- Email: [email protected]
Extremely severe vermis hypoplasia: a good clue for pontocerebellar hypoplasia type 8 diagnosis
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
P1-92 Clinical Course of MECP2-related disorders in male patients T. Kovacevic, P. Zacher, Th. Mayer. The Saxson Epilepsy Centre Kleinwachau, Radeberg, Germany Objective: Mutations of the MECP2-gene, located on the X chromosome, are associated with a spectrum of disorders that may vary widely, depending on the gender of the affected patient. Rett syndrome (RTT) is a neurodevelopmental disorder almost exclusively affecting females. The clinical features include a broad range of phenotypes -classical RTT, variant RTT and milder forms of learning disabilities in females. In approximately 88 % of patients with classical RTT and 43 % of cases of atypical RTT variants of the MECP2-gene can be detected. The incidence is about 1:15,000 live births. Pathogenic mutations in male carriers were assumed to be lethal in utero. Today we know that this assumption is not true, though the exact prevalence of male MECP2-mutated patients is unknown. In the rare surviving males a neonatal encephalopathy or intellectual disability with behavioral difficulties can be seen. In our experience the clinical picture of surviving male patients vary greatly. They frequently suffer from severe pharmacoresistent epilepsies, profound developmental disabilities and/or severe respiratory problems. They are often not correctly diagnosed, since the majority of clinicians are unaware of the possibility of a MECP2-related disorders in males. Methods: Retrospective data analysis of our MECP2-mutated male patients requiring optimization of their pharmacoresistent epilepsies. Results: We report on the course of disease progression (history, video-EEG, MRI) of six male patients with genetically confirmed MECP2-related disorders. The clinical phenotypes included are: early progressive encephalopathy, low- functioning atypical RTT, X-linked intellectual disability and Xq28-duplication syndrome. Conclusion: MECP2related disorder should be considered in the differential diagnosis of males with X-linked mental disability and a severe neurodevelopmental condition without obvious etiology. The patients present with serious progression of the disease most likely causing elevated mortality rates and will need support for the rest of their lives, leaving their families with substantial psychosocial burden.
http://dx.doi.org/10.1016/j.ejpn.2017.04.910 P1-93 Extremely severe vermis hypoplasia: a good clue for pontocerebellar hypoplasia type 8 diagnosis D. Haye, L. Perrin, S. Valence, D. Rodriguez, L. Burglen. Department of Genetics, H^ opital Trousseau, Paris, France Introduction: To date, six patients from three independent families with pontocerebellar hypoplasia type 8 (PCH8), caused by mutations of the chromatin-modifying protein 1A gene (CHMP1A), have been reported. The CHMP1A protein seems to act as a critical link between cytoplasmic signals and BMI1mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells. Methods: We identified a patient with PCH8, and analyzed him clinically and genetically. Results: We report a 14 month-old boy who had growth failure, severe microcephaly, developmental delay, brainstem and cerebellum hypoplasia (hemispheres and vermis) and thin corpus callosum. Direct sequencing of the CHMP1A gene identified a novel homozygous nonsense mutation c.427C>T (p.Gln143*) in exon 6, inherited from both
e57
heterozygous parents. Conclusion: Patients with PCH8 have moderate to severe psychomotor retardation, microcephaly, abnormal movements, hypotonia, spasticity, and frequently joint contractures. Brain MRI shows decreased cerebral white matter, a thin corpus callosum and a peculiar PCH with a highly severe hypoplasia of the vermis, relative preservation of the folia, and a thin brainstem without pontine bulbing. Only two others PCH may be associated with an extremely small vermis: VLDLR-associated PCH in which the cerebellar folia are not preserved and the phenotype is milder; and the severe CASKassociated PCH in males, in which the pontine bulbing is relatively spared. The case reported here has this specific pattern of vermis and brainstem hypoplasia which lead us to the direct sequencing of the CHMP1A gene and that should therefore make consider PCH8.
