Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia

• Published in: Brain (London, England : 1878) Vol. 120; no. 10; pp. 1723 - 1737
• Main Authors: ANDERSEN, P. M, NILSSON, P, KERÄNEN, M.-L, FORSGREN, L, HÄGGLUND, J, KARLSBORG, M, RONNEVI, L.-O, GREDAL, O, MARKLUND, S. L
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.1997; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis - genetics; Biological and medical sciences; Bulbar Palsy, Progressive - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Genetic Variation - genetics; Humans; Male; Medical sciences; Middle Aged; Motor Neuron Disease - genetics; Mutation; Neurology; Pedigree; Phenotype; Scandinavian and Nordic Countries; Superoxide Dismutase - genetics; Scandinavia; Europe; Scandinavian and Nordic Countries; Human; Nervous system diseases; Enzyme; Family study; Motor neuron disease; Exploration; Superoxide dismutase; Phenotype; Gene; Central nervous system disease; Degenerative disease; Oxidoreductases; Mutation; Spinal cord disease
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/120.10.1723

Four-hundred and fifty-one blood samples from Scandinavian patients with motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Forty-one (9.6%) of the 427 patients with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-associated mutation, and 14 of these patients were apparently sporadic cases. A mutation was found in 12 of the 51 families with recognized familial ALS. The five different mutations found (Ala4Val, Val14Gly, Asp76Tyr, Asp90Ala, Gly127insTGGG) have different genetic characteristics and are associated with very variable phenotypes spanning from rapidly progressing disease with only lower motor neuron signs to very slowly progressing disease with both the upper and lower motor neuron systems affected. The patients showed different sites of onset, though the progressive bulbar palsy form of the disease appears to be rare among patients with a CuZn-superoxide dismutase mutation. The progression of motor signs and symptoms followed the same basic pattern in patients with different mutations. Extra-motor system symptoms were frequent among patients with a CuZn-superoxide dismutase mutation. The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity. The Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the CuZn-superoxide dismutase gene.