Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?

Abstract

Background Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis. Methods We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. Results All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity. Conclusions This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency.

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

“…reported the same severe phenotype in C112X Hom children of Lebanese origin. 62 Supporting that the phenotype in C112X Hom children is caused by the absence of SOD1 enzyme activity is the discovery of a similar primarily neurological phenotype in an infant homozygous for another SOD1 mutation c.357_357 + 2delGGT. 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.…”

Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges

“…Diplopia and ophthalmoparesis may also be observed with FUS variants [ 56 ]. Furthermore, homozygous pathogenic variants in SOD1 have recently been associated with SOD1 deficiency and a very early-onset upper motor neuron-dominant phenotype, called Progressive Spastic Tetraplegia and Axial Hypotonia (STAHP) [ 57 ]. Autonomic disturbances and variable sensory neuropathy may be identified in VRK1 -related JALS and SPG11 variants [ 5 , 33 , 34 , 58 ].…”

Biomarkers for amyotrophic lateral sclerosis

“…The pathogenic mechanisms of mutations in SOD1 causing progressive degeneration of motor neurons are not fully understood. So far, destabilization of SOD1 protein with a toxic gain-of-function resulting in misfolding and intracellular aggregation and increased oxidative activity have been considered the most likely pathogenic mechanism [13,14,15 ▪ ].…”

“…Promoting the degradation of SOD1 -mRNA and, therefore, lowering the expression of mutant SOD1 protein is a potential target of therapeutic intervention, including ASO therapy [13,14,15 ▪ ]. ASO therapy has shown promising effects in animal models, reducing SOD1 protein concentrations in the CNS and SOD1 mRNA in spinal cord tissue by approximately 75%.…”

“…To date, the main hypothesis expects a toxic gain-of-function from SOD1 mutations. Interestingly, recent publications identified a homozygous mutation in the SOD1 protein resulting in a massive decrease or even total lack of SOD1 activity, associated with an early onset of rapidly progressive motor neuron disorder [13,20 ▪ ,21,22]. This indicates that not only a toxic gain-of-function but also a loss-of- SOD1 -function might be equally detrimental, making the therapeutic window for SOD1 -lowering therapies smaller.…”