Publications by authors named "Heiko Brennenstuhl"

15 Publications

  • Page 1 of 1

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: data from the iNTD registry.

J Inherit Metab Dis 2021 Jul 9. Epub 2021 Jul 9.

University Children's Hospital, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport or degradation of neurotransmitters or co-factors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter (DAT) deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: a) difference in IQ and subdomains of quality of life between BH deficiencies and primary neurotransmitter-related disorders, and b) previously underreported behavioral traits. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jimd.12416DOI Listing
July 2021

Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder.

Hum Mutat 2021 Jun 22. Epub 2021 Jun 22.

Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

SYNCRIP encodes for the Synaptotagmin-binding cytoplasmic RNA-interacting protein, involved in RNA-binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic-atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA-binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype-phenotype correlations. Our study provides further evidence for a SYNCRIP-associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic-atonic epilepsy.
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http://dx.doi.org/10.1002/humu.24245DOI Listing
June 2021

Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria.

J Inherit Metab Dis 2021 Jun 18. Epub 2021 Jun 18.

Division of Neuropaediatrics and Paediatric Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA and provide an in-silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0-51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.
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http://dx.doi.org/10.1002/jimd.12412DOI Listing
June 2021

The "Young Metabolic Society": An interest group for young professionals in the field of metabolic medicine.

J Inherit Metab Dis 2021 Jul 23;44(4):789. Epub 2021 Jun 23.

Children's Hospital Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany.

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http://dx.doi.org/10.1002/jimd.12409DOI Listing
July 2021

Patterns of extreme temperature-related catastrophic events in Europe including the Russian Federation: a cross-sectional analysis of the Emergency Events Database.

BMJ Open 2021 06 15;11(6):e046359. Epub 2021 Jun 15.

Pediatric Neurology and Metabolic Medicine, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany

Objective: To investigate reported extreme temperature-related catastrophic events and associated mortality on the European continent including the Russian Federation.

Design: Cross-sectional respecting Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.

Settings: Data source: Emergency Events Database (EM-DAT).

Participants: Search criteria: location-European continent including Russian Federation, time-years 1988 until 2019 (close of database 12 July 2019), catastrophic events-extreme temperatures.

Primary Outcome Measures: Numbers of heat waves, cold waves, severe winter conditions and associated number of deaths, overall, and per country and year, respecting STROBE criteria.

Results: The most frequent type of the 243 events recorded in EM-DAT were cold waves (54.7%). However, cold waves and severe winter conditions only accounted for 6460 deaths (4.5%), while heat waves were associated with 137 533 deaths (95.5%). The five most severe heat waves in 2003, 2006, 2010, 2013 and 2015 were associated with a total of 135 089 deaths. The most severe heat waves were geographically distributed over the Russian Federation (2010), as well as France, Italy, Spain and Germany, each in 2003.

Conclusion: Although cold waves are more frequently reported in EM-DAT, heat waves are the major cause for temperature-related deaths. In order to better protect the public, it is important to address resiliency and vulnerability of populations at risk and age groups.
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http://dx.doi.org/10.1136/bmjopen-2020-046359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208003PMC
June 2021

Refining Genotypes and Phenotypes in -Related Neurological Disorders.

Int J Mol Sci 2021 Mar 10;22(6). Epub 2021 Mar 10.

Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Pathogenic variants in , encoding for the voltage-gated potassium channel K1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of -associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)-valine(406)-proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of -related disorders. Our study provides further insights into the clinical spectrum, genotype-phenotype correlation, variability, and predicted functional impact of variants.
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http://dx.doi.org/10.3390/ijms22062824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999221PMC
March 2021

Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of .

Int J Mol Sci 2020 Nov 13;21(22). Epub 2020 Nov 13.

Institute of Biochemistry, Medical Faculty, University of Giessen, 35392 Giessen, Germany.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD) binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of to identify mutational hotspots.
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http://dx.doi.org/10.3390/ijms21228578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696157PMC
November 2020

Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants.

Pediatr Pulmonol 2020 11 7;55(11):3057-3066. Epub 2020 Sep 7.

Dr. von Haunersches Kinderspital, University of Munich, German Center for Lung Research (DZL), Munich, Germany.

Background: Pulmonary alveolar proteinosis (PAP) is a heterogeneous condition with more than 100 different underlying disorders that need to be differentiated to target therapeutic options, which are generally limited.

