Spastic paraplegias types 11 and 15

Introduction. A heterogeneous group of hereditary spastic paraplegias (HSP) with known causative genes, alongside the predominant autosomal dominant ones, includes numerous and diagnostically more complex autosomal recessive (AR) forms with diverse phenotypes. Massive parallele sequencing (MPS) techniques are widely used in HSP diagnosis. The aim of the study was to determine the clinical and molecular genetic characteristics of two AR-HSPs — SPG11 and SPG15 — in Russia based on the first study of HSP using MPS. Materials and methods. We examined 8 unrelated Russian families: seven with SPG11 and one with SPG15. Clinical and molecular analysis and multiplex ligation-dependent probe amplification (MLPA) were used. Results. SPG11, diagnosed in seven families, was the most common AR form, accounting for 5.1% of the total group of 120 families with verified HSP (4th common) and 30.5% of the AR-HSP subgroup. Three of the nine identified SPG11 mutations have not been previously described; 2 families had identical genotypes, with one of the allelic mutations consisting of a large duplication; one previously described mutation was detected three times. Two patients had an atypical late onset, six cases had complicating concomitant symptoms, such as ataxia and/or dysarthria, cognitive impairment, while 3 out of 6 patients showed thinning of the corpus callosum on MRI. SPG15 was diagnosed in one patient at 13 years; two new mutations were found in the ZFYVE26 gene with a reading frame shift in the compound heterozygous state. Clinical phenotype in this patient included progressive cognitive decline in addition to spastic paraparesis; there was no macular degeneration typical (but not mandatory) of SPG15 up to the age of 17 years (according to follow-up data). Conclusion . In a large group of patients in Russia, AR-HSP was represented by 12 different forms, with SPG11 being the most frequent and SPG15 also being present. A total of 11 mutations were found in the genes of both forms, 5 of which had not been previously described. Two complicated forms of HSP had a similar clinical presentation and were difficult to diagnose. MPS methods are indispensable in diagnosing diseases with pronounced genetic heterogeneity, such as HSP. Cases with major gene rearrangements confirm the importance of combining MPS with MLPA.