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Scientific Publications

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Unmet Needs in Human Genomic Variant Interpretation

The quality and the precision of a final diagnosis do not consist solely of correct variant classification and clinical interpretation. Diagnosis begins at the preanalytical level, and all subsequent interpretation can produce either a negative or a positive effect.

The quality and the precision of a final diagnosis do not consist solely of correct variant classification and clinical interpretation. Diagnosis begins at the preanalytical level, and all subsequent interpretation can produce either a negative or a positive effect, depending on the quality of the “wet-bench” preparation.

BiodatabankWESWGS
Author(s): Bauer, Dr. Peter, MD
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17q23.2q23.3 de Novo Duplication

We report a 7.5-year-old boy with amongst others speech and language disorder, learning difficulties, incoordination and stereotyped hand movement. Read more!

Chromosomal rearrangements involving 17q23 have been described rarely. Deletions at 17q23.1q23.2 have been reported in individuals with developmental delay and growth retardation, whereas duplications at 17q23.1q23.2 appear to segregate with clubfoot. We report a 7.5-year-old boy with speech and language disorder, learning difficulties, incoordination, fine motor skill impairment, infrequent seizures with abnormal EEG, and behavior disturbances (mild self-inflicted injuries, hyperactivity-inattention, and stereotyped hand movement.

Neurology
Author(s): Rolfs, Prof. Arndt, MD, Wessel, Karen, PhD, Kishore, Shivendra, PhD, Suleimann, Jehan, PhD, Khalaf, Tamam, El-Hattab, Ayman, MD
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Glucosylsphingosine Causes Hematological and Visceral Changes in Mice

We established a long-term infusion model in mice to examine the effect of lyso-Gb1 on representative hallmark parameters of Gaucher disease. Read more!

Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD.

BiomarkerMetabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Eichler, Sabrina, PhD, Lukas, Jan, PhD, Cozma, Dr. rer. nat. Claudia, MD, Kramp, Guido Johannes, PhD, Kropp, Prof. Peter, MD, Böttcher, Tobias, PhD, Witt, Prof. Martin, MD, Meyer, Anja, Yang, Fan, Neßlauer, Anna-Maria
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Functional Characterization of Rare RAB12 Variants

Mutations in RAB genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia.

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia.

Neurology
Author(s): Hebert, Eva
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VEGF-A Gene Polymorphisms and Responses to Intravitreal Ranibizumab Treatment in Patients with Diabetic Macular Edema

The purpose of this study was to investigate the association between VEGF gene polymorphisms and the responses to treatment with intravitreal ranibizumab in patients with diabetic macular edema. Read more!

The purpose of this study was to investigate the association between VEGF gene polymorphisms and the responses to treatment with intravitreal ranibizumab (IVR) in patients with diabetic macular edema (DME). This prospective study, conducted at the Kutahya Dumlupinar University Faculty of Medicine, included 95 patients with DME that were treated with IVR and 32 patients without DME despite proliferative diabetic retinopathy (PDR). The participants were divided into three groups: DME with non-proliferative diabetic retinopathy, DME with PDR, and PDR without DME; patients with DME who were treated with IVR were further divided into two groups based on their response to the treatment.

Ophthalmology
Author(s): Yüksel, Zafer, MD, Tetikoğlu, Mehmet, MD, Aktas, Serdar, MD, Sağdik, Haci Murat, Özcura, Fatih
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Clinical and Genetic Characteristics of Sporadic Adult-Onset Degenerative Ataxia

Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Learn more in this publication!

The objective of this study is to define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. The analysis was performed on 249 participants. Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset.

