Review
Neurosciences
S. H. Subramony, D. L. Lynch
Summary: The US FDA's approval of omaveloxolone as the first drug for inherited ataxia is exciting news for patients, families, healthcare providers, and investigators interested in rare diseases. This achievement is the result of collaboration among patients, families, clinicians, researchers, advocacy organizations, industry, and regulatory agencies. It has sparked discussions on outcome measures, biomarkers, trial design, and approval process for rare diseases, while offering hope for better therapies for genetic diseases in general.
Article
Cardiac & Cardiovascular Systems
Chiara Pane, Andrea Salzano, Assunta Trinchillo, Claudia Del Prete, Carlo Casali, Christian Marcotulli, Giovanni Defazio, Vincenzo Guardasole, Rossella Vastarella, Francesco Giallauria, Giorgia Puorro, Angela Marsili, Giovanna De Michele, Alessandro Filla, Antonio Cittadini, Francesco Sacca
Summary: This study aims to explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and compare the results with a matched cohort of healthy controls (HC) in terms of sex, age, and body mass index (BMI). The study found significant reductions in peak oxygen uptake and peak workload in FRDA patients compared to HC. Peak oxygen uptake was inversely correlated with the Scale for Assessment and Rating of Ataxia score, disease duration, and 9HPT performance, and directly correlated with activities of daily living.
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2022)
Article
Clinical Neurology
David R. Lynch, Angie Goldsberry, Christian Rummey, Jennifer Farmer, Sylvia Boesch, Martin B. Delatycki, Paola Giunti, J. Chad Hoyle, Caterina Mariotti, Katherine D. Mathews, Wolfgang Nachbauer, Susan Perlman, S. H. Subramony, George Wilmot, Theresa Zesiewicz, Lisa Weissfeld, Colin Meyer
Summary: This study compared data from an open-label extension study with FACOMS and found that omaveloxolone provided persistent benefit over 3 years for Friedreich ataxia patients. It demonstrates the importance of natural history studies in clinical trial evaluations.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Review
Behavioral Sciences
Simona Karamazovova, Veronika Matuskova, Zahinoor Ismail, Martin Vyhnalek
Summary: In addition to motor coordination, the cerebellum also plays an important role in cognitive and affective processes. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum that not only affect motor functions but also have cognitive and neuropsychiatric symptoms. This review discusses the prevalence, clinical features, and treatment approaches of neuropsychiatric impairments such as depression, anxiety, apathy, agitation, impulse dyscontrol, and psychosis in SCA and FRDA patients. Further research is needed to improve the detection and treatment options for these co-morbidities in ataxia patients due to their significant impact on quality of life.
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2023)
Article
Clinical Neurology
Louise A. Corben, Mireille M. Hermans, Alice Marks, Louise M. Crowe, Martin B. Delatycki
Summary: The study found that individuals with Friedreich ataxia (FRDA) experience challenges with sexual function and intimate relationships, including erectile dysfunction, altered genital sensation, and reduced confidence about their sexuality. Understanding the nature and extent of sexual dysfunction in FRDA is critical for developing interventions to improve sexual function and intimacy for these individuals.
JOURNAL OF NEUROLOGY
(2021)
Review
Neurosciences
Alessandra Rufini, Florence Malisan, Ivano Condo, Roberto Testi
Summary: Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It leads to reduced activity of mitochondrial enzymes, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response, resulting in the progressive loss of movement coordination and daily activity performance. Drug repositioning is a viable alternative for identifying a therapy for Friedreich ataxia.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Clinical Neurology
Virginie Destrebecq, Antonin Rovai, Nicola Trotta, Camille Comet, Gilles Naeije
Summary: This study found that passive movement paradigm led to lower activation in primary and secondary somatosensory cortices in FA compared to healthy subjects, while there was no significant difference in activation levels between healthy controls and FA in the tactile paradigm. Significant correlation was observed between activation levels in the primary somatosensory cortex in the tactile paradigm and clinical severity.
FRONTIERS IN NEUROLOGY
(2023)
Article
Neurosciences
Chiara Pane, Alberto Maria Marra, Ludovica Aliberti, Mario Campanile, Federica Coscetta, Giulia Crisci, Roberta D'Assante, Angela Marsili, Giorgia Puorro, Andrea Salzano, Antonio Cittadini, Francesco Sacca
Summary: This study aims to investigate the potential of DMF, an already available treatment for MS and psoriasis, in correcting the biological deficits of FRDA and improving mitochondrial respiration in-vivo. The study consists of a screening visit and two sequential 12-week phases: a core phase and an extension phase. The primary endpoint is the change in FXN gene expression level after 12 weeks of treatment, and secondary endpoints include measures of frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Endocrinology & Metabolism
Muhammad Yasir Qureshi, Marc C. Patterson, Vicki Clark, Jonathan N. Johnson, Margaret A. Moutvic, Sherilyn W. Driscoll, Jennifer L. Kemppainen, John Huston, Jeff R. Anderson, Andrew D. Badley, Peter J. Tebben, Philip Wackel, Devin Oglesbee, James Glockner, George Schreiner, Sundeep Dugar, Jillienne C. Touchette, Ralitza H. Gavrilova
Summary: The study showed that (+)-Epicatechin can improve cardiac function and structure in patients with FRDA, but did not result in significant improvement in primary neurological outcomes.
