Researchers have detailed the characteristics of a large cohort of patients with hereditary spastic paraplegias (HSPs).
They found that disease severity was linked to duration, genotype, complicating factors and age at onset, although, unlike many other progressive neurological diseases, an early age at onset was not associated with severe disease and faster progression.
In fact, the reverse was true; patients with earlier onset maintained their ability to walk independently for longer than those with later onset. Overall, it took a median of 22 years before patients lost their ability to walk without an aid and a median additional 16 years before they required a wheelchair.
Ludger Schöls (Eberhard-Karls-University, Tübingen, Germany) and co-researchers included 608 patients from 519 families in their study. Based on family history, the team suspected dominant inheritance in 43% of the families, a recessive trait in 10% and simplex disease (no family history) in 47%. SPG4 was the most common genotype, being present in 196 of 519 patients with an identifiable genotype.
There were roughly equal numbers of men and women among patients with confirmed mutations in autosomal HSP genes, but a disproportionate number of men (60%) among simplex cases without a genetic diagnosis, leading the researchers to suggest that many X-linked HSP genes remain to be discovered.
The age of onset varied widely, from infancy to 73 years old. Some genotypes tended to present earlier than others, and simplex cases tended to present later than those with clear inheritance patterns, but all types had a wide range of onset age.
“This wide spectrum observed in all genotypes and all modes of inheritance hampers phenotype–genotype predictions in individual cases”, the team writes in the Annals of Neurology.
Phenotypes were also highly variable, with three-quarters of patients having involvement of other neurological systems. More than half of the patients had sensory complications, while 28% had ataxia and 19% had peripheral motor involvement.
Dominantly inherited HSPs were the most likely to have a pure presentation, but even 46% of these were complicated. Indeed, “[n]ot a single genotype in our study presented exclusively with pure HSP”, say the researchers.
These complicating factors, although not all of them individually, were associated with more severe disease. Cognitive impairment, dysphagia, dysarthria and extrapyramidal and peripheral motor involvement were most strongly linked to severe disease, but the researchers note that these factors are probably just markers of the specific underlying mechanism that produces both the complication and severe disease.
Longer disease duration, later age at onset and female gender were also associated with severe disease. And among carriers of the most common genotypes, those with SPG11 were the most severely affected.
“Longitudinal studies are on the way to verify progression rates and provide prospective natural history data in a representative cohort of HSP patients”, say Schöls et al.
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