Purpose
To evaluate the brain volumetric changes caused by BRAF gene mutation in non-epileptic CFC patients and the influence of the age of epilepsy onset on brain development in 2 cohorts of ...epileptic CFC patients.
Methods
We enrolled CFC patients carrying BRAF gene mutations without epilepsy (4 patients) and with epilepsy (16 patients). CFC epileptic patients were divided into two cohorts based on the age of seizure onset: early-age onset (7 children) and late-age onset (9 adolescents). All three cohorts of patients underwent 3D FSPGR T1-weighted imaging to assess supratentorial and infratentorial brain volumes. Moreover, for each compartment, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) volumes were measured. All measurements were compared with those of age-matched controls without neuroimaging abnormalities.
Results
All CFC patients showed supratentorial and infratentorial WM reduction and supratentorial ventricular enlargement (
p
< 0.01).
However, patients with early age of epilepsy onset, compared with the other two cohorts of CFC patients, showed both GM and a more pronounced WM volume reduction (
p
< 0.01).
Conclusion
In non-epileptic CFC children, we demonstrated WM volumetric reduction suggesting a direct effect of BRAF gene mutation on brain development. Nevertheless, in CFC epileptic patients, the age of epilepsy onset may contribute to brain atrophy.
Brain atrophy in CFC patients, in part due to the natural history of the disease, may be worsened by epilepsy when it begins in the early ages because of interference with brain growth at that critical age of development.
•Patients with Dravet Syndrome display lower heart rate variability compared to healthy controls and patients different epilepsies.•Having a lower heart rate variability in DS is predicted by a ...recent history of SE.•Compared to the literature our cohort showed better HRV and lower mortality, reinforcing a possible association between them.
Preliminary data suggest that patients with Dravet Syndrome (DS) have a reduced heart rate variability (HRV). This seems particularly evident in patients who experienced sudden unexpected death in epilepsy (SUDEP). This study aims at confirming these findings in a larger cohort and at defining clinical, genetic or electroencephalographic predictors of HRV impairment in DS patients.
DS patients followed at our Institution performed a 24h-ECG Holter to derive HRV parameters. We used as control population patients with epilepsy (PWEs) and healthy controls (HCs). In DS patients, we assessed the impact of different clinical, neurophysiological and genetic features on HRV alterations through multiple linear regression. After a mean follow-up of 7.4 ± 3.2 years since the HRV assessment, all DS patients were contacted to record death or life-threatening events.
56 DS patients had a significantly reduced HRV compared to both HCs and PWEs. A recent history of status epilepticus (SE) was the only significant predictor of lower HRV in the multivariate analysis. At follow-up, only one patient died; her HRV was lower than that of all the controls and was in the low range for DS patients.
We describe for the first time an association between SE and HRV alterations in DS. Further studies on other SCN1A-related phenotypes and other epilepsies with frequent SE will help clarify this finding. Compared to the literature, our cohort showed better HRV and lower mortality. Although limited, this observation reinforces the role of HRV as a biomarker for mortality risk in DS.
Abstract Objective DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1 ‐related epilepsy has been reported in small cohorts. We ...dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1 ‐related epilepsy spectrum, and compare the genotype–phenotype correlations observed in our cohort with the literature. Methods Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. Results DYNC1H1 ‐related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox–Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug‐resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly–pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1 ‐related epilepsy spectrum. Significance We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug‐resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1‐ related epilepsy.
Behavioral profile in RASopathies Alfieri, Paolo; Piccini, Giorgia; Caciolo, Cristina ...
American journal of medical genetics. Part A,
April 2014, Letnik:
164A, Številka:
4
Journal Article
Recenzirano
Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused ...by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.
Gene variants that dysregulate signaling through the RAS‐MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi‐system disorder. Infantile epileptic spasms syndrome (IESS) and other ...forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype–phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11–16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1–24 months). Among 13/18 patients whose IESS resolved with anti‐seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre‐clinical models for severe epilepsy phenotypes.
Abstract The aim of this study was to investigate language disorders prospectively in patients with Dravet syndrome (DS) during the first years of life in order to identify their features and ...possibly the underlying mechanisms of the disease. At the Child Neurology Unit of Catholic University in Rome (Italy), thirteen patients with typical findings of DS were enrolled in the study. Full clinical observations, including neurological examination and long-term EEG monitoring, were prospectively and serially performed until a mean of 6 years of age (range: 4 years to 7 years and 8 months). The epileptic history was also collected in each case. In particular, developmental, cognitive, and detailed language assessments were performed with different tests according to the age of the patient. In addition to cognitive decline, characteristic language impairment was also found with a relative preservation of receptive abilities (comprehension) and a strong impairment of productive skills. This defect in sensorimotor verbal processing integration is discussed to highlight the possible mechanisms underlying cognitive decline.
In the present study we evaluated long term memory in twenty individuals with molecularly confirmed diagnosis of Noonan syndrome and LEOPARD syndrome, two disorders caused by mutations in genes ...coding transducers participating in the RAS-MAPK signaling cascade. The profile of explicit long term memory abilities was investigated using PROMEA, which includes a battery of tests specifically developed to assess memory and learning in verbal, visual and spatial domains. Ten individuals (50%) had impaired (≤5th percentile) or below average (≤15th percentile) performance on a delayed verbal free recall memory task, four (20%) on a delayed visual recognition memory task, and only one (5%) on a delayed spatial recognition memory task. Our data suggest that dysregulation of the RAS-MAPK cascade may be associated with a pattern of reduced verbal recall memory performance but relative sparing of visual and spatial recognition memory.
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