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Biallelic variants in the CACNA1A gene resulting in infantile epileptic encephalopathy, global developmental delay and cortical visual impairment
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) e 4 5 ee 6 6
P1-98 Neurodevelopment disorders and Array-CGH: Sensitivity and specificity using a checklist as criteria for performing a genetic test Alfonso Amado Puentes, Alfredo Reparaz Andrade, Aida del Campo Garcı´a, Manuel Oscar Blanco Barca, rez, Cristina Torreira Banzas, Victor del Campo Pe Ramo n Ferna ndez Lorenzo. Department of Pediatrics, Child Jose Neurology Unit, Alvaro Cunqueiro Hospital, Vigo, Spain Objective: Identify the most significant clinical variables associated with a positive outcome of microarray-based comparative genomic hybridization (aCGH) analyses in order to develop a simple clinical score. Methods: Descriptive study of a cohort of 576 patients (studied with aCGH) and a cross- sectional analytical study, comparing the genotype and phenotype of the cases (the presence of malformations, intellectual disability (ID) and / or autistic spectrum disorder (ASD). Results: aCGH identified structural chromosomal alterations responsible for the intellectual disability/developmental delay phenotype in 13,7% (CI95: 10,9e16,5) of our sample. Based on the most frequent phenotypic characteristics among patients with a pathogenic CNV, we have created a checklist with the following items: alteration of the cranial perimeter, size <¼“ disorders.¼” neurodevelopmental¼“ with¼” patients¼“ of¼” study¼“ the¼” in¼“ acgh¼” for¼“ indications¼” clinical¼“ improve¼” can¼“ approach¼” this¼“ -¼” higher.¼“ or¼” 3¼“ score¼” a¼“ individuals¼” on¼“ conduct¼” to¼“ need¼” emphasize¼“ want¼” we¼“ anomalies.¼” genetic¼“ screening¼” cost¼“ and¼” complexities¼“ technical¼” because¼“ essential¼” is¼“ preselection¼” effective¼“ 74%.¼” sensitivity¼“ 497)¼” (214¼“ 43%¼” specificity¼“ assuming¼” 0.003),¼“ (p¼” way¼“ significant¼” statistically¼“ cnv¼” pathogenic¼“ finding¼” probability¼“ greater¼” there¼“ higher,¼” points¼“ 2¼” dysmorphia¼“ more¼” point¼“ 1¼” asd¼“ malformations¼” ophthalmic¼“ brain¼” presence¼”
http://dx.doi.org/10.1016/j.ejpn.2017.04.916 P1-99 Biallelic variants in the CACNA1A gene resulting in infantile epileptic encephalopathy, global developmental delay and cortical visual impairment V.M.Y. Wong-Spracklen, O. Spasic-Boskovic, K. Baker, A. Maw. Paediatric Neurology Department, Addenbrooke's Hospital, Cambridge University Hospitals Trust, Cambridge, UK Objective: The effect of two variants in the CACNA1A gene is not well known, but has been reported once in literature. We report the case of biallelic variants of the CACNA1A gene found in a 5 year old girl with infantile onset epileptic encephalopathy, global developmental delay, visual impairment with bilateral anisometropia and myopia. The child's older brother had speech and language delay, mild learning disability and ADHD. There was learning disability and developmental delay in the extended family on the maternal side, but no history of episodic ataxia or migraine. There was no consanguinity. Methods: DNA sequence analysis of gene panels associated with epileptic encephalopathy were used to detect the variants. Results: The changes identified were C.2042_2043delAG, p.(Gln681fs) inherited from the child's mother, as well as a C.1693G>A, p.(Glu565Lys) mutation, inherited from her father. C.2042_2043delAG, p.(Gln681fs) variant has been
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previously reported as a pathogenic change associated with episodic ataxia type 2. The p.(Gin681fs) variant has shown variable expressivity in some reported families. The C.1693G>A, p.(Glu565Lys) mutation from the father has not been recorded previously in our clinical exome cohort and has not been reported by ExAC, ESP, 1000 genomes, ClinVar and HGMD. In-silico analyses classified this change as deleterious and disease-causing. Missense pathogenic variants in the CACNA1A gene are usually associated with familial and sporadic hemiplegic migraine. Occurrences of epileptic encephalopathy and autism associated with CACNA1A haploinsufficiency have been reported. Conclusion: In this child, two mutations of the CACNA1A gene have come together. One is typically an autosomal dominant trait with variable penetrance. The other, is of less understood properties and is associated with familial, sporadic hemiplegic migraine, epileptic encephalopathy and autism. Further studies may improve understanding of how these changes interact and help families with prognostification.
