RARS2 mutations in a sibship with infantile spasms

Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl‐tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic–clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype.     

STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern

Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression‐burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense‐mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one‐third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.     

Biallelic loss‐of‐function UBA5 mutations in a patient with intractable West syndrome and profound failure to thrive

Mutation of the gene encoding ubiquitin‐like modifier‐activating enzyme 5 (UBA5) causes autosomal recessive early‐onset epileptic encephalopathy. UBA5 acts as an E1‐activating enzyme in the ubiquitin‐fold modifier 1 pathway, which is important for unfolded protein elimination and regulation of apoptosis, and has been linked to human diseases. We identified biallelic mutations in UBA5 in a Japanese boy with intractable West syndrome, profound failure to thrive, and severe cerebral and cerebellar atrophy. The boy presented with epileptic spasms and hypsarrhythmia at the age of three months. He was diagnosed with West syndrome, however, treatments with adrenocorticotropic hormone and several antiepileptic drugs were ineffective. MRI findings were initially normal, but subsequently showed a progression of cerebellar and cerebral atrophy. By the age of seven years, he had not achieved any developmental milestones; he had daily epileptic spasms and tonic seizures and profound failure to thrive. Gene analysis revealed novel compound heterozygous mutations in UBA5; a microdeletion encompassing the entire UBA5 gene and a putative disease‐causing missense mutation in the catalytic domain. These biallelic variants may have caused loss of function, accounting for the observed clinical symptoms. Intractable infantile epileptic spasms, failure to thrive, and severe neurological impairment may be characteristic of patients with UBA5 mutations.     

A new paradigm for West syndrome based on molecular and cell biology

Symptomatic West syndrome has heterogeneous backgrounds. Recently, two novel genes, ARX and CDKL5, have been found to be responsible for cryptogenic West syndrome or infantile spasms. Both are located in the human chromosome Xp22 region and are mainly expressed and play roles in fetal brain. Moreover, several genes responsible for brain malformations including lissencephaly, which is frequently associated with West syndrome or infantile spasms, have been found, and the mechanisms responsible for the neural network disorders in these brain malformations are rapidly being determined. Findings of animal and in vitro studies and mutation analyses in humans are delineating the molecular and cellular basis of West syndrome. Mutations of the ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype-phenotype correlation. An expansion mutation of the first polyalanine tract of ARX is more strongly related to infantile spasms than is that of the second polyalanine tract. Although the phenotype of CDKL5 mutation is similar to Rett syndrome caused by MECP2 mutation, the former is characterized by early-onset seizures and association with West syndrome. Lissencephaly caused by LIS1 or DCX mutation frequently results in West syndrome, while lissencephaly due to ARX mutation is associated with the most severe form of epilepsy but never results in West syndrome nor infantile spasms. Both LIS1 and DCX participate in the development of GABAergic interneurons as well as pyramidal neurons, while ARX participates only in that of interneurons. Individuals with lissencephaly due to ARX mutation lack non-pyramidal or GABAergic interneurons. ARX is crucial for the development of GABAergic interneuron, so abnormal interneurons in patients with ARX mutation are thought to be implicated in the pathological mechanism, even though brain MRI is normal. Abnormal interneurons appear to play an essential role in the pathogenesis of West syndrome or infantile spasms, which can be considered an interneuronopathy.     

Mutations in PRRT2 are not a common cause of infantile epileptic encephalopathies

Heterozygous mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Homozygous mutations in PRRT2 have also been reported in two families with intellectual disability (ID) and seizures. Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal‐infantile epilepsy. Mutations in KCNQ2 and SCN2A also contribute to severe infantile epileptic encephalopathies (IEEs) in which seizures and intellectual disability co‐occur. We therefore hypothesized that PRRT2 mutations may also underlie cases of IEE. We examined PRRT2 for heterozygous, compound heterozygous or homozygous mutations to determine their frequency in causing epileptic encephalopathies (EEs). Two hundred twenty patients with EEs with onset by 2 years were phenotyped. An assay for the common PRRT2 c.649‐650insC mutation and high resolution‐melt analysis for mutations in the remaining exons of PRRT2 were performed. Neither the common mutation nor any other pathogenic variants in PRRT2 were detected in the 220 patients. Our findings suggest that mutations in PRRT2 are not a common cause of IEEs.     

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

Chromosome 1q41‐q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41‐q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41‐q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41‐q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41‐q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug‐resistant epilepsy, and hyperkinetic movement disorders.     

