Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity

Abstract

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1

“…This mutation results in the omission of either valine at position 119 or 120 of SOD1, and similar to the cases described here, neither SOD1 enzymatic activity nor mutant SOD1 protein was detected in erythrocyte lysates, again arguing that a loss rather than the gain of a toxic function is a principal component of the pathomechanism. 25 In addition to this new human case, a truncating homozygous loss-of-function mutation in SOD1 was recently identified in Markiesje dogs that exhibited progressive tetraparesis and muscle wasting, in addition to brainstem and spinal cord atrophy. 63 However, it is notable that Sod1 knockout mice do not replicate the severe motor neuron phenotype that develops in humans despite developing a significant, motor neuropathy in later life in addition to visceral symptoms such as liver tumours, sarcopenia, and ocular symptoms.…”

“…Immunoblots of erythrocyte lysates were performed as previously described. 25 Immunoblot analysis of soluble and detergent-insoluble fractions of SOD1 in patient skin biopsy-derived fibroblast cultures was carried out essentially as described before. 26 We used inhouse produced polyclonal rabbit anti-peptide antibodies specifically targeting aa 5–21 (5 µg/ml), aa 25–40 (1 µg/ml) of the SOD1 protein sequence, and the neo-peptide sequences of the p.G127X (2 µg/ml) and the p.C112X (10 µg/ml) mutant proteins.…”

Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation

“…The essentially normal enzymatic activity protects SOD1 D90Ahom patients from developing superoxide-free radical-induced damage. Nine other SOD1 mutations have in rare cases been reported in homozygous form, most notably the recently discovered p.C112Wfs*11 and p.V120delV SOD1 in children [ 5 , 16 , 38 ]. These mutations result in SOD1 proteins devoid of enzymatic activity and the children already have onset in infancy of a more generalized neuronal phenotype, but strikingly—as in the SOD1 D90Ahom patients—the first apparent symptoms are from the motor system with early involvement of the UMN system.…”

“…These mutations result in SOD1 proteins devoid of enzymatic activity and the children already have onset in infancy of a more generalized neuronal phenotype, but strikingly—as in the SOD1 D90Ahom patients—the first apparent symptoms are from the motor system with early involvement of the UMN system. These children also develop signs from some other organ systems; the most plausible explanation is the absence of SOD1 enzymatic activity [ 5 , 16 , 38 ]. In none of the nine SOD1 D90Ahom did we observe pathology outside the CNS attributable to the SOD1 D90Ahom genotype, even in the patients who had a symptomatic motor neuron disease for over 20 years.…”

Update on genetics of amyotrophic lateral sclerosis

“…However, a strong trend towards reduced levels of cerebrospinal fluid neurofilament levels and decelerated decline of clinical measures was observed indicating that Tofersen may have slowed down neurodegeneration. Recent reports about progressive motor neuron disease in children with homozygous SOD1 deficiency have emphasized the physiological significance of wildtype SOD1 activity for motor neuron health, thus, raising concerns about excessive downregulation of the wildtype SOD1 allele [42][43][44].…”