SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.

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.

A Case Report on Juvenile Neuromyelitis Optica: Early Onset, Long Remission Period, and Atypical Treatment Response.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system and preferentially targets the optic nerves and spinal cord. NMO is rare in children and clinical course of the disease is highly variable as described in studies. Here, we present a case report of a young girl presenting with a rare course of pediatric NMO with an early disease onset at the age of 12 years, a relapse free interval of 4 years, evidence of NMO immunoglobulin G (IgG) and an unusual response against immunosuppressive therapy. The aim of this report is to highlight the potentially long remission period between relapses complicating proper diagnosis despite well defined diagnostic criteria. In addition, we want to encourage the use of rituximab in pediatric NMO, although larger cohorts are warranted to establish B cell depleting therapies in juvenile NMO.

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

Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs*11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs*11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy-A Case Report.

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.

Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi-Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1).

Aicardi-Goutières syndrome (AGS) is a hereditary early onset encephalopathy. AGS patients display variable clinical manifestations including intracranial calcification, cerebral atrophy, white matter abnormalities and characteristic leukocytosis as well as a constitutive upregulation of type I IFN production indicative of a type I interferonopathy. Seven genes (SAMHD1, TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, IFIH1) have been associated with the AGS phenotype, up to now. Here, we describe the generation of three induced pluripotent stem cell lines from a patient with a deletion of coding exons 14 and 15 of the SAMHD1 gene.

Interval Timing in Pediatric Multiple Sclerosis: Impaired in the Subsecond Range but Unimpaired in the One-Second Range.

Background: For adult multiple sclerosis (MS) patients, impaired temporal processing of simultaneity/successiveness has been frequently reported although interval timing has been investigated in neither adult nor pediatric MS patients. We aim to extend previous research in two ways. First, we focus on interval timing (instead of simultaneity/successiveness) and differentiate between sensory-automatic processing of intervals in the subsecond range and cognitive processing of intervals in the one-second range. Second, we investigate whether impaired temporal information processing would also be observable in pediatric MS patients' interval timing in the subsecond and one-second ranges. Methods: Participants were 22 pediatric MS patients and 22 healthy controls, matched for age, gender, and psychometric intelligence as measured by the Culture Fair Test 20-R. They completed two auditory interval-timing tasks with stimuli in the subsecond and one-second ranges, respectively, as well as a frequency discrimination task. Results: Pediatric MS patients showed impaired interval timing in the subsecond range compared to healthy controls with a mean difference of the difference limen (DL) of 6.3 ms, 95% CI [1.7, 10.9 ms] and an effect size of Cohen's d = 0.830. The two groups did not differ significantly in interval timing in the one-second range (mean difference of the DL = 26.9 ms, 95% CI [-14.2, 67.9 ms], Cohen's d = 0.399) or in frequency discrimination (mean difference of the DL = 0.4 Hz, 95% CI [-1.1, 1.9 Hz], Cohen's d = 0.158). Conclusion: The results indicate that, in particular, the sensory-automatic processing of intervals in the subsecond range but not the cognitive processing of longer intervals is impaired in pediatric MS patients. This differential pattern of results is unlikely to be explained by general deficits of auditory information processing. A tentative explanation, to be tested in future studies, points to subcortical deficits in pediatric MS patients, which might also underlie deficits in speech and visuomotor coordination typically reported in pediatric MS patients.

Ketone body therapy with D/L-ß-hydroxybutyric acid solution in severe MADD.

OBJECTIVES: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a severe inborn disorder of mitochondrial fatty acid oxidation. The only treatment option for MADD is the use of exogenous ketone bodies, like sodium ß-hydroxybutyrate (NaßHB). However, the use of ketone body salts leads to a high intake of accompanying minerals, which can lead to additional side effects. The use of mineral-free formulations could improve tolerability. METHODS: In this report, the use of a ßHB acid (ßHBA) in a patient with MADD is described. The production of D/L-ßHBA was carried out using ion exchange chromatography (IEX) and using a precipitation method. During two inpatient treatment intervals, the tolerability as well as clinical and metabolic effects were monitored. D-ßHB in serum, blood gas analysis, and standard blood measurements (like minerals) were used as control parameters. RESULTS: Production of D/L-ßHBA using the precipitation method was more effective than using IEX. The tube feed solution used had a minimum pH of 3.5. Capillary D-ßHB measurements were between 0.1 and 0.4 mmol/L and venous were at 0.1 mmol/L or below. Minerals and serum pH were within the normal range. During application of D/L-ßHBA, gastrointestinal discomfort occurred and no clinical improvement was observed. CONCLUSIONS: The use of D/L-ßHBA in the therapy of severe MADD could be a good addition to the use of classical ketone body salts. The observed gastrointestinal side effects were of a mild nature and could not be specifically attributed to the D/L-ßHBA treatment. In short-term application, no clinical benefit and no substantial increase of D-ßHB in serum were noted. No tendency towards acidosis or alkalosis was observed during the entire period of treatment.

Evaluating the relationship between psychometric intelligence and cognitive functions in paediatric multiple sclerosis.

BACKGROUND: Processing speed is frequently reduced in patients suffering from multiple sclerosis (MS). Reduced processing speed can also lead to impaired working memory capacity (WMC) in adult MS patients. Less is known about the interplay of cognitive deficits in paediatric MS patients. OBJECTIVES: In the present study, we investigated whether processing speed and WMC are reduced in paediatric MS patients compared with healthy controls and whether reduced processing speed and WMC might explain potential differences in psychometric intelligence between MS patients and healthy controls. METHODS: Twenty-one paediatric MS patients and 21 healthy controls completed a reaction time (RT) task, a working memory task, and Cattell's Culture Fair Test (CFT20-R). RESULTS: Patients with MS had slower RT and lower intelligence scores than healthy controls. We could find no significant differences for WMC. An analysis of covariance revealed that group differences in intelligence could be partially explained by processing speed differences. CONCLUSION: The results indicate that processing speed is a good marker for MS-related impaired efficiency and increased error-proneness of the central nervous system in higher-order cognition as required by Cattell's CFT20-R.

CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing.

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vß genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.