The epileptology of GNB5 encephalopathy

Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss‐of‐function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.     

A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder

ARX mutations are associated with variable clinical phenotypes. We report a new neurodegenerative phenotype associated with a known ARX mutation and causing early abnormal neurodevelopment, a complex movement disorder, and early infantile epileptic encephalopathy with a suppression‐burst pattern (Ohtahara syndrome). A male infant presented at age 5 months with a dyskinetic movement disorder, which was initially diagnosed as infantile spasms. Clinical deterioration was accompanied by progressive cortical atrophy with a reduction in white matter volume and resulting in death in the first year of life; such a rapidly progressive and severe phenotype has not previously been described. ARX mutation testing should be undertaken in children aged less than 1 year with Ohtahara syndrome and a movement disorder, and in infants with unexplained neurodegeneration, progressive white matter loss, and cortical atrophy.     

Epileptic encephalopathy with microcephaly in a patient with asparagine synthetase deficiency: a video‐EEG report∗

Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5‐Mb region (chr7:95629078–100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].     

Pontocerebellar hypoplasia type 2 (PCH2): report of two siblings

We describe two sisters affected by pontocerebellar hypoplasia type 2 associated with microcephaly, hypertonia, severe choreiform movements, an almost complete lack of psychomotor development, and generalized tonic-clonic seizures. Clinical and neuroradiological findings ruled out other conditions associated with pontocerebellar hypoplasia, i.e. pontocerebellar hypoplasia type 1, carbohydrate-deficient glycoprotein syndrome, and olivopontocerebellar hypoplasia/atrophy.     

Brain malformation and infantile spasms in a SCAD deficiency patient

This report presents a case of short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency with a previously unreported presentation with brain malformations and infantile spasms. This female infant developed repeated tonic clonic seizures at the age of 3(1/2) months. She subsequently developed West syndrome at the age of 4 months. Her electroencephalogram disclosed hypsarrhythmia, and video-electroencephalographic monitoring confirmed the presence of infantile spasms. Magnetic resonance imaging revealed a small midline frontal meningocele, abnormal cortical gyration, and partial agenesis of the corpus callosum consistent with neuronal migrational disorder. Metabolic evaluation indicated ethylmalonic acidemia. Muscle biopsy with enzymatic assay of short-chain acyl-coenzyme A revealed low enzymatic activity confirming the diagnosis of short-chain acyl-coenzyme A dehydrogenase deficiency. To our knowledge, this is the first report of the coexistence of short-chain acyl-coenzyme A dehydrogenase deficiency, infantile spasms, and brain malformation. We conclude that short-chain acyl-coenzyme A dehydrogenase deficiency should be considered in the differential diagnosis of gyral abnormality, corpus callosal hypoplasia, and infantile spasms.     

Pontocerebellar hypoplasia type 3 with tetralogy of Fallot

We report a male infant with pontocerebellar hypoplasia type 3 and tetralogy of Fallot. He showed optic nerve atrophy, progressive microcephaly, severe psychomotor developmental delay, and vesicoureteral reflux. Magnetic resonance imaging revealed severe hypoplasia of the cerebellar vermis and hemisphere, and of the brainstem including the pons, and simplified gyral patterns in bilateral frontal lobes. An unknown etiology differing from other cases of PCH type 3 might have caused not only optic nerve atrophy and hypoplasia of the cerebellum and brainstem, but also cerebral and visceral malformations. To the best of our knowledge, this represents the first report of pontocerebellar hypoplasia with congenital cardiac malformation.     

Phenotypic and genetic spectrum of SCN8A‐related disorders,treatment options,and outcomes

Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN8A‐DEE is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic‐clonic manifestations. Spasm‐like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEGs) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild‐to‐moderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN8A‐DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN8A‐related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN8A‐DEEs occur de novo.     

