No abstract

The beta-actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser-Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple-peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated.Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild-type S. cerevisiae strain. There was an obvious growth defect of the yACT1 S348L/WT pseudoheterozygote compared to a yACT1 WT/WT strain when grown at 22 C but not when grown at 30 C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild-type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.

Aicardi‐Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus‐myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus‐myoclonus, and that the association between AGS and opsoclonus‐myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. There is a phenotypic association between opsoclonus‐myoclonus syndrome and Aicardi‐Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus.

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, nonneuronal 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.