- Email: [email protected]
Clinical and genetic characteristics of patients with neuronal ceroid lipofuscinosis over a 20-year period in Turkey
e162
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 1 6 1 ee 1 6 3
support the assumption that specific polymorphisms may contribute to location dependant lesion formation.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1199 OC101 ATP1A3 screening in patients with alternating hemiplegia of childhood and related phenotypes E. Panagiotakaki, J. Michel, D. Doummar, C. Mignot, E. Flamand-Roze, S. Nicole, H. Guilbert, P. Sabouraud, D. Sanlaville, A. Arzimanoglou, G. Lesca. Department of Clinical Epileptology, Sleep Disorders and Pediatric Functional Neurology, University Hospitals of Lyon, France Objective: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder character characterized by transient episodes of alternating hemiplegia/hemiparesis, dystonic attacks, paroxysmal abnormal ocular movements, epileptic seizuresand episodes of autonomic dysfunction, usually starting within the first year of life. In life. In 2012, mutations in ATP1A3, encoding the a3-subunit of the Na(+)/K(+)-ATPase pump, were shown to be the main cause of AHC. Mutations in ATP1A3 also cause other clinically-related neurological disorders: rapid-onset dystonia parkinsonism (RDP); CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; RECA (relapsing encephalopathy with cerebellar ataxia), and early infantile epileptic encephalopathy. We report the results of 4 years genetic screening of French patients with AHC or related disorders. Methods: Between 2012 and 2016, we have screened DNA sample from 162 patients for ATP1A3 mutations by Sanger sequencing or, more recently, by nextgeneration sequencing. Clinical records of all patients have been reviewed after genetic analysis. Results: We have found pathogenic or likely pathogenic ATP1A3 mutations in 59 index cases. A de novo mutation was found in all but 6 patients with clinical features fulfilling the criteria of AHC. The p.Glu818Lys mutation was found in two families with a clinical diagnosis of CAPOS. The p.Arg756Cys was found in 4 patients with a clinical diagnosis of RECA. The p.Arg756His mutations were found in a patient with RDP, but no mutations were identified in patients with isolated dystonia. Conclusion: This study confirms that ATP1A3 mutations are responsible for most cases of AHC, CAPOS or RECA. Analysis of clinical records led to identify only 6 patients with AHC without mutations on ATP1A3. These patients, together with patients from other countries have been included in an international genetic study, aiming at identifying other AHC-causing genes.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1200 OC102 Natural history of Alexander disease: A multicentric survey of 75 patients (reporting clinical, radiological and genetic characteristics in.) F. Renaldo, C. Mignot, D. Tonduti, D. Doummar, E. Bertini, S. Paquay, M. Abuawad, I. Dorboz, S. Samaan, M. Elmaleh, F. Chalard, Working group on Alexander Disease, O. Boespflug-Tanguy, L. Burglen, D. Rodriguez. AP-HP Service de Neurologie Pediatrique et Maladies Metaboliques H^ opital Robert Debre, Centre de Reference des Leucodystrophies, INSERM UMR 1141, Paris Diderot Universite, Sorbonne Paris Cite, Paris, France Alexander disease (AxD) is rare neurodegenerative disease caused by dominant mutations in the glial fibrillary acidic protein (GFAP). Based on clinical and radiological characteristics, patients have been historically classified in three age-dependent subtypes: Infantile forms (>2 years), juvenile forms (2e13 years) and
adult forms. Recently, a new classification has been proposed, dividing patients in type I and type II according to the age at onset (before versus after 4 years). We report retrospectively on 75 patients, 66 children and 9 adults, all diagnosed in France and mostly still followed in European neuropediatric centers. We were interested in age at onset, presence of psychomotor delay before appearance of neurologic symptoms, types of clinical signs, acute episodes of aggravation, neurological deterioration, age of death. We analysed all available brain MRI for each patient and attempted to establish a phenotype-genotype correlation. 49 (65%) patients began before 2 years old, 10 (13%) between 2 and 13, 6 (8%) after 13. First signs were developmental delay (71%) and regression (20%) before 2 years old, anorexia, vomiting, bulbar signs (41%) between 2 and 13, motor disabilities (100%) after 13. The evolution was characterised by occurrence of motor symptoms in all patients (100%), epilepsy in 42 (56%), regression in 39 (52%), and macrocephaly in 25 patients (33%). Natural history of some patients was also marked by recurrent acute episodes of vomiting, comas, for which different pathological hypothesis are discussed based on MRI analysis. 