Insight into impaired functions and underlying mechanisms
Over the last 10 years, the HSPs have been shown to have huge genetic heterogeneity and diversity; fuzzy borders between recessive and dominant forms and complicated/uncomplicated forms; and increasingly common overlap with other neurological conditions.
PURPOSE OF REVIEW: Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in complex forms by additional neurological signs. We review here the major steps toward understanding the molecular basis of these diseases made over the last 10 years.
RECENT FINDINGS: Our perception of the intricate connections between clinical, genetic, and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which > 60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations, and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects.
Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function and based on studies on patient samples and animal models. These mechanisms include mainly abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination, and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected.
Recent major advances in our understanding of these diseases have revealed unifying pathogenic models that could be targeted in the much-needed development of new treatments.
SOURCE: Curr Neurol Neurosci Rep. 2019 Feb 28;19(4):18. doi: 10.1007/s11910-019-0930-2. PMID: 30820684
Update on the Genetics of Spastic Paraplegias.
1 Institut du Cerveau et de la Moelle épinière, Sorbonne Université UMR_S1127, INSERM Unit 1127, CNRS UMR7225, 75013, Paris, France.
2 Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres (PSL) Research University, 75013, Paris, France.
3 Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
4 UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
5 Institut du Cerveau et de la Moelle épinière, Sorbonne Université UMR_S1127, INSERM Unit 1127, CNRS UMR7225, 75013, Paris, France. [email protected]
6 Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres (PSL) Research University, 75013, Paris, France. [email protected]
Precise definition & new classification framework needed for HSPs
Expanding clinical spectrum and increasing disease overlap
Precise disease definition (called ‘objective case definition’) and a new classification framework (called ’nosology’) for neurogenetic disorders like HSP are needed to help identify biomarkers and develop therapeutic treatments.
Definitive diagnosis of neurogenetic disorders including the HSPs is becoming increasingly difficult with the constant expansion of the clinical spectrum of these diseases and the discovery of new genes, many of which point to overlapping diseases.
Hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders characterized by progressive lower limb weakness and spasticity as core symptoms of the degeneration of the corticospinal motor neurons.
Even after exclusion of infectious and toxic mimickers of these disorders, the definitive diagnosis remains tricky, mainly in sporadic forms, as there is significant overlap with other disorders. Since their first description, various attempts failed to reach an appropriate classification. This was due to the constant expansion of the clinical spectrum of these diseases and the discovery of new genes, a significant number of them involved in overlapping diseases.
Areas covered: In this perspective review, an extensive literature study was conducted on the historical progress of HSP research. We also revised the previous and the current classifications of HSP and the closely related neurogenetic disorders and analyzed the areas of overlap.
Expert opinion: There is undeniable need for objective case definition and reclassification of all neurogenetic disorders including HSPs, a prerequisite to improve patient follow-up, identify biomarkers and develop therapeutics. The challenge is to understand why mutations can give rise to multiple phenotypic presentations along this spectrum of diseases in which the corticospinal tract is affected.
SOURCE: Expert Rev Neurother. 2019 May;19(5):409-415. doi: 10.1080/14737175.2019.1608824. Epub 2019 Apr 30. PMID: 31037979
Hereditary spastic paraplegias: time for an objective case definition and a new nosology for neurogenetic disorders to facilitate biomarker/therapeutic studies.
1 a Faculty of Medicine , University of Khartoum , Khartoum , Sudan.
2 b Basic to Translational Neurogenetics team , Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Université UMR_S1127 , Paris , France.
3 c Neurogenetics team , Ecole Pratique des Hautes Etudes, EPHE, PSL Research University , Paris , France.
Getting a diagnosis for everyone affected by a rare disease
Hundreds of millions of lives are affected by an estimated 10,000 unique genetically determined diseases. Achieving an accurate and timely molecular diagnosis will largely depend on progress in the discovery of the genes and genetic mechanisms associated with rare diseases (RDs). While the exact number of RDs is debated (Hartley et al., 2018), it is estimated that thousands of RD genes and disease mechanisms remain undiscovered.
Three focus areas are essential to progress:
the continued importance of exome sequencing (ES) for genetic testing in both the clinic and the research environment
the next wave of technologies on the horizon, and
the next frontiers for RD discovery,
moving toward the ultimate goal of diagnostic clarity for each and every family affected by a RD.
Exome Sequencing (ES)
To realize the theoretical maximal diagnostic yield of ES will require a globally coordinated change in thinking; every patient must have the opportunity to be a research patient. More international and less restrictive data sharing is critical to drive disease gene discovery, facilitate variant interpretation, enhance control datasets, and develop new computational tools.
New Technologies – to discover disease mechanisms
Regardless of the ultimate capability of ES to provide diagnoses for RD patients, some disease mechanisms are difficult or impossible to detect using this approach. Short and long-read Genome Sequencing (GS) will increase the diagnostic yield of a genome-wide clinical test by at least 10% in the near term. As clinical GS data accumulate and understanding of genetic variation improves, this yield will significantly increase over the years.
Despite the excitement around GS, few RD discoveries have been made outside of the protein-coding regions of the genome. Comprehensive analysis of the noncoding genome on a broader scale represents a significant frontier. The opportunity lies in the interpretation of noncoding variation, which is exponentially more difficult given the unresolved complexity of how noncoding DNA regulates gene expression, lack of adequate control datasets, and computational tools.
The vision of IRDiRC, for each RD patient to receive a diagnosis within 1 year, is achievable only if we collectively take up this grand opportunity on a global scale.
* Gareth Baynam is a distinguished West Australian clinical geneticist and Chair of the Diagnostics Scientific Committee of the International Rare Diseases Research Consortium (IRDiRC). Assoc Prof Baynam is also a policy advisor at the WA Department of Health, the Head of the West Australian Register of Developmental Anomalies, and a member of the Governance Board of the National Centre for Indigenous Genomics, amongst other appointments.
The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances.
To provide diagnostic clarity to all of these patients, however, there is a critical need for the field to develop and implement strategies to understand the mechanisms underlying all rare diseases and translate these to clinical care.
SOURCE: Cell. 2019 Mar 21;177(1):32-37. doi: 10.1016/j.cell.2019.02.040. Copyright © 2019 Elsevier Inc. All rights reserved. PMID: 30901545
A Diagnosis for All Rare Genetic Diseases: The Horizon and the Next Frontiers.
1 Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada. Electronic address: [email protected]
2 Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
3 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
4 Human Genome Sequencing Center, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, USA.
5 Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
7 Illumina, Madison, WI, USA; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
8 Victor Chang Cardiac Research Institute, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
9 Microsoft Research, Seattle, Washington, USA.
10 Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
11 Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, Hampshire, UK.
12 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, CA, USA; DOE Joint Genome Institute, CA, USA; The University of California at Merced, CA, USA.
13 Faculty of Health and Medical Sciences, University of Western Australia Medical School, Perth, WA, Australia; Western Australian Register of Developmental Anomalies, Genetic Services of Western Australia, Perth, WA, Australia; Office of Population Health Genomics, Western Australian Department of Health, Perth, WA, Australia.