NeurologyNGS
Author(s): Klopstock, Prof. Thomas, MD, Bauer, Dr. Peter, MD, Dudesek, Ales, MD, Sturm, Marc, PhD, Giordano, Ilaria, MD, Harmuth, Florian, Jacobi, Heike, MD, Paap, Brigitte, PhD, Vielhaber, Stefan, MD, Machts, Judith, Schöls, Ludger, MD, Synofzik, Matthis, MD, Tallaksen, Chantal, MD, Wedding, Iselin, MD, Boesch, Sylvia, MD, Eigentler, Andreas, MD, van de Warrenburg, Bart, MD, van Gaalen, Judith, MD, Kamm, Christoph, MD, Kang, Jun-Suk, MD, Timmann, Dagmar, MD, Silvestri, Gabriella, MD, Masciullo, Marcella, MD, Neuhofer, Christiane, MD, Ganos, Christos, MD, Filla, Alessandro, MD, Tezenas du Montcel, Sophie, MD, PhD, Klockgether, Thomas, MD

Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

The observations in this publication confirmed the conclusion that impaired FXN transcription determines the pathologic phenotype of Friedreich ataxia. Read more!

In a small percentage of patients with Friedreich ataxia (FA), the pathogenic mutation is compound heterozygous, consisting of a guanine–adenine–adenine (GAA) trinucleotide repeat expansion in one allele, and a deletion, point mutation, or insertion in the other. In 2 cases of compound heterozygous FA, the GAA expansion was inherited from the mother, and deletions from the father.

Neurology
Author(s): Bauer, Dr. Peter, MD, Becker, Alyssa, Qian, Jiang, PhD, Gelman, Benjamin, PhD, MD, Yang, Michele, MD, Koeppen, Arnulf, MD
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Activation of PKC Triggers Rescue of NPC1 Patient Specific iPSC Derived Glial Cells from Gliosis

As an analysis of affected cells is unfeasible in NPC1-patients, we developed an in vitro model system, based on cells derived from NPC1-patient specific iPSCs. Read more!

Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. The pathological mechanisms, underlying NPC1 are not yet completely understood. Especially the contribution of glial cells and gliosis to the progression of NPC1, are controversially discussed. As an analysis of affected cells is unfeasible in NPC1-patients, we recently developed an in vitro model system, based on cells derived from NPC1-patient specific iPSCs.

Metabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Frech, Moritz J, PhD, Peter, Franziska, Rost, Sebastian
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Reductions in Glucosylsphingosine

Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Find out more about phase 3 clinical trials on our website!

Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine,lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and onitoring of patients with GD.

BiomarkerMetabolic Disorders
Author(s): Eichler, Sabrina, PhD, Elstein, Deborah, Zimran, Ari, MD, Cozma, Dr. rer. nat. Claudia, MD, Böttcher, Tobias, PhD, Mellgard, Björn, PhD MD, Dinh, Quinn, MD, Lan, Lan, Qiu, Yongchang, PhD
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Fluorescent Probes for Selective Protein Labeling in Lysosomes: A Case of α-Galactosidase A

This study demonstrated fluorescent probes for selective protein labeling in lysosomes in a case of α-galactosidase A. Read more in this scientific publication!

This study demonstrated fluorescent probes for selective protein labeling in lysosomes in a case of α-galactosidase A, contributing further to the knowledge about diagnostics and pathology of Fabry disease. The newly investigated fluorescence-based live-cell-imaging technology of specifically tagged lysosomal protein using an improved biarsenical probe showed that it can be used to identify novel compounds that promote proper trafficking of mutant α-galactosidase to lysosomal compartments and rescue the mutant phenotype.

BiomarkerMetabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Lukas, Jan, PhD, Bohl, Cornelius, Pomorski, Adam, PhD, Seemann, Susanne, Knospe, Anne-Marie, Zheng, Chaonan, Krężel, Artur, PhD
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C26-Ceramide as Highly Sensitive Biomarker for the Diagnosis of Farber Disease

Studies revealed that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for Farber disease. Read more in this publication!

