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William A. Gahl - One of the best experts on this subject based on the ideXlab platform.
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Generation and characterization of four Chediak-Higashi Syndrome (CHS) induced pluripotent stem cell (iPSC) lines.
Stem cell research, 2020Co-Authors: Jenny Serra-vinardell, William A. Gahl, Maxwell B. Sandler, Evgenia Pak, Wei Zheng, Amalia Dutra, Wendy J. Introne, May Christine V. MalicdanAbstract:Abstract Chediak-Higashi Syndrome (CHS) is a lysosome-related organelle (LRO) disorder caused by biallelic mutations in the lysosomal trafficking regulator gene, LYST. The clinical features of CHS include oculocutaneous albinism, primary immunodeficiency, bleeding diathesis, risk for development of hemophagocytic lymphohistiocytosis, and progressive neurological problems. The pathophysiological mechanisms underlying this disease are unknown, so developing therapeutic options remains challenging. In this study, four induced pluripotent stem (iPSC) lines from unrelated CHS patients have been generated and successfully characterized for exploring the role of LYST in health and disease in diverse cell types.
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a clinical report of Chediak Higashi Syndrome in infancy with a novel genotype from the indian subcontinent
International Journal of Dermatology, 2016Co-Authors: Ankur Singh, Andrew R. Cullinane, William A. Gahl, Melanie M Bryan, Joseph C Roney, Nita Khurana, Seema KapoorAbstract:Chediak-Higashi Syndrome (CHS; OMIM no. 214500) is an inherited multisystem disorder presenting with hypopigmentation and a propensity to infections due to immunological dysfunction. CHS generally presents in infancy with a fatal outcome, but less severe cases can present in adulthood. Treatment with bone marrow transplantation can be life-saving, so establishing a correct diagnosis is critical. The presence of large granules on examination of peripheral blood smears is suggestive of the diagnosis of CHS in most centers. However, sequencing of the lysosomal trafficking, LYST, gene confirms the diagnosis and can provide a prognosis regarding disease severity. In the case presented here, we performed molecular testing to identify the causative mutation and tabulated published mutation data from 2009 to 2014. We found a novel frameshift mutation in our case and concluded that frameshift and nonsense are the most common types of mutation in CHS, but this may be biased due to underdiagnosis of the milder and atypical forms of the disease.
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rapid ultrastructural detection of success or failure after bone marrow transplantation in the Chediak Higashi Syndrome
Platelets, 2013Co-Authors: James G White, William A. Gahl, Richard A Hess, Wendy J. IntroneAbstract:The present study has used electron microscopic techniques to rapidly detect the success or failure of bone marrow transplantation in three patients with the Chediak-Higashi Syndrome (CHS). The most rapid procedure was the whole mount technique to determine the presence or absence of dense bodies, which are inherently electron-opaque, serotonin-containing storage organelles in platelets. Dense bodies were present in normal numbers in platelets from two patients with successful transplantation and absent in thrombocytes from another patient in whom the transplant had failed.
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two novel mutations identified in an african american child with Chediak Higashi Syndrome
Case Reports in Medicine, 2010Co-Authors: Kerry Morrone, James G White, William A. Gahl, Yanhua Wang, Marjan Huizing, Elie Sutton, Karen MoodyAbstract:Background. Chediak-Higashi Syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in the CHS1/LYST gene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in the CHS1 gene: c.3622C > T (p.Q1208X) and c.11002G > T (p.E3668X). Conclusions. Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in the CHS1 gene, the first mutation analysis published of an African-American child with Chediak-Higashi Syndrome. These two mutations predict a severe phenotype and thus identification of these mutations has an important clinical significance in CHS.
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Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome
2010Co-Authors: Kerry Morrone, James G White, William A. Gahl, Yanhua Wang, Marjan Huizing, Elie Sutton, Karen MoodyAbstract:Copyright © 2010 Kerry Morrone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Chediak-Higashi Syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in the CHS1/LYST gene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in the CHS1 gene: c.3622C> T (p.Q1208X) and c.11002G> T (p.E3668X). Conclusions. Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in the CHS1 gene, the first mutation analysis published of a
Marcondes Cavalcante França Junior - One of the best experts on this subject based on the ideXlab platform.
