Relationships between long-term observations of motor milestones and genotype analysis results in childhood-onset Japanese spinal muscular atrophy patients

Abstract

Aim: To clarify the long-term natural history of SMA in Japanese patients by investigating the peak motor milestones of cases 7months through 57years of age, in efforts to contribute to evaluating outcomes of new therapeutic interventions.

Methods: We sub-classified 112 SMA type I-III cases into type Ia, type Ib, type IIa, type IIb, type IIIa and type IIIb, according to peak motor milestone achieved, and analyzed the SMN1, SMN2 and NAIP genes in relation to clinical subtypes.

Results: In type I cases, there was a significant difference (p<0.0001), depending on whether or not head control was obtained, in the time of ventilation support being required. In type II cases as well, the time at which the ability to maintain the sitting position independently was lost also differed significantly (p<0.01) between those acquiring the ability to sit unaided within eight months after birth and those acquiring this ability after eight months of age. In type III cases, being able versus unable to climb stairs was associated with a significant difference (p=0.02) in the median time until loss of walking independently. Positive correlations were also seen between copy numbers and the clinical severity of SMA.

Conclusion: Our long-term results show peak motor milestone evaluations distinguishing between subtypes to be useful not only as outcome measures for assessing treatment efficacy in clinical trials but also for predicting the clinical courses of Japanese SMA patients.

Keywords: Clinical severity; Gene copy number; Motor milestones; NAIP; SMN2; Spinal muscular atrophy.