By Wenhua Zhu

Publication

A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry. Cortese A, Beecroft SJ, Facchini S, Curro R, Cabrera-Serrano M, Stevanovski I, Chintalaphani SR, Gamaarachchi H, Weisburd B, Folland C, Monahan G, Scriba CK, Dofash L, Johari M, Grosz BR, Ellis M, Fearnley LG, Tankard R, Read J, Merve A, Dominik N, Vegezzi E, Schnekenberg RP, Fernandez-Eulate G, Masingue M, Giovannini D, Delatycki MB, Storey E, Gardner M, Amor DJ, Nicholson G, Vucic S, Henderson RD, Robertson T, Dyke J, Fabian V, Mastaglia F, Davis MR, Kennerson M; OPDM study group; Quinlivan R, Hammans S, Tucci A, Bahlo M, McLean CA, Laing NG, Stojkovic T, Houlden H, Hanna MG, Deveson IW, Lockhart PJ, Lamont PJ, Fahey MC, Bugiardini E, Ravenscroft G. Nat Commun. 2024 Jul 27;15(1):6327. doi: 10.1038/s41467-024-49950-2.

PMID: 39068203 Free PMC article.

https://www.nature.com/articles/s41467-024-49950-2

Summary

Oculopharyngodistal myopathy (OPDM) is a progressive muscle disorder first described in 1977, characterised by adult-onset ptosis, external ophthalmoplegia, and muscle weakness, including the facial and distal limb muscles. The pathogenic mutations responsible for OPDM were only discovered with the recent widespread use of long-read sequencing (LRS) technology. While CGG repeat expansions in several genes have been linked to OPDM in Asian populations, European cases remained genetically unexplained for years.

Cortese et al. identified CCG expansions in the 5′-untranslated region (UTR) of the ABCD3 gene, a novel locus for OPDM, in eight unrelated European families. Two Australian families were subjected to linkage analysis, which yielded a maximum LOD score of 2.98. Whole-genome sequencing of one individual confirmed the presence of 72 CGG repeats in ABCD3. Independent analysis using the Genomics England 100,000 Genome Project identified the same repeat expansion, confirming the locus's association with OPDM in European populations. Repeat-primed PCR further validated the ABCD3 expansion in affected individuals from the UK, Australia, and France, demonstrating its segregation with the disease.

In total, 19 affected individuals were found to carry a single allele with expanded CGG repeats, ranging from 118 to 694 repeats. Notably, the expansion was longer (356 vs 185 repeats on average) and more variable (range 576 vs 180 repeats) in length in females than in males, suggesting greater instability in females. Methylation profiling indicated that in most cases, expanded alleles were unmethylated, except in two females with very large expansions, where hypermethylation may have mitigated the phenotype. A shared ancestral haplotype spanning 560 kb around the ABCD3 locus was identified among all OPDM patients, suggesting a common origin of the repeat expansion.

OPDM-ABCD3 typically presents in the second to third decade of life, with an average age of onset of 26.7 years. Ptosis was the most common initial symptom, followed by other features such as facial weakness, ophthalmoparesis, and distal limb weakness. Muscle biopsies revealed typical OPDM-like features such as rimmed vacuoles, internal nuclei, and autophagic vacuoles. Immunohistochemistry in affected tissues showed rare p62-positive intranuclear inclusions. Sex-based differences were observed: females tended to have earlier disease onset (~5 years earlier than males), and maternal transmission of the repeat expansion was associated with lower penetrance.

RNA sequencing showed elevated ABCD3 expression in OPDM muscle tissue compared to other neuromuscular diseases and controls. Fluorescent in situ hybridization detected increased levels of ABCD3 transcript, forming nuclear foci in patient-derived fibroblasts and muscle samples, consistent with pathological mechanisms seen in other repeat expansion disorders.

This is the first report of an OPDM-related gene in European cases. Notably, while GIPC1, RILPL1, NOTCH2NLC, and LRP12 account for ~75% of Asian OPDM cases, over 70 European OPDM probands in this study remain genetically unexplained, indicating the potential for high genetic heterogeneity underlying this condition. Further investigation into the ABCD3 5′-UTR repeat expansions in other neurodegenerative disorders such as ALS will help fully elucidate the clinical spectrum. The possibly underlying pathogenic mechanisms, such as RNA and/or repeat peptide toxicity, remain to be explored in detail to establish therapeutic strategies for this disease, which shares a common pathogenic mechanism underlying both muscle and neurodegeneration, regardless of the specific repeat-containing genes.

About the author

Profile photo of Andrea Cortese. Andrea is in front of a dark background. He wears a dark sweater over a lighter coloured shirt and round glasses.Dr Andrea Cortese

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

 

Published on 23 October 2024.

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