Purpose: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance.
Methods: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis.
Results: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA.
Conclusion: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710562 | PMC |
| http://dx.doi.org/10.1038/s41436-020-0924-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Pathogenic variants of GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by axonal degeneration. GDAP1, an atypical glutathione S-transferase, localizes to the outer mitochondrial membrane (OMM), regulating this organelle's dynamics, transport, and membrane contact sites (MCSs). It has been proposed that GDAP1 functions as a cellular redox sensor.
View Article and Find Full Text PDFHow hidden is hidden hearing loss? Self-reported listening problems in charcot Marie tooth disease.
J Commun Disord
December 2024
Radboud University, Behavioural Science Institute, Nijmegen, The Netherlands. Electronic address:
Introduction: Laboratory studies have revealed hidden hearing loss in patients with Charcot-Marie-Tooth (CMT) disease, the most prevalent inherited neuropathy, which may impact their quality of life. The current study distinguished between CMT type 1, which involves demyelination of the peripheral nerves, and type 2, which concerns dysfunction of peripheral nerves due to axonopathy. The self-reported effects were investigated of CMT1 and CMT2 on listening problems and related social and attentional problems in everyday communicative situations.
View Article and Find Full Text PDFCell type-specific gene therapy confers protection against motor neuron disease caused by a TFG variant.
Proc Natl Acad Sci U S A
November 2024
Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
Article Synopsis
- Inherited motor neuron diseases (MND) like hereditary spastic paraplegias (HSP) involve the death or dysfunction of nerve cells that control muscle activity, but genetic variants may also affect other supportive cells.
- Researchers used a rat model with a specific TFG mutation that mimics human HSP symptoms, such as motor deficits and spasticity, to investigate the source of axonopathy in the corticospinal tract.
- Results showed that introducing the normal TFG gene into specific neurons significantly improved motor function, while targeting supportive glial cells did not yield similar benefits, highlighting the importance of neuron-focused therapies for TFG-related HSP.
Lower limb nerve ultrasound: A four-way comparison of acquired and inherited axonopathy, inherited neuronopathy and healthy controls.
Muscle Nerve
December 2024
Department of Neurology, Auckland District Health Board, Auckland, New Zealand.
Article Synopsis
- The study analyzed lower limb nerve ultrasound measurements to differentiate between inherited neuronopathy, inherited axonopathy, and acquired axonopathy in patients.
- Researchers compared nerve sizes in 34 healthy controls with three patient groups, finding significant size variations particularly in the tibial and sural nerves.
- Results indicated that inherited conditions (CANVAS and CMT2) had smaller nerve sizes compared to the acquired condition, suggesting ultrasound can help in diagnosing these neurological diseases more effectively.
Spectrum of Leukodystrophy and Genetic Leukoencephalopathy in Indian Population Diagnosed by Clinical Exome Sequencing and Clinical Utility.
Neurol Genet
October 2024
From the Department of Neurology (K.Y.M., A.F., P.P., S.S.N., A.C., K.P.D.); Pediatric Neurology and Neurodevelopmental Disorders (R.M., S.S.); and Department of Imaging Sciences and Intervention Radiology (B.T.), Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Thiruvananthapuram, Kerala, India.
Background And Objectives: Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!