Farber disease (FD) is a rare autosomal recessive disease caused by mutations in the acid ceramidase gene (ASAH1). Low ceramidase activity results in the accumulation of fatty substances, mainly ceramides. Hallmark symptoms at clinical level are periarticular nodules, lipogranulomas, swollen and painful joints and a hoarse voice. FD phenotypes are heterogeneous varying from mild to very severe cases, with the patients not surviving past their first year of life. This study has the highest number of enrolled Farber patients and carriers reported to present. Liquid chromatography multiple reaction mass spectrometry (LC/MRM-MS) studies revealed that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for FD (p < 0.0001). The new biomarker can be determined directly in the dried blood spot extracts with low sample consumption. This allows for easy sample preparation, high reproducibility and use in high throughput screenings.

BiomarkerMetabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Brandau, Oliver, MD, Giese, Anne Katrin, MD, Eichler, Sabrina, PhD, Lukas, Jan, PhD, Cozma, Dr. rer. nat. Claudia, MD, Böttcher, Tobias, PhD, Hovakimyan, Marina, PhD, Iurașcu, Marius-Ionuț, Zielke, Susanne
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Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

We analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1-/- mice and observed considerable loss of mature olfactory receptor neurons. Read more!

Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1-/- mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells.

Metabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Wree, Prof. Andreas, MD, Witt, Prof. Martin, MD, Meyer, Anja, Günther, René, Schmitt, Prof. Oliver, MD
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AMPA-Receptor Specific Biogenesis Complexes Control Synaptic Transmission and Intellectual Ability

Here insights are provided into the early biogenesis of AMPARs and its pronounced impact on synaptic transmission and brain function is demonstrated. Read more!

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.

Neurology
Author(s): Brechet, Aline, PhD, Reis, Prof. Andre, PhD, MD, Sticht, Prof. Heinrich, PhD, Al-Sannaa, Nouriya, Rolfs, Prof. Arndt, MD, Kulik, Akos, PhD, Schulte, Uwe, PhD, Colleaux, Laurence, PhD, Jamra, Rami Abou, MD, Nitschke, Patrick, Bole-Feysot, Christine, PhD, Buchert, Rebecca, Schwenk, Jochen, PhD, Boudkkazi, Sami, PhD, Zolles, Gerd, PhD, Siquier-Pernet, Karine, Schaber, Irene, Bildl, Wolfgang, PhD, Saadi, Abdelkrim, Fakler, Prof. Bernd, MD
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Novel Homozygous PCK1 Mutation

A novel homozygous PCK1 mutation was detected in all in this study affected individuals. Whole exome sequencing was performed. Read more!

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925GNA (p.G309R) mutation was detected in all affected individuals.

Metabolic DisordersWES
Author(s): Rolfs, Prof. Arndt, MD, Vieira, Päivi, Cameron, Jessie, PhD, Rahikkala, Elisa, PhD, MD, Zhang, Lin-Hua, PhD, Santra, Saikat, Matthews, Allison, PhD, Myllynen, Päivi, PhD, MD, Nuutinen, Matti, PhD, MD, Moilanen, Jukka, PhD, MD, Rodenburg, Richard, PhD, Uusimaa, Johanna, PhD, MD, van Karnebeek, Clara D.M., PhD, MD
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Dataset in Support of the Generation of Niemann-Pick Type C1

Data presented in this article demonstrate the generation and characterization of two novel NPC1 patient-specific induced pluripotent stem cell lines. Read more!

Data presented in this article demonstrate the generation and characterization of two novel Niemann-Pick disease Type C1 (NPC1) patient-specific induced pluripotent stem cell (iPSC) lines. For reprogramming fibroblasts, carrying the novel homozygous mutation c.1180T>C and the prevalent homozygous mutation c.3182T>C, were used. Reprogramming into patient-specific iPSCs was induced by retroviral transduction of the transcription factors Sox2, Klf4, Oct4 and c-Myc, and confirmed according to their pluripotency.

Metabolic Disorders
Author(s): Rolfs, Prof. Arndt, MD, Frech, Moritz J, PhD, Peter, Franziska, Trilck, Michaela, PhD, Rabenstein, Michael
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