http://dx.doi.org/10.1016/j.ejpn.2017.04.917 P1-100 A novel familial mutation in Alexander disease with marked variation in clinical severity M.A. Karalexi, K. Anagnostopoulou, M. Spanou, S. Mouskou, M. Giorgi, M. Tsirouda, A. Dinopoulos. 3rd Department of Pediatrics, University Hospital “Attiko”, Medical School of the University of Athens, Athens, Greece Objective: Alexander disease is a rare, often lethal disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein (GFAP). The disease typically results from dominant mutations in GFAP that arise de novo. However, series of familial cases with variable clinical manifestations have been described suggesting a potential recessive inheritance or germline mosaicism. We report a male infant with typical Alexander disease, inherited by his asymptomatic father with positive neuroimaging markers of the disease. Methods: Clinical histories were obtained and whole exome sequencing (WES) analyses in blood samples were performed through next generation sequencing. Results: We report a 6-month male, born of an uneventful term pregnancy, who presented with generalized hypotonia, chorioathetosis and drugresistant seizures, without macrocephaly. Brain MRI showed symmetrical abnormalities of the basal ganglia, subcortical white matter abnormalities, mainly of the frontal area with contrast enhancement along with high intensity periventricular rim on T1. WES analysis of the patient revealed a heterozygous missense mutation, c.1120G>A (p.Glu374Lys) in GFAP gene, resulting in the substitution of the aminoacid glutamic acid with lysine at the protein level. Although this genetic change is novel, it was considered as pathogenic from in silico analysis. We therefore proceeded to genetic analyses of the remaining members of the family that revealed the same mutation in the asymptomatic father. A subsequent brain MRI showed white matter abnormalities suggestive of adult-onset Alexander disease. Conclusion: We present a familial case of Alexander disease caused by a novel mutation on GFAP gene. There is a marked discrepancy on clinical presentation between the father and the affected child imposing that there is a striking variation on penetrance of the mutated
P1-98 Neurodevelopment disorders and Array-CGH: Sensitivity and specificity using a checklist as criteria for performing a genetic test Alfonso Amado Puentes, Alfredo Reparaz Andrade, Aida del Campo Garcı´a, Manuel Oscar Blanco Barca, rez, Cristina Torreira Banzas, Victor del Campo Pe Ramo n Ferna ndez Lorenzo. Department of Pediatrics, Child Jose Neurology Unit, Alvaro Cunqueiro Hospital, Vigo, Spain Objective: Identify the most significant clinical variables associated with a positive outcome of microarray-based comparative genomic hybridization (aCGH) analyses in order to develop a simple clinical score. Methods: Descriptive study of a cohort of 576 patients (studied with aCGH) and a cross- sectional analytical study, comparing the genotype and phenotype of the cases (the presence of malformations, intellectual disability (ID) and / or autistic spectrum disorder (ASD). Results: aCGH identified structural chromosomal alterations responsible for the intellectual disability/developmental delay phenotype in 13,7% (CI95: 10,9e16,5) of our sample. Based on the most frequent phenotypic characteristics among patients with a pathogenic CNV, we have created a checklist with the following items: alteration of the cranial perimeter, size <¼“ disorders.¼” neurodevelopmental¼“ with¼” patients¼“ of¼” study¼“ the¼” in¼“ acgh¼” for¼“ indications¼” clinical¼“ improve¼” can¼“ approach¼” this¼“ -¼” higher.¼“ or¼” 3¼“ score¼” a¼“ individuals¼” on¼“ conduct¼” to¼“ need¼” emphasize¼“ want¼” we¼“ anomalies.¼” genetic¼“ screening¼” cost¼“ and¼” complexities¼“ technical¼” because¼“ essential¼” is¼“ preselection¼” effective¼“ 74%.¼” sensitivity¼“ 497)¼” (214¼“ 43%¼” specificity¼“ assuming¼” 0.003),¼“ (p¼” way¼“ significant¼” statistically¼“ cnv¼” pathogenic¼“ finding¼” probability¼“ greater¼” there¼“ higher,¼” points¼“ 2¼” dysmorphia¼“ more¼” point¼“ 1¼” asd¼“ malformations¼” ophthalmic¼“ brain¼” presence¼”
