Muscle Biopsy of the Proband at Age 3 Yrs
Frozen hematoxylin-eosin-stained section shows bundles of larger-diameter fibers adjacent to bundles of very small fibers. Intermingled with the large fibers are a few angular fibers, singly and in small groups. There is no abundance of central nuclei, necrosis, regeneration, or other fiber structural changes. Collagen encircling atrophic fibers is observed.

Homozygous VRK1 Nonsense Mutation in SMA-PCH
(A) Genomic sequence of the VRK1 exon 12 region in informative family members. The proband is homozygous for a C>T transition that creates a TGA termination codon.
(B) Schematic representation of the VRK1 protein, including the ATP binding site, kinase domain, and nuclear leader sequence (NLS). Amino acid sequence of the NLS is indicated below, with the R358X mutation shown in red.
(C) Species conservation of amino acids in the R358X region.
(D) Allele-specific expression of VRK1 in R358X carriers. VRK1 exons 8 (ex8) and 12 (ex12) were sequenced in both genomic DNA and cDNA of a carrier of the R358X mutation. cDNA was extracted from an Epstein-Barr virus (EBV)-transformed B cell line. Exon 8 contains a known polymorphism (rs2230532) that also segregates in this family, and the exon 12 R358X mutation corresponds to 1072C>T in the cDNA (NM_003384). Top: genomic DNA sequences, showing equal biallelic content in both exon 8 and exon 12 sequences. Bottom: Unequal allelic expression in cDNA, where the wild-type allele predominates over the mutant (>70%).

Linkage and Homozygosity Mapping of Markers on 14q32 to SMA-PCH in a Consanguineous Family
Affected individuals are shown in black. STR genotypes in the critical region are shown below each sampled individual, where numbers indicate amplicon size (bp). The disease-associated haplotype is shaded in yellow or yellow-orange. Only IV-12 is homozygous by descent for the region boxed in red.

Brain CT Scan of the Proband's Sister at Age 7 Yrs, in 1989
(A) Cerebellar vermis hypoplasia, communicating fourth ventricle and cisterna magna (arrow).
(B) Cerebellar vermis hypoplasia (arrow).
(C) Large cisterna magna and cerebellar hemisphere hypoplasia.