http://dx.doi.org/10.1016/j.ejpn.2017.04.911 P1-94 Non progressive congenital ataxia or early onset slowly progressive ataxia? Identification of novel compound heterozygous variants in MRE11A (ataxia telangiectasia like disorder) in one patient confirms the clinical utility of exome sequencing phanie Valencea,b,c, Thierry Billette de Villemeura,b,c, Ste Alice Fieveta,b,c, Dominique Stoppa Lyonneta,b,c, a,b,c a,b,c a , Lydie Burglen . APHP, GHUEP, H^ opital Diana Rodriguez Trousseau, Pediatric Neurology, Paris, France. bCentre de Reference “Malformations et maladies congenitales du cervelet”, Paris-LyonLille, France. cGRC ConCer-LD, Sorbonne Universites, UPMC Univ 06, Paris, France Non-progressive congenital ataxia (NPCA) is a heterogeneous group of cerebellar disorders, characterized by the early-onset of cerebellar symptoms and the absence of clinical degeneration during the course of the disease. It is sometimes difficult to differentiate NPCA from early-onset, slowly progressive ataxia which, although degenerative, may occur at early age in a child who makes progress, at least during the first years of the disease. Objective-Methods: We report here a patient referred for a nonprogressive congenital ataxia in which the definitive diagnosis was ataxia telangiectasia like disorder (ATLD), an early slowly progressive ataxia. Results: The proband was a girl, first child of non-consanguineous Caucasian parents. Gait ataxia was note at 13 months. At 3 years she presented cerebellar symptoms, dysarthria, oculomotor apraxia and a normal Brain MRI. At age 7, the course of the disease seemed stable with mild learning disabilities, suggesting a congenital ataxia. Metabolic and chromosomal screening was normal, as well as alphafoetoprotein and immunoglobulins levels. A clinical exome sequencing revealed compound heterozygous variants (p.Arg576X andp.Asp142Asn) in MRE11A, gene involved in ATLD. Unfortunately, follow-up showed from age 8, a progression of the disease with increased ataxia, drop, tremor, choreo-athetosic movements and cerebellar atrophy on Brain MRI. At 9 years (last evaluation), she was able to walk unaided few steps but need a wheelchair in daily activities. ATLD is an autosomal recessive neurological disorder in patients with clinical resemblance to ataxia telangiectasia (early onset of ataxia, cerebellar atrophy) but without telangiectasia, immunodeficiency, cancer susceptibility or radiation sensitivity. Moreover, these patients had no chromosomal instability and normal alpha fetoprotein level. Interestingly, patients have mutations in
P1-92 Clinical Course of MECP2-related disorders in male patients T. Kovacevic, P. Zacher, Th. Mayer. The Saxson Epilepsy Centre Kleinwachau, Radeberg, Germany Objective: Mutations of the MECP2-gene, located on the X chromosome, are associated with a spectrum of disorders that may vary widely, depending on the gender of the affected patient. Rett syndrome (RTT) is a neurodevelopmental disorder almost exclusively affecting females. The clinical features include a broad range of phenotypes -classical RTT, variant RTT and milder forms of learning disabilities in females. In approximately 88 % of patients with classical RTT and 43 % of cases of atypical RTT variants of the MECP2-gene can be detected. The incidence is about 1:15,000 live births. Pathogenic mutations in male carriers were assumed to be lethal in utero. Today we know that this assumption is not true, though the exact prevalence of male MECP2-mutated patients is unknown. In the rare surviving males a neonatal encephalopathy or intellectual disability with behavioral difficulties can be seen. In our experience the clinical picture of surviving male patients vary greatly. They frequently suffer from severe pharmacoresistent epilepsies, profound developmental disabilities and/or severe respiratory problems. They are often not correctly diagnosed, since the majority of clinicians are unaware of the possibility of a MECP2-related disorders in males. Methods: Retrospective data analysis of our MECP2-mutated male patients requiring optimization of their pharmacoresistent epilepsies. Results: We report on the course of disease progression (history, video-EEG, MRI) of six male patients with genetically confirmed MECP2-related disorders. The clinical phenotypes included are: early progressive encephalopathy, low- functioning atypical RTT, X-linked intellectual disability and Xq28-duplication syndrome. Conclusion: MECP2related disorder should be considered in the differential diagnosis of males with X-linked mental disability and a severe neurodevelopmental condition without obvious etiology. The patients present with serious progression of the disease most likely causing elevated mortality rates and will need support for the rest of their lives, leaving their families with substantial psychosocial burden.