JOURNAL OF INHERITED METABOLIC DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Jordi Tamarit, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Arabela Sanz-Alcazar, Elisa Cabiscol, Joaquim Ros
Summary: This review discusses how iron and calcium dyshomeostasis impacts cellular functions, and suggests strategies for finding an effective therapy for Friedreich Ataxia, a neuro-cardiodegenerative disease caused by frataxin deficiency.
Review
Biochemistry & Molecular Biology
Jordi Tamarit, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Arabela Sanz-Alcazar, Elisa Cabiscol, Joaquim Ros
Summary: Friedreich Ataxia is a neuro-cardiodegenerative disease caused by the deficiency of the mitochondrial protein frataxin. Evidence suggests that the imbalance of iron and calcium homeostasis plays a crucial role in the pathogenesis of the disease and finding effective therapeutic strategies is essential.
Article
Clinical Neurology
Gabriella Paparella, Cristina Straga, Marinela Vavla, Nicola Pesenti, Vasco Merotto, Gian A. Martorel, Sara Zalunardo, Maria Armellin, Jimmy Comiotto, Andrea Martinuzzi
Summary: The study demonstrates that inpatient rehabilitation significantly improves motor performance and ataxia symptoms in patients with FRDA, showing significant functional improvement in all outcome measures used. The findings suggest that IR programs in FRDA can provide meaningful clinical improvement in terms of outcome measures, which could be beneficial for approaching progressive neurological disorders.
FRONTIERS IN NEUROLOGY
(2023)
Article
Neurosciences
Virginie Imbault, Chiara Dionisi, Gilles Naeije, David Communi, Massimo Pandolfo
Summary: This study aimed to identify potential biomarkers in FRDA patients by analyzing changes in cerebrospinal fluid (CSF) proteins. The researchers found 172 differentially expressed proteins between FRDA patients and controls, indicating possible involvement of various signaling pathways and pathogenic mechanisms.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Genetics & Heredity
Massimo Pandolfo, Kathrin Reetz, Alejandra Darling, Francisco Javier Rodriguez de Rivera, Pierre-Gilles Henry, James Joers, Christophe Lenglet, Isaac Adanyeguh, Dinesh Deelchand, Fanny Mochel, Francoise Pousset, Silvia Pascual, Delphine Van den Eede, Itziar Martin-Ugarte, Anna Vila-Brau, Adriana Mantilla, Maria Pascual, Marc Martinell, Uwe Meya, Alexandra Durr
Summary: The study found that leriglitazone did not significantly affect the spinal cord area in patients with FRDA. Secondary endpoints provided evidence supporting the mode of action of leriglitazone, and with acceptable safety data, larger studies in patients with FRDA are warranted.
NEUROLOGY-GENETICS
(2022)
Article
Neurosciences
Sarah C. Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M. Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Theresa Zesiewicz, Martin B. Delatycki, Louise A. Corben
Summary: The study identified that FARS USS and BBS are highly responsive in detecting changes in individuals with FRDA, while the most suitable measure for therapeutic effects in children is DGI.
Review
Clinical Neurology
Quang Tuan Remy Nguyen, Juan Dario Ortigoza Escobar, Jean-Marc Burgunder, Caterina Mariotti, Carsten Saft, Lena Elisabeth Hjermind, Katia Youssov, G. Bernhard Landwehrmeyer, Anne-Catherine Bachoud-Levi
Summary: This study examines the diagnosis of HD phenocopies and proposes guidance that combines the detection of clinical red flags with the classification of paraclinical testing options. The study utilizes a literature review and physician surveys to provide a diagnostic approach for HD phenocopies.
FRONTIERS IN NEUROLOGY
(2022)
Review
Clinical Neurology
Lorenzo Nanetti, Daniela Di Bella, Stefania Magri, Mario Fichera, Elisa Sarto, Anna Castaldo, Alessia Mongelli, Silvia Baratta, Silvia Fenu, Marco Moscatelli, Maria Teresa Bonati, Andrea Martinuzzi, Caterina Mariotti, Franco Taroni
Summary: Pathogenic variants in the PNPLA6 gene are associated with a wide range of neurodegenerative diseases, including spastic paraplegia, cerebellar ataxia, and hypogonadotropic hypogonadism. This study identified novel PNPLA6 gene variants in eight patients, with age of onset ranging from infancy to adulthood.
