Severe Infantile Epileptic Encephalopathy Research Articles

A novel homozygous PIGO mutation associated with severe infantile epileptic encephalopathy, profound developmental delay and psychomotor retardation: structural and 3D modelling investigations and genotype-phenotype correlation.

The PIGO gene encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor serving to attach various proteins to their cell surface. These proteins are intrinsic for normal neuronal and embryonic development. In the current research work, a clinical investigation was conducted on a patient from a consanguineous family suffering from epileptic encephalopathy, characterized by severe seizures, developmental delay, hypotonia, ataxia and hyperphosphatasia. Molecular analysis was performed using Whole Exome Sequencing (WES). The molecular investigation revealed a novel homozygous variant c.1132C > T in thePIGOgene, in which a highly conserved Leucine was changed to a Phenylalanine (p.L378F). To investigate the impact of the non-synonymous mutation, a 3D structural model of the PIGO protein was generated using the AlphaFold protein structure database as a resource for template-based tertiary structure modeling. A structural analysis by applying some bioinformatic tools on both variants 378L and 378F models predicted the pathogenicity of the non-synonymous mutation and its potential functional and structural effects on PIGO protein. We also discussed the phenotypic and genotypic variability associated with the PIGO deficiency. To our best knowledge, this is the first report of a patient diagnosed with infantile epileptic encephalopathy showing a high elevation of serum alkaline phosphatase level. Our findings, therefore, widen the genotype and phenotype spectrum of GPI-anchor deficiencies and broaden the cohort of patients withPIGOassociated epileptic encephalopathy with an elevated serum alkaline phosphatase level.

West syndrome and multiple sclerosis association

Introduction. West syndrome is a rare and severe infantile epileptic encephalopathy, beginning around the age of six months, characterized by a classic electro-clinical triad. This is a pathology totally different from multiple sclerosis (MS) which is a demyelinating disease of the central nervous system caused, affecting young adults, especially females. The association of these two pathologies has never been described. Observation. We report here an exceptional presentation of MS in a 14-year-old girl with a history of West syndrome. She had normal development until the age of six months, when she began to have flexion spasms. The diagnosis of West syndrome was made with a normal MRI. The infantile spasms disappeared after treatment with vigabatrin and adrenocorticotropic hormone (ACTH). It had generally progressed to Lennox Gastaut encephalopathy, with delayed psychomotor development and epileptic sequelae. At 14, she presented with left hemiparesis within a few days. A cerebral MRI showed multiple nodular hyperintensities of the supra and infratentorial white matter, with the presence of an active lesion, fulfilling the diagnostic criteria for multiple sclerosis. CSF analysis was normal. Anti-AQP4, anti-MOG, anti-NMDA and anti-GABA (AB) antibodies were absent in the blood. Antibodies against HIV and viral hepatitis were. Biotinidase activity and autoimmunity tests were correct. The patient received high doses of methylprednisolone IV (1g/day) for three days with remarkable clinical improvement after 15 days. Discussion. MS is a complex and heterogeneous central nervous system (CNS) demyelinating disease. It is not uncommon for epilepsy to be the first symptom of multiple sclerosis. Seizures, on the other hand, are more common after disease progression. Although the disease is characterized by inflammatory lesions of the white matter, various neuropathological and radiological studies have shown that the disease also affects the grey matter. Several studies have shown that seizures are three to six times more common in MS patients than in the general population. Even though MS can start with epilepsy and a seizure may be the only symptom of a relapse of MS, it is still not known whether the two diseases coexist or whether MS predisposes to seizures. Conclusion. The association of these two totally different pathologies can lead us to say that the mechanism of multiple sclerosis may begin in childhood and that the clinical signs appear in adulthood.

A New Variant of the IER3IP1 Gene: The First Case of Microcephaly, Epilepsy, and Diabetes Syndrome 1 from Turkey.

Microcephaly, Epilepsy, and Diabetes Syndrome 1 (MEDS1) is a rare autosomal recessive disorder and caused by defects in the IER3IP1 (Immediate Early Response 3 Interacting Protein 1) gene. Only 9 cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to the date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who is homozygous for the c.53C >T p.(Ala18Val) variant. The case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain MRI, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1.