http://dx.doi.org/10.1016/j.ejpn.2017.04.916 P1-99 Biallelic variants in the CACNA1A gene resulting in infantile epileptic encephalopathy, global developmental delay and cortical visual impairment V.M.Y. Wong-Spracklen, O. Spasic-Boskovic, K. Baker, A. Maw. Paediatric Neurology Department, Addenbrooke's Hospital, Cambridge University Hospitals Trust, Cambridge, UK Objective: The effect of two variants in the CACNA1A gene is not well known, but has been reported once in literature. We report the case of biallelic variants of the CACNA1A gene found in a 5 year old girl with infantile onset epileptic encephalopathy, global developmental delay, visual impairment with bilateral anisometropia and myopia. The child's older brother had speech and language delay, mild learning disability and ADHD. There was learning disability and developmental delay in the extended family on the maternal side, but no history of episodic ataxia or migraine. There was no consanguinity. Methods: DNA sequence analysis of gene panels associated with epileptic encephalopathy were used to detect the variants. Results: The changes identified were C.2042_2043delAG, p.(Gln681fs) inherited from the child's mother, as well as a C.1693G>A, p.(Glu565Lys) mutation, inherited from her father. C.2042_2043delAG, p.(Gln681fs) variant has been
e59
previously reported as a pathogenic change associated with episodic ataxia type 2. The p.(Gin681fs) variant has shown variable expressivity in some reported families. The C.1693G>A, p.(Glu565Lys) mutation from the father has not been recorded previously in our clinical exome cohort and has not been reported by ExAC, ESP, 1000 genomes, ClinVar and HGMD. In-silico analyses classified this change as deleterious and disease-causing. Missense pathogenic variants in the CACNA1A gene are usually associated with familial and sporadic hemiplegic migraine. Occurrences of epileptic encephalopathy and autism associated with CACNA1A haploinsufficiency have been reported. Conclusion: In this child, two mutations of the CACNA1A gene have come together. One is typically an autosomal dominant trait with variable penetrance. The other, is of less understood properties and is associated with familial, sporadic hemiplegic migraine, epileptic encephalopathy and autism. Further studies may improve understanding of how these changes interact and help families with prognostification.
http://dx.doi.org/10.1016/j.ejpn.2017.04.917 P1-100 A novel familial mutation in Alexander disease with marked variation in clinical severity M.A. Karalexi, K. Anagnostopoulou, M. Spanou, S. Mouskou, M. Giorgi, M. Tsirouda, A. Dinopoulos. 3rd Department of Pediatrics, University Hospital “Attiko”, Medical School of the University of Athens, Athens, Greece Objective: Alexander disease is a rare, often lethal disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein (GFAP). The disease typically results from dominant mutations in GFAP that arise de novo. However, series of familial cases with variable clinical manifestations have been described suggesting a potential recessive inheritance or germline mosaicism. We report a male infant with typical Alexander disease, inherited by his asymptomatic father with positive neuroimaging markers of the disease. Methods: Clinical histories were obtained and whole exome sequencing (WES) analyses in blood samples were performed through next generation sequencing. Results: We report a 6-month male, born of an uneventful term pregnancy, who presented with generalized hypotonia, chorioathetosis and drugresistant seizures, without macrocephaly. Brain MRI showed symmetrical abnormalities of the basal ganglia, subcortical white matter abnormalities, mainly of the frontal area with contrast enhancement along with high intensity periventricular rim on T1. WES analysis of the patient revealed a heterozygous missense mutation, c.1120G>A (p.Glu374Lys) in GFAP gene, resulting in the substitution of the aminoacid glutamic acid with lysine at the protein level. Although this genetic change is novel, it was considered as pathogenic from in silico analysis. We therefore proceeded to genetic analyses of the remaining members of the family that revealed the same mutation in the asymptomatic father. A subsequent brain MRI showed white matter abnormalities suggestive of adult-onset Alexander disease. Conclusion: We present a familial case of Alexander disease caused by a novel mutation on GFAP gene. There is a marked discrepancy on clinical presentation between the father and the affected child imposing that there is a striking variation on penetrance of the mutated