RESUMO
Background: 22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100 000 live births, and it is a multisystem condition with variable phenotypic presentations. Methods: We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms. Results: Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2 Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome. Conclusion: Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician.
RESUMO
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.