Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.

Swallowing markers in spinal and bulbar muscular atrophy

“…There was no significant difference in age between the two groups ( P =  0.16). The characteristics of this study population, including age, CAG repeat length, disease duration, and ALSFRS‐R scores, were similar to those of previous studies 11, 23, 24. Fifty‐three of the 111 SBMA patients reported having subjective dysphagia (Table 1).…”

“…Longitudinal changes in VFSS findings, especially in the presence of pharyngeal residue in SBMA patients, is another major limitation, partly caused by poor reproducibility of VFSS findings 23. In this study, we found that reproducibility of quantitative markers could be improved by measuring multiple swallows and using the average values of three swallows.…”

Creatinine/cystatin C ratio as a surrogate marker of residual muscle mass in amyotrophic lateral sclerosis

“…A parameter that reflects muscle volume would enable estimation of disease severity. [6][7][8] The serum level of creatinine (Cr) is currently considered to be the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy 9 ; serum Cr levels were found to be correlated with the ALS Functional Rating Scale-Revised (ALSFRS-R) score in patients with spinal and bulbar muscular atrophy (correlation coefficient = 0.566, P < 0.001). However, because serum Cr almost exclusively originates from the skeletal muscle and its levels are dependent of renal function, we considered that the use of serum Cr levels as an accurate marker in ALS patients might be questioned.…”

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…Creatinine, a marker of muscle mass and metabolism, showed significant change over a three-year period [107]. Similarly, urinary 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, also showed significant change over a two-year period in SBMA patients [114].…”

“…Grip strength is a parameter used in different neuromuscular diseases to easily depict muscle weakness progression. Significant changes in grip strength have been observed in a 3-year longitudinal study of SBMA patients [107] but no significant change over a one year period was detected in another study [103]. A recent study evaluated the measure of tongue pressure using an intraoral pressure probe [108].…”