Rare autosomal recessive spastic paraplegias

Objective: hereditary spastic paraplegias (HSP) are a heterogeneous group including about 80 forms: SPGs (Spastic Paraplegia Gene) numbered chronologically. Massive parallel sequencing MPS greatly improved possibilities of new SPGs disclosure and of practical DNA diagnostics. First Russian HSP complex investigation of HSP using MPS is being performed in FSBI PCMG. By now, the group of genetically diagnosed cases numbers 114 families with 20 different SPGs, including rare autosomal recessive forms poorly known to geneticists and neurologists. Aim: to present first Russian cases of rare autosomal recessive (AR) forms: SPG5, SPG26, SPG35, and SPG39. The genes, CYP7B1, B4GALNT1, FA2H, and FA2H correspondingly, are involved in lipid metabolism. Materials: initial group: about 200 Russian families with preliminary clinical diagnosis of HSP or alike disorders; index group: 114 SPG-confirmed families; paper material: the four families. Methods: clinical investigation, genealogical analysis; molecular methods: custom MPS-panel “paraplegias” (63 genes), Sanger sequencing, multiplex ligation-dependent probe amplification MLPA (selectively), whole-exome sequencing WES (selectively); bioinformatic analysis. Results. Subgroup of AR SPG included 22 families/12 forms. SPG5, 26, 35, 39 were detected in single families. SPG5: a 17-year-old youth in a Russian family; onset in 15 years, moderate spastic paraparesis, mild ataxia; CYP7B1 genotype: two earlier reported mutations .334С>T (p.Arg112Ter) и c.1190C>T (p.Pro397Leu) in the patient and in unaffected younger sister (preclinical stage), parents - heterozygous carries. SPG26: a 13-year old boy in a Russian non-consanguineous family; early-childhood onset, slowly progressing paraparesis, dysarthria, cognitive and behavioral impairment; B4GALNT1 genotype: novel homozygous mutation c.1514G>C (p.Arg505Pro) in the boy, heterozygosity in parents; homozygosity for a very rare gene (14th SPG26 world case) in a Russian non-consanguineous family is unusual. SPG35: a 5-year-old boy in a Sibirian ethnically mixed family (Russian mother, father of Tatar-Buryat ethnicity); onset in 4 years, rapidly progressing paraparesis with no other signs, normal MRI; FA2H genotype: reported earlier с.805С>T (p.Arg269Cys) / novel c.106C>T (p.Leu36Phe). SPG39: a 10-year-old boy in a Russian-Tatar family; onset in 5 years, slowly progressing paraparesis with no other signs; PNPLA6 genotype: reported earlier intronic с.199-2A>T novel c.2033G>A (p.Gly678Asp), parents - heterozygous carriers. Conclusions. HSP in Russian patients present a wide spectrum including rare AR SPG in non-consanguineous Russian families and in families of mixed ethnicity. Our SPG5, SPG26, SPG35 and SPG39 cases are first in Russia; of 7 mutations detected in the 4 genes 3 mutations were novel. MPS is method of choice in DNA diagnostics of heterogeneous disorders like HSP.

спастические параплегии типов 5, гены CYP7B1, панельное экзомное секвенирование, SPG types 5, genes CYP7B1, panel exome sequencing, гены B4GALNT1, гены FA2H, гены PNPLA6, спастические параплегии типов26, спастические параплегии типов35, спастические параплегии типов39, мутации, фенотипы, SPG types 5, SPG types26, SPG types35, SPG types39, genes B4GALNT1, genes FA2H, genes PNPLA6, mutations, phenotypes