HEREDITARY SPASTIC PARAPLEGIA - ADVANCES IN GENETIC RESEARCH

Hereditary spastic paraplegia (HSP) is a diverse group of inherited di sorders characterized by progressive lower-extremity spasticity and we akness. Insight into the genetic basis of these disorders is expanding rapidly. Uncomplicated autosomal dominant, autosomal recessive, and X -linked HSP are genetically heterogeneous: different genes cause clini cally indistinguishable disorders. A locus for autosomal recessive HSP is on chromosome 8q. Loci for autosomal dominant HSP have been identi fied on chromosomes 2p, 14q, and 15q. One locus (Xq22) has been identi fied for X-linked, uncomplicated HSP and shown to be due to a proteoli poprotein gene mutation in one family. The existence of HSP families f or whom these loci are excluded indicates the existence of additional, as yet unidentified HSP loci. There is marked clinical similarity amo ng HSP families linked to each of these loci, suggesting that gene pro ducts from HSP loci may participate in a common biochemical cascade, w hich, if disturbed, results in axonal degeneration that is maximal at the ends of the longest CNS axons. Identifying the single gene defects that cause HSPs distal axonopathy may provide insight into factors re sponsible for development and maintenance of axonal integrity. We revi ew clinical, genetic, and pathologic features of HSP and present diffe rential diagnosis and diagnostic criteria of this important group of d isorders. We discuss polymorphic microsatellite markers useful for gen etic linkage analysis and genetic counseling in HSP.