Spastic Paraplegia: What Can Genetics Tell Us?

Laurie L. Barclay, MD


May 07, 2013

Autosomal Dominant Spastic Paraplegias: A Review of 89 Families Resulting From a Portuguese Survey

Loureiro JL, Brandão E, Ruano L, et al
JAMA Neurol. 2013;70:481-487

Study Summary

Mutations in 3 genes (SPG4, SPG3, and SPG31) are implicated in one half of the autosomal dominant hereditary spastic paraplegias, which are part of the larger group of hereditary spastic diplegias associated with corticospinal tract degeneration. A population-based survey from 1993-2004 and a retrospective medical record review allowed a systematic review of clinical, genetic, and epidemiologic features of 89 Portuguese families, who had a total of 239 patients with autosomal dominant hereditary spastic paraplegia.

The prevalence was 2.4 in 100,000 persons. After 20 years of disease, only 12% of patients could not walk. Of 31 distinct mutations segregated in 41% of the families, 26 were in SPG4, 4 in SPG3, and 1 in SPG31. Of the SPG4 mutations, 7 were novel. Deletions accounted for 7% of all SPG4 mutations.

Among patients with disease onset before 10 years of age, 31% had SPG4 mutations and 27% had SPG3 mutations. Among patients with SPG4 mutations, disease onset was earliest in those with large deletions, followed by those with missense, frameshift, nonsense, and alternative-splicing mutations. Multivariate analysis showed that patients with SPG3 and SPG4 mutations did not differ significantly in rate of disease progression. Among patients with SPG4 mutations, those with later-onset disease had worse disease progression.


This study showed a similar prevalence of autosomal dominant hereditary spastic paraplegia and frequency of SPG3 and SPG4 mutations to those described previously. Unlike in earlier studies, however, the frequency of SPG4 deletions was lower, and SPG31 mutations were rare. Even in patients with early-onset disease, the likelihood of SPG4 mutation was greater than that of SPG3 mutations.

Limitations of this study include the difficulty in ascertaining age at onset, retrospective design, and insufficient longitudinal data to evaluate whether disease progression is linear over time. Nevertheless, the investigators concluded that genotype was associated with age at onset but not with differences in disease progression. They identified 7 new SPG4 mutations, and the nature of the SPG4 mutations predicted the age at onset.