Maria Stella Vari

Management of genetic epilepsies: From empirical treatment to precision medicine

Despite the over 20 antiepileptic drugs (AEDs) now licensed for epilepsy treatment, seizures can be effectively controlled in about ∼70% of patients. Thus, epilepsy treatment is still challenging in about one third of patients and this may lead to a severe medically, physically, and socially disabling condition. However, there is clear evidence of heterogeneity of response to existing AEDs and a significant unmet need for effective intervention. A number of studies have shown that polymorphisms may influence the poor or inadequate therapeutic response as well as the occurrence of adverse effects. In addition, the new frontier of genomic technologies, including chromosome microarrays and next-generation sequencing, improved our understanding of the genetic architecture of epilepsies. Recent findings in some genetic epilepsy syndromes provide insights into mechanisms of epileptogenesis, unrevealing the role of a number of genes with different functions, such as ion channels, proteins associated to the vesical synaptic cycle or involved in energy metabolism. The rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis are revolutionizing the practice and it is a fact that for some monogenic epilepsies the molecular confirmation may influence the choice of the treatment. Moreover, the novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized (or precision) medicine.

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies—An Italian observational multicenter study

PURPOSE To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. PATIENTS AND METHODS This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. RESULTS 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. CONCLUSION PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

Confirmation of mutations in PROSC as a novel cause of vitamin B6-dependent epilepsy

Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPL or ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPO explain a major fraction of cases. Very recently biallelic mutations in PROSC were shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6 plasma profiles on pyridoxine did not enable the differentiation of patients with PROSC mutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with PROSC mutations was indistinguishable from ALDH7A1 and PNPO deficiency. We therefore confirm PROSC as a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6 profile under pyridoxine treatment.

Todd Paralysis in Rolandic Epilepsy

Investigators from University of Gaziantep, Turkey described the clinical and EEG findings of patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) experiencing postictal Todd paralysis.

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

A novel Xp22.13 microdeletion in Nance-Horan syndrome

BACKGROUND Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder characterized by congenital cataract, dental anomalies and facial dysmorphisms. Notably, up to 30% of NHS patients have intellectual disability and a few patients have been reported to have congenital cardiac defects. Nance-Horan syndrome is caused by mutations in the NHS gene that is highly expressed in the midbrain, retina, lens, tooth, and is conserved across vertebrate species. Although most pathogenic mutations are nonsense mutations, a few genomic rearrangements involving NHS locus have been reported, suggesting a possible pathogenic role of the flanking genes. METHODS Here, we report a microdeletion of 170,6 Kb at Xp22.13 (17.733.948-17.904.576) (GRCh37/hg19), detected by array-based comparative genomic hybridization in an Italian boy with NHS syndrome. RESULTS The microdeletion harbors the NHS, SCLML1, and RAI2 genes and results in a phenotype consistent with NSH syndrome and developmental delay. CONCLUSION We compare our case with the previous Xp22.13 microdeletions and discuss the possible pathogenetic role of the flanking genes. Birth Defects Research 109:866-868, 2017.

A review of safety and efficacy of zonisamide for treatment of pediatric partial epilepsy

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Pediatric Health, Medicine and Therapeutics 2014:5 155–160 Pediatric Health, Medicine and Therapeutics Dovepress

Erratum to “De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy” [Seizure 57 (2018) 63–65]

Erratum to “De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy” [Seizure 57 (2018) 63–65] Maria Stella Vari, Monica Traverso, Tommaso Bellini, Francesca Madia, Francesca Pinto, Pasquale Striano*, Carlo Minetti, Federico Zara a Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health University of Genoa, “G. Gaslini” Institute, Genova, Italy b Laboratory of Neurogenetics and Neuroscience, “G. Gaslini” Institute, Genova, Italy

ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.

A novel homozygous MFN2 mutation associated with severe and atypical CMT2 phenotype

BACKGROUND Charcot-Marie-Tooth (CMT) neuropathies represent the most common forms of inherited polyneuropathies. CMT2A, the axonal form, accounts for about one third of all CMT cases. Variants in the MFN2 gene have been recognized to be a major cause of CMT2A. To date, more than 100 pathogenetic mutations in MFN2 have been identified, leading to different neurological clinical spectrum, varying from hereditary neuropathies to more severe clinical phenotypes. Pathogenic variants in MFN2 mainly act in a dominant manner, although in a few sporadic or familial cases, homozygous or compound heterozygous mutations have been reported. RESULTS We describe a child carrying a novel homozygous MFN2 mutation leading to an early-onset sensorimotor axonal neuropathy with an atypical and severe phenotype. CONCLUSION The case highlights a very rare mechanism of inheritance for MFN2 mutations and expands the clinical and allelic variance of severe CMT2A phenotype. Moreover, it proposes the involvement of cerebellar peduncles observed at neuroimaging as a novel clue to suspect the diagnosis and address genetic testing.