16 patients (20%) died, mostly between 2 and 13 years (11), three during the first year of life. R239 mutations seem to be responsible for severest presentations. Our data precise the natural history of AxD in a cohort of 75 patients, highlight some neuroradiological particularities and support a real phenotype-genotype correlation.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1201 OC103 Clinical and genetic characteristics of patients with neuronal ceroid lipofuscinosis over a 20-year period in Turkey Didem Ardicli, Deniz Yuksel, Kader Karli Oguz, Meral Topcu. Hacettepe University Children's Hospital, Department of Pediatric Neurology Objective: Neuronal ceroid lipofuscinosis (NCL) is the most common pediatric neurodegenerative disorder characterized by accumulation of ‘ceroid lipofuscin’ in neuronal and extraneuronal cells. Clinical features include seizures, progressive cognitive and motor retardation, ataxia, myoclonus, and visual impairment. Currently, there are 14 different genetic subtypes of NCL. We report the clinical and genetic features of patients with NCL over a 20-year period in Turkey. Methods: We reviewed the data of 117 patients clinically diagnosed with NCL between 1996 and 2016 at Hacettepe University Children's Hospital. Demographic and clinical features, onset of symptoms, laboratory and radiological findings, and genetic data were analyzed retrospectively. Results: Sixty-four patients with a certain molecular diagnosis of NCL were included. The mean age at first presentation was 3.9 years (ranged 6 monthse8 years). The most common presenting symptoms were epilepsy (68%) and psychomotor regression (64%). Consanguinity was present in 77% of parents. Genetic mutations were detected in the CLN1, CLN2, CLN3, CLN5, CLN6, CLN7 and CLN8 genes. Most common mutations were in CLN7 (28%), CLN2 (23%) and CLN8 (19%) respectively. Electroencephalogram (EEG) showed abnormal features predominantly in posterior hemisphere regions. Brain magnetic resonance imaging demonstrated prominent cerebral and cerebellar atrophy in 88% of the patients. Conclusion: Clinical picture of NCL in advanced stages of disease is similar regardless of the subtype. Enzymatic studies are available for CLN1 and CLN2, therefore differential diagnosis with other NCL subtypes is based on molecular genetic studies.
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 1 6 1 ee 1 6 3
Early molecular diagnosis of NCL is essential for disease-specific management, genetic counseling, and new promising therapies especially for CLN2 disease.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1202 OC104 The natural disease course of Vanishing White Matter M.S. van der Knaap, E.M.C. Hamilton, H.D.W. van der Lei, R.J.B.J. Gemke, B.M.J. Uitdehaag, R. de Vet, B.I. Witte. Department of Child Neurology, VU University Medical Centre and Amsterdam Neuroscience, Amsterdam, The Netherlands Objective: Vanishing White Matter (VWM) is characterized by chronic and stress-provoked neurological decline. Little is known about disease course and impact on daily life. This study assesses the degree of disability of VWM patients in relation to age of onset and disease duration to improve counselling of families and provide natural history data for future therapeutic trials. Methods: We performed a longitudinal multicentre study among 296 VWM patients. We obtained Health Utilities Index 3 (HUI3) assessments in patients from 2 years on and Guy's Neurological Disability Scale (GNDS) from 8 years on. These questionnaires measure health
e163
status and enable health index calculation on the basis of 8 (HUI) and 12 (GNDS) domains. Results: HUI3 data were available for 178 patients and follow-up data in 63. GNDS scores were obtained in 125 patients and follow-up in 40. Disease duration at assessment ranged from 6 months to 38 years. Mean health index was 0.39 (SD 0.44) on the HUI3 scale that ranges from 0.36 (most disabled state) to 1 (no handicap) and 21 (SD 15) on the GNDS scale that ranges from 0 (normal) to 60 (most disabled). Earlier disease onset was associated with higher mortality and more severe handicap. The disease course was faster for patients with onset before age 4 years, whereas the rate of deterioration was rather similar for all ages of onset from 4 years on. The domains ambulation and dexterity were most severely affected, especially in young children, followed by cognition, which was affected earlier in older patients. In later disease stages, patients were more likely to develop problems with speech and bladder function. Vision and hearing remained relatively intact. Conclusion: VWM disease spectrum is highly variable, ranging from limited handicap to profound disability in various domains. This study provides better insight in the natural disease course.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1203
