Spinal muscular atrophy (SMA) is the second most common autosomal recessive disorder, with an overall incidence of about 1 in 6,000 to 10,000 live births and a carrier frequency of about 1/40 [1]. The disease is charac terized by degeneration of the a-motor neurons of the anterior horns of the spinal cord, which leads to progres sive symmetrical weakness and wasting in the proximal muscles. Three types of SMA have been distinguished on the basis of clinical severity and age of onset: type I (Warding-Hoffman disease) is the most severe form with clinical onset generally before the age of 6 months. Affected individuals cannot sit unaided and death usually occurs before the age of 2 years; type II is an intermediate form characterized by early onset, inability to walk and usually survive beyond the age of 10 years; type III (Kugelberg-Vilander disease), is the mild form being char acterized by late age at onset and variable clinical severity. Affected individuals are able to walk independently and may have a normal life (17 with type I, eight with type II and five with type III form of the disease), 30 parents and 30 unrelated expectancy [2].

All three forms of SMA have been linked to markers at 5q11.2-q13.3 [3,4]. Deletional events within this region have been associated with SMA, and two candidate genes within this region identified: the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes [5-9]. This region of the genome is inherently unsta ble, and contains with two almost identical copies of the SMN gene, one centro meric (SMNcen or cBCD541) and one telomeric (SMNtel) and multiple copies of pseudo genes of NAIP [10]. The two copies of the SMN gene differ in sequence by only five nucleotide changes along 20 kb and both are transcribed [9]. It has been reported that most SMA patients (>95%) are homozygous for dele tions of the SMN telomeric copy, but no specific muta tions explaining the three SMA phenotypes have been found [9,11]. One full NAIP gene and several truncated copies are present in the SMA region. Specific exons of NAIP are deleted in SMA patients and also in 2% of unaf fected carrier individuals. Deletions in the NAIP gene vary in frequency in different populations from 67.9 to 0% and appear to be higher in type I patients than in types II and III [7-18]. The NAIP gene shows similarity with baculoviral genes involved in inhibition of apoptosis in infected insect cells [7].Thus, loss of the NAIP gene is not suffi cient to cause the disease. The NAIP gene is probably involved in modification of the severity of SMA. Recent studies have shown that a gene conversion event, in which the SMNtel is replaced by its centromeric counterpart (SMNcen), is a common mechanism in the genesis of mild SMA alleles, and an increased number of SMNcen genes may partially compensate for deficiency of SMNtel [19, 20].

We here present our data on the molecular analysis of the SMN and NAIP genes in patients with SMA from the Republic of Macedonia.