Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG)
We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement.
Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages.
Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = −0.578, p = 0.012 and r = −0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001).
Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.
KeywordsSpinocerebellar Ataxia Volumetric Analysis Cerebellar Atrophy Focal Epilepsy Cerebellar Volume
We thank the patients and their families for their kind collaboration in all our projects, and particularly in this study.
We are grateful to the doctors and institutions from the Spanish national network for the study of glycosylation disorders for their collaboration. This work was supported by national grant PI14/00021 from the National Plan on I+D+I, cofinanced by ISC-III (Subdirección General de Evaluación y Fomento de la Investigación Sanitaria) and FEDER (Fondo Europeo de Desarrollo Regional) and IPT-2012- 0561-010000 from MINECO.
Collaborators of the CDG Spanish-Consortium
Sergio Aguilera-Albesa, MD PhD,1 Ramón Cancho Candela, MD PhD,2 Mª Llanos Carrasco Marina, MD,3 Francisco Carratalá, MD PhD,4 Mª Luz Couce, MD PhD,5 Ana Felipe, MD,6 Óscar García, MD,7 Mª Teresa García-Silva, MD PhD,8 Luis G Gutiérrez-Solana, MD PhD,9 Alfons Macaya, MD PhD,6 Mª Concepción Miranda, MD PhD,10 Laura López, MD,9 Eduardo López-Laso, MD PhD,11 M Pilar Póo, MD PhD,12 Pilar Quijada-Fraile, MD PhD8 Bernabé Robles, MD,PhD,13 Concepción Sierra-Córcoles, MD,14 Ramón Velázquez-Fragua, MD,15
1. Pediatric Neurology Unit, Department of Pediatrics, Navarra Hospital, Pamplona, Spain
2. Pediatric Neurology Unit. Pediatrics Department. Hospital Universitario Rio Hortega. Valladolid, Spain.
3. Neuropediatric Department, Pediatric Service, Hospital Universitario Severo Ochoa. Leganés, Madrid, Spain.
4. Pediatric Neurology Department, University Hospital Sant Joan d’Alacant, Spain.
5. Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. Department of Pediatrics. Hospital Clínico Universitario de Santiago. CIBERER. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
6. Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Secció de Neurologia Pediàtrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain.
7. Pediatric Department, Hospital Virgen de la Salud, Toledo, Spain.
8. Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias. Dpto. de Pediatría, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre- CIBERER-ISCIII, Universidad Complutense de Madrid,Spain.
9. Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, Madrid, Spain
10. Pediatric Neurology Unit, H.G.U Gregorio Marañón, Madrid, Spain
11. Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Pediatric Neurology Unit, Reina Sofia University Hospital, CIBERER, Córdoba, Spain.
12. Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, Barcelona, Spain. U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain.
13. Neurology Department, Hospital General de Sant Boi, Parc Sanitari Sant Joan de Déu, Sant Boi, Barcelona, Spain.
14. Unidad de Neuropediatría, Hospital de Jaén, Jaén, Spain.
15. Pediatric Neurology Department, Hospital Universitario La Paz, Madrid, Spain.
Compliance with ethical standards
Details of funding
The authors report no disclosure relevant to the manuscript. We did not have any sponsor in any phase of the study.
Conflict of interest