The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A ...is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.
Objective:
Rare copy number variants (CNVs)—deletions and duplications—have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of ...the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed.
Methods:
We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high‐density, exon‐focused, whole‐genome oligonucleotide array.
Results:
We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one‐half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.
Interpretation:
Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study. ANN NEUROL 2011;70:974–985
Aim
Polymicrogyria (PMG) is one of the most common forms of cortical malformation yet the mechanism of its development remains unknown. This study describes the histopathological aspects of PMG in a ...large series including a significant proportion of fetal cases.
Method
We have reviewed the neuropathology and medical records of 44 fetuses and 27 children and adults in whom the cortical architecture was focally or diffusely replaced by one or more festooning bands of neurons.
Results
The pial surface of the brain overlying the polymicrogyric cortex was abnormal in almost 90% of cases irrespective of the aetiology. This accords with animal studies indicating the importance of the leptomeninges in cortical development. The aetiology of PMG was highly heterogeneous and there was no correlation between cortical layering patterns and aetiology. PMG was almost always associated with other brain malformations.
Interpretation
The inclusion of many fetal cases has allowed us to examine the early developmental stages of PMG. The study indicates the significance of surface signals responsible for human corticogenesis and the complex interaction between genetic and environmental factors leading to this common endpoint of cortical maldevelopment.
What this paper adds
Fetal cases allow study of the early developmental stages of polymicrogyria (PMG).
PMG is commonly associated with pial disruption, regardless of aetiology.
Abnormal festooning of the cortical neuronal band can occur well before normal cortical folding is expected to start.
PMG is very often associated with other brain malformations.
This article is commented on by Ten Donkelaar on page 7 of this issue.
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of ...Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, ...and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations corrected.Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
Summary
This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage‐gated sodium channels (protein name: Nav1.1). Mutations in this ...gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.
Summary
Objective: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet ...syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).
Methods: Multiplex ligation‐dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).
Results: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence‐based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early‐onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5–6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.
Discussion: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA‐detected SCN1A CNVs with an overall frequency of about 2–3%. MLPA is the established second‐line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.
Purpose: Choreoacanthocytosis (ChAc) is an autosomal recessive disorder caused by mutations in VPS13A on chromosome 9q21 and characterized by neurodegeneration and red cell acanthocytosis. Seizures ...are not uncommon in ChAc but have not been well characterized in the literature. We report two ChAc families in which patients presented with temporal lobe epilepsy.
Methods: Detailed medical and family histories were obtained. EEG, video‐telemetry, brain magnetic resonance imaging (MRI) with volumetric studies of amygdala and hippocampus, as well as neuropsychological testing were performed. Blood smears were examined for acanthocytosis. Mutation analysis of VPS13A was carried out in five patients.
Results: Six patients in three sibships were initially seen with seizures. Age at seizure onset ranged from 22 to 38 years. Seizures preceded other clinical manifestations of ChAc by ≤15 years. The epileptic aura consisted of a sensation of déjà‐vu, fear, hallucinations, palpitations, or vertigo. EEG with video‐telemetry showed epileptiform discharges originating either from one or both temporal lobes. Epilepsy was generally well controlled, but some patients had periods of increased seizure frequency requiring treatment with multiple antiepileptic drugs (AEDs). Both families shared a deletion of exons 70–73 of VPS13A, extending to exons 6–7 of GNA14.
Conclusions: Temporal lobe epilepsy may be the presenting feature of ChAc and may delay its diagnosis. Epilepsy in ChAc patients represents a challenge, because seizures may at times be difficult to control, and some AEDs may worsen the involuntary movements. Mutations in VPS13A or GNA14 or both may be associated with clinical features of temporal lobe epilepsy.
The concept of genetic focal epilepsies is relatively new as compared to awareness of the importance of genetic factors in the generalized epilepsies. However, in the past decade, there has been ...increasing recognition of families with dominantly inherited partial epilepsies.
Better definition of the phenotypes allows identification of distinct syndromes. The main familial focal epilepsies are autosomal‐dominant nocturnal frontal lobe epilepsy (ADNFLE), familial mesial TLE (FMTLE), familial lateral TLE (FLTLE), and familial partial epilepsy with variable foci (FPEVF).
The only genes identified so far are those for ADNFLE and FLTLE. In these disorders, functional studies are the next step and could provide advances leading to clarification of the pathophysiology as well as to new therapeutic strategies. At present, we can provide genetic counseling and a more accurate prognosis for most of the familial focal epilepsies. Greater awareness of the genetic basis in this group of disorders by the treating physicians is essential for identification of new families. This will allow further linkage studies, candidate gene screening, and identification of new genes, which will hopefully result in genetically based prevention and treatment.
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