Autosomal dominant spastic paraplegia with anticipation maps to a 4-cM interval on chromosome 2p21-p24 in a large German family

Abstract

Autosomal dominant familial spastic paraplegias (AD-FSP) are a group of genetically heterogeneous diseases characterised by a progressive spasticity of the lower limbs. Three loci have already been identified by genetic linkage studies on chromosomes 2p, 14q and 15q. Here we present linkage data from a large German family displaying AD-FSP with anticipation which confirms the existence of the FSP2 locus on chromosome 2p. The recombination events observed in our family define the critical region for the FSP2 gene to be within a 4-cM interval, flanked by markers D2S400 and D2S367. Moreover, clinical data from our family show evidence of anticipation, a phenomenon caused by trinucleotide expansion in several other neurodegenerative diseases.

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

“…Evidence for anticipation has been reported in autosomal dominant 'pure' HSP. 30 Inspection of ped1001 indicates a lower age of onset in the third generation, with an average age of onset in the third generation of 49 years compared to average age of onset in the fourth generation of 29 years. There are only three parentoffspring pairs with a known age of onset and although these show a reduction in the age of onset in the fourth generation, the numbers are small and cannot be used as an accurate estimate for anticipation.…”

“…Critical crossover analysis has previously mapped the SPG4 locus to a 4 cM region flanked by D2S400 and D2S367. 30 Although there is evidence of a skipped generation in ped1001, close inspection of affected family members indicates an incomplete penetrance. Seven of the fourteen offspring of the third generation were affected with spastic paraparesis and/or cognitive impairment as expected for a completely penetrant autosomal dominant disorder with a segregation ratio of 0.5.…”

Hereditary spastic paraplegia caused by mutations in the SPG4 gene

“…We had clinically observed a striking decrease in the age of onset in family 1 of 10.8 years on average per transmitting meiosis. 8 However, looking for expanded trinucleotide repeats by the repeat expansion detection method, 25 we found that anticipation was not associated with expansion of repeats (Hatchwell and Bürger, unpublished). We show here, that this family anticipates a missense mutation in the SPG4 gene, D441G.…”

“…Patient 1 is from the original family in whom we previously reported linkage to the SPG4 locus and evidence for anticipation. 8 All patients were seen and investigated clinically by experienced neurologists. The age of onset varied widely from 1 to 55 years.…”

“…1 Several types of HSP have been mapped to different loci, demonstrating extensive genetic heterogeneity. AD-HSP has been mapped to chromosome 14q11.2-q24.3 (SPG3) in French, American, German and Tibetan families, [2][3][4][5] to chromosome 2p21-p24 (SPG4) in French, Dutch, North American, Tunisian, Belgian and German families, 3,[6][7][8] to 15q (SPG6) in one family of Irish descent, 9 to 8q23-24 (SPG8) in a North American kindred of German descent and in an English family 10,11 and to 12q13 (SPG10) in an English family. 12 There must be at least one further AD-HSP locus, since in one family linkage to all these five loci has been excluded.…”