Deep neurological phenotyping in oculo-dento-digital syndrome

Objectives Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant congenital malformation syndrome characterized by high penetrance and great phenotypic heterogeneity. Neurological manifestations are thought to occur in about one third of cases, but systematic studies are not available. We performed deep neurological phenotyping of 10 patients in one ODDD pedigree. Methods Retrospective case series. We analyzed in depth the neurological phenotype of a three-generation family segregating the heterozygous c.416 T > C, p.(Ile139Thr) in GJA1 . Clinical and neuroradiological features were retrospectively evaluated. Brain MRI and visual evoked potentials were performed in 8 and 6 cases, respectively. Results Central nervous system manifestations occurred in 5 patients, the most common being isolated ataxia either in isolation or combined with spasticity. Furthermore, sphincteric disturbances (neurogenic bladder and fecal incontinence) were recognized as the first manifestation in most of the patients. Subclinical electrophysiological alteration of the optic pathway occurred in all the examined patients. Neuroimaging was significant for supratentorial hypomyelination pattern and hyperintense superior cerebellar peduncle in all examined patients. Conclusion The neurological involvement in ODDD carriers is often missed but peculiar clinical and radiological patterns can be recognized. Deep neurological phenotyping is needed to help untangle ODDD syndrome complexity and find genotype–phenotype correlations.