Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment.
BACKGROUND
Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data.


METHODS
Our observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ.


RESULTS
ICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was "almost perfect" (ICC = 0.99), with a "good" internal reliability (Cronbach's alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs -0.85, p = 0.003) and IQ (rs -0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype.


CONCLUSIONS
ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain. mserrano@hsjdbcn.org.
Mercedes
M
Serrano
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
Víctor
V
de Diego
Radiology Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain.
Jordi
J
Muchart
Statistics Department, Fundació Sant Joan de Déu, Barcelona, Spain.
Daniel
D
Cuadras
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.
Ana
A
Felipe
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.
Alfons
A
Macaya
Neurology Department, Hospital Universitario La Paz, Madrid, Spain.
Ramón
R
Velázquez
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
M Pilar
MP
Poo
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
Carmen
C
Fons
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
M Mar
MM
O'Callaghan
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
Angels
A
García-Cazorla
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
Cristina
C
Boix
Neurology Department, Hospital General de Sant Boi, Parc Sanitari Sant Joan de Déu, Sant Boi, Barcelona, Spain.
Bernabé
B
Robles
Neurology Department, Hospital Sant Joan d'Alacant, Alicante, Spain.
Francisco
F
Carratalá
Hospital Clinic-IBC, IDIBAPS, Instituto de Salud Carlos III, U-737 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Marisa
M
Girós
Hospital Clinic-IBC, IDIBAPS, Instituto de Salud Carlos III, U-737 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Paz
P
Briones
Hospital Clinic-IBC, IDIBAPS, Instituto de Salud Carlos III, U-737 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Laura
L
Gort
Clinical Biochemistry Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain.
Rafael
R
Artuch
Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, Madrid, Spain.
Celia
C
Pérez-Cerdá
Center for Metabolic Disease, KULeuven, Leuven, Belgium.
Jaak
J
Jaeken
Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, Madrid, Spain.
Belén
B
Pérez
Neuropediatric Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona, Spain.
Belén
B
Pérez-Dueñas
D000293:Adolescent; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D017875:Phosphotransferases (Phosphomutases) / Q000172:deficiency* / Q000235:genetics; D012720:Severity of Illness Index
D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human