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 1 6 1 ee 1 6 3
support the assumption that specific polymorphisms may contribute to location dependant lesion formation.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1199 OC101 ATP1A3 screening in patients with alternating hemiplegia of childhood and related phenotypes E. Panagiotakaki, J. Michel, D. Doummar, C. Mignot, E. Flamand-Roze, S. Nicole, H. Guilbert, P. Sabouraud, D. Sanlaville, A. Arzimanoglou, G. Lesca. Department of Clinical Epileptology, Sleep Disorders and Pediatric Functional Neurology, University Hospitals of Lyon, France Objective: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder character characterized by transient episodes of alternating hemiplegia/hemiparesis, dystonic attacks, paroxysmal abnormal ocular movements, epileptic seizuresand episodes of autonomic dysfunction, usually starting within the first year of life. In life. In 2012, mutations in ATP1A3, encoding the a3-subunit of the Na(+)/K(+)-ATPase pump, were shown to be the main cause of AHC. Mutations in ATP1A3 also cause other clinically-related neurological disorders: rapid-onset dystonia parkinsonism (RDP); CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; RECA (relapsing encephalopathy with cerebellar ataxia), and early infantile epileptic encephalopathy. We report the results of 4 years genetic screening of French patients with AHC or related disorders. Methods: Between 2012 and 2016, we have screened DNA sample from 162 patients for ATP1A3 mutations by Sanger sequencing or, more recently, by nextgeneration sequencing. Clinical records of all patients have been reviewed after genetic analysis. Results: We have found pathogenic or likely pathogenic ATP1A3 mutations in 59 index cases. A de novo mutation was found in all but 6 patients with clinical features fulfilling the criteria of AHC. The p.Glu818Lys mutation was found in two families with a clinical diagnosis of CAPOS. The p.Arg756Cys was found in 4 patients with a clinical diagnosis of RECA. The p.Arg756His mutations were found in a patient with RDP, but no mutations were identified in patients with isolated dystonia. Conclusion: This study confirms that ATP1A3 mutations are responsible for most cases of AHC, CAPOS or RECA. Analysis of clinical records led to identify only 6 patients with AHC without mutations on ATP1A3. These patients, together with patients from other countries have been included in an international genetic study, aiming at identifying other AHC-causing genes.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1200 OC102 Natural history of Alexander disease: A multicentric survey of 75 patients (reporting clinical, radiological and genetic characteristics in.) F. Renaldo, C. Mignot, D. Tonduti, D. Doummar, E. Bertini, S. Paquay, M. Abuawad, I. Dorboz, S. Samaan, M. Elmaleh, F. Chalard, Working group on Alexander Disease, O. Boespflug-Tanguy, L. Burglen, D. Rodriguez. AP-HP Service de Neurologie Pediatrique et Maladies Metaboliques H^ opital Robert Debre, Centre de Reference des Leucodystrophies, INSERM UMR 1141, Paris Diderot Universite, Sorbonne Paris Cite, Paris, France Alexander disease (AxD) is rare neurodegenerative disease caused by dominant mutations in the glial fibrillary acidic protein (GFAP). Based on clinical and radiological characteristics, patients have been historically classified in three age-dependent subtypes: Infantile forms (>2 years), juvenile forms (2e13 years) and
adult forms. Recently, a new classification has been proposed, dividing patients in type I and type II according to the age at onset (before versus after 4 years). We report retrospectively on 75 patients, 66 children and 9 adults, all diagnosed in France and mostly still followed in European neuropediatric centers. We were interested in age at onset, presence of psychomotor delay before appearance of neurologic symptoms, types of clinical signs, acute episodes of aggravation, neurological deterioration, age of death. We analysed all available brain MRI for each patient and attempted to establish a phenotype-genotype correlation. 49 (65%) patients began before 2 years old, 10 (13%) between 2 and 13, 6 (8%) after 13. First signs were developmental delay (71%) and regression (20%) before 2 years old, anorexia, vomiting, bulbar signs (41%) between 2 and 13, motor disabilities (100%) after 13. The evolution was characterised by occurrence of motor symptoms in all patients (100%), epilepsy in 42 (56%), regression in 39 (52%), and macrocephaly in 25 patients (33%). Natural history of some patients was also marked by recurrent acute episodes of vomiting, comas, for which different pathological hypothesis are discussed based on MRI analysis. 