FRONTIERS IN NEUROLOGY
(2022)
Letter
Clinical Neurology
Megan M. Shen, Layne N. Rodden, Kellie McIntyre, Adriana Arias, Victoria Profeta, Kimberly Schadt, David R. Lynch
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner, Mark Midei
Summary: This study tested the effects of a deuterated form of linoleic acid (RT001) on disease severity in Friedreich ataxia patients and found no significant benefits at the tested dosages.
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
David R. R. Lynch, Melanie P. P. Chin, Sylvia Boesch, Martin B. B. Delatycki, Paola Giunti, Angie Goldsberry, J. Chad Hoyle, Caterina Mariotti, Katherine D. D. Mathews, Wolfgang Nachbauer, Megan O'Grady, Susan Perlman, S. H. Subramony, George Wilmot, Theresa Zesiewicz, Colin J. J. Meyer
Summary: The study evaluated the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia. The results showed a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia.
MOVEMENT DISORDERS
(2023)
Article
Cell Biology
Sharla M. Birch, Michael W. Lawlor, Thomas J. Conlon, Lee-Jae Guo, Julie M. Crudele, Eleanor C. Hawkins, Peter P. Nghiem, Mihye Ahn, Hui Meng, Margaret J. Beatka, Brittany A. Fickau, Juan C. Prieto, Martin A. Styner, Michael J. Struharik, Courtney Shanks, Kristy J. Brown, Diane Golebiowski, Amanda K. Bettis, Cynthia J. Balog-Alvarez, Nathalie Clement, Kirsten E. Coleman, Manuela Corti, Xiufang Pan, Stephen D. Hauschka, J. Patrick Gonzalez, Carl A. Morris, Joel S. Schneider, Dongsheng Duan, Jeffrey S. Chamberlain, Barry J. Byrne, Joe. N. Kornegay
Summary: Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin. This study evaluated the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (mu Dys5) construct in a dystrophin-deficient golden retriever muscular dystrophy (GRMD) dog model. The results showed dose-dependent increases in tissue vector genome copy numbers and mu Dys5 protein, improvement in muscle function, and reduction of histopathologic lesions. Systemically administered AAV-microdystrophin was well tolerated and could potentially provide therapeutic benefit for DMD patients.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Genetics & Heredity
Paulina Cunha, Emilien Petit, Marie Coutelier, Giulia Coarelli, Caterina Mariotti, Jennifer Faber, Judith Van Gaalen, Joana Damasio, Zofia Fleszar, Michele Tosi, Clarissa Rocca, Giovanna De Michele, Martina Minnerop, Claire Ewenczyk, Filippo M. Santorelli, Anna Heinzmann, Thomas Bird, Matthias Amprosi, Elisabetta Indelicato, Alberto Benussi, Perrine Charles, Claudia Stendel, Silvia Romano, Marina Scarlato, Isabelle Le Ber, Maria Teresa Bassi, Mercedes Serrano, Tanja Schmitz-Hubsch, Sarah Doss, Gijs A. J. Van Velzen, Quentin Thomas, Antonio Trabacca, Juan Dario Ortigoza-Escobar, Stefano D'Arrigo, Dagmar Timmann, Chiara Pantaleoni, Andrea Martinuzzi, Elsa Besse-Pinot, Luca Marsili, Ettore Cioffi, Francesco Nicita, Alejandro Giorgetti, Isabella Moroni, Romina Romaniello, Carlo Casali, Penina Ponger, Giorgio Casari, Susanne T. De Bot, Giovanni Ristori, Lubov Blumkin, Barbara Borroni, Cyril Goizet, Cecilia Marelli, Sylvia Boesch, Mathieu Anheim, Alessandro Filla, Henry Houlden, Enrico Bertini, Thomas Klopstock, Matthis Synofzik, Florence Riant, Ginevra Zanni, Stefania Magri, Daniela Di Bella, Lorenzo Nanetti, Jorge Sequeiros, Jorge Oliveira, Bart Van de Warrenburg, Ludger Schoels, Franco Taroni, Alexis Brice, Alexandra Durr
Summary: Although most spinocerebellar ataxias (SCAs) are caused by triplet repeat expansions, there are many SCAs that are not. This study screened individuals with variants in non-expansion SCA-associated genes and identified 756 subjects with single-nucleotide variants or deletions in seven different genes. Comparison of disease features and progression revealed no reliable distinguishing factors between these SCAs, and certain genes were associated with both adult-onset and infantile-onset forms of the disease. However, the overall progression of the disease was slow, with STUB1-associated disease progressing the fastest. Variants in CACNA1A showed wide ranges in age at onset, and the type of variant and protein charge change greatly affected the phenotype.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Clinical Neurology
