(1994) detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.īrzustowicz et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al.
The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein. Most patients reported improvement within a few months of beginning treatment. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months.
The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea.
The authors suggested a potential use for PBA in treatment of various types of SMA. PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). (2004) found a significant increase in SMN2 gene ( 601627) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). In fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al.