Clinical Heterogeneity of Autosomal Recessive Spastic Paraplegias

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Abstract
HEREDITARY spastic paraplegias (HSPs) are a heterogeneous group of genetic diseases characterized by slowly progressive spasticity of the lower limbs. Classically they are divided into pure forms (comprising patients whose manifestations are limited to corticospinal signs until later stages of the disease) and complicated forms (comprising patients whose manifestations are associated with signs of involvement of other systems, such as mental retardation; epilepsy; retinal degeneration or optic atrophy; cerebellar, extrapyramidal, or peripheral signs; and cutaneous lesions). We believe that "complicated" is not an appropriate designation and will therefore use the term "complex" for them. Dominant, recessive, and X-linked modes of inheritance have been described. For the dominant forms, which include mostly pure forms, 4 different loci have been identified: 14q11.2-24.3,1 15q11-12,2 2p21-24,3,4 and 8q23-24.5 The first 3 loci account for 40% to 45% of the families.6,7 CAG repeat expansions were reported8 in 6 Danish families linked to chromosome 2. For recessive forms, a linkage to the centromeric region of chromosome 8 was found in 4 Tunisian families.9 In 1998, an additional locus was identified on chromosome 16 in 3 late-onset families, 2 of which had a pure form and the other a complex form of the disease. All the affected members carry a deletion or mutations, which involve part of a gene encoding a nuclear metalloprotease.10 Recently, a new locus on chromosome 15q13-15 was suggested in 8 (of 9) American and European kindreds.11 X-linked forms, although rare, have been linked to 3 different loci: Xq28,12 Xq21,13 and Xq11.14