Lorenzo Nanetti, Stefania Magri, Mario Fichera, Anna Castaldo, Anna Nigri, Chiara Pinardi, Alessia Mongelli, Lidia Sarro, Davide Pareyson, Marina Grisoli, Cinzia Gellera, Daniela Di Bella, Caterina Mariotti, Franco Taroni
Summary: This study identified a form of spinocerebellar ataxia (SCA) characterized by the presence of an intermediate-length expansion in the TATA-box binding protein gene (TBP40-46) and a pathogenic variant in the Stip1-homologous and U-Box containing protein 1 gene (STUB1), representing the first example of digenic inheritance in a cerebellar disorder. Patients with SCA(TBP/STUB1) exhibited multi-domain dementia and more severe impairment compared to those carrying only fully expanded SCA17 alleles. Neuroimaging analysis revealed reduced cerebellar volume and thickness in SCA(TBP/STUB1) patients, as well as basal ganglia volume reduction in both patient groups. The findings have implications for diagnosis and genetic counseling in families with hereditary and sporadic ataxia.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Anna Castaldo, Mariangela Farinotti, Mario Fichera, Lorenzo Nanetti, Filippo Fortuna, Caterina Mariotti, Alessandra Solari
Summary: This study translated and culturally adapted the PROM-Ataxia questionnaire into Italian and conducted cognitive interviews. Italian patients found the questionnaire to be complete, but identified some redundant or ambiguous items. The translation and cultural adaptation are necessary for the subsequent psychometric validation of the scale.
NEUROLOGICAL SCIENCES
(2023)
Article
Clinical Neurology
Layne N. Rodden, Kellie McIntyre, Medina Keita, Mckenzie Wells, Courtney Park, Victoria Profeta, Amy Waldman, Christian Rummey, Laura J. Balcer, David R. Lynch
Summary: This study characterized features of vision loss in a large cohort of adults and children with Friedreich ataxia (FRDA). Results showed that most patients, including children, had pathologically thin retinal nerve fiber layers (RNFLs) and low-contrast vision deficits early in the disease course. The data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Correction
Clinical Neurology
David Lynch
ANNALS OF NEUROLOGY
(2023)
Review
Biochemistry & Molecular Biology
Kia H. Markussen, Manuela Corti, Barry J. Byrne, Craig W. Vander Kooi, Ramon C. Sun, Matthew S. Gentry
Summary: This review discusses the primary role of glycogen in carbohydrate storage and energy metabolism in the liver and muscle, as well as its critical metabolic and non-metabolic roles in the brain. Perturbed glycogen functions are observed in various brain disorders, including neurological glycogen storage diseases. The study of glycogen and its treatment strategies is of great significance for human diseases.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Clinical Neurology
Andrea Horta-Barba, Saul Martinez-Horta, Jesus Perez-Perez, Arnau Puig-Davi, Natascia de Lucia, Giuseppe de Michele, Elena Salvatore, Stefanie Kehrer, Josef Priller, Simone Migliore, Ferdinando Squitieri, Anna Castaldo, Caterina Mariotti, Veronica Mananes, Jose Luis Lopez-Sendon, Noelia Rodriguez, Asuncion Martinez-Descals, Filipa Julio, Cristina Januario, Marianna Delussi, Marina de Tommaso, Sandra Noguera, Jesus J. Ruiz-Idiago, Emilia Sitek, Renata Wallner, Angela Nuzzi, Javier Pagonabarraga, Jaime Kulisevsky
Summary: This study developed a specific assessment tool, the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), to evaluate the cognitive status of Huntington's disease patients and monitor the progression of cognitive impairment. Through evaluating 180 gene-positive patients, criteria for classifying normal cognition, mild cognitive impairment, and dementia were established, and the PD-CRS demonstrated good sensitivity and specificity. Additionally, the PD-CRS captured cognitive progression in different cognitive groups and showed sensitivity to change in mild cognitive impairment and dementia.
JOURNAL OF NEUROLOGY
(2023)
Editorial Material
Clinical Neurology
Joaquin A. Vizcarra, Rachel A. Paul, Ali G. Hamedani, David R. Lynch, Whitley W. Aamodt
Summary: This report reviews the clinical characteristics of a rare late-onset autosomal recessive cerebellar ataxia and emphasizes the importance of pursuing targeted gene testing to avoid diagnostic delays.