Insights into the heterogeneity of oculopharyngeal muscular dystrophy.
| Title: | Insights into the heterogeneity of oculopharyngeal muscular dystrophy. |
|---|---|
| Authors: | Kekou K; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece. kkekou@med.uoa.gr.; Papadopoulos C; 1 st Department of Neurology, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Svingou M; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Research University institute for the study and prevention of genetic and malignant disease of childhood, Athens, Greece.; Chrysanthou-Piterou M; 1 st Department of Psychiatry, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Nitsa E; Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Athens, Greece.; Veltra D; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Research University institute for the study and prevention of genetic and malignant disease of childhood, Athens, Greece.; Marinakis N; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Research University institute for the study and prevention of genetic and malignant disease of childhood, Athens, Greece.; Laboratory of Genetics, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.; Tilemis FN; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Research University institute for the study and prevention of genetic and malignant disease of childhood, Athens, Greece.; Dimitrios P; 2nd Department of Neurology, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.; Arnaoutoglou M; 1 st Department of Neurology, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.; Moschou M; 1 st Department of Neurology, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.; Xirou S; 1 st Department of Neurology, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Bakirtzis C; 2nd Department of Neurology, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.; Tsivgoulis G; 2nd Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Papadimas GK; 1 st Department of Neurology, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Sofocleous C; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece. |
| Source: | Neurogenetics [Neurogenetics] 2025 Sep 24; Vol. 26 (1), pp. 68. Date of Electronic Publication: 2025 Sep 24. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Springer-Verlag Country of Publication: United States NLM ID: 9709714 Publication Model: Electronic Cited Medium: Internet ISSN: 1364-6753 (Electronic) Linking ISSN: 13646745 NLM ISO Abbreviation: Neurogenetics Subsets: MEDLINE |
| Imprint Name(s): | Publication: : [New York, N.Y.?] : Springer-Verlag; Original Publication: Oxford, UK : Oxford University Press, c1997- |
| MeSH Terms: | Muscular Dystrophy, Oculopharyngeal*/genetics ; Muscular Dystrophy, Oculopharyngeal*/pathology ; Poly(A)-Binding Protein I*/genetics; Trinucleotide Repeat Expansion/genetics ; Humans ; Male ; Female ; Adult ; Middle Aged ; Pedigree ; Phenotype ; Age of Onset ; Genotype ; Aged ; Genetic Heterogeneity ; Greece ; Young Adult ; Adolescent |
| Abstract: | Oculopharyngeal muscular dystrophy (OPMD) is a rare, adult-onset, autosomal dominant myopathy characterized by variability in the age of onset and disease progression. However, its pathogenesis and phenotypic variability remain poorly understood. The disorder is caused by an expansion of a short polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. This study presents data from 23 patients across 19 Greek families with pathogenic PABPN1 expansions, including demographic and laboratory data, as well as molecular and electron microscopy findings. Eight distinct trinucleotide expansion genotypes were identified. Electron microscopy consistently demonstrated mitochondrial abnormalities, including swelling, disrupted cristae and atypical lipid inclusions. Clinical heterogeneity was observed at both inter- and intrafamilial levels, and milder phenotypes were generally linked to smaller alleles. Notably, maternally inherited expansions were associated with an earlier disease onset and more severe progression in affected offspring. Given the genetic variability observed in the cohort, the presence of a founder effect could not be supported. A significant degree of underdiagnosis or diagnostic delay was noted, largely attributable to the rarity and clinical heterogeneity of the disease. The observed intrafamilial heterogeneity - particularly in maternally inherited expansions - supports previous reports suggesting that mitochondrial dysfunction may contribute to transgenerational disease progression in the context of a dominant, causative nuclear variant.; (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Competing interest: The authors have no competing interests to declare that are relevant to the content of this article. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1 including. |
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| Contributed Indexing: | Keywords: Anticipation; Mitochondrial dysfunction; OPMD; Triplet expansion |
| Substance Nomenclature: | 0 (PABPN1 protein, human); 0 (Poly(A)-Binding Protein I) |
| Entry Date(s): | Date Created: 20250924 Date Completed: 20250924 Latest Revision: 20260128 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12460444 |
| DOI: | 10.1007/s10048-025-00849-0 |
| PMID: | 40991068 |
| Database: | MEDLINE |
Journal Article