Article
Medicine, General & Internal
Lina Men, Jinxing Feng, Weimin Huang, Mingguo Xu, Xiaoli Zhao, Ruixin Sun, Jianfang Xu, Liming Cao
Summary: Lip cyanosis is an important initial symptom of Leigh syndrome, and mild upper respiratory tract infections can induce and aggravate the disease. Brain MRI in the early stages of LS may not show abnormal changes, so multiple MRI scans, blood lactic acid tests, and genetic testing are necessary for accurate diagnosis.
Article
Biology
C. J. Kelly, Reid K. Couch, Vivian T. Ha, Camille M. Bodart, Judy Wu, Sydney Huff, Nicole T. Herrel, Hyunsung D. Kim, Azaad O. Zimmermann, Jessica Shattuck, Yu-Chen Pan, Matt Kaeberlein, Anthony S. Grillo
Summary: Mice lacking Complex I subunit NDUFS4 exhibit mitochondrial dysfunction and the abnormal iron homeostasis may contribute to the progression of Leigh Syndrome and other mitochondrial disorders.
Article
Biochemistry & Molecular Biology
Tom J. J. Schirris, Sergio Rossell, Ria de Haas, Sanne J. C. M. Frambach, Charlotte A. Hoogstraten, G. Herma Renkema, Julien D. Beyrath, Peter H. G. M. Willems, Martijn A. Huynen, Jan A. M. Smeitink, Frans G. M. Russel, Richard A. Notebaart
Summary: The failure of the mitochondrial oxidative phosphorylation system is associated with disease symptoms, for which there is currently no approved drug treatment. Research has shown that fibrates can regulate cholesterol metabolism, improve cell growth and motor function, and prolong survival time.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Xiaojun Tang, Wuhen Xu, Xiaozhen Song, Haiyun Ye, Xiang Ren, Yongchen Yang, Hong Zhang, Shengnan Wu, Xiaoping Lan
Summary: This study reported a case of Leigh syndrome patient with compound heterozygous mutations in the NDUFV1 gene, one of which has been confirmed as pathogenic. The other mutation, not previously reported, was found to be rare in Asian populations.
Review
Biochemistry & Molecular Biology
Sifan Wang, Yuanbo Kang, Ruifeng Wang, Junqi Deng, Yupei Yu, Jun Yu, Junpu Wang
Summary: This review provides a comprehensive summary of the current knowledge about the structural function of NDUFS8, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus. It offers potential pathogenesis, progress, and therapeutic targets for different diseases related to NDUFS8.
Review
Biology
Flora Kahlhoefer, Max Gansen, Volker Zickermann
Summary: NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex in the respiratory chain, with mutations in the accessory subunit NDUFS4 in the matrix arm associated with neuromuscular and neurodegenerative diseases.
Article
Genetics & Heredity
Alessandra Torraco, Alessia Nasca, Daniela Verrigni, Alessandra Pennisi, Maha S. Zaki, Giorgia Olivieri, Zahra Assouline, Diego Martinelli, Reza Maroofian, Teresa Rizza, Michela Di Nottia, Federica Invernizzi, Eleonora Lamantea, Daniela Longo, Henry Houlden, Holger Prokisch, Agnes Rotig, Carlo Dionisi-Vici, Enrico Bertini, Daniele Ghezzi, Rosalba Carrozzo, Daria Diodato
Summary: Isolated biochemical deficiency of mitochondrial complex I is commonly associated with a wide range of clinical symptoms, with Leigh syndrome being a frequent finding. This study identified novel NDUFA12 variants in seven patients from four unrelated families, with six presenting Leigh syndrome. Despite the absence of NDUFA12 protein in all patients, they exhibited different disease onset and clinical courses, highlighting the phenotypic variability associated with NDUFA12 defect.
Review
Cell Biology
Massimo Zeviani, Carlo Viscomi
Summary: Mitochondria are vital organelles responsible for generating energy in cells. Mutations in mtDNA or nuclear genes can lead to complex neurological disorders. Understanding these diseases is essential for the field of mitochondrial medicine due to the diverse genetic and phenotypic heterogeneity.
