Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Spinal Muscular Atrophy, Type I – III (IV) (SMA1,2,3,4) [G12.9]

OMIM numbers: 253300253550253400271150600354 (SMN1)

Dr. rer. biol. hum. S. Chahrokh-Zadeh, Dr. med. Imma Rost

Scientific Background

With an incidence of more than 1 in 10,000 and a carrier frequency of approx. 1 in 35-50, the autosomal recessive spinal muscular atrophies type I–III, IV are among the most frequently occurring recessive diseases. Muscular atrophy is a secondary condition caused by loss of the anterior horn cells and the motor cells of the cranial nerve nuclei in the brain stem. There are 4 clinical forms:

Type I (Werdnig-Hoffmann): Onset of the disease is prior to the 6th month of life; affected children are never able to sit unaided; death usually occurs within the first years of life. Severe muscle weakness is a major symptom; absence of deep tendon reflexes is frequent; electromyogram shows a typical neurogenic pattern. Patients may have muscle fasciculation, especially of the tongue muscle. The patients show good cognitive skills.

Type II (intermediate type): Patients are able to sit, but cannot walk unaided. Onset is within the first 18 months of life. Muscle weakness progresses slower than in type I; secondary contractures of the joints and scoliosis may occur. Survival until adulthood is possible.

Type III (Kugelberg Welander): Patients can walk unaided; onset of the disease is usually after the 2nd year of life. Unstable gait and reduced deep tendon reflexes are frequently the first signs observed. Life expectancy is not severely reduced.

Type IV (adult SMA): Muscle weakness starting from the 2nd and 3rd decade with ability to walk and variable progression. Life expectancy is normal. Inheritance is autosomal recessive in approx. 30% of all cases. In 70% of all cases, an autosomal dominant pattern is observed; however, the gene location on chromosome 5 is not responsible and so far DNA diagnostics have not been available.

SMA is caused by changes in the SMN1 gene (survival motor neuron gene). Two extremely homologous genes, SMN1 and SMN2, which only differ in 5 base pairs, are located, along with other genes and pseudogenes, in an inversely duplicated region, 500 kb of size, on chromosome 5q13. The SMN1 copy is located towards the telomere, the SMN2 copy towards the centromere. Two of the five base differences are located in the region of exons 7 and 8 and are used in diagnostics to differentiate the 2 genes.

More than 95% of all patients carry a homozygous deletion of the exon 7 and/or 8 of the SMN1 gene, independently of the clinical type. A smaller proportion of all patients carries the above-mentioned deletion on one allele and a point mutation (compound heterozygous) on the other allele. Failure to detect the SMN1 gene can be due to a gene conversion of SMN1 to SMN2, which causes the number of the copies of the SMN2 gene to rise. Due to the fact that such a gene conversion and an increased number of SMN2 copies are found rather in SMA II and III, it is assumed that SMN2 is capable of partially compensating the loss of SMN1. This knowledge is increasingly used in the development of therapy concepts for the treatment of SMA: for instance, in the testing of medication such as valproic acid, phenylbutyrate and others, which increase the functioning of SMN2 in vitro.