http://dx.doi.org/10.1016/j.ejpn.2017.04.910 P1-93 Extremely severe vermis hypoplasia: a good clue for pontocerebellar hypoplasia type 8 diagnosis D. Haye, L. Perrin, S. Valence, D. Rodriguez, L. Burglen. Department of Genetics, H^ opital Trousseau, Paris, France Introduction: To date, six patients from three independent families with pontocerebellar hypoplasia type 8 (PCH8), caused by mutations of the chromatin-modifying protein 1A gene (CHMP1A), have been reported. The CHMP1A protein seems to act as a critical link between cytoplasmic signals and BMI1mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells. Methods: We identified a patient with PCH8, and analyzed him clinically and genetically. Results: We report a 14 month-old boy who had growth failure, severe microcephaly, developmental delay, brainstem and cerebellum hypoplasia (hemispheres and vermis) and thin corpus callosum. Direct sequencing of the CHMP1A gene identified a novel homozygous nonsense mutation c.427C>T (p.Gln143*) in exon 6, inherited from both
e57
heterozygous parents. Conclusion: Patients with PCH8 have moderate to severe psychomotor retardation, microcephaly, abnormal movements, hypotonia, spasticity, and frequently joint contractures. Brain MRI shows decreased cerebral white matter, a thin corpus callosum and a peculiar PCH with a highly severe hypoplasia of the vermis, relative preservation of the folia, and a thin brainstem without pontine bulbing. Only two others PCH may be associated with an extremely small vermis: VLDLR-associated PCH in which the cerebellar folia are not preserved and the phenotype is milder; and the severe CASKassociated PCH in males, in which the pontine bulbing is relatively spared. The case reported here has this specific pattern of vermis and brainstem hypoplasia which lead us to the direct sequencing of the CHMP1A gene and that should therefore make consider PCH8.
http://dx.doi.org/10.1016/j.ejpn.2017.04.911 P1-94 Non progressive congenital ataxia or early onset slowly progressive ataxia? Identification of novel compound heterozygous variants in MRE11A (ataxia telangiectasia like disorder) in one patient confirms the clinical utility of exome sequencing phanie Valencea,b,c, Thierry Billette de Villemeura,b,c, Ste Alice Fieveta,b,c, Dominique Stoppa Lyonneta,b,c, a,b,c a,b,c a , Lydie Burglen . APHP, GHUEP, H^ opital Diana Rodriguez Trousseau, Pediatric Neurology, Paris, France. bCentre de Reference “Malformations et maladies congenitales du cervelet”, Paris-LyonLille, France. cGRC ConCer-LD, Sorbonne Universites, UPMC Univ 06, Paris, France Non-progressive congenital ataxia (NPCA) is a heterogeneous group of cerebellar disorders, characterized by the early-onset of cerebellar symptoms and the absence of clinical degeneration during the course of the disease. It is sometimes difficult to differentiate NPCA from early-onset, slowly progressive ataxia which, although degenerative, may occur at early age in a child who makes progress, at least during the first years of the disease. Objective-Methods: We report here a patient referred for a nonprogressive congenital ataxia in which the definitive diagnosis was ataxia telangiectasia like disorder (ATLD), an early slowly progressive ataxia. Results: The proband was a girl, first child of non-consanguineous Caucasian parents. Gait ataxia was note at 13 months. At 3 years she presented cerebellar symptoms, dysarthria, oculomotor apraxia and a normal Brain MRI. At age 7, the course of the disease seemed stable with mild learning disabilities, suggesting a congenital ataxia. Metabolic and chromosomal screening was normal, as well as alphafoetoprotein and immunoglobulins levels. A clinical exome sequencing revealed compound heterozygous variants (p.Arg576X andp.Asp142Asn) in MRE11A, gene involved in ATLD. Unfortunately, follow-up showed from age 8, a progression of the disease with increased ataxia, drop, tremor, choreo-athetosic movements and cerebellar atrophy on Brain MRI. At 9 years (last evaluation), she was able to walk unaided few steps but need a wheelchair in daily activities. ATLD is an autosomal recessive neurological disorder in patients with clinical resemblance to ataxia telangiectasia (early onset of ataxia, cerebellar atrophy) but without telangiectasia, immunodeficiency, cancer susceptibility or radiation sensitivity. Moreover, these patients had no chromosomal instability and normal alpha fetoprotein level. Interestingly, patients have mutations in