Alejandra Darling1, Sergio Aguilera-Albesa2, Cristina Aisha Tello3, Mercedes Serrano4, Miguel Tomás5, Rafael Camino-León6, Joaquín Fernández-Ramos6, Adriano Jiménez-Escrig7, Pilar Poó1, Mar O'Callaghan1, Carlos Ortez1, Andrés Nascimento1, Ramón Candau Fernández Mesaque8, Marcos Madruga8, Luisa Arrabal9, Susana Roldan9, Hilario Gómez-Martín10, Cristina Garrido11, Teresa Temudo11, Cristina Jou-Muñoz12, Jordi Muchart13, Thierry A G M Huisman14, Andrea Poretti14, Vincenzo Lupo3, Carmen Espinós3, Belén Pérez-Dueñas15. 1. Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. 2. Pediatric Neurology Unit, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, Pamplona, Spain. 3. Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe, Valencia, Spain. 4. Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, CIBERER, Instituto de Salud Carlos III, Spain. 5. Pediatric Neurology Department, Hospital Universitario Politécnico La Fe, Valencia, Spain. 6. Pediatric Neurology Department, Hospital Universitario Reina Sofía, Córdoba, Spain. 7. Neurology Department, Hospital Ramón y Cajal, Madrid, Spain. 8. Pediatric Neurology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 9. Pediatric Neurology Department, Hospital Virgen de las Nieves, Granada, Spain. 10. Pediatric Neurology Department, Hospital San Pedro de Alcántara, Complejo Hospitalario Universitario de Cáceres, Spain. 11. Pediatric Neurology Department, Centro Materno-Infantil, Centro Hospitalario do Porto, Porto, Portugal. 12. Pathology Department, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, CIBERER, Instituto de Salud Carlos III, Spain. 13. Neuroradiology Department, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain. 14. Division of Pediatric Radiology and Pediatric Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. 15. Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain; Pediatric Neurology Research Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. Electronic address: belen.perez@vhir.org.
Abstract
INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.
INTRODUCTION:PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS:Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.