Article
Biochemistry & Molecular Biology
Biyi Chen, Nastaran Daneshgar, Hsiang-Chun Lee, Long-Sheng Song, Dao-Fu Dai
Summary: Mitochondrial oxidative stress plays a role in aging and various cardiovascular diseases. Its involvement in bradyarrhythmia is less understood. In a mouse model of Leigh Syndrome (LS), mitochondrial antioxidant treatment improved bradyarrhythmia and extended lifespan. Increased reactive oxygen species (ROS) in the LS heart were observed and abolished by mitochondrial antioxidant treatment. This study suggests the direct mechanistic roles of mitochondrial ROS in bradyarrhythmia and highlights the potential clinical application of mitochondrial-targeted antioxidants in LS patients.
Article
Clinical Neurology
Pin-Shiuan Chen, Ni-Chung Lee, Chieh-Ju Sung, Ya-Wen Liu, Wen-Chin Weng, Pi-Chuan Fan, Wang-Tso Lee, Yin-Hsiu Chien, Chao-Szu Wu, Yueh-Feng Sung, Ming-Chen Tsai, Yi-Chung Lee, Hsueh-Wen Hsueh, Sabrina Mai-Yi Fan, Meng-Chen Wu, Hsun Li, Huan-Yun Chen, Han- Lin, Chih-Hsin Ou-Yang, Wuh-Liang Hwuh, Chin-Hsien Lin
Summary: This study describes the clinical characteristics and functional findings in a cohort of patients with NDUFAF5 mutations, and reveals significant heterogeneity and divergent prognosis based on age at onset. This research is important for understanding the association between NDUFAF5 mutations and Leigh syndrome.
MOVEMENT DISORDERS
(2023)
Review
Genetics & Heredity
Allison Hanaford, Simon C. Johnson
Summary: Genetic mitochondrial diseases pose a significant challenge to human health, and recent evidence suggests that the immune system plays a key role in the pathogenesis of at least some forms of these diseases.
ORPHANET JOURNAL OF RARE DISEASES
(2022)
Article
Multidisciplinary Sciences
Patricia Gonzalez-Rodriguez, Enrico Zampese, Kristen A. Stout, Jaime N. Guzman, Ema Ilijic, Ben Yang, Tatiana Tkatch, Mihaela A. Stavarache, David L. Wokosin, Lin Gao, Michael G. Kaplitt, Jose Lopez-Barneo, Paul T. Schumacker, D. James Surmeier
Summary: Loss of functional mitochondrial complex I in dopaminergic neurons can lead to a shift in metabolism in mice, causing Parkinson's disease-like symptoms. This study challenges the traditional paradigm of Parkinson's disease by showing that dysfunction of mitochondrial complex I alone is sufficient to cause progressive parkinsonism.
Article
Genetics & Heredity
Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, Isabella Moroni
Summary: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with mitochondrial dysfunction. This study reviewed data from 122 genetically confirmed LS patients, finding that central nervous system involvement was predominant and often associated with complex I and IV deficiencies. SURF1 mutations were linked to poor prognosis in this large cohort.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Cell Biology
Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A. Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello
Summary: This study aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome. Through mitochondrial bioenergetic investigations and whole exome sequencing, three heterozygous nuclear variants associated with Leigh syndrome were identified, providing insights for the development of diagnostic and therapeutic strategies for atypical Leigh syndrome.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Clinical Neurology
Elizabeth McCormick, Kierstin P. Keller, Julie J. Taylor, Alison Coffey, Lishuang Shen, Danuta Krotoski, Brian Harding, Xiaowu J. Gai, Marni Falk, Zarazuela Zolkipli-Cunningham, Shamima Rahman
Summary: The Clinical Genome Resource's expert panel has systematically evaluated the gene-disease relationships for Leigh syndrome, a type of mitochondrial disease. They identified 114 genes associated with Leigh syndrome, which will improve diagnostic accuracy, expedite genetic diagnosis, and facilitate the development of precision medicine.
ANNALS OF NEUROLOGY
(2023)
Article
Clinical Neurology
Tim W. Rattay, Maximilian Voelker, Maren Rautenberg, Christoph Kessler, Isabel Wurster, Natalie Winter, Tobias B. Haack, Tobias Lindig, Holger Hengel, Matthis Synofzik, Rebecca Schule, Peter Martus, Ludger Schoels
Summary: This study explores early changes in the most common subtype of hereditary spastic paraplegia, SPG4, and identifies subclinical markers of disease activity in the prodromal stage. The findings suggest that certain clinical signs, such as increased reflexes and muscle weakness, may be more frequent in individuals who carry the genetic mutation associated with SPG4.