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G>A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature

Congenital Disorders of Glycosylation (CDG) are new and rapidly expanding neurometabolic disorders with multisystem involvements, broad phenotypic manifestations, and variable severity. The majority results from a defect of one of the steps involved with protein or lipid N-glycosylation pathway. Almost all are inherited in autosomal recessive patterns with a few exceptions such as the X-linked ALG13. Mutations of ALG13 are reported, so far in only 10 patients, all were ascertained through exome/genome sequencing. Specifically, the ALG13 c.320A > G (p.Asn107Ser) variant was reported only in females and in all were de novo mutations. These findings may suggest an X-linked dominant inheritance of this mutation with embryonic male lethality. These patients presented with severe infantile epileptic encephalopathy, global developmental delay, and multisystem abnormalities. Only two of these females had glycosylation studies done, and both showed normal pattern of glycosylated serum transferrin isoforms, and none had their X-chromosome inactivation patterns studied.Here, we report on another female patient who is heterozygous for the same ALG13 c.320A > G (p.Asn107Ser) variant. She presented with infantile spasms, epileptic encephalopathy, hypsarrhythmia, hypotonia, developmental delay, intellectual disability, abnormal coagulation profile, feeding problems, hypotonia, and dysmorphic features. The diagnosis of CGD was suspected clinically, but glycosylation studies were done twice and showed normal patterns on both occasions. Her X-inactivation study was also done and, surprisingly, showed a random pattern of X-inactivation, with no evidence of skewness.

Knockout of sodium pump α3 subunit gene (Atp1a3−/−) results in perinatal seizure and defective respiratory rhythm generation

ATP1A3 encodes a neuron-specific human α3 subunit isoform of the sodium pump that plays an important role in neuronal excitability. Point and deletion mutations in ATP1A3 have been recognized in diverse neurological disorders. Three ATP1A3 disorders, alternating hemiplegia of childhood (AHC); apnea; and severe infantile epileptic encephalopathy often appear shortly after birth. To gain insight into the pathophysiology of these disorders and to understand the functional roles of the sodium pump α3 subunit in the brain in vivo during this period of development, we examined the phenotype of Atp1a3 knockout homozygous mouse fetuses (Atp1a3−/−). We focused on fetuses just before birth because at birth, about half of them showed severe seizure, and none could continue effective breathing and died soon after birth, without any gross anatomical anomalies. We examined c-Fos expression in the brains of Atp1a3−/− and found a significantly increased number of c-Fos-expressing cells in various regions of the brains, with unique distribution in the cerebellum, when compared with wild-type littermates (Atp1a3+/+). We also measured contents of monoamine neurotransmitters in the brains and found higher contents, especially of dopamine and noradrenaline, in the brains of Atp1a3−/− compared with those of Atp1a3+/+. In addition, we found various abnormal respiratory rhythms produced in the brainstem of Atp1a3−/−. These results suggest that Atp1a3 plays a critical role in neural function during development and at birth.

Compound Heterozygous COQ4 Missense Mutations Cause Coenzyme Q10 Deficiency Associated with Severe Infantile Epileptic Encephalopathy and Cerebellar Cysts

Compound Heterozygous COQ4 Missense Mutations Cause Coenzyme Q10 Deficiency Associated with Severe Infantile Epileptic Encephalopathy and Cerebellar Cysts

Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect

Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encodedalanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.

Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum

Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C β1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1. A case note review and molecular genetic investigations were performed for a child, approximately 10 months of age, admitted to Johns Hopkins University Hospital for developmental delay and new-onset seizures. The patient presented at 6 months of age with developmental delay, followed by the onset of intractable, focal, and generalized seizures associated with developmental regression from 10 months of age. Presently, at 2 years of age, the child has severe motor and cognitive delays. Diagnostic microarray revealed a heterozygous 476kb deletion of 20p12.3 (encompassing PLCB1), which was also detected in the mother. The genomic breakpoints for the heterozygous deletion were determined. In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father. Advances in molecular genetic testing have greatly improved diagnostic rates in EIEE, and this report further confirms the important role of microarray investigation in this group of disorders. PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes.

NECAP1 loss of function leads to a severe infantile epileptic encephalopathy

BackgroundEpileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically.ObjectiveTo describe a multiplex extended consanguineous family that defines a molecularly novel subtype of early infantile epileptic encephalopathy.MethodsAutozygosity mapping...

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations inIER3IP1: insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.

Microcephaly with Simplified Gyration, Epilepsy, and Infantile Diabetes Linked to Inappropriate Apoptosis of Neural Progenitors

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly inanimal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.

Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features

Mutations in CDKL5, which encodes cyclin dependent kinase-like 5, cause a form of severe infantile epileptic encephalopathy (EIEE2, OMIM 300672) predominantly in girls [1–3]. The clinical consequences of CDKL5 mutations characteristically comprise infantile spasms, early-onset seizures, and severe mental retardation. Clinically, there is some overlap with Rett syndrome (RTT, OMIM 312750), and female patients with CDKL5 mutations are often considered as suffering from atypical RTT or the Hanefeld variant of RTT. Other genes associated with atypical RTT are FOXG1, MEF2C, and NTNG1 [4]. To date, about 80 patients have been reported with CDKL5 mutations. The distribution of mutations over most of the presently known coding exons indicates that there are no mutational hotspots. The function of CDKL5/Cdkl5 is largely unexplored. Its gene product interacts with MeCP2, which is mutated in over 90% of patients with classic RTT. More recent studies have shown that CDKL5 controls the morphology of nuclear speckles [5] and that Cdkl5 is required for neuronal morphogenesis. By performing RT-PCR experiments on mouse total brain RNA with different primer pairs, we obtained products of the expected size, but also an additional larger product in each reaction (data not shown). Sequencing of the larger products revealed an insertion of 123 bp between exons 16 and 17. We have termed this insert “exon 16a.” This exon is predicted to code for an in-frame addition of 41 amino acids into the presently known Cdkl5 gene variants (Fig. 1). In the meantime, Fichou et al. reported that in the mouse, Cdkl5 transcripts containing this exon are expressed in all brain regions tested [6]. RT-PCR analysis using RNA from different Electronic supplementary material The online version of this article (doi:10.1007/s10048-011-0277-6) contains supplementary material, which is available to authorized users. N. Rademacher :M. Hambrock :U. Fischer : B. Moser : A. Tzschach :V. M. Kalscheuer (*) Max Planck Institute for Molecular Genetics, Department of Human Molecular Genetics, Ihnestr. 73, D-14195 Berlin, Germany e-mail: kalscheu@molgen.mpg.de

De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin

BackgroundDravet syndrome is a severe infantile epileptic encephalopathy caused in approximately 80% of cases by mutations in the voltage gated sodium channel subunit gene SCN1A. The majority of these mutations...

Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency

Adenylosuccinate lyase (ADSL) catalyzes two steps in purine nucleotide metabolism—the 8th step in the de novo pathway: conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR), and conversion of adenylosuccinate (S-AMP) to adenylate (AMP) in the purine nucleotide cycle. To date, over 50 patients have been reported suffering from ADSL deficiency. We report all seven so far diagnosed Polish patients with this defect. Most of our patients shared intractable seizures and psychomotor retardation since the neonatal period and had biochemical evidence of severe (type I) deficiency. Two patients with type II suffered only from mild/moderate psychomotor retardation and showed a transientvisual contact disturbance. One patient had a fatal neonatal form of ADSL deficiency with lack of spontaneous movement, respiratory failure, severe encephalopathy and intractable seizures. Analysis of the ADSL gene showed that four apparently unrelated patients carried a R426H mutation (two homozygous and two compound heterozygous). With the exception of the latter mutation, a Y114H mutation that had been reported previously, and a novel mutation T242I, all other mutations (including D268H and three novel S23R, D215H and I351T mutations) were found only in single families in single alleles. A search for this disorder should be included in the screening program of all infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy, developmental delay, hypotonia, and/or autistic features.

SCN1A gene mutations in two patients with severe infantile epileptic encephalopathy

SCN1A gene mutations in two patients with severe infantile epileptic encephalopathy

Neurologic aspects of adenylosuccinate lyase deficiency.

Adenylosuccinate lyase deficiency is an autosomal-recessive disorder of the purine de novo synthesis pathway, diagnosed up to now in approximately 40 patients. The clinical presentation is characterized by severe neurologic involvement including seizures, developmental delay, hypotonia, and autistic features. Neonatal seizures and a severe infantile epileptic encephalopathy are often the first manifestations of this disorder. The existence of genetic heterogeneity for the adenylosuccinate lyase defect could account for variability of the clinical presentation. Deficiency of purine nucleotides, impairment of energy metabolism, and toxic effects are potential mechanisms of cerebral damage. Laboratory investigations show the presence in urine and cerebrospinal fluid of succinylpurines, which are normally undetectable. Currently, no effective treatment is available for adenylosuccinate lyase deficiency. A search for this disorder should be included in the screening program of children with unexplained neonatal seizures or severe infantile epileptic encephalopathy.