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PP05.12 – 2659: Congenital cataract with facial dysmorphism and neuropathy (CCFDN): Clinical presentation and genetic correlation
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
It belongs to the family of DNA repair and transcription disorders together with xeroderma pigmentosum and trichothiodystrophy. Clinical and genetic diagnosis still remains challenging. Our goal was to develop a unique and efficient mutation-screening strategy for Cockayne syndrome and related disorders and to improve our understanding of the clinical spectrum of these conditions. Methods: We have designed a novel targeted high-throughput sequencing approach for the diagnosis of Cockayne syndrome and related DNA repair disorders. We have studied 30 patients presenting with the cardinal clinical features of Cockayne syndrome or related DNA repair disorders. Results: We have identified the causative mutations in 14 of the 30 patients. Three patients showed biallelic mutations in the ERCC6/CSB gene, 2 patients in the ERCC8/CSA gene, 1 patient in the ERCC2/XPD gene, 1 patient in the ERCC3/XPB, 1 patient in the ERCC5/XPG, 6 in the POLH gene. We present the clinical, neurological and radiological phenotypes of these patients with regard to our experience of a well-characterized cohort of more than 100 Cockayne patients previously studied in our center and we discuss the implications for diagnosis and prognosis purposes. Conclusion: This novel approach enables us to rapidly confirm the genetic diagnosis of Cockayne syndrome and related disoders and to unravel the molecular defect in atypical and overlapping clinical presentations.
PP05.11 - 3025 A new syndrome with postnatal microcephaly, mental retardation, spastic quadriplegia and pontocerebellar atrophy in Caucasus-Jewish families A. Fattal-Valevski, L. Ben-Sira, R. Straussberg, S. Edvardson, A. Mimouni-Bloch, R. Kaufmann, H. Mandel, O. Konen, J. Fox, O. Elpeleg, B. Ben-Zeev. Pediatric Neurology Unit, Dana Children’s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel Objective: A recently described mutation within the newly discovered gene MED17 was found to be responsible for causing primary microcephaly in Caucasus-Jewish families. The gene is located on chromosome 11 and codes for a subunit of the Mediator complex of mRNA synthesis. We describe the clinical course and MRI pattern of a cohort of 12 children of Caucasus-Jewish origin from several unrelated families with the same founder mutation in the MED17 gene. Methods: The medical charts of the patients were reviewed as well as their MRI scans and EEG records. Results: The cohort consists of 8 males and 4 females from 8 families of which 6 were consanguineous. Their ages range from 6 months to 18 years old. Soon after birth each affected child displayed jitteriness, irritability, poor feeding and increased muscle tone. Head circumference percentiles of all patients were normal at birth and declined within a few months to 6 standard deviations below the mean. The clinical neurological manifestations consisted of progressive spastic quadriplegia, epilepsy and profound psychomotor retardation. Brain MRI revealed marked cerebral and cerebellar atrophy with ventral flattening of the pons consistent with pontocerebellar hypoplasia. The early EEGs showed discontinuous low amplitude dysmature background with intermittent sharp waves and burst suppression evolving to generalized monotonous non-reactive low amplitude background. Conclusion: Recognition of the disease and its clinical course is of importance to prevent recurrence among families of Caucasus-Jewish ancestry.
19s (2015) S1 – S152
S49
PP05.12 - 2659 Congenital cataract with facial dysmorphism and neuropathy (CCFDN): Clinical presentation and genetic correlation A. Mosquera Gorostidi, S.E. Zarikian Denis, E. Gembero Arroyo, M.A. Ramos Arroyo, M.E. Yoldi Petri, S. Aguilera Albesa. Paediatric Neurology Unit, Department of Paediatrics, Navarra Health Service Hospital, Pamplona, Spain Objective: Congenital cataracts and peripheral nerve disease are described in a heterogeneous group of disorders. Other clinical features and genetic testing can guide the differential diagnosis. We present the clinical features and genetic correlation of a patient with congenital cataracts, peripheral neuropathy and associated choreoathetosis. Methods: Case description providing the results of complementary tests. Results: Previously known patient from Romania since she was 9 months old, presented to our hospital with bilateral congenital cataracts, which were operated in her country of origin. She showed signs of motor and intellectual development delay (she sat well unsupported at 24 months and started walking at 4 yo), ataxic gait and choreiform movements that increased when standing or with purposeful movements. Additionally, she presented bilateral atrophy of short extensor muscles of the toes, valgus feet, absent osteotendinous reflexes, obesity and slight facial dysmorphism (rounded face and microphthalmia). MRI and EEG were normal. Motor conduction studies showed slowing into the demyelinating range, with no sensory component. Molecular study ruled out mutation in the SIL1 gene (Marinesco-Sjogren syndrome) but showed a homozygous mutation in the CTDP1 gene (c.863+389C>T), thus confirming the suspected diagnosis. Conclusion: CCFDN is a rare autosomal recessive disorder that is prevalent among Gypsies from central Europe. A patient showing abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), motor and intellectual development delay and ataxic gait should be considered for the molecular study of CTDP1 gene. Occasionally patients may associate mild dysmorphic facial features and cerebellar dysfunction. Choreoathetosis may be prominent and interferes with daily activities. The differential diagnosis should include Marinesco-Sjogren syndrome and disorders involving demyelinating peripheral neuropathy.
