Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants.

RAC1 is a member of the Rac/Rho GTPase subfamily within the RAS superfamily of small GTP-binding proteins, comprising 3 paralogs playing a critical role in actin cytoskeleton remodeling, cell migration, proliferation and differentiation. De novo missense variants in RAC1 are associated with a rare neurodevelopmental disorder (MRD48) characterized by DD/ID and brain abnormalities coupled with a wide range of additional features. Structural and functional studies have documented either a dominant negative or constitutively active behavior for a subset of mutations. Here, we describe two individuals with previously unreported de novo missense RAC1 variants. We functionally demonstrate their pathogenicity proving a gain-of-function (GoF) effect for both. By reviewing the clinical features of these two individuals and the previously published MRD48 subjects, we further delineate the clinical profile of the disorder, confirming its phenotypic variability. Moreover, we compare the main features of MRD48 with the neurodevelopmental disease caused by GoF variants in the paralog RAC3, highlighting similarities and differences. Finally, we review all previously reported variants in RAC proteins and in the closely related CDC42, providing an updated overview of the spectrum and hotspots of pathogenic variants affecting these functionally related GTPases.

Gestural automatisms during syncope related to cervical malignancy.

Cervical malignancies are a rare but well-known cause of syncope. Gestural automatisms during syncope have only rarely been reported. We describe a patient presenting with bimanual automatisms during syncopal episodes caused by parapharyngeal carcinoma involving the right laterocervical region. Ictal phenomenology was strongly suggestive of focal seizures and only video-polygraphic recording including EEG and ECG allowed the correct diagnosis to be established. Syncopal episodes ceased after partial removal of the mass. Although gestural automatisms in the context of a sudden spell with loss of consciousness are strongly suggestive of focal (mainly frontal or temporal) seizures, the diagnosis of syncope must be taken in account and confirmed or excluded by appropriate neurophysiological investigations.

Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype.

Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor ß/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

Epileptogenic role of occult temporal encephalomeningocele: Case-control study.

OBJECTIVE: The purpose of this case-control study is to evaluate the prevalence of occult temporal encephalomeningocele (OTE) in patients with temporal lobe epilepsy (TLE) of unknown etiology presenting to an epilepsy center, independently from drug sensitivity. METHODS: We studied 95 patients with TLE (51 female, mean age 49.4 ± 17.1 years) and 151 controls (88 female, mean age 54.1 ± 21.0 years) using a 1.5T brain MRI, including balanced steady-state gradient echo sequences, targeted to the temporal lobes. RESULTS: OTE was found in 5.2% of the TLE population (9.5% of drug-resistant TLE) and in none of the controls (p = 0.008). Two patients with OTE and drug-resistant TLE became seizure-free after lesionectomy (follow-up 18-24 months). CONCLUSION: OTE is not a rare finding in unselected patients with TLE of unknown origin, provided that it is carefully searched. The absence of OTE in a large group of nonepileptic controls adds evidence to its epileptogenic role.

Multiple watershed cerebral infarcts.

The case of a 63-year-old female patient affected by arterial hypertension under home therapy, with disordered consciousness and confusion, is discussed. At the emergency department of another hospital she underwent cranial CT which showed mild swelling of right cerebral hemisphere. Based on the clinical suspicion of herpes simplex encephalitis compatible with a first MRI examination of the brain, the patient was admitted to the department of infectious disease of the polyclinic to confirm the diagnosis and plan the therapeutic approach. MRI was repeated and completed with EPI-DWI sequences and PRESS spectroscopy. It did not rule out categorically the infectious/inflammatory pattern but, based on a careful evaluation of the anatomic distribution of acute lesions, the most likely diagnostic hypothesis was the presence of multiple watershed cerebral infarcts on the right side.

Unusual lesion of the thalamic pineal region: role of conventional MRI and DWI in the differential diagnosis.

The case of a 53-year-old female patient admitted to the Emergency department with symptoms from right third cranial nerve of acute onset, is presented. Cranial CT, performed in emergency, documented an intra-axial mass which required an in-depth diagnostic study with cranial MRI after contrast administration. Conventional MRI and DWI helped in correct lesion characterization and in the differential diagnosis with other brain disorders.

Primary central nervous system lymphoma: role of DWI in the differential diagnosis.

The case of a female patient admitted to the hospital for a syncopal episode characterized by mental confusion, retrograde amnesia, agnosia, lack of sphincter control and behavior disorders, is presented. Cranial CT showed a frontal bihemispheric lesion. MRI completed with DWI was then performed to better define the nature of the lesion and for an in-depth diagnostic study. The diagnostic role of conventional MRI combined with DWI and the importance of the latter in the differential diagnosis between primary central nervous system lymphoma (confirmed at histology) and glioblastoma multiforme is discussed.

DWI and MR-spectroscopy in the differential diagnosis of focal brain lesions.

The case of a patient with a previous history of cerebral infarction, shown to be positive for a brain neoformation on control CT, is presented. Subsequent MRI for an in-depth diagnostic study was completed with DWI and MR spectroscopy to define the nature of the lesion. The differential diagnosis of the lesion is discussed. In conclusion, the major diagnostic role of combined standard MRI with DWI sequences and MR-spectroscopy in the radiologic study of focal brain lesions, is stressed.