Proteinosis was first suspected when he presented with blisters and erosions at 4 years, a history of life-long dysphonia and a previous epileptic convulsion. The diagnosis was confirmed by histology and identification of a homozygous frameshift mutation, 501insC, in exon 6 of the gene encoding extracellular matrix protein 1, ECM1. Lipoid Proteinosis may show protean clinical features and be difficult to diagnose on clinical grounds alone. This case report illustrates that Lipoid Proteinosis may show protean clinical features and yet remain undiagnosed for many years. Although the gold standard for definite diagnosis remains histology, molecular characterisation of the gene mutation will add to our understanding of genotype-phenotype correlation and perhaps to the development of a rationale for future therapeutics.
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generalized dystonia and striatal calcifications with Lipoid Proteinosis
Neurology, 2004Co-Authors: H A G Teive, Takahiro Hamada, Eduardo Rafael Pereira, Jorge A Zavala, Marcos Christiano Lange, L De Paola, Salmo Raskin, Lineu Cesar Werneck, John A McgrathAbstract:Lipoid Proteinosis (LP) is an autosomal recessive disease that typically presents with papular, verrucous, poxlike, or acneiform scars and lesions and hoarseness. LP was recently mapped to the 1q21 locus and shown to result from mutations in the extracellular matrix protein 1 gene (ECM1). Epilepsy, mental retardation, and hippocampal calcifications can occur. The authors describe a patient with generalized dystonia caused by striatal calcifications.
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molecular basis of Lipoid Proteinosis in a libyan family
Clinical and Experimental Dermatology, 2003Co-Authors: Ien Chan, Takahiro Hamada, Noritaka Oyama, A Elzurghany, B Zendah, M Benghazil, John A McgrathAbstract:Lipoid Proteinosis is an autosomal recessive condition associated with variable scarring and infiltration of skin and mucosae. The disorder has recently been shown to result from loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1) on 1q21. Extracellular matrix protein 1 has important physiological and biological roles in aspects of epidermal differentiation, binding of dermal collagens and proteoglycans, and in regulation of angiogenesis. Thus far pathogenic mutations have been described in 16 different families with Lipoid Proteinosis throughout the world. In this report, we describe the clinico-pathological features of a 10-year-old boy with Lipoid Proteinosis from a consanguineous Libyan family. By direct sequencing of the affected individual's genomic DNA, we identified a homozygous nonsense mutation in exon 2 of the ECM1 gene, Q32X. This mutation is the most 5' of all ECM1 mutations described thus far and is predicted to ablate the ECM1a, ECM1b and ECM1c splice variants of the ECM1 gene and to result in a severe clinical phenotype. Sequencing of DNA from the affected individual's five siblings revealed that four were heterozygous carriers of Q32X, findings that have important implications for genetic counselling given the high frequency of consanguineous marriages in Libya.
I. Chan - One of the best experts on this subject based on the ideXlab platform.
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the molecular basis of Lipoid Proteinosis mutations in extracellular matrix protein 1
Experimental Dermatology, 2007Co-Authors: I. Chan, Lu Liu, Takahiro Hamada, Gomathy Sethuraman, John A McgrathAbstract:Lipoid Proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in Lipoid Proteinosis. In this article, we provide an update on the molecular pathology of Lipoid Proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.
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extracellular matrix protein 1 gene ecm1 mutations in Lipoid Proteinosis and genotype phenotype correlation
Journal of Investigative Dermatology, 2003Co-Authors: I. Chan, Takahiro Hamada, Noritaka Oyama, Andrew P South, Vesarat Wessagowit, G H S Ashton, Apatorn Siriwattana, Prachiya Jewhasuchin, S CharuwichitratanaAbstract:The autosomal recessive disorder Lipoid Proteinosis results from mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, Lipoid Proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with Lipoid Proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in Lipoid Proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in Lipoid Proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous Lipoid Proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.
Sabine Hoffjan - One of the best experts on this subject based on the ideXlab platform.
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A Novel ECM1 Splice Site Mutation in Lipoid Proteinosis: Case Report plus Review of the Literature
Molecular Syndromology, 2016Co-Authors: Jürgen Kohlhase, Katrin Möllenhoff, Joerg T Epplen, Gabriele Dekomien, Sabine HoffjanAbstract:Lipoid Proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in ECM1. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the ECM1 gene and summarize the current knowledge on ECM1 mutations and possible genotype-phenotype correlations.
S Charuwichitratana - One of the best experts on this subject based on the ideXlab platform.
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extracellular matrix protein 1 gene ecm1 mutations in Lipoid Proteinosis and genotype phenotype correlation
Journal of Investigative Dermatology, 2003Co-Authors: I. Chan, Takahiro Hamada, Noritaka Oyama, Andrew P South, Vesarat Wessagowit, G H S Ashton, Apatorn Siriwattana, Prachiya Jewhasuchin, S CharuwichitratanaAbstract:The autosomal recessive disorder Lipoid Proteinosis results from mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, Lipoid Proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with Lipoid Proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in Lipoid Proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in Lipoid Proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous Lipoid Proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.