16 patients (20%) died, mostly between 2 and 13 years (11), three during the first year of life. R239 mutations seem to be responsible for severest presentations. Our data precise the natural history of AxD in a cohort of 75 patients, highlight some neuroradiological particularities and support a real phenotype-genotype correlation.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1201 OC103 Clinical and genetic characteristics of patients with neuronal ceroid lipofuscinosis over a 20-year period in Turkey Didem Ardicli, Deniz Yuksel, Kader Karli Oguz, Meral Topcu. Hacettepe University Children's Hospital, Department of Pediatric Neurology Objective: Neuronal ceroid lipofuscinosis (NCL) is the most common pediatric neurodegenerative disorder characterized by accumulation of ‘ceroid lipofuscin’ in neuronal and extraneuronal cells. Clinical features include seizures, progressive cognitive and motor retardation, ataxia, myoclonus, and visual impairment. Currently, there are 14 different genetic subtypes of NCL. We report the clinical and genetic features of patients with NCL over a 20-year period in Turkey. Methods: We reviewed the data of 117 patients clinically diagnosed with NCL between 1996 and 2016 at Hacettepe University Children's Hospital. Demographic and clinical features, onset of symptoms, laboratory and radiological findings, and genetic data were analyzed retrospectively. Results: Sixty-four patients with a certain molecular diagnosis of NCL were included. The mean age at first presentation was 3.9 years (ranged 6 monthse8 years). The most common presenting symptoms were epilepsy (68%) and psychomotor regression (64%). Consanguinity was present in 77% of parents. Genetic mutations were detected in the CLN1, CLN2, CLN3, CLN5, CLN6, CLN7 and CLN8 genes. Most common mutations were in CLN7 (28%), CLN2 (23%) and CLN8 (19%) respectively. Electroencephalogram (EEG) showed abnormal features predominantly in posterior hemisphere regions. Brain magnetic resonance imaging demonstrated prominent cerebral and cerebellar atrophy in 88% of the patients. Conclusion: Clinical picture of NCL in advanced stages of disease is similar regardless of the subtype. Enzymatic studies are available for CLN1 and CLN2, therefore differential diagnosis with other NCL subtypes is based on molecular genetic studies.
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 1 6 1 ee 1 6 3
Early molecular diagnosis of NCL is essential for disease-specific management, genetic counseling, and new promising therapies especially for CLN2 disease.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1202 OC104 The natural disease course of Vanishing White Matter M.S. van der Knaap, E.M.C. Hamilton, H.D.W. van der Lei, R.J.B.J. Gemke, B.M.J. Uitdehaag, R. de Vet, B.I. Witte. Department of Child Neurology, VU University Medical Centre and Amsterdam Neuroscience, Amsterdam, The Netherlands Objective: Vanishing White Matter (VWM) is characterized by chronic and stress-provoked neurological decline. Little is known about disease course and impact on daily life. This study assesses the degree of disability of VWM patients in relation to age of onset and disease duration to improve counselling of families and provide natural history data for future therapeutic trials. Methods: We performed a longitudinal multicentre study among 296 VWM patients. We obtained Health Utilities Index 3 (HUI3) assessments in patients from 2 years on and Guy's Neurological Disability Scale (GNDS) from 8 years on. These questionnaires measure health
e163
status and enable health index calculation on the basis of 8 (HUI) and 12 (GNDS) domains. Results: HUI3 data were available for 178 patients and follow-up data in 63. GNDS scores were obtained in 125 patients and follow-up in 40. Disease duration at assessment ranged from 6 months to 38 years. Mean health index was 0.39 (SD 0.44) on the HUI3 scale that ranges from 0.36 (most disabled state) to 1 (no handicap) and 21 (SD 15) on the GNDS scale that ranges from 0 (normal) to 60 (most disabled). Earlier disease onset was associated with higher mortality and more severe handicap. The disease course was faster for patients with onset before age 4 years, whereas the rate of deterioration was rather similar for all ages of onset from 4 years on. The domains ambulation and dexterity were most severely affected, especially in young children, followed by cognition, which was affected earlier in older patients. In later disease stages, patients were more likely to develop problems with speech and bladder function. Vision and hearing remained relatively intact. Conclusion: VWM disease spectrum is highly variable, ranging from limited handicap to profound disability in various domains. This study provides better insight in the natural disease course.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1203