PP05.13 - 2693 Functional MRI score predicts neurodevelopmental outcome in infants with intraventricular hemorrhage K. Goeral, G. Kasprian, R. Fuiko, L. Schmidt, M. Weninger, A. Berger, M. Olischar, K. Klebermass-Schrehof. Department of Pediatrics and Adolescent Medicine – Division of Neonatology, Intensive Care and Neuropediatrics; Medical University of Vienna, Austria Objective: Intraventricular hemorrhage (IVH) is a significant cause of morbidity and mortality in premature infants. There is a well known correlation between IVH grade and outcome. However, only a few studies take into account the site of the lesion. The aim of the present study was to create a tool which could serve as a prognostic indicator with regard to the severity of brain damage and outcome by assessing the functional areas affected by the bleeding. Methods: Infants with grade III IVH with and without parenchymal involvement who had MRI scans obtained and assessment of neurodevelopmental outcome were included into this analysis. MRIs were analyzed by the computation of a white matter (WMS), grey matter (GMS) and a combined MRI score (cS) which included the following functional areas and pathologies: WMS: Pyramidal tract, Corpus callosum, Radiatio optica and Crossroad. GMS: Gyrus precentralis and postcentralis, Hippocampus and Basal ganglia. cS was calculated by the sum of WMS and GMS. Further points were added in the presence of periventricular leukomalacia, hydrocephalus and for lesions in the Cerebellum. Neurodevelopmental outcome was evaluated
It belongs to the family of DNA repair and transcription disorders together with xeroderma pigmentosum and trichothiodystrophy. Clinical and genetic diagnosis still remains challenging. Our goal was to develop a unique and efficient mutation-screening strategy for Cockayne syndrome and related disorders and to improve our understanding of the clinical spectrum of these conditions. Methods: We have designed a novel targeted high-throughput sequencing approach for the diagnosis of Cockayne syndrome and related DNA repair disorders. We have studied 30 patients presenting with the cardinal clinical features of Cockayne syndrome or related DNA repair disorders. Results: We have identified the causative mutations in 14 of the 30 patients. Three patients showed biallelic mutations in the ERCC6/CSB gene, 2 patients in the ERCC8/CSA gene, 1 patient in the ERCC2/XPD gene, 1 patient in the ERCC3/XPB, 1 patient in the ERCC5/XPG, 6 in the POLH gene. We present the clinical, neurological and radiological phenotypes of these patients with regard to our experience of a well-characterized cohort of more than 100 Cockayne patients previously studied in our center and we discuss the implications for diagnosis and prognosis purposes. Conclusion: This novel approach enables us to rapidly confirm the genetic diagnosis of Cockayne syndrome and related disoders and to unravel the molecular defect in atypical and overlapping clinical presentations.
