PMC2822627_01
Ten ARJALS families linked to the SPG11 locus. Their origin is reported in brackets. The solid symbols refer to affected individuals as well as carriers of the SPG11 mutations; circles = females; squares = males and slashes = deceased. The code numbers of all sampled individuals (asterisks) are reported below the symbols. Colour barcodes designate haplotypes in each pedigree. Haplotypes created with markers D15S146, D15S537 and D15S123 (from top to bottom) are reported under each family member investigated. The SPG11 gene is localized between markers D15S537 and D15S123. Inferred alleles are indicated by parentheses and question marks represent alleles not able to be inferred. Key recombination events are observed between markers D15S537 and D15S123 in Patient 1810 (Family RM171) as well as among markers D15S537 and D15S123 in Patient 3011 (Family RM303).
awp325f1.jpg
PMC2822627_02_awp325f1.jpg
F1
Subject 2562 of pedigree RM 257 (Figs 1 and 2) was a 49-year-old Italian man; at the age of 18, he developed a slowly progressive lower and upper motoneuron syndrome. TOR015) showed homozygous haplotypes and produced positive logarithm of odds scores with microsatellite markers D15S146, D15S537 and D15S123 in all affected subjects, showing a cumulative two-point logarithm of odds score of 11.51 at the recombination fraction theta = 0.0 for marker D15S537 (Fig. 1). The other ARJALS families (RM306 and TK005) showed heterozygous haplotypes and produced negative or slightly significant cumulative logarithm of odds scores by the genetic program HOMOG (data not shown) (Ott,).
PMC2822627_02
Ten ARJALS families linked to the SPG11 locus. Their origin is reported in brackets. The solid symbols refer to affected individuals as well as carriers of the SPG11 mutations; circles = females; squares = males and slashes = deceased. The code numbers of all sampled individuals (asterisks) are reported below the symbols. Colour barcodes designate haplotypes in each pedigree. Haplotypes created with markers D15S146, D15S537 and D15S123 (from top to bottom) are reported under each family member investigated. The SPG11 gene is localized between markers D15S537 and D15S123. Inferred alleles are indicated by parentheses and question marks represent alleles not able to be inferred. Key recombination events are observed between markers D15S537 and D15S123 in Patient 1810 (Family RM171) as well as among markers D15S537 and D15S123 in Patient 3011 (Family RM303).
awp325f1.jpg
PMC2822627_02_awp325f1.jpg
F1
Subject 2562 of pedigree RM 257 (Figs 1 and 2) was a 49-year-old Italian man; at the age of 18, he developed a slowly progressive lower and upper motoneuron syndrome. TOR015) showed homozygous haplotypes and produced positive logarithm of odds scores with microsatellite markers D15S146, D15S537 and D15S123 in all affected subjects, showing a cumulative two-point logarithm of odds score of 11.51 at the recombination fraction theta = 0.0 for marker D15S537 (Fig. 1). The other ARJALS families (RM306 and TK005) showed heterozygous haplotypes and produced negative or slightly significant cumulative logarithm of odds scores by the genetic program HOMOG (data not shown) (Ott,).
(A) Family RM 257. Black symbols designate affected individuals and carriers of SPG11 mutation. White symbols symbolize unaffected subjects. Circles indicate females and squares represent males. The proband is designated with an arrow. The numbers are an internal reference for each subject. Asterisks indicate sampled individuals. (B) Electropherogram of exon/intron 30 of the SPG11 gene. The new homozygous substitution (G > A) is clearly defined in the affected individuals (Subjects 2539, 2561 and 2562) as well as the heterozygous status in the parents (Subjects 2532 and 2534) and in a sibling (Subject 2537). (C) Restriction digestion assay in the family members. Heterozygous individuals showed two bands at 600 and 500 base pairs, wild-type samples showed one band at 500 base pairs and the homozygous affected individuals remain uncleaved after digestion with EcoP15I.
awp325f2.jpg
PMC2822627_02_awp325f2.jpg
F2
Subject 2562 of pedigree RM 257 (Figs 1 and 2) was a 49-year-old Italian man; at the age of 18, he developed a slowly progressive lower and upper motoneuron syndrome. Eleven mutations had already been reported while IVS30 + 1 G > A, affecting the consensus splice site junction, was novel (Table 2 and Fig. 2).
Histopathological findings on spinal cord post-mortem samples in Patient 1737 from Family RM168. (A) Low magnification photomicrograph of the anterior horn at L1 shows a striking decrease of large motoneurons. (B) At higher magnification, several large motoneurons display central chromatolysis. (C) Most of the remaining neurons are laden with dark lipofuscin granules (pigmentary degeneration) and contain round hyaline inclusions (arrows). Kluver-Barrera staining. Bar = 800 microm (A); 100 microm (B, C).
awp325f3.jpg
PMC2822627_02_awp325f3.jpg
F3
Moreover, microscopic analysis showed marked loss of anterior horn large motoneurons at all spinal cord levels, associated with loss of large myelinated fibres in the anterolateral columns (Fig. 3A). Most of the remaining spinal motoneurons displayed pathological features, such as central chromatolysis (Fig. 3B), pigmentary degeneration and round hyaline inclusions (Fig. 3C).