Instrumented Assessment of Gait Disturbance in PMM2-CDG Adults: a Feasibility Analysis

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2024 Feb 3

PMID 38308356

Authors

Lara Cirnigliaro

Fabio Pettinato

Maria Stella Valle

Antonino Casabona

Agata Fiumara

Michele Vecchio

Valerio Amico

Renata Rizzo

Jaak Jaeken

Rita Barone

Matteo Cioni

Affiliations

Soon will be listed here.

Abstract

Background: Congenital disorders of glycosylation (CDG) are genetic diseases caused by impaired synthesis of glycan moieties linked to glycoconjugates. Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent CDG, is characterized by prominent neurological involvement. Gait disturbance is a major cause of functional disability in patients with PMM2-CDG. However, no specific gait assessment for PMM2-CDG is available. This study analyses gait-related parameters in PMM2-CDG patients using a standardized clinical assessment and instrumented gait analysis (IGA).

Results: Seven adult patients with a molecular diagnosis of PMM2-CDG were followed-up from February 2021 to December 2022 and compared to a group of healthy control (HC) subjects, matched for age and sex. Standardized assessment of disease severity including ataxia and peripheral neuropathy along with isometric muscle strength and echo-biometry measurements at lower limbs were performed. IGA spatiotemporal parameters were obtained by means of a wearable sensor in basal conditions. PMM2-CDG patients displayed lower gait speed, stride length, cadence and symmetry index, compared to HC. Significant correlations were found among the used clinical scales and between disease severity (NCRS) scores and the gait speed measured by IGA. Variable reduction of knee extension strength and a significant decrease of lower limb muscle thickness with conserved echo intensity were found in PMM2-CDG compared to HC.

Conclusions: The study elucidates different components of gait disturbance in PMM2-CDG patients and shows advantages of using wearable sensor-based IGA in this frame. IGA parameters may potentially serve as quantitative measures for follow-up or outcome quantification in PMM2-CDG.

References

Buckley E, Mazza C, McNeill A . A systematic review of the gait characteristics associated with Cerebellar Ataxia. Gait Posture. 2017; 60:154-163. DOI: 10.1016/j.gaitpost.2017.11.024. View

Iyer S, Sam F, DiPrimio N, Preston G, Verheijen J, Murthy K . Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis Model Mech. 2019; 12(11). PMC: 6899038. DOI: 10.1242/dmm.040584. View

Indelicato E, Raccagni C, Runer S, Hannink J, Nachbauer W, Eigentler A . Instrumented gait analysis defines the walking signature of CACNA1A disorders. J Neurol. 2021; 269(6):2941-2947. PMC: 9120104. DOI: 10.1007/s00415-021-10878-y. View

Pascoal C, Ferreira I, Teixeira C, Almeida E, Slade A, Brasil S . Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals. Orphanet J Rare Dis. 2022; 17(1):398. PMC: 9618201. DOI: 10.1186/s13023-022-02551-y. View

Valle M, Bosco G, Poppele R . Cerebellar compartments for the processing of kinematic and kinetic information related to hindlimb stepping. Exp Brain Res. 2017; 235(11):3437-3448. DOI: 10.1007/s00221-017-5067-4. View

Schiff M, Roda C, Monin M, Arion A, Barth M, Bednarek N . Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature. J Med Genet. 2017; 54(12):843-851. DOI: 10.1136/jmedgenet-2017-104903. View

Monin M, Mignot C, de Lonlay P, Heron B, Masurel A, Mathieu-Dramard M . 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. Orphanet J Rare Dis. 2014; 9:207. PMC: 4266234. DOI: 10.1186/s13023-014-0207-4. View

Witters P, Andersson H, Jaeken J, Tseng L, van Karnebeek C, Lefeber D . D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial. Orphanet J Rare Dis. 2021; 16(1):138. PMC: 7980351. DOI: 10.1186/s13023-020-01609-z. View

Coffman K, Dum R, Strick P . Cerebellar vermis is a target of projections from the motor areas in the cerebral cortex. Proc Natl Acad Sci U S A. 2011; 108(38):16068-73. PMC: 3179064. DOI: 10.1073/pnas.1107904108. View

10.

Achouitar S, Mohamed M, Gardeitchik T, Wortmann S, Sykut-Cegielska J, Ensenauer R . Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression. J Inherit Metab Dis. 2011; 34(4):923-7. PMC: 3232068. DOI: 10.1007/s10545-011-9325-5. View

11.

Middleton A, Fritz S, Lusardi M . Walking speed: the functional vital sign. J Aging Phys Act. 2014; 23(2):314-22. PMC: 4254896. DOI: 10.1123/japa.2013-0236. View

12.

Barone R, Carrozzi M, Parini R, Battini R, Martinelli D, Elia M . A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. J Neurol. 2014; 262(1):154-64. DOI: 10.1007/s00415-014-7549-7. View

13.

Maughan R, Watson J, Weir J . Relationships between muscle strength and muscle cross-sectional area in male sprinters and endurance runners. Eur J Appl Physiol Occup Physiol. 1983; 50(3):309-18. DOI: 10.1007/BF00423237. View

14.

Sturiale L, Barone R, Garozzo D . The impact of mass spectrometry in the diagnosis of congenital disorders of glycosylation. J Inherit Metab Dis. 2011; 34(4):891-9. DOI: 10.1007/s10545-011-9306-8. View

15.

Zhou H, Nguyen H, Enriquez A, Morsy L, Curtis M, Piser T . Assessment of gait and balance impairment in people with spinocerebellar ataxia using wearable sensors. Neurol Sci. 2021; 43(4):2589-2599. DOI: 10.1007/s10072-021-05657-6. View

16.

Serrano N, De Diego V, Cuadras D, Martinez Monseny A, Velazquez-Fragua R, Lopez L . A quantitative assessment of the evolution of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG). Orphanet J Rare Dis. 2017; 12(1):155. PMC: 5602850. DOI: 10.1186/s13023-017-0707-0. View

17.

Taday R, Gruneberg M, DuChesne I, Reunert J, Marquardt T . Dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG). Orphanet J Rare Dis. 2020; 15(1):258. PMC: 7510076. DOI: 10.1186/s13023-020-01528-z. View

18.

Ostergaard J . Gait phenotype in Batten disease: A marker of disease progression. Eur J Paediatr Neurol. 2021; 35:1-7. DOI: 10.1016/j.ejpn.2021.09.004. View

19.

Al-Maawali A, Blaser S, Zhao X, Yoon G . Prospective study of activities of daily living outcomes in children with cerebellar atrophy. Dev Med Child Neurol. 2013; 56(5):460-7. DOI: 10.1111/dmcn.12289. View

20.

Buckley C, Alcock L, McArdle R, Rehman R, Del Din S, Mazza C . The Role of Movement Analysis in Diagnosing and Monitoring Neurodegenerative Conditions: Insights from Gait and Postural Control. Brain Sci. 2019; 9(2). PMC: 6406749. DOI: 10.3390/brainsci9020034. View