Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA )is considered the third most common lethal autosomal recessive disease in Greece, following thalassemia and cystic fibrosis. The estimated prevalence of SMA among Caucasians ranges is about  1:10,000 live births, while carrier frequency is estimated at 1/38–1/50. The distinct disease characteristic is the progressive waste of lower motor neurons situated in the anterior horn of the spinal cord resulting mainly in muscle weakness and atrophy. The patients’ life expectancy depends primarily on the pulmonary function and so much on motor abilities. The disease according age of onset is classified in three major subtypewQ

  1.   The SMAI (Werdning-Hoffmann or infantile form) is the most devastating type with symptoms including generalized hypotonia, muscle weakness and respiratory distress, becoming obvious before the age of 6 months, while complications arise by 18 months.
  2.   The SMA II (intermediate SMA or chronic infantile SMA) manifests before the 18th month and the patients, although initially able to sit unaided, lose the ability to stand or walk unassisted.
  3.     The milder SMA type III (Kugelberg-Welander or Juvenile type) symptoms present after 18 months or much later in life, usually in adolescence. A more detailed classification proposes at least 2 more types including the even more devastating SMA type 0 where death comes before 6 months and the mildest SMA type IV where adult onset and mild clinical progression are observed.

The gene involved in all forms of SMA is the Survival of Motor Neuron 1 (SMN1) gene located within an inverted repeat region on chromosomal locus 5q13, containing the highly homologous SMN2 gene. The coded SMN protein seems to have a multifunctional role. TheSMN1 geneparalog,SMN2, contains a C>T transition in exon 7 (c.840C>T), which alters the splicing pattern of SMN2 mRNA, thus severely reducing the  levels of full-length SMN protein produced.

In about 95% of SMA patients the disease is caused by the homozygous deletion of exon 7, or exons 7 and 8, of the SMN1 gene. In a minority of patients the disease is caused by compound heterozygosity of anSMN1deletion variant (either exon 7or exons 7 and 8) and a small lesion within the SMN1 gene.

The diagnosis of the disease in LMG is established by identification of a SMN1 gene deletion (exons 7 and/or 8) by MLPA for the majority of patients and subsequent sequencing analysis in patients with one SMN1 deleted allele .