Article
Genetics & Heredity
Claudia S. Priglinger, Guenter Rudolph, Irene Schmid, Pascale Mazzola, Tobias B. Haack, Milda Reith, Katarina Stingl, Nicole Weisschuh
Summary: This study presents clinical and genetic characteristics of two sisters diagnosed with optic atrophy and cone dystrophy. Genome sequencing revealed two novel variants in the NBAS gene, adding to the understanding of the genotypic and phenotypic spectrum of NBAS-related disorders.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Dmitrijs Rots, Taryn E. Jakub, Crystal Keung, Vissers E. L. M. Lisenka, Siddharth Banka, Rolph Pfundt, Bert B. A. de Vries, Richard H. van Jaarsveld, Saskia M. J. Hopman, Ellen van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kortuem, Francois Lecoquierre, Alice Goldenberg, Jens Michael Hertz, Charlotte Brasch Andersen, Maria Kibaek, Eloise J. Prijoles, Roger E. Stevenson, David B. Everman, Wesley G. Patterson, Linyan Meng, Charul Gijavanekar, Karl De Dios, Shenela Lakhani, Tess Levy, Matias Wagner, Dagmar Wieczorek, Paul J. Benke, Maria Soledad Lopez Garcia, Renee Perrier, Sergio B. Sousa, Pedro M. Almeida, Maria Jose Simoes, Bertrand Isidor, Wallid Deb, Andrew A. Schmanski, Omar Abdul-Rahman, Christophe Philippe, Ange-Line Bruel, Laurence Faivre, Antonio Vitobello, Christel Thauvin, Jeroen J. Smits, Livia Garavelli, Stefano G. Caraffi, Francesca Peluso, Laura Davis-Keppen, Dylan Platt, Erin Royer, Lisette Leeuwen, Margje Sinnema, Alexander P. A. Stegmann, Constance T. R. M. Stumpel, George E. Tiller, Danielle G. M. Bosch, Stephanus T. Potgieter, Shelagh Joss, Miranda Splitt, Simon Holden, Matina Prapa, Nicola Foulds, Sofia Douzgou, Kaija Puura, Regina Waltes, Andreas G. Chiocchetti, Christine M. Freitag, F. Kyle Satterstrom, Silvia De Rubeis, Joseph Buxbaum, Bruce D. Gelb, Aleksic Branko, Itaru Kushima, Jennifer Howe, Stephen W. Scherer, Alessia Arado, Chiara Baldo, Olivier Patat, Demeer Benedicte, Diego Lopergolo, Filippo M. Santorelli, Tobias B. Haack, Andreas Dufke, Miriam Bertrand, Ruth J. Falb, Angelika Riess, Peter Krieg, Stephanie Spranger, Maria Francesca Bedeschi, Maria Iascone, Sarah Josephi-Taylor, Tony Roscioli, Michael F. Buckley, Jan Liebelt, Aditi I. Dagli, Emmelien Aten, Anna C. E. Hurst, Alesha Hicks, Mohnish Suri, Ermal Aliu, Sunil Naik, Richard Sidlow, Juliette Coursimault, Gael Nicolas, Hanna Kuepper, Florence Petit, Veyan Ibrahim, Deniz Top, Francesca Di Cara, Raymond J. Louie, Elliot Stolerman, Han G. Brunner, Lisenka E. L. M. Vissers, Jamie M. Kramer, Tjitske Kleefstra
Summary: This study examines the clinical and molecular spectrum of individuals with KDM6B variants and challenges the accuracy of the current description of the disorder. Cognitive deficits are consistently observed, but the overall phenotype varies greatly. The study also demonstrates the disruptive effect of certain KDM6B variants on protein structure and introduces a functional testing paradigm for assessing these variants. The findings highlight the importance of international collaboration and rigorous functional analysis in diagnosing rare disorders.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Clinical Neurology
Alessia Nasca, Niccolo E. Mencacci, Federica Invernizzi, Michael Zech, Ignacio J. Keller Sarmiento, Andrea Legati, Chiara Frascarelli, Bernabe Bustos, Luigi M. Romito, Dimitri Krainc, Juliane Winkelmann, Miryam Carecchio, Nardo Nardocci, Giovanna Zorzi, Holger Prokisch, Steven J. Lubbe, Barbara Garavaglia, Daniele Ghezzi
Summary: Nasca et al. have discovered a new candidate gene for dystonia, ATP5F1B, which encodes a subunit of the mitochondrial ATP synthase. This gene is associated with early-onset isolated dystonia in two families with autosomal dominant inheritance and incomplete penetrance. Functional studies showed a dominant-negative effect of the identified ATP5F1B variants, leading to reduced activity of complex V and impaired mitochondrial function.