Methods: The clinical course of two brothers with pathogenic variants in the methionyl-tRNA synthetase (MARS)1 gene was compared to previously published patients. Functional studies in patient-derived fibroblasts were performed and therapeutic options evaluated.

Results: The younger brother was diagnosed with PAP at the age of 1 year. Exome sequencing revealed the homozygous MARS1 variant p.(Arg598Cys), leading to interstitial lung and liver disease (ILLD). At 2 years of age, following surgery hypoglycemia was detected, the pulmonary condition deteriorated, and the patient developed multiorgan failure. Six therapeutic whole lung lavages (WLL) were necessary to improve respiratory insufficiency. Methionine supplementation was started and a high protein diet ensured, leading to complete respiratory recovery. The older brother, homozygous for the same MARS1 variant, had a long-known distinct eating preference of methionine-rich food and showed a less severe clinical phenotype. Decreased aminoacylation activity confirmed the pathogenicity of p.(Arg598Cys) in vitro. In agreement with our review of currently published ILLD patients, the presence of hepatopathy, developmental delay, muscular hypotonia, and anemia support the multisystemic character of the disease.

Conclusions: Catabolic events can provoke a severe deterioration of the pulmonary situation in ILLD with a need for repetitive WLL. Although the precise role of oral methionine supplementation and high protein intake are unknown, we observed an apparent treatment benefit, which needs to be evaluated systematically in controlled trials.
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http://dx.doi.org/10.1002/ppul.25031DOI Listing
November 2020

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1.

Genet Med 2020 11 23;22(11):1863-1873. Epub 2020 Jul 23.

Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings.

Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts.

Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro.

Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
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http://dx.doi.org/10.1038/s41436-020-0904-4DOI Listing
November 2020

Semi-quantitative detection of a vanillactic acid/vanillylmandelic acid ratio in urine is a reliable diagnostic marker for aromatic L-amino acid decarboxylase deficiency.

Mol Genet Metab 2020 Sep - Oct;131(1-2):163-170. Epub 2020 Jul 7.

University Children's Hospital Heidelberg, Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, Heidelberg, Germany. Electronic address:

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a primary neurotransmitter defect of the biosynthesis of catecholamines and serotonin. The phenotype consists of varying degrees of neurological impairment, including motor and non-motor symptoms. Treatment outcomes correlate with the time point of diagnosis and treatment initiation; therefore, reliable diagnostic markers are necessary. Increased vanillactic acid (VLA) concentrations in the analysis of organic acids in urine have been reported in AADC deficiency. However, this elevation is often subtle and easily missed. In this study, we evaluate the semi-quantitative determination of VLA and vanillylmandelic acid (VMA) concentrations and establish the ratio of a VLA/VMA as a novel diagnostic marker for AADC deficiency.

Methods: Urine samples obtained from 10,095 non-AADC deficient controls and 14 confirmed AADC deficient patients were used for organic acid analysis by liquid-liquid extraction of the acidified samples and gas chromatographic-mass spectrometric separation after trimethylsilylation. The semi-quantitative determination of VLA and VMA concentrations and the calculation of a VLA/VMA ratio were evaluated as a diagnostic marker for AADC deficiency.

Results: The mean VLA and VMA concentrations in 10,095 non-AADCD samples was 0.3 mmol/mol creatinine (SD = 1.18, range 0-57.79) and 5.59 mmol/mol creatinine (SD = 3.87, range 0.04-60.62), respectively. The mean concentration of VLA in 14 patient-derived samples was 10.24 mmol/mol creatinine, (SD = 11.58, range = 0.37-33.06) and 0.45 mmol/mol creatinine for VMA (SD = 0.29, range 0.11-1.27). The mean VLA/VMA ratio in non-AADC controls was 0.07 (SD = 0.37, range 0.0-23.24), whereas AADC deficient patients revealed a mean VLA/VMA ratio of 23.16 (SD = 22.83, range 0.97-74.1). The VLA/VMA ratio thus allows a reliable identification of patients with AADC deficiency, especially in the young age cohort as it decreases with age. To take this into account, age-adjusted thresholds have been developed.