Recurrent episodes of rhabdomyolysis in pontocerebellar hypoplasia type 2

Pontocerebellar hypoplasia type 2 is an autosomal recessive disorder characterized by hypoplasia and atrophy of the cerebellum and pons, leading to microcephaly, dystonia/dyskinesia, seizures, and severe cognitive impairment. Until lately it was considered a CNS-refined disease, but recent reports have associated it with muscular defects, as well. A 5-year-old boy with genetically confirmed pontocerebellar hypoplasia type 2 is described. The patient had all the clinical and radiological features of the disease, but he, additionally, exhibited two episodes of rhabdomyolysis precipitated by respiratory infections. The possible mechanisms associating encephalopathy and myopathy in pontocerebellar hypoplasia type 2 are discussed.     

Evidence of linkage to chromosome 5p13.2‐q11.1 in a large inbred family with genetic generalized epilepsy

The clinical genetics of genetic generalized epilepsy suggests complex inheritance; large pedigrees, with multiple affected individuals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks; in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic–clonic seizures were seen in 11. One individual had generalized tonic–clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected individual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2‐q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein‐coding variants within the highly significant linkage region that includes HCN1 as a promising candidate.     

Lateralizing signs during seizures in infants

Abstract. Objective: To identify lateralizing features during seizures in infants and assess their reliability. Methods: Infants were included if they had video-EEG monitoring at our institution, and were seizure-free for at least 12 months after epilepsy surgery. Lateralizing signs and seizure symptomatology were classified based on blinded video review. Results: We analyzed 100 seizures from 19 infants (1 to 32, mean 13 months of age) (1 to 14 seizures per patient). Potential lateralizing signs were seen in 58 seizures from 12 infants, including unilateral clonic jerking (8 patients); forced, sustained tonic version of the eyes to one side (7 patients); predominantly unilateral infantile spasms (5 patients); unilateral tonic stiffening of an arm and leg (2 patients); nystagmus (2 patients) and postictal hemiparesis (1 patient). Except for tonic eye version, each of the signs was contralateral to the hemisphere of seizure-onset in all but one patient who had predominantly ipsilateral spasms and clonic arm activity. Tonic eye version was contralateral in 3 patients, ipsilateral in 1 patient, and toward either side in different seizures in 3 patients. Conclusion: Reliable lateralizing signs included focal clonic activity and predominantly unilateral spasms. Focal tonic activity, nystagmus and postictal hemiparesis were also consistently contralateral but were observed only in few patients. Tonic eye version was unreliable and could not be used to lateralize seizure onset. The sequence of eye and head version evolving to generalized tonic clonic convulsions was not seen in this age group.Author T. L. was supported by Innovative Medizinische Forschung, WWU Münster (FoeKz. LO 610101) and NRW-Nachwuchsgruppe Kn2000, Federal Ministry of Education and Research (Foe.1KS9604/0), Interdisciplinary Center of Clinical Research Münster,Germany (IZKF Project NWG2).     

The EEG in selected generalized seizures.

This article reviews the ictal and interictal EEG findings associated with a select group of generalized seizures. These include absence seizures, myoclonic seizures seen in juvenile myoclonic epilepsy, idiopathic generalized tonic clonic seizures, infantile spasms, and atypical absence, tonic, and atonic seizures associated with the Lennox Gastaut syndrome.     

Septo-optic dysplasia with infantile spasms

A 21-month-old boy with septo-optic dysplasia and infantile spasms is reported. Eighteen hours after birth he had generalized convulsions, dyspnea, and hypoglycemia which were followed by recurrent clonic seizures despite administration of phenobarbital and valproic acid. At 16 months of age he had hypoglycemia and apnea attacks during varicella infection. At 19 months of age left hemiconvulsions and left hemiparesis occurred; his mental and motor development, which had been delayed but progressive, deteriorated. Tonic spasms appeared at 21 months of age and electroencephalography revealed multifocal spikes. At 27 months of age electroencephalography disclosed hypsarrhythmia. Cranial computed tomography depicted brain atrophy, right microphthalmia, and intact septum pellucidum. Magnetic resonance imaging demonstrated hypoplasia of the corpus callosum and a small pituitary gland. Coloboma of the right optic disc was detected. Physical examination revealed short stature, left hemiparesis, micropenis, and cryptorchidism. Endocrinologic loading tests revealed hypofunction of the hypophysial anterior lobe.     