Letter
Oncology
Christian P. Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jaeger, Sebastian M. Waszak, Anika Grosshennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M. Pfister, Holger Prokisch, Tim Ripperger, David Malkin
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2023)
Article
Genetics & Heredity
Nils Wagner, Muhammed H. Celik, Florian R. Hoelzlwimmer, Christian Mertes, Holger Prokisch, Vicente A. Yepez, Julien Gagneur
Summary: AbSplice predicts aberrant splicing in 50 human tissues by integrating deep learning models, DNA variation, and RNA-seq data. It increases prediction precision by mapping and quantifying tissue-specific splice site usage and modeling isoform competition. By incorporating RNA-sequencing data from clinically accessible tissues, precision in aberrant splicing prediction is improved to 60%.
Article
Clinical Neurology
James Fasham, Antje K. Huebner, Lutz Liebmann, Reham Khalaf-Nazzal, Reza Maroofian, Nderim Kryeziu, Saskia B. Wortmann, Joseph S. Leslie, Nishanka Ubeyratna, Grazia M. S. Mancini, Marjon van Slegtenhorst, Martina Wilke, Tobias B. Haack, Hanan E. Shamseldin, Joseph G. Gleeson, Mohamed Almuhaizea, Imad Dweikat, Bassam Abu-Libdeh, Muhannad Daana, Maha S. Zaki, Matthew N. Wakeling, Lucy McGavin, Peter D. Turnpenny, Fowzan S. Alkuraya, Henry Houlden, Peter Schlattmann, Kai Kaila, Andrew H. Crosby, Emma L. Baple, Christian A. Huebner
Summary: A novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 has been identified, which exhibits learning difficulties, seizures, and characteristic brain imaging features. Dysfunction of GABAergic transmission may contribute to the disorder.
Review
Endocrinology & Metabolism
Dmitrii Smirnov, Nikita Konstantinovskiy, Holger Prokisch
Summary: Over the past decade, high-throughput DNA sequencing approaches, such as whole exome and whole genome sequencing, have become standard procedures for diagnosing Mendelian diseases. However, the diagnostic rates vary widely and many patients remain undiagnosed. Advances in omics technologies and computational analysis offer opportunities to increase the diagnostic rates by providing evidence for disease-causing variant validation and prioritisation. This review provides an overview of the current application of various omics technologies for the diagnosis of rare genetic diseases, particularly inborn errors of metabolism.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Endocrinology & Metabolism
Luisa Averdunk, Eva Thimm, Dirk Klee, Tobias B. Haack, Felix Distelmaier
Summary: This case illustrates that classical homocystinuria is a treatable differential diagnosis of dystonia, leading to acute episodes of dystonia and brain abnormalities.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Clinical Neurology
Lorenzo Nanetti, Mary Kearney, Sylvia Boesch, Lucie Stovickova, Juan Dario Ortigoza-Escobar, Alfons Macaya, David Gomez-Andres, Emmanuel Roze, Maria-Judit Molnar, Nicole I. Wolf, Alejandra Darling, Gessica Vasco, Enrico Bertini, Elisabetta Indelicato, David Neubauer, Tobias B. Haack, Judit C. Sagi, Federica R. Danti, Deborah Sival, Ginevra Zanni, Anneli Kolk, Odile Boespflug-Tanguy, Ludger Schols, Bart van de Warrenburg, Marie Vidailhet, Michel A. Willemsen, Annemieke I. Buizer, Enrico Orzes, Sophie Ripp, Carola Reinhard, Isabella Moroni, Caterina Mariotti
Summary: This study investigated the transition process in the treatment network for rare neurological diseases. The findings revealed significant variations in clinical practices among different treatment centers, providing valuable data for existing transition programs and highlighting key challenges in managing transitions for patients with rare neurological disorders.