Conclusion: Determination of individual concentrations of VLA and VMA in urine does not allow a reliable diagnosis of AADC deficiency. In this study, we could demonstrate that a semi-quantitative analysis of organic acids in urine allows the formation of metabolite ratios and that the VLA/VMA ratio is a reliable, easily accessible, new parameter for the diagnosis of AADC deficiency.
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http://dx.doi.org/10.1016/j.ymgme.2020.07.001DOI Listing
June 2021

Succinic Semialdehyde Dehydrogenase Deficiency: An Update.

Cells 2020 02 19;9(2). Epub 2020 Feb 19.

Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.
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http://dx.doi.org/10.3390/cells9020477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072817PMC
February 2020

High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots.

J Inherit Metab Dis 2020 05 6;43(3):602-610. Epub 2020 Jan 6.

Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.

Aromatic l-amino-acid decarboxylase (AADC) deficiency is an inherited disorder of biogenic amine metabolism with a broad neurological phenotype. The clinical symptoms overlap with other diseases resulting in an often delayed diagnosis. Innovative disease-changing treatment options, particularly gene therapy, have emphasised the need for an early diagnosis. We describe the first method for 3-O-methyldopa (3-OMD) analysis in dried blood spots (DBS) suitable for high throughput newborn screening (NBS). We established a novel tandem mass spectrometry method to quantify 3-OMD in DBS and successfully tested it in 38 888 unaffected newborns, 14 heterozygous DDC variant carriers, seven known AADC deficient patients, and 1079 healthy control subjects. 3-OMD concentrations in 38 888 healthy newborns revealed a mean of 1.16 μmol/L (SD = 0.31, range 0.31-4.6 μmol/L). 1079 non-AADC control subjects (0-18 years) showed a mean 3-OMD concentration of 0.78 μmol/L (SD = 1.75, range 0.24-2.36 μmol/L) with a negative correlation with age. Inter- and intra-assay variability was low, and 3-OMD was stable over 32 days under different storage conditions. We identified seven confirmed AADC deficient patients (mean 3-OMD 9.88 μmol/L [SD = 13.42, range 1.82-36.93 μmol/L]). The highest concentration of 3-OMD was found in a NBS filter card of a confirmed AADC deficient patient with a mean 3-OMD of 35.95 μmol/L. 14 DDC variant carriers showed normal 3-OMD concentrations. We demonstrate a novel high-throughput method to measure 3-OMD in DBS, which allows integration in existing NBS programs enabling early diagnosis of AADC deficiency.
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http://dx.doi.org/10.1002/jimd.12208DOI Listing
May 2020

Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment.

Neuropediatrics 2019 02 29;50(1):2-14. Epub 2018 Oct 29.

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Children's Hospital Heidelberg, Heidelberg, Germany.

Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.
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http://dx.doi.org/10.1055/s-0038-1673630DOI Listing
February 2019

IκBζ, an atypical member of the inhibitor of nuclear factor kappa B family, is induced by γ-irradiation in glioma cells, regulating cytokine secretion and associated with poor prognosis.

Int J Oncol 2015 Nov 14;47(5):1971-80. Epub 2015 Sep 14.

Hertie Institute for Clinical Brain Research and Center Neurology, Molecular Neurology, Karl Eberhards University of Tübingen, Tübingen, Germany.

The inhibitor of nuclear factor kappa B zeta (IκBζ) is an atypical member of the IκB protein family. Its function in regulating the activity of the transcription factor nuclear factor kappa B (NFκB) as well as its involvement in cancer-associated processes is poorly understood. In glioma patients, enhanced expression of IκBζ in tumor specimen is associated with poor prognosis. Here we report that IκBζ is upregulated in a glioma cell line resistant towards NFκB-dependent non-apoptotic cell death. Upon γ-irradiation of glioma cells, IκBζ expression is enhanced, and subsequently serves as a transcriptional activator of the tumor promoting cytokines interleukin (IL-6), IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1) that are known to be involved in glioma associated inflammatory processes. In contrast, shRNA-mediated knockdown of IκBζ reduces the expression of the aforementioned cytokines. We propose a previously unappreciated role of IκBζ in the inflammatory micromilieu as well as progression in glioma.
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http://dx.doi.org/10.3892/ijo.2015.3159DOI Listing
November 2015

Modulation of immune responses by histone deacetylase inhibitors.

Crit Rev Oncog 2015 ;20(1-2):139-54

Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, University of Tubingen, Tubingen, Germany.

Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases.
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http://dx.doi.org/10.1615/critrevoncog.2014012393DOI Listing
September 2015
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