Expanding the Spectrum of Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures (CONDSIAS)

Lindskov, Filippa Orlien; Karlsson, William Kristian; Skovbølling, Sara Lyngby; Nielsen, Emilie Neerup; Dunø, Morten; Stokholm, Jette; Henriksen, Otto Mølby; Langkilde, Annika Reynberg; Nielsen, Jørgen Erik

doi:10.1007/s12311-023-01582-w

Cited by 4 publications

(2 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, p.H182Y was identified as a compound heterozygous variant alongside p.Y188* and is reported as likely pathogenic in CONDSIAS, further supporting the pathogenicity of His182 missense variants ( Figure 1F ). 21…”

Section: Resultsmentioning

confidence: 99%

“…Emerging from the identification of approximately 40 different variants in CONDSIAS is a story of loss of ARH3 function followed by steady-state accumulation of Ser-MAR and, to an even greater extent, following cellular damage. [14][15][16][17][18][19][20][21][22][23][24][25][26] In this study, we identified a novel homozygous ADPRS variant (c.545A>G, p.His182Arg, H182R) in two siblings with a clinical picture consistent with CONDSIAS. Using in vitro cell models, we found that the H182R variant conferred loss of ARH3 function.…”

Section: Introductionmentioning

confidence: 81%

See 1 more Smart Citation

A novel variant inADPRSdisrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

Bannister,

Bray,

Aggarwal

et al. 2024

Preprint

View full text Add to dashboard Cite

PurposeADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in theADPRSgene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS).MethodsGenetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change.ResultsThe ARH3H182Rvariant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3H182Radditionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3H182Rresulted in accumulation of mono-ADP ribosylated species in cells.ConclusionsThe children’s clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 81%

A novel variant inADPRSdisrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

Bannister,

Bray,

Aggarwal

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Multiple drugs

2024

Reactions Weekly

View full text Add to dashboard Cite

Clinical, Genetic, and Pathological Studies in Two Brothers with Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures: A Case Report

Tompa,

Tolvaj,

Vadvari

et al. 2024

Case Rep Neurol

View full text Add to dashboard Cite

Introduction: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive disorder caused by biallelic pathogenic variants in the ADPRS gene. Since its first description in 2018, less than fifty cases have been reported worldwide, but thus far, without histopathology of the nervous system. Case Presentation: We summarize the clinical, paraclinical, and genetic characteristics of the disease in the proband, and the pathological workup in his older brother who passed away more than a decade ago. The characteristics of CONDSIAS in the two brothers overlapped with those of Friedreich ataxia. A final clarification of the diagnosis was made possible by whole exome sequencing (WES) that identified the homozygous pathogenic variants in the ADPRS gene. Conclusion: CONDSIAS is a rare disorder with highly variable presentation. Based on solely clinical and even pathological workup, establishing a definite diagnosis may be challenging. In the two brothers, we observed clinical and histopathological features of the disease suggesting, though not completely fulfilling, the diagnosis of Friedreich’s ataxia. WES allowed us to rapidly identify the underlying genetic abnormality and to make a shortcut to the right diagnosis amongst recessive ataxias. As of today, no specific treatment for CONDSIAS is available. Repurposing of certain approved modalities that also target the affected pathway in CONDSIAS recently arose, though as yet without proven success. Knowing the biological relevance of the affected gene product offers potential targets for the development of disease-modifying drugs for this highly disabling disease in the near future.

show abstract

Expanding the Spectrum of Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures (CONDSIAS)

Cited by 4 publications

References 21 publications

A novel variant inADPRSdisrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

A novel variant inADPRSdisrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

Multiple drugs

Clinical, Genetic, and Pathological Studies in Two Brothers with Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures: A Case Report

Contact Info

Product

Resources

About