Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy

Developmental and epileptic encephalopathy is a group of conditions characterized by the co‐occurrence of epilepsy and intellectual disability, in which there is additional developmental impairment independent of epileptic activity. Biallelic variants of SZT2, a known seizure threshold regulator gene, have been linked to a wide spectrum of clinical features, ranging from severe intellectual disability with refractory seizures to mild intellectual disability without seizures. Here, we describe a child with developmental and epileptic encephalopathy whose genetic testing led to the identification of novel biallelic variants of SZT2, a paternally inherited c.2798C>T, p.(Ser933Phe) variant and a maternally inherited c.4549C>T, p.(Arg1517Trp) variant. Our patient showed common clinical and radiographic features among patients with SZT2‐related encephalopathy. However, neonatal‐onset seizures and suppression‐burst EEG activity, not previously associated with SZT2‐related encephalopathy, were observed in this case. Although the seizures were controlled with carbamazepine, the developmental consequences remained profound, suggesting that the developmental impairments might be attributed to a direct effect of the SZT2 variants rather than the epileptic activity. We propose that SZT2 variants should be regarded among those that are believed to cause neonatal‐onset developmental and epileptic encephalopathy with a suppression‐burst pattern on EEG.     

Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum

BackgroundPyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported.Methods and ResultsWe present a phenotypic spectrum of antiquitin deficiency based on a literature review (2006 to 2015) of reports (n = 49) describing the clinical presentation of confirmed patients (n > 200) and a further six patient vignettes. Possible presentations include perinatal asphyxia; neonatal withdrawal syndrome; sepsis; enterocolitis; hypoglycemia; neuroimaging abnormalities (corpus callosum and cerebellar abnormalities, hemorrhage, white matter lesions); biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities); and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions.DiscussionThe phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is refractory seizures during the first year of life. Given its amenability to treatment with lysine-lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of pyridoxine-dependent epilepsy is essential. All infants presenting with unexplained seizures should be screened for antiquitin deficiency by determination of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.     

The therapeutic implication of a novel SCN2A mutation associated early-onset epileptic encephalopathy with Rett-like features

Epileptic encephalopathies are highly heterogeneous and phenotypical disorders with different underlying genetic defects. Mutations in the SCN2A gene cause different epilepsy syndromes, including epilepsy of infancy with migrating focal seizures, Ohtahara syndrome, and West syndrome. We utilized a targeted next generation sequencing (NGS) approach on a girl with early-onset seizures and Rett-like features, including autistic behavior, limited hand function with chorea, and profound intellectual disability, to identify novel missense mutation (c.1270G>A; p.V424M) in the SCN2A gene, which encodes the αII-subunit of the voltage-gated Na⁺ channel (Na_v1.2). The identified SCN2A mutation responsible for the development of the disease is confirmed to be de novo for the proband. Our findings broaden the clinical spectrum of SCN2A mutations, which resembles clinical phenotypes of SCN1A mutations by manifesting as fever sensitive seizures, and highlights that SCN2A mutations are an important cause of early-onset epileptic encephalopathies with movement disorders. In addition, the use of levetiracetam to treat SCN2A epileptic encephalopathy, when Na⁺ channel-blocking anticonvulsants are ineffective, is also recommended.     

Early‐life epileptic encephalopathy secondary to SZT2 pathogenic recessive variants

Advances in genetic testing have led to the identification of increasing numbers of novel gene mutations that underlie infantile‐onset epileptic encephalopathies. Recently, a mutagenesis screen identified a novel gene, SZT2, with no known protein function that has been linked to epileptogenesis in mice. Thus far, two clinical reports have identified children with different recessive mutations in SZT2 and varying clinical phenotypes. One case report described patients with epileptic encephalopathy and the other noted patients with cognitive deficiencies, but normal MRI and no epilepsy. This case report identifies novel mutations (a compound heterozygous frameshift and a nonsense variant) in the SZT2 gene with distinct clinical and radiographic findings relative to those previously reported. Our patient presented with intractable epilepsy at 2 months of age. Seizures were refractory to numerous antiepileptic medications and the patient finally achieved seizure cessation at age 3 years with a combination of divalproex and lamotrigine. Our patient had similar facial dysmorphisms (macrocephaly, high forehead, and down‐slanted palpebral fissures) to a previous case with truncating mutation. While developmental delay and cognitive deficiencies were present, our case had unique MRI findings suggesting migrational abnormalities not previously reported in other cases.     

