Next Article in Journal
Differential Diagnosis of Anemia Using the Erythrocyte Filterability Method
Previous Article in Journal
Rare Variants May Influence Disease Risk and Clinical Features in Sporadic Late-Onset Chinese Parkinson’s Disease Patients
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 27
Issue 17
10.3390/ijms27177655
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Case Report

Phenotypic and Molecular Features of a Large ODDD Family: Expanding the Spectrum of CX43-Related Disorder

by
Irene Ambrosetti
1,
Flavia Palombo
2,
Diego D’Angeli
3,
Danara Ormanbekova
2,
Claudio Fiorini
2,
Andrea Pietra
3,
Carlotta Pia Cristalli
4,
Raffaele Lodi
3,5,
Caterina Tonon
3,5,
Rocco Liguori
3,6,
Valerio Carelli
2,3,
Giovanni Rizzo
3,6 and
Alessandro Vaisfeld
7,8,*
1
Clinical Genetics Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy
2
Programma di Neurogenetica, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
3
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
4
IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy
5
Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
6
UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
7
Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
8
Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(17), 7655; https://doi.org/10.3390/ijms27177655
Submission received: 30 June 2026 / Revised: 10 August 2026 / Accepted: 18 August 2026 / Published: 26 August 2026
(This article belongs to the Special Issue Research in Genetic Causes of Adult-Onset Disorders)
Review Reports Versions Notes

Abstract

We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.
Keywords: oculodentodigital dysplasia (ODDD); GJA1; connexin 43 (Cx43); hereditary paraplegia; hypomyelinating leukodystrophy; genotype-phenotype correlation; phenotypic expansion oculodentodigital dysplasia (ODDD); GJA1; connexin 43 (Cx43); hereditary paraplegia; hypomyelinating leukodystrophy; genotype-phenotype correlation; phenotypic expansion

Share and Cite

MDPI and ACS Style

Ambrosetti, I.; Palombo, F.; D’Angeli, D.; Ormanbekova, D.; Fiorini, C.; Pietra, A.; Cristalli, C.P.; Lodi, R.; Tonon, C.; Liguori, R.; et al. Phenotypic and Molecular Features of a Large ODDD Family: Expanding the Spectrum of CX43-Related Disorder. Int. J. Mol. Sci. 2026, 27, 7655. https://doi.org/10.3390/ijms27177655

AMA Style

Ambrosetti I, Palombo F, D’Angeli D, Ormanbekova D, Fiorini C, Pietra A, Cristalli CP, Lodi R, Tonon C, Liguori R, et al. Phenotypic and Molecular Features of a Large ODDD Family: Expanding the Spectrum of CX43-Related Disorder. International Journal of Molecular Sciences. 2026; 27(17):7655. https://doi.org/10.3390/ijms27177655

Chicago/Turabian Style

Ambrosetti, Irene, Flavia Palombo, Diego D’Angeli, Danara Ormanbekova, Claudio Fiorini, Andrea Pietra, Carlotta Pia Cristalli, Raffaele Lodi, Caterina Tonon, Rocco Liguori, and et al. 2026. "Phenotypic and Molecular Features of a Large ODDD Family: Expanding the Spectrum of CX43-Related Disorder" International Journal of Molecular Sciences 27, no. 17: 7655. https://doi.org/10.3390/ijms27177655

APA Style

Ambrosetti, I., Palombo, F., D’Angeli, D., Ormanbekova, D., Fiorini, C., Pietra, A., Cristalli, C. P., Lodi, R., Tonon, C., Liguori, R., Carelli, V., Rizzo, G., & Vaisfeld, A. (2026). Phenotypic and Molecular Features of a Large ODDD Family: Expanding the Spectrum of CX43-Related Disorder. International Journal of Molecular Sciences, 27(17), 7655. https://doi.org/10.3390/ijms27177655

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop