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PP03.1 – 3059: Mutations in ECHS1: A defect in a multifunctional enzyme causing a mitochondrial disorder
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EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
PP02.12 - 2719 Assessment of speech and language delay among 0–3 year old children attending well baby clinics using Language Evaluation Scale Trivandrum (LEST 0–3) A. Mishra. Department of Cognitive Science, Indian Institute of Technology, Gandhinagar, India Objective: 0–3 years children seem to be at increased risk for speech and language disorders. Methods: Parents of 202 children within age 0–3 years (141 male, 61 female) completed screening questionnaires and the child was evaluated on the language scale. The screening battery included the Risk Factor Assessment Questionnaire for socio demographic profile, Home Screening Questionnaire (HSQ) and LEST. Children with disabilities were excluded. Results: Twelve children (5.9%) screened positive for LEST delay. Among them 10 children (83.3%) had negative home environment while 2 children (16.7%) had positive environment on Home Screening Questionnaires. Of the 12 children who showed LEST delay 8 (66.7%) were boys and 4 (33.3%) were girls. LEST total delay showed a similar trend on the basis of religion as 8 (66.7%) were Hindus and 4 (33.3%) were Muslims. The overall socio economic status of majority of families was 73 (38.4%) lower middle class with 7 (58.3%) showing LEST delay. The mean age of mother in case of LEST delay was 23.42 (SD 2.234) and mean age of father in case of LEST delay was 26.42 (SD 2.644). The average birth weight noticed was 3158.33 grams (SD 511.163) with P value 0.047. There was no significant relation with gestational age and the LEST delay as 11 (91.7%) of the children were born at term and 1 (8.3%) was born preterm. There was relation in LEST delay and place of residence as 10 (83.3%) were urban dwellers and 2 (18.7%) were from rural background. Conclusion: Our results indicate a higher prevalence of speech and language delay in children with negative home environment compared to the general population prevalence. The speech and language delay was associated with male child. There was more so prevalence in urban children without any relation to the preterm gestation. Our findings support the simultaneous use of more than one screening tests in order to increase screening sensitivity
PP02.13 - 2983 Human neural stem cells improve water maze learning after rat pup moderate ischemic injury without affecting injury volume S. Ashwal, R. Hartman, N. Ghosh, B. Tone, E. Snyder, A. Obenaus. Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, US Objective: Stem cell (SC) transplantation is being evaluated for treatment of neonatal hypoxic-ischemic injury (HII). One issue is whether the potential for SCs to improve functional recovery depends on the degree of HII severity. We examined whether HII severity affected the potential reparative effects of human neural SC (hNSC) transplantation in a rat pup HII model. Methods: We transplanted hNSCs (250k-500k) into the contralateral ventricle of rat pups 3d after unilateral HII. We examined lesion (total, core, penumbra) and hNSC volumes using MRI at 1, 4, 30 and 90d postinjury and behavior at 90d followed by histology and compared animals classified as mild, moderate and severe HII based on a rat pup severity score (RPSS). Results: hNSC transplantation did not significantly reduce total, core or penumbral lesion volume in the mild or moderate injury groups. However, in the severe group, total and core ischemic volumes at 90d were greater in hNSC than in saline-treated pups. Also, we saw a reduction in the ability of hNSCs to replicate over 90d depending on the severity of the initial HII (% increase in hNSC volume: mild injury = 385%; moderate, 299%; severe, 210%). At 90d, moderate hNSC animals exhibited significantly improved spatial learning compared to moderate saline animals (p<0.05), whereas hNSC
19s (2015) S1 – S152
treatment did not improve behavior after mild or severe HII. Conclusion: Our data suggest that the degree of injury severity following neonatal HII is an important factor that needs to be considered if stem cells are to be evaluated in human newborns, as we found that behavioral improvements were observed only in moderate HII pups. Of interest is that hNSC transplantation resulted in increased lesion volume but only in severe HII pups at 90d post HII, but this was not associated with a worse behavioral outcome.[Support: NIH-1R01NS059770-01A2].
PP03: Metabolic Disorders PP03.1 - 3059 Mutations in ECHS1: A defect in a multifunctional enzyme causing a mitochondrial disorder P. Freisinger, T.B. Haack, S. Kölker, M. Schülke-Gerstenfeld, J. Mayr, T. Klopstock, R. Rodenburg, R. Trollmann, J.M. Nuoffer, W. Sperl, R. Taylpr, I. Krägeloh-Mann, T. Meitinger, H. Prokisch. Dept. of Pediatrics, Klinikum Reutlingen, Germany ECHS1 encodes the short chain enoyl coenzyme A (CoA) hydratase an enzyme located in the inner mitochondrial Matrix,which catalyzes the second step of fatty acid oxidation and is involved in the metabolism of valine and isoleucine. Recently two siblings with mutations in ECHS1 have been described presenting a clinical picture with symmetrical basal ganglia alterations and encephalopathy suggesting a mitochondrial disease. This disorder can be diagnosed by increased excretion of S-(2carboxypropyl) cysteine and methacrylyl-CoA and acryloyl-CoA in urine (Peters et al. Brain 2014 Nov;137:2903–8). Method: We report 12 patients from 8 families with mutations in ECHS1 and demonstrate the large phenotypic spectrum of this defect. Results: In all patients severe dystonia, mental retardation and deafness were the leading symptoms. In 7/12 epilepsy was described; in 4/12 there was cardiomyopathy. No other inner organs were involved. The beginning of symptoms varies from birth to 3 years of age. The oldest patient is 32 years old. 4/12 died between 4 months and 8 years of age. In 7/12 patients brain MRI revealed symmetrical changes of the basal ganglia and in 3/11 white matter disease. Elevated lactate in blood/CSF was found in 7/12 patients. Only 2/8 patients showed abnormal results in the activity of pyruvate dehydrogenase complex (PDHc) and respiratory chain complexes (RCC)in muscle. Conclusion: ECHS1-deficiency is a newly recognized metabolic disorder with a “mitochondrial” phenotype but frequently normal activity of PDHc and RCC. This combination should prompt to investigate S(2-carboxypropyl)cysteine, methacrylyl-CoA and acryloyl-CoA for early diagnosis. This will be particularly important, if a treatment is available: a diet reduced in valine and isoleucine, the precursors of the potentially toxic metabolites might be a promising approach.
PP03.2 - 2683 Next generation sequencing allows the identification of NDUFS4 defect in a patient with fatal early Leigh syndrome and deficiencies in pyruvate dehydrogenase and multiple respiratory chain complexes J.D. Ortigoza Escobar, A. Oyarzabal, R. Montero, R. Artuch, L. Gort, P. Briones, B. Pérez González, P. Rodriguez-Pombo, B. Pérez Dueñas. Department of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain Objective: Respiratory chain complex (RCC) I is the second most common biochemical abnormality causing Leigh syndrome (LS), an early-onset neurodegenerative disorder. NDUFS4 gene presents a hotspot of mutations leading to an inappropriate as-
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
PP02.12 - 2719 Assessment of speech and language delay among 0–3 year old children attending well baby clinics using Language Evaluation Scale Trivandrum (LEST 0–3) A. Mishra. Department of Cognitive Science, Indian Institute of Technology, Gandhinagar, India Objective: 0–3 years children seem to be at increased risk for speech and language disorders. Methods: Parents of 202 children within age 0–3 years (141 male, 61 female) completed screening questionnaires and the child was evaluated on the language scale. The screening battery included the Risk Factor Assessment Questionnaire for socio demographic profile, Home Screening Questionnaire (HSQ) and LEST. Children with disabilities were excluded. Results: Twelve children (5.9%) screened positive for LEST delay. Among them 10 children (83.3%) had negative home environment while 2 children (16.7%) had positive environment on Home Screening Questionnaires. Of the 12 children who showed LEST delay 8 (66.7%) were boys and 4 (33.3%) were girls. LEST total delay showed a similar trend on the basis of religion as 8 (66.7%) were Hindus and 4 (33.3%) were Muslims. The overall socio economic status of majority of families was 73 (38.4%) lower middle class with 7 (58.3%) showing LEST delay. The mean age of mother in case of LEST delay was 23.42 (SD 2.234) and mean age of father in case of LEST delay was 26.42 (SD 2.644). The average birth weight noticed was 3158.33 grams (SD 511.163) with P value 0.047. There was no significant relation with gestational age and the LEST delay as 11 (91.7%) of the children were born at term and 1 (8.3%) was born preterm. There was relation in LEST delay and place of residence as 10 (83.3%) were urban dwellers and 2 (18.7%) were from rural background. Conclusion: Our results indicate a higher prevalence of speech and language delay in children with negative home environment compared to the general population prevalence. The speech and language delay was associated with male child. There was more so prevalence in urban children without any relation to the preterm gestation. Our findings support the simultaneous use of more than one screening tests in order to increase screening sensitivity
PP02.13 - 2983 Human neural stem cells improve water maze learning after rat pup moderate ischemic injury without affecting injury volume S. Ashwal, R. Hartman, N. Ghosh, B. Tone, E. Snyder, A. Obenaus. Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, US Objective: Stem cell (SC) transplantation is being evaluated for treatment of neonatal hypoxic-ischemic injury (HII). One issue is whether the potential for SCs to improve functional recovery depends on the degree of HII severity. We examined whether HII severity affected the potential reparative effects of human neural SC (hNSC) transplantation in a rat pup HII model. Methods: We transplanted hNSCs (250k-500k) into the contralateral ventricle of rat pups 3d after unilateral HII. We examined lesion (total, core, penumbra) and hNSC volumes using MRI at 1, 4, 30 and 90d postinjury and behavior at 90d followed by histology and compared animals classified as mild, moderate and severe HII based on a rat pup severity score (RPSS). Results: hNSC transplantation did not significantly reduce total, core or penumbral lesion volume in the mild or moderate injury groups. However, in the severe group, total and core ischemic volumes at 90d were greater in hNSC than in saline-treated pups. Also, we saw a reduction in the ability of hNSCs to replicate over 90d depending on the severity of the initial HII (% increase in hNSC volume: mild injury = 385%; moderate, 299%; severe, 210%). At 90d, moderate hNSC animals exhibited significantly improved spatial learning compared to moderate saline animals (p<0.05), whereas hNSC
19s (2015) S1 – S152
treatment did not improve behavior after mild or severe HII. Conclusion: Our data suggest that the degree of injury severity following neonatal HII is an important factor that needs to be considered if stem cells are to be evaluated in human newborns, as we found that behavioral improvements were observed only in moderate HII pups. Of interest is that hNSC transplantation resulted in increased lesion volume but only in severe HII pups at 90d post HII, but this was not associated with a worse behavioral outcome.[Support: NIH-1R01NS059770-01A2].
PP03: Metabolic Disorders PP03.1 - 3059 Mutations in ECHS1: A defect in a multifunctional enzyme causing a mitochondrial disorder P. Freisinger, T.B. Haack, S. Kölker, M. Schülke-Gerstenfeld, J. Mayr, T. Klopstock, R. Rodenburg, R. Trollmann, J.M. Nuoffer, W. Sperl, R. Taylpr, I. Krägeloh-Mann, T. Meitinger, H. Prokisch. Dept. of Pediatrics, Klinikum Reutlingen, Germany ECHS1 encodes the short chain enoyl coenzyme A (CoA) hydratase an enzyme located in the inner mitochondrial Matrix,which catalyzes the second step of fatty acid oxidation and is involved in the metabolism of valine and isoleucine. Recently two siblings with mutations in ECHS1 have been described presenting a clinical picture with symmetrical basal ganglia alterations and encephalopathy suggesting a mitochondrial disease. This disorder can be diagnosed by increased excretion of S-(2carboxypropyl) cysteine and methacrylyl-CoA and acryloyl-CoA in urine (Peters et al. Brain 2014 Nov;137:2903–8). Method: We report 12 patients from 8 families with mutations in ECHS1 and demonstrate the large phenotypic spectrum of this defect. Results: In all patients severe dystonia, mental retardation and deafness were the leading symptoms. In 7/12 epilepsy was described; in 4/12 there was cardiomyopathy. No other inner organs were involved. The beginning of symptoms varies from birth to 3 years of age. The oldest patient is 32 years old. 4/12 died between 4 months and 8 years of age. In 7/12 patients brain MRI revealed symmetrical changes of the basal ganglia and in 3/11 white matter disease. Elevated lactate in blood/CSF was found in 7/12 patients. Only 2/8 patients showed abnormal results in the activity of pyruvate dehydrogenase complex (PDHc) and respiratory chain complexes (RCC)in muscle. Conclusion: ECHS1-deficiency is a newly recognized metabolic disorder with a “mitochondrial” phenotype but frequently normal activity of PDHc and RCC. This combination should prompt to investigate S(2-carboxypropyl)cysteine, methacrylyl-CoA and acryloyl-CoA for early diagnosis. This will be particularly important, if a treatment is available: a diet reduced in valine and isoleucine, the precursors of the potentially toxic metabolites might be a promising approach.
PP03.2 - 2683 Next generation sequencing allows the identification of NDUFS4 defect in a patient with fatal early Leigh syndrome and deficiencies in pyruvate dehydrogenase and multiple respiratory chain complexes J.D. Ortigoza Escobar, A. Oyarzabal, R. Montero, R. Artuch, L. Gort, P. Briones, B. Pérez González, P. Rodriguez-Pombo, B. Pérez Dueñas. Department of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain Objective: Respiratory chain complex (RCC) I is the second most common biochemical abnormality causing Leigh syndrome (LS), an early-onset neurodegenerative disorder. NDUFS4 gene presents a hotspot of mutations leading to an inappropriate as-