Basic mechanisms of catastrophic epilepsy – Overview from animal models

Infantile spasms are age-specific seizures of infantile epileptic encephalopathies that are usually associated with poor epilepsy and neurodevelopmental outcomes. The current treatments are not always effective and may be associated with significant side effects. Various mechanisms have been proposed as pathogenic for infantile spasms, including cortical or brainstem dysfunction, disruption of normal cortical–subcortical communications, genetic defects, inflammation, stress, developmental abnormalities. Many of these have been recently tested experimentally, resulting into the emergence of several animal models of infantile spasms. The stress theory of spasms yielded the corticotropin releasing hormone (CRH)-induced model, which showed the higher proconvulsant potency of CRH in developing rats, although only limbic seizures were observed. Models of acute induction of infantile spasms in rodents include the N-methyl-d-aspartate (NMDA) model of emprosthotonic seizures, the prenatal betamethasone and prenatal stress variants of the NMDA model, and the γ-butyrolactone induced spasms in a Down’s syndrome mouse model. Chronic rodent models of infantile spasms include the tetrodotoxin model and the multiple-hit models in rats, as well as two genetic mouse models of interneuronopathies with infantile spasms due to loss of function of the aristaless X-linked homeobox-related gene (ARX). This review discusses the emerging mechanisms for generation of infantile spasms and their associated chronic epileptic and dyscognitive phenotype as well as the recent progress in identifying pathways to better treat this epileptic encephalopathy.     

Phenotypic manifestations between male and female children with CDKL5 mutations

BackgroundCyclin-dependent kinase-like 5 (CDKL5), which maps to chromosome Xp22.13 and contains 20 coding exons, has been recognized as the gene responsible for early-onset epileptic encephalopathy (EoEE). A retrospective study is carried out to analyze potential genotypic and phenotypic differences between male and female patients with CDKL5 mutations.Materials and methodsTargeted next-generation DNA sequencing was employed to search for mutations in patients with cryptogenic EE. A total of 44 patients with EoEE/infantile spasms (ISs)/West syndrome were enrolled for pathogenic mutation screening. The clinical phenotypes of patients with CDKL5 mutations were analyzed and compared with those of 166 published cases.ResultsOne novel and three recurrent mutations were found in four enrolled patients (two boys and two girls). One female patient had partial seizures during the early infantile period and epileptic spasms and tonic seizures several weeks thereafter. The other female patient had IS with hypsarrhythmia. The two male patients had IS without typical hypsarrhythmia and were bedridden. Brain MRIs of the male patients revealed brain atrophy and white matter hyperintensity. The female patients exhibited autistic features with hand stereotypies.ConclusionOur study highlights that both girls and boys with IS harbor CDKL5 mutations. Male children with CDKL5 mutations demonstrate a higher frequency of infantile spasms and brain atrophy, whereas female children often exhibit atypical Rett syndrome with EoEE. In addition, male children have a more severe phenotype than female children.     

Pontocerebellar hypoplasia type III (CLAM): Extended phenotype and novel molecular findings

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by abnormally small cerebellum and brainstem. Recently a rare, novel form of PCH has been reported called cerebellar atrophy with progressive microcephaly (CLAM). Here we report a second family of CLAM with additional phenotypic features and novel molecular findings. Three-year old index patient had severe developmental delay and presented with short stature and microcephaly. Her cranial magnetic resonance imaging revealed hypoplasia of the cerebellum, brainstem and cerebrum associated with hypoplasia of the corpus callosum. Brainstem auditory evoked potentials revealed hearing loss and visual evoked potentials confirmed the optic atrophy. She also had seizures with two posterior epileptic foci on electroencephalogram. Molecular analysis revealed a homozygous haplotype between the markers D7S802 and D7S630 within the originally linked region, narrowing the critical region from 20 Mb to 7 Mb. Two highly relevant candidate genes, CROT and SLC25A40 located in this region were sequenced, but no causative mutations identified. Our case provides additional clinical characteristics on the previously described features of this new entity, and reducing the critical region will now allow systematic positional cloning efforts to identify the causative gene.     

Increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice

Malaria is considered a neglected disease and public health problem, affecting >200 million people worldwide. In the present study we used the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (CM) in C57BL/6 mice. After rescue from CM and parasite clearance, animals were submitted to a seizure susceptibility test (45 days after infection) using a low dose of pentylenetetrazol (PTZ, 30 mg/kg) and monitored with use of behavioral and electroencephalography (EEG) methods. Mice rescued from CM presented a reduced latency to myoclonic and tonic–clonic seizures and an increased duration of tonic–clonic seizures. In addition, quantitative analysis of EEG revealed a decrease in relative power at beta frequency band in PbA‐infected animals after PTZ injection. Our results suggest that CM may lead to increased susceptibility to seizures in mice.     

New subtype of PCH1C caused by novel EXOSC8 variants in a 16-year-old Spanish patient

We report the case of a 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. Whole exome sequencing (WES) uncovered three variants (two of them novel) in a compound heterozygous in EXOSC8 gene (NM_181503.3:c.[390+1delG];[628C>T;815G>C]) that encodes the exosome complex component RRP43 protein (EXOSC8). In order to assess the pathogenicity of these variants, expression experiments of RNA and protein for EXOSC8 were carried out. The c.[390+1delG] variant produces the elimination of exon 7 (r.[345_390del]; p.[Ser116LysfsTer27]) and a decrease of the RNA expression in relation to the other allele (p.[Pro210Ser;Ser272Thr]). Furthermore, total mRNA expression is reduced by 30% and the protein level by 65%. EXOSC8 is an essential protein of the exosome core, a ubiquitously expressed complex responsible for RNA processing and degradation. Recessive mutations in EXOSC8 cause pontocerebellar hypoplasia type 1C (PCH1C), and currently, only two homozygous variants in this gene have been described. However, unlike PCH1C-affected individuals with EXOSC8 variants, our patient presents a normal supratentorial cerebral tissue (neither corpus callosum hypoplasia nor hypomyelination) with a less severe phenotype and longer survival. In conclusion, our data expand both genetic and phenotypic spectrum associated with EXOSC8 variants.     

Spectrum of epilepsy in tuberous sclerosis

Tuberous sclerosis (TS) is an autosomal dominant disease that affects the brain, skin, eye, heart and kidney. The diagnostic criteria for tuberous sclerosis complex (TSC) have recently been revised. There are relatively few Indian studies on this disorder. Twenty-six patients diagnosed as having TS over a period of 18 years are being reported. The onset of seizures ranged from infancy to adolescence. The patterns of epilepsy encountered were generalized tonic clonic seizures (13), complex partial seizures (10), simple partial seizures (9) and myoclonic jerks (4) including infantile spasms (3). Patients often had more than one seizure type. Nineteen patients were mentally subnormal. Cutaneous manifestations were facial angiofibroma i.e. adenoma sebaceum (20), shagreen patches (7), hypopigmented macules (6), ash leaf spots (4), café-au-lait spots (2), facial hypoplasia (2) and periungual fibromas (1). One patient each had retinal phakoma and renal angiomyolipoma. CT scan revealed sub-ependymal calcifications (12), parenchymal tubers (3), cerebral edema (3) and cortical atrophy (1). One patient had enhancement of peri-ventricular sub-ependymal lesions on MRI. Anticonvulsants prescribed were phenobarbitone (20), diphenyl hydantoin (14), carbamazepine (8), sodium valproate (4), benzodiazepines (4), ACTH (2), prednisone (1), mysoline (1) and vigabatrin (1). Most patients were on combinations of anti-convulsants and response to therapy was usually not very satisfactory. However, the child treated with vigabatrin did well.