LAUSR

We thank Dr Maeda et al for their careful review and for their contribution of an additional case related to our previous report, “Severe Brain Involvement in 5q Spinal Muscular Atrophy Type 0.” We would like to reply to some of the comments in their letter. The case they reported showed severe diffuse atrophy, compromising the supraand infratentorial central nervous system with seizures. This case represents another example of evolutionary brain atrophy that becomes worse with time in patients with type 0 spinal muscular atrophy (SMA), who survive longer through artificial invasive ventilation. Although the 3 cases that we reported did not show evident cerebellar compromise or seizures, there are previous reports of type 0 SMA with cerebellar involvement and seizures that we commented on in our paper. Maeda et al ascribe the extreme severity of their patient to the presence of 1 SMN2 copy and the absence of the NAIP gene. In addition to the SMN1 gene, 2 other genes located in the 5q13.2 region, NAIP (neuronal apoptosis inhibitory protein, currently BIRC1) and SERF1A (small EDRK-rich factor 1A), have been postulated as possible modifier genes because they are deleted in approximately one-half the patients with severe SMA. However, the roles of these genes have not been unequivocally established, and there is a consensus that the association of these genes with the phenotype may be the result of large-scale rearrangements causing deletion of multiple genes (including the SMNs and other adjacent genes), as previously described by other groups. Thus, true deletions of SMN1 or null alleles are usually associated with the deletion of surrounding genes. NAIP mutations were not specifically studied in our patients. However, 1 of them, who also developed distal necrosis (Patient 3), had 1 allele with the presence of SMN1 and a point pathogenic variant in exon 6, suggesting the presence of surrounding genes, including NAIP. Bernal et al reported that 8 patients with 2 SMN2 copies (usually expected to develop severe type I disease) showed better phenotypes because of the presence of the c.859G>C variant in exon 7 of the SMN2 gene (type II sitter or type III walker). These patients also showed homozygous deletion of NAIP, further supporting the hypothesis that the absence of NAIP is not primarily involved in worsening of the SMA phenotype.