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Case Reports
. 2019 Aug 1;142(8):2230-2237.
doi: 10.1093/brain/awz182.

SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis

Julien H Park  1 , Christiane Elpers  1 , Janine Reunert  1 , Michael L McCormick  2 , Julia Mohr  3 , Saskia Biskup  3 , Oliver Schwartz  1 , Stephan Rust  1 , Marianne Grüneberg  1 , Anja Seelhöfer  1 , Ulrike Schara  4 , Eugen Boltshauser  5 , Douglas R Spitz  2 , Thorsten Marquardt  1
Affiliations
Case Reports

SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis

Julien H Park et al. Brain. .

Abstract

Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; hyperekplexia; oxidative damage; superoxide dismutase.

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Figures

Figure 1
Figure 1
Pedigree of the index patient. His parents are first degree cousins. No other affected individuals were reported. Notably, there are no known cases of (familial) ALS in the kinship, while many of the reported individuals are at or above the mean age of onset observed in SOD1-related familial ALS.
Figure 2
Figure 2
Phenotype of the index patient at 6 years of age. Dysmorphic features such as low set, posteriorly rotated ears and overlapping toes are present. A clinical examination demonstrating hyperekplexia-like symptoms is available online.
Figure 3
Figure 3
T2-weighted cranial MRI of the index patient at the age of 6 years. In general, mild cerebellar atrophy is present. The cerebellar interfoliar spaces at the anterior vermis are discreetly enlarged (indicated by arrows) as are the cerebellar hemispheres in the lateral view (D).
Figure 4
Figure 4
SOD1 activity measurement of the patient and heterozygous carriers compared to wild-type controls. Measurements were performed on isolated blood leucocytes. The index patient had no detectable SOD1 activity. Heterozygous carriers showed an approximately halved SOD1 activity of 12 and 11 units/mg protein, corresponding to 55% and 51% of the activity measured in wild-type (WT) controls, respectively.
See this image and copyright information in PMC

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