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Inflammatory demyelinating neuropathy heralding accelerated Chediak-Higashi Syndrome.
Muscle & nerve, 2017Co-Authors: Ingrid Faber, Joana Rosa Marques Prota, Alberto R. M. Martinez, Anamarli Nucci, Iscia Lopes-cendes, Marcondes Cavalcante França JuniorAbstract:Introduction: Chediak-Higashi Syndrome (CHS) is a very rare autosomal recessive disorder (gene CHS1/LYST) characterized by partial albinism, recurrent infections, and easy bruising. Survivors develop a constellation of slowly progressive neurological manifestations. Methods: We describe clinical, laboratory, electrophysiological, and genetic findings of a patient who developed an immune-mediated demyelinating neuropathy as the main clinical feature of CHS. Results: The patient presented with subacute flaccid paraparesis, absent reflexes, and reduced vibration sense. Protein and immunoglobulins were elevated in the CSF. Electrodiagnostic tests indicated an acquired chronic demyelinating polyneuropathy. Intravenous immunoglobulin (IVIG) and immunosuppressant treatment resulted in neurological improvement. The patient later developed organomegaly and pancytopenia. Bone-marrow smear revealed giant azurophilic granules pathognomonic of CHS. Two novel mutations in the LYST gene were identified through Whole Exome Sequencing [c.7786C>T and c.9106 + 1G>T]. Conclusion: This case expands the clinical phenotype of CHS and highlights inflammatory demyelinating neuropathy as a manifestation of the disease. This article is protected by copyright. All rights reserved.
Ingrid Faber - One of the best experts on this subject based on the ideXlab platform.
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Inflammatory demyelinating neuropathy heralding accelerated Chediak-Higashi Syndrome.
Muscle & nerve, 2017Co-Authors: Ingrid Faber, Joana Rosa Marques Prota, Alberto R. M. Martinez, Anamarli Nucci, Iscia Lopes-cendes, Marcondes Cavalcante França JuniorAbstract:Introduction: Chediak-Higashi Syndrome (CHS) is a very rare autosomal recessive disorder (gene CHS1/LYST) characterized by partial albinism, recurrent infections, and easy bruising. Survivors develop a constellation of slowly progressive neurological manifestations. Methods: We describe clinical, laboratory, electrophysiological, and genetic findings of a patient who developed an immune-mediated demyelinating neuropathy as the main clinical feature of CHS. Results: The patient presented with subacute flaccid paraparesis, absent reflexes, and reduced vibration sense. Protein and immunoglobulins were elevated in the CSF. Electrodiagnostic tests indicated an acquired chronic demyelinating polyneuropathy. Intravenous immunoglobulin (IVIG) and immunosuppressant treatment resulted in neurological improvement. The patient later developed organomegaly and pancytopenia. Bone-marrow smear revealed giant azurophilic granules pathognomonic of CHS. Two novel mutations in the LYST gene were identified through Whole Exome Sequencing [c.7786C>T and c.9106 + 1G>T]. Conclusion: This case expands the clinical phenotype of CHS and highlights inflammatory demyelinating neuropathy as a manifestation of the disease. This article is protected by copyright. All rights reserved.
James G White - One of the best experts on this subject based on the ideXlab platform.
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rapid ultrastructural detection of success or failure after bone marrow transplantation in the Chediak Higashi Syndrome
Platelets, 2013Co-Authors: James G White, William A. Gahl, Richard A Hess, Wendy J. IntroneAbstract:The present study has used electron microscopic techniques to rapidly detect the success or failure of bone marrow transplantation in three patients with the Chediak-Higashi Syndrome (CHS). The most rapid procedure was the whole mount technique to determine the presence or absence of dense bodies, which are inherently electron-opaque, serotonin-containing storage organelles in platelets. Dense bodies were present in normal numbers in platelets from two patients with successful transplantation and absent in thrombocytes from another patient in whom the transplant had failed.
