Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey.
JAMA Neurol. 2013-04-01; 70(4): 481
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1. JAMA Neurol. 2013 Apr;70(4):481-7. doi: 10.1001/jamaneurol.2013.1956.
Autosomal dominant spastic paraplegias: a review of 89 families resulting from a
Loureiro JL(1), Brandão E, Ruano L, Brandão AF, Lopes AM, Thieleke-Matos C,
Miller-Fleming L, Cruz VT, Barbosa M, Silveira I, Stevanin G, Pinto-Basto J,
Sequeiros J, Alonso I, Coutinho P.
(1)Serviço de Neurologia, Centro Hospitalar entre Douro e Vouga, Rua Dr. Cândido
de Pinho, 4520-211 Santa Maria da Feira, Portugal.
IMPORTANCE: Hereditary spastic paraplegias (HSPs) are a group of diseases caused
by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31)
are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This
study is a systematic review of families with HSP resulting from a
population-based survey. Novel genotype-phenotype correlations were established.
OBJECTIVE: To describe the clinical, genetic, and epidemiological features of
Portuguese AD-HSP families.
DESIGN: Retrospective medical record review.
SETTING: A population-based systematic survey of hereditary ataxias and spastic
paraplegias conducted in Portugal from 1993 to 2004.
PARTICIPANTS: Families with AD-HSP.
MAIN OUTCOME MEASURE: Mutation detection in the most prevalent genes.
RESULTS: We identified 239 patients belonging to 89 AD-HSP families. The
prevalence was 2.4 in 100 000. Thirty-one distinct mutations (26 in SPG4, 4 in
SPG3, and 1 in SPG31) segregated in 41% of the families (33.7%, 6.2%, and 1.2%
had SPG4, SPG3 and SPG31 mutations, respectively). Seven of the SPG4 mutations
were novel, and 7% of all SPG4 mutations were deletions. When disease onset was
before the first decade, 31% had SPG4 mutations and 27% had SPG3 mutations. In
patients with SPG4 mutations, those with large deletions had the earliest disease
onset, followed by those with missense, frameshift, nonsense, and
alternative-splicing mutations. Rate of disease progression was not significantly
different among patients with SPG3 and SPG4 mutations in a multivariate analysis.
For patients with SPG4 mutations, disease progression was worst in patients with
CONCLUSIONS AND RELEVANCE: The prevalence of AD-HSP and frequency of SPG3 and
SPG4 mutations in the current study were similar to what has been described in
other studies except that the frequency of SPG4 deletions was lower. In contrast,
the frequency of SPG31 mutations in the current study was rare compared with
other studies. The most interesting aspects of this study are that even in
patients with early-onset disease the probability of finding a SPG4 mutation was
higher than for patients with SPG3 mutations; there was no difference in disease
progression with genotype but an association with the age at onset; 7 new SPG4
mutations were identified; and for the first time, to our knowledge, the nature
of the SPG4 mutations was found to predict the age at onset.
PMID: 23400676 [Indexed for MEDLINE]