Natural History of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay: a 4-Year Longitudinal Study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurologic disorder with generally well-known clinical manifestations. However, few studies assessed their progression rate using a longitudinal design. This study aimed to document the natural history of ARSACS over a 4-year period in terms of upper and lower limb functions, balance, walking capacity, performance in daily living activities, and disease severity. Forty participants were assessed on three occasions over 4 years. Participant performance was reported in raw data as well as in percentage from reference values to consider the normal aging process. Severe balance and walking capacity impairments were found, with a significant performance decrease over the 4 years. Balance reached a floor score of around 6 points on the Berg Balance Scale for participants aged >40 years, while other participants lost about 1.5 points per year. The mean loss in walking speed was 0.044 m/s per year and the mean decrease in the distance walked in 6 min was 20.8 m per year for the whole cohort. Pinch strength, balance, walking speed, and walking distance decreased over time even when reported in percentage from reference values. Major impairments and rapid progression rates were documented in the present study for upper limb coordination, pinch strength, balance, and walking capacity in the ARSACS population. A progression rate beyond the normal aging process was observed. These results provide fundamental insights regarding the disease prognosis that will help to better inform patients, develop specific rehabilitation programs, and improve trial readiness.

Documenting the psychometric properties of the scale for the assessment and rating of ataxia to advance trial readiness of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.

BACKGROUND: The Scale for the Assessment and Rating of Ataxia (SARA) is a commonly used scale measuring the severity of cerebellar ataxia and is a candidate for outcome measurement in foreseeable clinical trials in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). Documenting its psychometric properties in this population will accelerate clinical trial readiness. The objectives of this study were to document the content and construct validity, the internal consistency, and to explore the 2-year responsiveness and the 4-year interpretability of the SARA in ARSACS. METHODS: The first phase of the study consisted of an international Delphi survey to document the content validity. The second phase consisted of a methodological study from the secondary analysis of a longitudinal study to document the construct validity in 69 participants. Responsiveness to change and interpretability of the SARA was explored among a sub-sample of participants (n = 32 and n = 16, respectively). RESULTS: The SARA demonstrates adequate content validity with possible influence of pyramidal and/or neuropathic involvement. It demonstrates excellent construct validity (rs = 0.77-0.95) and internal consistency (Cronbach's α = 0.89). The responsiveness to change was not significant, and the interpretation of change score increased by 1.9 ± 2.5 falling below the minimal detectable change threshold of 3.06. CONCLUSIONS: The SARA has shown evidences of adequate content validity and excellent construct validity in ARSACS. Responsiveness to change and interpretability will need to be further documented among a larger sample over a longer period of time.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), which is caused by mutations in SACS gene, is a very rare neurodegenerative disorder characterized by the clinical triad of early onset cerebellar ataxia, pyramidal tract features, and sensorimotor polyneuropathy. Herein, we report a 35-year-old Korean male who presented with gait disturbance and lower extremity weakness. Neuroimaging and ophthalmologic evaluation revealed features consistent with ARSACS. Mutation in SACS gene was demonstrated in clinical exome sequence analysis and the patient was finally diagnosed as ARSACS.

Validity and Reliability of Outcome Measures Assessing Dexterity, Coordination, and Upper Limb Strength in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.

OBJECTIVE: To document in adults affected by autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) the intra- and interrater reliability, standard error of measurement, agreement, minimal detectable change, and construct validity of the 9-Hole Peg Test (NHPT), the Standardized Finger-to-Nose Test (SFNT), and grip strength. DESIGN: Metrologic study. SETTING: Neuromuscular rehabilitation clinic. PARTICIPANTS: Genetically confirmed adult patients with ARSACS (N=42; 21 women; mean age, 38.6y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intra- and interrater reliability was determined using the intraclass correlation coefficient (ICC). Construct validity was determined by assessing the capacity of the NHPT, the SFNT, and grip strength to distinguish between participants based on sex, mobility stages, and age groups, and on performance on the Archimedes spiral and fast alternating hand movements tests. RESULTS: All 3 tests have shown excellent reliability (ICC=.90-.98). However, the limit of agreement was influenced by the participant's performance on the NHPT, and the minimal detectable change was very different for both hands (right=9.7 vs left=28.0). Construct validity was confirmed for the SFNT and NHPT, but it was not demonstrated for grip strength. CONCLUSIONS: Given the metrologic properties assessed in this study, the SFNT is an excellent measure to assess upper limb coordination, whereas the NHPT must be used with caution. The grip strength is reliable but does not seem to reflect disease severity.