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two novel mutations identified in an african american child with Chediak Higashi Syndrome
Case Reports in Medicine, 2010Co-Authors: Kerry Morrone, James G White, William A. Gahl, Yanhua Wang, Marjan Huizing, Elie Sutton, Karen MoodyAbstract:Background. Chediak-Higashi Syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in the CHS1/LYST gene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in the CHS1 gene: c.3622C > T (p.Q1208X) and c.11002G > T (p.E3668X). Conclusions. Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in the CHS1 gene, the first mutation analysis published of an African-American child with Chediak-Higashi Syndrome. These two mutations predict a severe phenotype and thus identification of these mutations has an important clinical significance in CHS.
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Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome
2010Co-Authors: Kerry Morrone, James G White, William A. Gahl, Yanhua Wang, Marjan Huizing, Elie Sutton, Karen MoodyAbstract:Copyright © 2010 Kerry Morrone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Chediak-Higashi Syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in the CHS1/LYST gene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in the CHS1 gene: c.3622C> T (p.Q1208X) and c.11002G> T (p.E3668X). Conclusions. Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in the CHS1 gene, the first mutation analysis published of a
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two novel chs1 lyst mutations clinical correlations in an infant with Chediak Higashi Syndrome
Molecular Genetics and Metabolism, 2005Co-Authors: Wafika Zarzour, James G White, Robert Kleta, Haydar Frangoul, Pim Suwannarat, Anna Jeong, Su Young Kim, Alan S Wayne, Meral Gunayaygun, Alexandra H FilipovichAbstract:Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C>T, CGA>TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein's BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT.
Wendy J. Introne - One of the best experts on this subject based on the ideXlab platform.
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Generation and characterization of four Chediak-Higashi Syndrome (CHS) induced pluripotent stem cell (iPSC) lines.
Stem cell research, 2020Co-Authors: Jenny Serra-vinardell, William A. Gahl, Maxwell B. Sandler, Evgenia Pak, Wei Zheng, Amalia Dutra, Wendy J. Introne, May Christine V. MalicdanAbstract:Abstract Chediak-Higashi Syndrome (CHS) is a lysosome-related organelle (LRO) disorder caused by biallelic mutations in the lysosomal trafficking regulator gene, LYST. The clinical features of CHS include oculocutaneous albinism, primary immunodeficiency, bleeding diathesis, risk for development of hemophagocytic lymphohistiocytosis, and progressive neurological problems. The pathophysiological mechanisms underlying this disease are unknown, so developing therapeutic options remains challenging. In this study, four induced pluripotent stem (iPSC) lines from unrelated CHS patients have been generated and successfully characterized for exploring the role of LYST in health and disease in diverse cell types.
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Chediak-Higashi Syndrome: A review of the past, present, and future
Drug discovery today. Disease models, 2019Co-Authors: Prashant Sharma, Jenny Serra-vinardell, May Christine V. Malicdan, Camilo Toro, Elena-raluca Nicoli, Marie Morimoto, Wendy J. IntroneAbstract:Since the initial description of Chediak-Higashi Syndrome (CHS), over 75 years ago, several studies have been conducted to underscore the role of the lysosomal trafficking regulator (LYST) gene in the pathogenesis of disease. CHS is a rare autosomal recessive disorder, which is caused by biallelic mutations in the highly conserved LYST gene. The disease is characterized by partial oculocutaneous albinism, prolonged bleeding, immune and neurologic dysfunction, and risk for the development of hemophagocytic lympohistiocytosis (HLH). The presence of giant secretory granules in leukocytes is the classical diagnostic feature, which distinguishes CHS from closely related Griscelli and Hermansky-Pudlak Syndromes. While the exact mechanism of the formation of the giant granules in CHS patients is not understood, dysregulation of LYST function in regulating lysosomal biogenesis has been proposed to play a role. In this review, we discuss the clinical characteristics of the disease and highlight the functional consequences of enlarged lysosomes and lysosome-related organelles (LROs) in CHS.