PP05.11 - 3025 A new syndrome with postnatal microcephaly, mental retardation, spastic quadriplegia and pontocerebellar atrophy in Caucasus-Jewish families A. Fattal-Valevski, L. Ben-Sira, R. Straussberg, S. Edvardson, A. Mimouni-Bloch, R. Kaufmann, H. Mandel, O. Konen, J. Fox, O. Elpeleg, B. Ben-Zeev. Pediatric Neurology Unit, Dana Children’s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel Objective: A recently described mutation within the newly discovered gene MED17 was found to be responsible for causing primary microcephaly in Caucasus-Jewish families. The gene is located on chromosome 11 and codes for a subunit of the Mediator complex of mRNA synthesis. We describe the clinical course and MRI pattern of a cohort of 12 children of Caucasus-Jewish origin from several unrelated families with the same founder mutation in the MED17 gene. Methods: The medical charts of the patients were reviewed as well as their MRI scans and EEG records. Results: The cohort consists of 8 males and 4 females from 8 families of which 6 were consanguineous. Their ages range from 6 months to 18 years old. Soon after birth each affected child displayed jitteriness, irritability, poor feeding and increased muscle tone. Head circumference percentiles of all patients were normal at birth and declined within a few months to 6 standard deviations below the mean. The clinical neurological manifestations consisted of progressive spastic quadriplegia, epilepsy and profound psychomotor retardation. Brain MRI revealed marked cerebral and cerebellar atrophy with ventral flattening of the pons consistent with pontocerebellar hypoplasia. The early EEGs showed discontinuous low amplitude dysmature background with intermittent sharp waves and burst suppression evolving to generalized monotonous non-reactive low amplitude background. Conclusion: Recognition of the disease and its clinical course is of importance to prevent recurrence among families of Caucasus-Jewish ancestry.
19s (2015) S1 – S152
S49
PP05.12 - 2659 Congenital cataract with facial dysmorphism and neuropathy (CCFDN): Clinical presentation and genetic correlation A. Mosquera Gorostidi, S.E. Zarikian Denis, E. Gembero Arroyo, M.A. Ramos Arroyo, M.E. Yoldi Petri, S. Aguilera Albesa. Paediatric Neurology Unit, Department of Paediatrics, Navarra Health Service Hospital, Pamplona, Spain Objective: Congenital cataracts and peripheral nerve disease are described in a heterogeneous group of disorders. Other clinical features and genetic testing can guide the differential diagnosis. We present the clinical features and genetic correlation of a patient with congenital cataracts, peripheral neuropathy and associated choreoathetosis. Methods: Case description providing the results of complementary tests. Results: Previously known patient from Romania since she was 9 months old, presented to our hospital with bilateral congenital cataracts, which were operated in her country of origin. She showed signs of motor and intellectual development delay (she sat well unsupported at 24 months and started walking at 4 yo), ataxic gait and choreiform movements that increased when standing or with purposeful movements. Additionally, she presented bilateral atrophy of short extensor muscles of the toes, valgus feet, absent osteotendinous reflexes, obesity and slight facial dysmorphism (rounded face and microphthalmia). MRI and EEG were normal. Motor conduction studies showed slowing into the demyelinating range, with no sensory component. Molecular study ruled out mutation in the SIL1 gene (Marinesco-Sjogren syndrome) but showed a homozygous mutation in the CTDP1 gene (c.863+389C>T), thus confirming the suspected diagnosis. Conclusion: CCFDN is a rare autosomal recessive disorder that is prevalent among Gypsies from central Europe. A patient showing abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), motor and intellectual development delay and ataxic gait should be considered for the molecular study of CTDP1 gene. Occasionally patients may associate mild dysmorphic facial features and cerebellar dysfunction. Choreoathetosis may be prominent and interferes with daily activities. The differential diagnosis should include Marinesco-Sjogren syndrome and disorders involving demyelinating peripheral neuropathy.
PP05.13 - 2693 Functional MRI score predicts neurodevelopmental outcome in infants with intraventricular hemorrhage K. Goeral, G. Kasprian, R. Fuiko, L. Schmidt, M. Weninger, A. Berger, M. Olischar, K. Klebermass-Schrehof. Department of Pediatrics and Adolescent Medicine – Division of Neonatology, Intensive Care and Neuropediatrics; Medical University of Vienna, Austria Objective: Intraventricular hemorrhage (IVH) is a significant cause of morbidity and mortality in premature infants. There is a well known correlation between IVH grade and outcome. However, only a few studies take into account the site of the lesion. The aim of the present study was to create a tool which could serve as a prognostic indicator with regard to the severity of brain damage and outcome by assessing the functional areas affected by the bleeding. Methods: Infants with grade III IVH with and without parenchymal involvement who had MRI scans obtained and assessment of neurodevelopmental outcome were included into this analysis. MRIs were analyzed by the computation of a white matter (WMS), grey matter (GMS) and a combined MRI score (cS) which included the following functional areas and pathologies: WMS: Pyramidal tract, Corpus callosum, Radiatio optica and Crossroad. GMS: Gyrus precentralis and postcentralis, Hippocampus and Basal ganglia. cS was calculated by the sum of WMS and GMS. Further points were added in the presence of periventricular leukomalacia, hydrocephalus and for lesions in the Cerebellum. Neurodevelopmental outcome was evaluated