A quantitative assessment of the evolution of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG)

Abstract

BackgroundWe aim to delineate the progression of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG) using the International Cooperative Ataxia Rating Scale (ICARS). We sought correlation between cerebellar volumetry and clinical situation. We prospectively evaluated PMM2-CDG patients aged from 5 to 18 years through ICARS at two different time points set apart by at least 20 months. We reviewed available MRIs and performed volumetric analysis when it was possible.ResultsFrom the eligible 24, four patients were excluded due to severe mental disability (n = 2) and supratentorial lesions (n = 2). Two different ICARS evaluations separated by more than 20 months were available for 14 patients showing an improvement in the cerebellar syndrome: ICARS1: 35.71 versus ICARS2: 30.07 (p < 0.001). When we considered time, we saw an improvement of 2.64 points in the ICARS per year with an SD of 1.97 points (p < 0.001). The ICARS subscales results improved with time, reaching statistical significance in “Posture and gait” (p < 0.001), “Kinetic functions” (p = 0.04) and “Speech abnormalities” (p = 0.045). We found a negative correlation between the ICARS results and total cerebellar volume (r = −0.9, p = 0.037) in a group of five patients with available volumetric study, meaning that the higher the ICARS score, the more severe was the cerebellar atrophy.ConclusionsOur study shows a stabilization or mild improvement in the cerebellar functions of paediatric PMM2-CDG patients despite cerebellar volume loss. ICARS is a valid scale to quantify the evolution of cerebellar syndrome in PMM2-CDG patients. The availability of ICARS and other reliable and sensitive follow-up tools may prove essential for the evaluation of potential therapies.Electronic supplementary materialThe online version of this article (10.1186/s13023-017-0707-0) contains supplementary material, which is available to authorized users.

Clinical Assessment of Dysarthria in Children with Cerebellar Syndrome Associated with PMM2-CDG

“…9 However, this is the first study evaluating a large sample of PMM2-CDG pediatric patients to use repetition of syllables for characterization of ataxic speech, together with the ICARS scale. 5,6 In the present study, differences in PATA rate between PMM2-CDG patients and controls were important and statistically significant, as well as are difficulties in coordinating speech with breathing, evaluated through the need of breathing pauses. Regarding the correlation between neuroimaging (MVRD) and PATA rate, patients with greater atrophy (lower MVRD) showed lower PATA rates.…”

“…[1][2][3] Recently, the International Cooperative Ataxia Rating Scale (ICARS) 4 was validated for children above 5 years of age suffering from PMM2-CDG. 5,6 Speech ICARS subscore involves a sentence repetition task evaluating fluency and clarity of speech. However, to monitor the evolution of dysarthria, it seems insufficient, with only two items subjectively scored 0-to-4 points.…”

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

“…40 Experimental CaV2.1 hypo-N-glycosylation causes a gain of function, 9 which subsequently probably leads to increased entry of Ca 2+ in the Purkinje cell. 40 Experimental CaV2.1 hypo-N-glycosylation causes a gain of function, 9 which subsequently probably leads to increased entry of Ca 2+ in the Purkinje cell.…”

“…9 With this background, a responder at the end of the initial period (25 weeks) was defined as a patient presenting one of the following: (1) an improvement of 3 points compared with basal ICARS; or (2) for patients with very low ICARS at the beginning (15 points or less), a clinically relevant improvement, defined as at least 20% compared to basal ICARS (V 0 ). 9 With this background, a responder at the end of the initial period (25 weeks) was defined as a patient presenting one of the following: (1) an improvement of 3 points compared with basal ICARS; or (2) for patients with very low ICARS at the beginning (15 points or less), a clinically relevant improvement, defined as at least 20% compared to basal ICARS (V 0 ).…”

“…[4][5][6] Cerebellar atrophy is more pronounced during the first decade of life. 8,9 Among the acute neurological complications that may occur in PMM2-CDG patients, strokelike episodes (SLEs) are the most frightening events, as the underlying mechanism is unknown and there are no guidelines on management and prevention. 6,7 However, there is a stabilization or even an amelioration of cerebellar motor symptoms through the first and second decades of life, assessed with the International Cooperative Ataxia Rating Scale (ICARS) validated for children with PMM2-CDG.…”