DIFFERENT ENTITIES OF PROXIMAL SPINAL MUSCULAR-ATROPHY WITHIN ONE FAMILY

The molecular analysis of the survival motor neuron (SMN) gene and sev eral closely flanking polymorphic markers in an atypical pedigree with four patients suffering from spinal muscular atrophy (SMA) over two g enerations has raised new aspects concerning the etiology and the mole cular spectrum of autosomal recessive SMA. Three patients in two gener ations show homozygous deletions of exons 7 and 8 of the telomeric cop y of SMN (telSMN), thus confirming the presence of autosomal recessive SMA, with localisation on chromosome 5q12. The fourth SMA patient wit h mild neurogenic atrophy (confirmed by muscle biopsy and electromyogr aphy) shows no homozygous deletion of telSMN but carries a heterozygou s deletion of telSMN, as can be deduced from her two affected homozygo usly deleted children. No intragenic mutation has been identified in t he remaining telSMN. In addition, she shares only one SMA chromosome w ith her affected brother, is haploidentical with two healthy brothers, and has a 31-year-old healthy son, who has inherited an SMN-deleted p aternal chromosome and the SMN non-deleted maternal chromosome. These results suggest that this patient either has a neurogenic atrophy of a different origin or exhibits an unusual heterozygous manifestation of SMA 5q12. Interestingly, the two haploidentical telSMN-deleted affect ed sibs in the second generation show a strikingly discordant clinical picture indicating that, in addition to telSMN mutations, other facto rs influence the phenotype of SMA in the reported pedigree.