Genetic Basis of Brain Malformations Parrini, Elena; Conti, Valerio; Dobyns, William B. ...
Molecular syndromology,
09/2016, Letnik:
7, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly ...involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the LIS1, DCX, ARX, RELN, VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and DYNC1H1), regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms.
To assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.
This multicenter, randomized, double-blind, placebo-controlled, ...parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2 to 18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine 0.2 mg/kg/day, or fenfluramine 0.7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose, 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure (MCSF) frequency during baseline and during the combined titration-maintenance period in patients given fenfluramine 0.7 mg/kg/day vs. patients given placebo.
169 patients were screened and 143 were randomized to treatment. Mean age was 9.3±4.7 years (±SD), 51% were male, and median baseline MCSF in the 3 groups ranged from 12.7-18.0 per 28 days. Patients treated with fenfluramine 0.7 mg/kg/day demonstrated a 64.8% (95% CI, 51.8%-74.2%) greater reduction in MCSF compared with placebo (P<0.0001). Following fenfluramine 0.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% of the placebo group (P<0.0001). The median longest seizure-free interval was 30 days in the fenfluramine 0.7 mg/kg/day group compared with 10 days in the placebo group (P<0.0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected.
The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the anti-seizure response of fenfluramine in children with Dravet syndrome.
Summary
Objectives
To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of ...life.
Methods
We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data.
Results
Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst‐suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure‐free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure‐free thereafter. Twelve patients had moderate‐to‐severe developmental delay at follow‐up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment.
Significance
Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first‐line treatment in patients with KCNQ2 encephalopathy. Voltage‐gated sodium and potassium channels co‐localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium‐channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.
Extensive mapping of neuronal connections in the central nervous system requires high-throughput µm-scale imaging of large volumes. In recent years, different approaches have been developed to ...overcome the limitations due to tissue light scattering. These methods are generally developed to improve the performance of a specific imaging modality, thus limiting comprehensive neuroanatomical exploration by multi-modal optical techniques. Here, we introduce a versatile brain clearing agent (2,2'-thiodiethanol; TDE) suitable for various applications and imaging techniques. TDE is cost-efficient, water-soluble and low-viscous and, more importantly, it preserves fluorescence, is compatible with immunostaining and does not cause deformations at sub-cellular level. We demonstrate the effectiveness of this method in different applications: in fixed samples by imaging a whole mouse hippocampus with serial two-photon tomography; in combination with CLARITY by reconstructing an entire mouse brain with light sheet microscopy and in translational research by imaging immunostained human dysplastic brain tissue.
The genetics of Dravet syndrome Marini, Carla; Scheffer, Ingrid E.; Nabbout, Rima ...
Epilepsia (Copenhagen),
April 2011, 2011-Apr, 2011-04-00, 20110401, Letnik:
52, Številka:
s2
Journal Article
Recenzirano
Summary
Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between ...70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice‐site and missense mutations, most of which fall into the pore‐forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2–3% of patients. A small percentage of female patients with a DS‐like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
Purpose
In this descriptive review, we describe current models of transition in rare and complex epilepsy syndromes and propose alternative approaches for more holistic management based on disease ...biology.
Recent Findings
Previously published guidance and recommendations on transition strategies in individuals with epilepsy have not been systematically and uniformly applied. There is significant heterogeneity in models of transition/transfer of care across countries and even within the same country.
Summary
We provide examples of the most severe epilepsy and related syndromes and emphasise the limited data on their outcome in adulthood. Rare and complex epilepsy syndromes have unique presentations and require high levels of expertise and multidisciplinary approach. Lifespan clinics, with no transition, but instead continuity of care from childhood to adulthood with highly specialised input from healthcare providers, may represent an alternative effective approach. Effectiveness should be measured by evaluation of quality of life for both patients and their families/caregivers.
The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well ...as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.
Lissencephaly (“smooth brain,” LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum ...includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS—LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS‐associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS‐SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS‐SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based‐ classification).
The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has ...facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive.
Objective
Dravet syndrome (DS) is a drug‐resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, ...fenfluramine (FFA) proved to be safe and effective in DS.
Methods
DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add‐on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.
Results
Fifty‐two patients were enrolled, with a median age of 8.6 years (interquartile range IQR = 4.1‐13.9). Forty‐five (86.5%) patients completed the efficacy analysis. The median follow‐up was 9.0 months (IQR = 3.2‐9.5). At last follow‐up visit, there was a 77.4% median reduction in convulsive seizures. Thirty‐two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure‐free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.
Significance
In this real‐world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.
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