Benign spasms of infancy: a mimicker of infantile epileptic disorders*

Benign spasms of infancy (BSI), previously described as benign non‐epileptic infantile spasms or benign myoclonus of early infancy, are non‐epileptic movements manifesting during the first year of life and spontaneously resolving in the second year of life. BSI are characterized by spasms typically lasting 1–2 seconds, involving, to varying degrees, the head, neck, trunk, shoulders and upper extremities. Ictal and interictal EEG recordings are normal. BSI are not associated with developmental regression and do not require treatment. Distinction between BSI and infantile epileptic disorders, such as epileptic spasms or myoclonic epilepsy of infancy, can be challenging given the clinical similarities. Moreover, interictal EEGs can be normal in all conditions. Epileptic spasms and myoclonic epilepsy require timely treatment to improve neurodevelopmental outcomes. We describe a six‐month‐old infant presenting with spasm‐like movements. His paroxysms as well as a positive family history for epileptic spasms were in keeping with a likely diagnosis of West syndrome. Surprisingly, ictal video‐EEG did not reveal epileptiform activity, and suggested a diagnosis of BSI. We emphasize that ictal video‐EEG is the gold standard for classification of infantile paroxysms as epileptic or non‐epileptic, thereby avoiding over‐treatment for BSI and facilitating timely targeted treatment of infantile epilepsies. [Published with video sequences]     

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.     

A possible association of responsiveness to adrenocorticotropic hormone with specific GRIN1 haplotypes in infantile spasms

Aim Adrenocorticotropic hormone (ACTH) has been used as the major therapy for infantile spasms since 1958 because it effectively suppresses seizures; it also normalizes the electroencephalogram in the short‐term treatment of infantile spasms. G protein‐regulated inducer of neurite outgrowth 1 (GRIN1, also known as N‐methyl‐d ‐aspartate receptor 1, NMDAR1), a glutamate receptor, is the main component of functional N‐methyl‐d ‐aspartic acid receptors that are involved in the glucocorticoid‐induced neuronal damage. Thus, it may be a candidate gene to be tested for responsiveness to ACTH in infantile spasms. In the present study, polymorphisms in the GRIN1 gene in infantile spasms were investigated using a case–control design. Method Twelve single nucleotide polymorphisms in the GRIN1 gene were genotyped in a Chinese case–control set consisting of 97 unrelated patients with infantile spasms (60 males, 37 females; mean age 6.4mo, SD 2.7) and 96 healthy individuals (63 males, 33 females; mean age 7.3mo, SD 3.8). Association analysis was performed on the genotyped data. Results Five estimated haplotypes with a frequency of more than 3% were detected. Results of the study showed that responsiveness to treatment with ACTH in homozygous carriers of the CTA haplotype was higher than that in heterozygous carriers and non‐carriers (p=0.022). Furthermore, CTG, a rare haplotype, was strongly associated with infantile spasms (p=0.013). Interpretation The results suggest that haplotypes of GRIN1 may influence responsiveness to ACTH. The findings necessitate further study for confirmation.     

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.     

Prognostic significance of genetic biomarkers in isocitrate dehydrogenase‐wild‐type lower‐grade glioma: the need to further stratify this tumor entity – a meta‐analysis

The clinical outcomes of isocitrate dehydrogenase‐wild‐type (IDH‐wt) lower‐grade glioma (LGG) have been the subject of debate for some time. In this meta‐analysis, we aimed to assess the prognostic values of several known genetic markers (e.g. TERT promoter mutation, H3F3A mutation, CDKN2A loss) in this tumor group. Four electronic databases, including PubMed, Scopus, Web of Science and Virtual Health Library, were searched for relevant articles. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival were calculated using a random‐effect model weighted by an inverse variance method. A total of 11 studies were finally selected from 2274 articles for meta‐analyses. Several genetic alterations were demonstrated to have a negative impact on prognosis of IDH‐wt LGGs, specifically TERT promoter mutation (HR, 1.96; 95% CI, 1.42–2.70), H3F3A mutation (HR, 3.21; 95% CI, 1.86–5.55) and EGFR amplification (HR, 1.67; 95% CI, 1.02–2.74). However, CDKN loss, ATRX mutation and coexisting gain of chromosome 7/loss of chromosome 10 showed no clinical significance in this glioma entity. Our study results demonstrated that IDH‐wt LGGs are heterogeneous in clinical outcome and not all tumors have a poor prognosis. The presence of TERT promoter mutation, H3F3A mutation and EGFR amplification showed negative prognostic impacts in this tumor entity. These genetic events can be used to better stratify patient outcomes.     

Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy

Purpose : Mutations of the X‐linked gene cyclin‐dependent kinase‐like 5 (CDKL5) cause an X‐linked encephalopathy with early onset intractable epilepsy, including infantile spasms and other seizure types, and a Rett syndrome (RTT)–like phenotype. Very limited information is available on the frequency and phenotypic spectrum associated with CDKL5 deletions/duplications. We investigated the role of CDKL5 deletions/duplications in causing early onset intractable epilepsy of unknown etiology in girls. Methods : We studied 49 girls with early onset intractable epilepsy, with or without infantile spasms, and developmental impairment, for whom no etiologic factors were obvious after clinical examination, brain magnetic resonance imaging (MRI) and expanded screening for inborn errors of metabolism. We performed CDKL5 gene mutation analysis in all and multiplex ligation dependent probe amplification assay (MLPA) in those who were mutation negative. Custom Array‐comparative genomic hybridization (CGH), breakpoint polymerase chain reaction (PCR) analysis, and X‐inactivation studies were performed in patients in whom MLPA uncovered a genomic alteration. Results : We found CDKL5 mutations in 8.2% (4 of 49) of patients and genomic deletions in 8.2% (4 of 49). Overall, abnormalities of the CDKL5 gene accounted for 16.3% (8 of 49) of patients. Discussion : CDKL5 gene deletions are an under‐ascertained cause of early onset intractable epilepsy in girls. Genetic testing of CDKL5, including both mutation and deletion/duplication analysis, should be considered in this clinical subgroup.     

Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3

Mutations in NPRL3, one of three genes that encode proteins of the mTORC1‐regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel‐ or DEPDC5‐associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms.     

GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy

The gamma‐aminobutyric acid type A receptor β3 gene (GABRB3) encodes the β3‐subunit of the gamma‐aminobutyric acid type A (GABA_A) receptor, which mediates inhibitory signalling within the central nervous system. Recently, GABRB3 mutations have been identified in a few patients with infantile spasms and Lennox–Gastaut syndrome. We report the clinical and electrographic features of a novel case of GABRB3‐related early‐onset epileptic encephalopathy. Our patient presented with neonatal hypotonia and feeding difficulties, then developed pharmacoresistant epileptic encephalopathy, characterized by multiple seizure types from 3 months of age. Electroencephalography demonstrated ictal generalized and interictal multifocal epileptiform abnormalities. Using a SureSelectXT custom multiple gene panel covering 48 early infantile epileptic encephalopathy/developmental delay genes, a novel de novo GABRB3 heterozygous missense mutation, c.860C>T (p.Thr287Ile), was identified and confirmed on Sanger sequencing. GABRB3 is an emerging cause of early‐onset epilepsy. Novel genetic technologies, such as whole‐exome/genome sequencing and multiple gene panels, will undoubtedly identify further cases, allowing more detailed electroclinical delineation of the GABRB3‐related genotypic and phenotypic spectra.     

De novo KCNT1 mutations in early‐onset epileptic encephalopathy

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1‐targeted next‐generation sequencing (207 samples) and/or whole‐exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K⁺ conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1–4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.     

A homozygous mutation of voltage‐gated sodium channel βI gene SCN1B in a patient with Dravet syndrome

Dravet syndrome is a severe form of epileptic encephalopathy characterized by early onset epileptic seizures followed by ataxia and cognitive decline. Approximately 80% of patients with Dravet syndrome have been associated with heterozygous mutations in SCN1A gene encoding voltage‐gated sodium channel (VGSC) α_I subunit, whereas a homozygous mutation (p.Arg125Cys) of SCN1B gene encoding VGSC β_I subunit was recently described in a patient with Dravet syndrome. To further examine the involvement of homozygous SCN1B mutations in the etiology of Dravet syndrome, we performed mutational analyses on SCN1B in 286 patients with epileptic disorders, including 67 patients with Dravet syndrome who have been negative for SCN1A and SCN2A mutations. In the cohort, we found one additional homozygous mutation (p.Ile106Phe) in a patient with Dravet syndrome. The identified homozygous SCN1B mutations indicate that SCN1B is an etiologic candidate underlying Dravet syndrome.     

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.     

PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels

Aberrations in the glycosylphosphatidylinositol (GPI)–anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI‐anchor synthesis, and PGAP2, which is involved in fatty‐acid GPI‐anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI‐anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI‐anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.     

Frequency of CNKSR2 mutation in the X‐linked epilepsy‐aphasia spectrum

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.     

The mystery of the Doctor's son, or the riddle of West syndrome

Although the eponym "West syndrome" is used widely for infantile spasms, the originators of the term and the time frame of its initial use are not well known. This article provides historical details about Dr. West, about his son who had infantile spasms, and about the circumstances leading to the coining of the term West syndrome.