Разнообразие фенотипов, связанных с геном VCP : клиническое наблюдение и обзор литературы

Background. Gene VCP encoding multifunctional protein valosin produces a number of rare autosomal dominant late-onset disorders with multiple symptoms (muscular dystrophy with inclusion bodies in part of cases, Paget disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis and few others) in different combinations often varying in one family. Rare unusual phenotypes are difficult for recognition. Molecular methods facilitate diagnostics. Objective: to describe first Russian VCP -related familial case detected by exome sequencing and present a review on poorly known disorder. Materials and methods. In a Russian family with 4 patients in 2 generations 6 persons were examined: 2 patients, 3 clinically unaffected possible heterozygous carriers and patient’s mother with no genetic risk; medical information was received about two deceased patients. Methods: clinical and genealogical; biochemical: blood creatine kinase, alpha-glucosidase; molecular: clinical exome sequencing, Sanger familial sequencing, bioinformatical analysis. Results. In 48-year-old proband and 50-year-old brother whose former diagnosis was hereditary neuropathy proximal muscular dystrophy with onset in 43–45 years, rapid progression and moderately raised creatine kinase (341–572 U/l) was found out. Since 45 years the proband also had Paget disease. Both brothers had no evident dementia (neuropsychological examination was not performed). The younger brother since 32 years suffered typical amyotrophic lateral sclerosis, evidently combined with dementia, he died in 43 years being severely disabled; brain is not described in autopsy record. The father had rapidly progressing walking difficulties since 40 years without mental, speech or swallowing disturbances; he was never examined and died in 48 years of heart disease (?). Clinical exome sequencing in the proband detected in VCP exon 5 one of common mutations с.463С>T (p.Arg155Cys) in heterozygous state. Familial Sanger sequencing found out the mutation in him, in the brother and in clinically unaffected 36-year-old sister, 22-year-old daughter and 15-year old son, thus diagnosing preclinical stage of the disease. Conclusions. The case illustrates diversity of VCP -related disorders and necessity to take into consideration all phenotype spectrum. DNA-confirmed diagnosis permits genetic counseling.