Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG)

Fabio Pettinato,Fabio Sirchia,Serena Gasperini,Giuseppe Sortino,Renata Rizzo,Amelia Morrone,Annalisa Madeo,Daniele Frattini,Jaak Jaeken,Agata Fiumara,Roberta Battini,Gert Matthijs,Giovanni Mostile,Luisa Sturiale,Rossella Parini,Domenico Garozzo,Maja Di Rocco,Elisa Biamino,Diego Martinelli,Rita Barone

doi:10.1007/s12311-021-01242-x

Abstract

We aimed to identify clinical, molecular and radiological correlates of activities of daily living (ADL) in patients with cerebellar atrophy caused by PMM2 mutations (PMM2-CDG), the most frequent congenital disorder of glycosylation. Twenty-six PMM2-CDG patients (12 males; mean age 13 ± 11.1 years) underwent a standardized assessment to measure ADL, ataxia (brief ataxia rating scale, BARS) and phenotype severity (Nijmegen CDG rating scale, NCRS). MRI biometry of the cerebellum and the brainstem were performed in 23 patients (11 males; aged 5 months–18 years) and 19 control subjects with equal gender and age distributions. The average total ADL score was 15.3 ± 8.5 (range 3–32 out of 36 indicating severe functional disability), representing variable functional outcome in PMM2-CDG patients. Total ADL scores were significantly correlated with NCRS (r2 = 0.55, p < 0.001) and BARS scores (r2 = 0.764; p < 0.001). Severe intellectual disability, peripheral neuropathy, and severe PMM2 variants were all significantly associated with worse functional outcome. Higher ADL scores were significantly associated with decreased diameters of cerebellar vermis (r2 = 0.347; p = 0.004), hemispheres (r2 = 0.436; p = 0.005), and brainstem, particularly the mid-pons (r2 = 0.64; p < 0.001) representing the major radiological predictor of functional disability score in multivariate regression analysis. We show that cerebellar syndrome severity, cognitive level, peripheral neuropathy, and genotype correlate with ADL used to quantify disease-related deficits in PMM2-CDG. Brainstem involvement should be regarded among functional outcome predictors in patients with cerebellar atrophy caused by PMM2-CDG.

Highlights

Congenital disorders of glycosylation (CDG) are caused by pathogenic variants in the genes coding for proteins involved in the assembly and remodelling of the oligosaccharide moieties of glycoproteins and glycolipids
Smaller midpons diameter was associated with worse functional abilities after controlling for age and studied magnetic resonance imaging (MRI) parameters inserted into a multiple linear regression model
We evaluated for the first time the capability to fulfil daily tasks on an activities of daily living (ADL) scale in Phosphomannomutase 2 (PMM2)-CDG, a rare disease with congenital cerebellar atrophy

Summary

Introduction

Congenital disorders of glycosylation (CDG) are caused by pathogenic variants in the genes coding for proteins involved in the assembly and remodelling of the oligosaccharide moieties of glycoproteins and glycolipids. PMM2 is required in the early steps of the N-glycosylation pathway, and its deficiency is associated with hypoglycosylation of numerous serum and membrane glycoproteins [1, 2]. PMM2-CDG is a multisystem disease with a broad neurological phenotype including cerebellar hypotrophy/atrophy, psychomotor delay/ intellectual disability, acquired microcephaly, strabismus and retinopathy, epilepsy, stroke-like episodes and peripheral neuropathy [3]. Hyperkinetic movement disorders such as dystonia and choreo-athetosis can be part of this spectrum [4]. There is a major involvement of the anterior lobe of the vermis, enlargement of cerebellar fissures, and the fourth ventricle often associated with cortical hyperintensity (“bright cerebellum”) and mildly hyperintense subcortical white matter [12]

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