A Chinese patient with epilepsy and WWOX compound heterozygous mutations

Early infantile epileptic encephalopathy type 28 is a refractory epilepsy with early onset, poor prognosis, and hereditary causes. WW domain‐containing oxidoreductase (WWOX) gene mutation can result in epileptic encephalopathy, but the mechanism remains unclear. We present the case of a patient with epilepsy and WWOX compound heterozygous mutations. The seizures manifested as tonic‐clonic, convulsive and were refractory to drugs. Magnetic resonance imaging showed a widened subarachnoid space and thin corpus callosum. The patient died from asphyxia at the age of one year and 23 days. Peripheral blood was taken from the patient and his parents, and whole‐exome sequencing was investigated to determine possible gene mutation. Two compound heterozygous mutations were identified: c.172+1G>C (with no amino acid change) and c.984C>G (amino acid change: p.Tyr328Ter). The pathophysiology of epileptic encephalopathy related to the WWOX gene remains to be determined, and further studies are required to elucidate possible mechanisms.     

Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia‐induced status epilepticus. A novel de novo SCN1A mutation was identified by whole‐exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A‐associated epileptic encephalopathy. [Published with video sequences]     

Neuronal migration disorders, genetics, and epileptogenesis

Several malformation syndromes with abnormal cortical development have been recognized. Specific causative gene defects and characteristic electroclinical patterns have been identified for some. X-linked periventricular nodular heterotopia is mainly seen in female patients and is often associated with focal epilepsy. FLN1 mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of periventricular nodular heterotopia owing to ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay, and early-onset seizures. Lissencephaly-pachygyria and subcortical band heterotopia represent a malformative spectrum resulting from mutations of either the LIS1 or the DCX (XLIS) gene. LIS1 mutations cause a more severe malformation posteriorly. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior subcortical band heterotopia owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in male patients and subcortical band heterotopia in female patients. Mutations of the coding region of DCX were found in all reported pedigrees and in about 50% of sporadic female patients with subcortical band heterotopia. Mutations of XLIS have also been found in male patients with anterior subcortical band heterotopia and in female patients with normal brain magnetic resonance imaging. The thickness of the band and the severity of pachygyria correlate with the likelihood of developing severe epilepsy. 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 infantile spasms with suppression-burst electroencephalograms. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Schizencephaly has a wide anatomoclinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Initial reports of heterozygous mutations in the EMX2 gene have not been confirmed. 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.     

Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation

IntroductionPitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy.Case reportThe patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy.ConclusionsTo our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.     

Effect of total callosotomy on KCNQ2-related intractable epilepsy

AimTo describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy.Case reportOur patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)).ConclusionThis case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.     

SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet

SCN2A mutations have been identified in various encephalopathy phenotypes, ranging from benign familial neonatal-infantile seizure (BFNIS) to more severe forms of epileptic encephalopathy such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizure (EIMFS). Thus far, no particularly effective treatment is available for severe epileptic encephalopathy caused by SCN2A mutations in children.We present the case of a boy who developed seizures on the third day of life and received a diagnosis of EIMFS based on his clinical presentations and electroencephalography reports. Antiepileptic drugs, namely oxcarbazepine, phenytoin, valproate, levetiracetam, and clonazepam, as well as adrenocorticotropic hormone therapy failed to reduce the severity of the seizures. Seizure pattern changed to infantile spasm with extensor thrust since 5?months of age. A ketogenic diet consisting of a medium-chain triglyceride recipe was introduced at 8?months of age and the seizures were resolved in the following 10?months. A de novo mutation in SCN2A (c.573G?>?T; p.W191C) was proven through next-generation sequencing.     

CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report

We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.     

De novo DNM1 mutations in two cases of epileptic encephalopathy

Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin‐mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox‐Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.     

CHD2 mutations in Lennox–Gastaut syndrome

Lennox–Gastaut syndrome (LGS) is an epileptic encephalopathy with a heterogeneous etiology. In this study, we aimed to explore the role of CHD2 in LGS, as CHD2 mutations have been described recently in various epileptic encephalopathies. We have previously identified one patient with a large deletion affecting the CHD2 gene in a group of 22 patients with LGS or LGS-like epilepsy. In the remaining 17 patients without known etiology, Sanger sequencing revealed a de novo 1-bp duplication in the CHD2 gene in another patient. This mutation leads to a frameshift and, consequently, a premature stop codon 49 bp downstream of the mutation. The patient had prominent myoclonic seizures and photosensitivity, thus, sharing phenotypic features with previously reported patients with CHD2-related epilepsy. In our original material of 22 patients with LGS features, we have now found two (9%) with mutations in the CHD2 gene. Our findings suggest that CHD2 mutations are important in the etiological spectrum of LGS.     

Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage-gated sodium channel Na_V1.6. To date, it is unclear if and how inhibitory interneurons, which express Na_V1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.SIGNIFICANCE STATEMENT SCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Na_v1.6. Inhibitory neurons express Na_V1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.     

Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum

Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits. Brain magnetic resonance imaging showed signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing was performed on the proband and her parents, and novel compound heterozygous mutations at c.936_938del (p.Phe313del) and c.1503dupC (p.Ile502Hisfs*106) in MCOLN1 (NM_020533.2) were identified in the proband. Additional biochemical examinations revealed elevated serum gastrin level and iron deficiency anemia, leading to the diagnosis of MLIV. More reports of such pathogenic mutations are expected to broaden the understanding of the channel function of mucolipin-1 and genotype-phenotype correlations.     

A novel variant in NEUROD2 in a patient with Rett-like phenotype points to Glu130 codon as a mutational hotspot

BackgroundNEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay.Case reportWe describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients.ConclusionsOur results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.     

CDKL5 alterations lead to early epileptic encephalopathy in both genders

Purpose: Genetic mutations of the cyclin‐dependent kinase‐like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe‐to‐profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG‐binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.     

A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome

BackgroundAutism spectrum disorder is a major neurodevelopmental disorder. Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum.MethodsWe report a case of a male child who presented with global developmental delay, and autism. Additional clinical features in the child were prominent eyes, long palpebral fissures with eversion of lateral third of the lower eyelid, hypoplastic nipples, and persistent fetal fingertip pads. The clinical features were in favor of Kabuki-like syndrome. MRI brain revealed corpus callosal dysgenesis, mild cerebellar para-vermian, and vermian atrophy.ResultsTrio exome sequencing has revealed a novel pathogenic compound heterozygous variant c.145A >T (p.Lys49Ter) and c.224_242del (p.Val85GlufsTer88) in exon 2 of the C12orf57 gene.ConclusionThis is the first case of Temtamy syndrome reported from India with additional novel phenotypic features not reported previously and broadens the phenotypic spectrum of the disorder. In addition, it expands the spectrum of pathogenic variants in the C12orf57 gene.     

Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation

A heterozygous mutation in the fibroblast growth factor 12 (FGF12) gene, which elevates the voltage dependence of neuronal sodium channel fast inactivation, was recently identified in some patients with epileptic encephalopathy. Here we report 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). These 2 patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole-exome sequencing. This mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy. One of our cases exhibited EIMFS, and this case responded to phenytoin and high-dose phenobarbital (PB). FGF12-related epileptic encephalopathy may exhibit diverse phenotypes and may respond to sodium channel blockers or high-dose PB.