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Chediak Higashi Syndrome
2015Co-Authors: Camilo Toro, May Christine V. Malicdan, Elena-raluca Nicoli, David R Adams, Wendy J. IntroneAbstract:Clinical characteristics Chediak-Higashi Syndrome (CHS) is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition. All affected individuals including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood. Diagnosis/testing The diagnosis of CHS is established in a proband with giant inclusions within leukocytes on peripheral blood smear and/or by the identification of biallelic pathogenic variants in LYST on molecular genetic testing. Management Treatment of manifestations: Initial chemoimmunotherapy followed by transition to continuation therapy for the accelerated phase; allogenic HSCT as soon as possible to cure hematologic and immunologic defects; L-dopa may be considered for those with parkinsonism; home modifications and intensive rehabilitation for those with ataxia and other neurologic complications; corrective lenses to improve visual acuity; sunglasses to protect sensitive eyes from UV light; sunscreen to prevent sun damage and skin cancer. Prevention of secondary complications: Prompt aggressive use of antibiotics and antiviral agents for bacterial and viral illnesses; routine inactivated immunizations; intravenous DDAVP prior to invasive procedures to help control bleeding. Platelet transfusions as needed for serious bleeding. Surveillance: Routine monitoring for chimerism, as 20%-30% donor chimerism is likely enough to protect against reactivation. Yearly ophthalmologic, neurologic, and dermatologic examinations. For atypical or adolescent- or adult-onset CHS: annual abdominal ultrasound examination for hepatosplenomegaly; complete blood count for cytopenias; measurement of serum ferritin concentration and soluble interleukin-2 receptor; and monitoring for liver dysfunction. Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs, which can exacerbate the bleeding tendency; live vaccines. Genetic counseling CHS is inherited in an autosomal recessive manner. When both parents are heterozygous, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing of CHS is possible if the pathogenic variants have been identified in the family.
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Chediak-Higashi Syndrome presenting as young-onset levodopa-responsive parkinsonism.
Movement disorders : official journal of the Movement Disorder Society, 2013Co-Authors: Vikas Bhambhani, Andrew R. Cullinane, Wendy J. Introne, Codrin Lungu, Camilo ToroAbstract:Chediak-Higashi Syndrome (CHS) (OMIM #214500) is a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene, LYST, or CHS1. Typically, CHS presents, with variable degrees of oculocutaneous albinism, immunodeficiency, bleeding diathesis and hemophagocytic lymphohistiocytosis (HLH or the “accelerated phase”).1 Neurological involvement in CHS can include intellectual impairment, sensory-motor neuropathy, cerebellar disease, and dementia.2, 3 Parkinsonism and its response to dopaminergic therapy has rarely been reported.2,4,5 A subset of CHS patients have a muted pigmentary or hematological presentation while their neurological symptoms dominate their disease.6, 7 We a provide video illustration of his therapeutic response to levodopa along with skin pigment dilution features, brain imaging and leukocyte morphology in a young adult male with CHS whose clinical presentation is dominated by motor and non-motor parkinsonian symptoms with a brisk and sustained therapeutic response to levodopa therapy.
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rapid ultrastructural detection of success or failure after bone marrow transplantation in the Chediak Higashi Syndrome
Platelets, 2013Co-Authors: James G White, William A. Gahl, Richard A Hess, Wendy J. IntroneAbstract:The present study has used electron microscopic techniques to rapidly detect the success or failure of bone marrow transplantation in three patients with the Chediak-Higashi Syndrome (CHS). The most rapid procedure was the whole mount technique to determine the presence or absence of dense bodies, which are inherently electron-opaque, serotonin-containing storage organelles in platelets. Dense bodies were present in normal numbers in platelets from two patients with successful transplantation and absent in thrombocytes from another patient in whom the transplant had failed.