NEUROLOGICAL SCIENCES
(2023)
Article
Clinical Neurology
C. Thiels, T. Lucke, T. Rothoeft, C. Lukas, H. P. Nguyen, J. C. von Kleist-Retzow, H. Prokisch, M. Grimmel, T. B. Haack, S. Hoffjan
Summary: Mitchell syndrome is a rare genetic disorder caused by a specific de novo gain-of-function variant in ACOX1. Only five patients have been reported worldwide. We present two additional unrelated German patients with the same ACOX1 N237S variant. The clinical features include progressive hearing loss, ataxia, ichthyosis, and progressive visual impairment. Mitchell syndrome often mimics autoimmune-inflammatory diseases.
Article
Oncology
Michael Menzel, Stephan Ossowski, Sebastian Kral, Patrick Metzger, Peter Horak, Ralf Marienfeld, Melanie Boerries, Steffen Wolter, Markus Ball, Olaf Neumann, Sorin Armeanu-Ebinger, Christopher Schroeder, Uta Matysiak, Hannah Goldschmid, Vincent Schipperges, Axel Fuerstberger, Michael Allgaeuer, Timo Eberhardt, Jakob Niewoehner, Andreas Blaumeiser, Carolin Ploeger, Tobias Bernd Haack, Timothy Kwang Yong Tay, Olga Kelemen, Thomas Pauli, Martina Kirchner, Klaus Kluck, Alexander Ott, Marcus Renner, Jakob Admard, Axel Gschwind, Silke Lassmann, Hans Kestler, Falko Fend, Anna Lena Illert, Martin Werner, Peter Moeller, Thomas Theodor Werner Seufferlein, Nisar Malek, Peter Schirmacher, Stefan Froehling, Daniel Kazdal, Jan Budczies, Albrecht Stenzinger
Summary: With the increasing number of druggable targets and national initiatives for precision oncology, broad genomic profiling for cancer patients has become necessary. Whole exome sequencing (WES) provides unbiased analysis of coding sequences and accurate determination of complex biomarkers. Evaluating the inter-institution variability of clinical WES is important for the development of quality control frameworks.
NPJ PRECISION ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Melanie T. Achleitner, Judith J. M. Jans, Laura Ebner, Johannes Spenger, Vassiliki Konstantopoulou, Rene G. Feichtinger, Karin Brugger, Doris Mayr, Ron A. Wevers, Christian Thiel, Saskia B. Wortmann, Johannes A. Mayr
Summary: Two siblings showed increased levels of galactose and related metabolites in neonatal screening, but diagnostic tests did not identify abnormalities in known disease-causing enzymes. Whole-exome sequencing revealed a homozygous missense variant in the PPA1 gene, which was found to reduce enzyme activity and protein stability. The observed metabolic derangement is hypothesized to be a mild manifestation of PPA1 deficiency.
Article
Endocrinology & Metabolism
Sebastian Gippert, Matias Wagner, Theresa Brunet, Riccardo Berruti, Melanie Brugger, Eva M. C. Schwaibold, Tobias B. Haack, Georg F. Hoffmann, Markus Bettendorf, Daniela Choukair
Summary: This study used exome sequencing to diagnose endocrine disorders in children and found that the overall diagnostic yield was 34.9%. The diagnostic yield varied significantly between different subgroups. The study also identified rare diseases and contributed to the identification of gene-disease associations.
Meeting Abstract
Clinical Neurology
S. Efthymiou, N. Dominik, X. Miao, C. Record, R. Maroofian, G. Aughrey, M. Motazacker, C. Armirola-Ricaurte, V. Lupo, T. Sevilla, N. Basak, S. Gungor, B. Aynekin, H. Per L. Van de Vondel, E. Karimiani, S. Zuchner, H. Topaloglu, A. Jordanova, R. Horvath, T. B. Haack, M. Reilly, J. Jepson, N. Lamarche-Vane, H. Houlden
EUROPEAN JOURNAL OF NEUROLOGY
(2023)