Confirmatory testing in clinically suspected SMA at any age, especially in SMA types with early onset, detection of homozygous deletion, especially with regard to future pregnancies, prenatal diagnostics in persons at risk, specification of heterozygous carriers.
Spinal Muscular Atrophies, SMA type 0-IV - SMN1
SMA type 0, congenital form, SMA type I, Werdnig-Hoffmann;SMA type II late infantile form;SMA type III juvenile form (Kugelberg-Welander);SMA type IV adult form
Clinical Features
The spinal muscular atrophies are characterized by progressive muscle weakness and atrophy caused by degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. The so-called proximal spinal muscle atrophies represent approx. 90 % of all spinal muscle atrophies and affect the muscle groups close to the trunk. The different subtypes 0-IV are classified according to the disease course. SMA type 0 decribes the congenital manifestation with contractures (arthrogryposis multiplex congenita). SMA type I manifests before or a few weeks after birth ("floppy infant"), types II to IV manifest between children's to adult age. Diagnosis is based on EMG, CK levels are usually not or only mildly elevated.
Genetic Information
The SMA types with early onset of clinical symptoms are nearly exclusively autosomal recessive conditions. They are caused by a genetic defect on both copies of the SMN1 gene (Survival-Motor-Neuron-1 gene, OMIM 600354) on chromosome 5 (5q12.2-q13.3). Most individuals with SMA are homozygous for the absence of both exon 7 and exon 8 of SMN1, in some individuals only exon 7 is deleted. These SMN1 deletions are found in about 95 % of the clinically severe forms of SMA, and in more than 85% of the milder forms. About 4-6% of SMA cases with linkage to SMN1 are compound heterozygotes for absence of exons 7 and 8 of SMN1 and a point mutation in SMN1. The number of copies of the nearly identical SMN2 gene, located close to the SMN1 gene on chromosome 5, may influence the SMA phenotype in terms of onset and course of disease.
Prenatal diagnostic is possible for a pregnancy subsequent to an affected child (repeat risk 25 %).
The adult SMA types (SMA type IV) with onset after the age of 30 years usually are autosomal dominant conditions. Since the disease-causing genetic defect is still unknown, molecular genetic testing is not yet available.
Prevalence
1 : 5 000 to 1 : 10 000
approx. every 35th individual is symptom-free carrier.
Diagnostic
Indication
Method
MLPA to detect homozygous and heterozygous
deletions of exon 7 and exon 8 of the SMN1 gene.
Sample Requirement
2 - 4 ml of EDTA blood
Duration
approx. 3 weeks