An Indian child with CONDSIAS due to a novel variant in ADPRHL2 gene

Bajaj, Shruti; Shah, Poornima; Shah, Ankur; Setty, PhaniN; Seenappa, Venu; Hingwala, Divyata Rajendra

doi:10.4103/aian.aian_558_22

Cited by 4 publications

(5 citation statements)

References 8 publications

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“…5 Cerebellar atrophy and vermis atrophy were frequently reported MRI findings in the literature, along with cerebral atrophy, spinal cord atrophy, basal ganglia involvement, corpus callosum hyperintensity, and other abnormalities. 4,5,[7][8][9][10][11][12][13][14][15] Even while some patients' MRI results might be normal or show mild atrophy, such as our first patient, these changes might be time dependent and atrophy might occur and progress over the course of the illness. 4,5,[8][9][10][11] This neurodegenerative disease was also described in five adult patients.…”

Section: Discussionmentioning

confidence: 87%

“…We identified 12 articles describing 47 patients with ADPRHL2/ADPRS/ARH3 mutation during the literature search. 4,5,[7][8][9][10][11][12][13][14][15][16] Of these studies, two were large reports in which the disease was first described (n ¼ 16, and n ¼ 12 respectively), three were single-case reports, three were letters involving four patients, and four were original/research article involving 12 patients. Characteristics of the ADPRHL2/ADPRS/ARH3 mutation found in the literature up to February 3rd, 2023 and our cases are summarized in ►Table 1.…”

Section: Results Of the Systematic Reviewmentioning

confidence: 99%

“…There have been 47 cases described so far in the literature, 21 of which have deceased. 4,5,7,8,10,12,15 Respiratory failure and cardiopulmonary arrest were the main reasons for mortality in the majority of cases. Respiratory failure and autonomic dysfunction may underlie the fatal course in our first patient as well.…”

Section: Discussionmentioning

confidence: 99%

“…Our patients in line with the so far reported patients, clinically evolved from episodic ataxia to a neurodegenerative course with central hypoventilation syndrome, further complicated by multisystemic involvement including endocrine dysfunction. Patients with ADPRHL2 variants can show a wide clinical phenotype at different age groups and different prognoses from progressive fatal course in childhood to a static course with survival up to third decade in adulthood 4,5,[7][8][9][10][11][12][13][14][15][16] (►Table 1). A clear genotype-phenotype correlation is quite challenging to establish based on current knowledge.…”

Section: Adprhl2 Mutations öZ Yıldız Et Al 163mentioning

confidence: 99%

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Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature

Öz Yıldız,

Yalnızoğlu,

Şimsek Kiper

et al. 2024

Neuropediatrics

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ADPRHL2 is involved in posttranslational modification and is known to have a role in physiological functions such as cell signaling, DNA repair, gene control, cell death, and response to stress. Recently, a group of neurological disorders due to ADPRHL2 variants is described, characterized by childhood-onset, stress-induced variable movement disorders, neuropathy, seizures, and neurodegenerative course. We present the diagnostic pathway of two pediatric patients with episodic dystonia and ataxia, who later had a neurodegenerative course complicated by central hypoventilation syndrome due to the same homozygous ADPRHL2 variant. We conducted a systematic literature search and data extraction procedure following the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 statement in terms of patients with ADPRHL2 variants, from 2018 up to 3 February, 2023. In total, 12 articles describing 47 patients were included in the final analysis. Median age at symptom onset was 2 (0.7–25) years, with the most common presenting symptoms being gait problems (n = 19, 40.4%), seizures (n = 16, 34%), ataxia (n = 13, 27.6%), and weakness (n = 10, 21.2%). Triggering factors (28/47; 59.5%) and regression (28/43; 60.4%), axonal polyneuropathy (9/23; 39.1%), and cerebral and cerebellar atrophy with white matter changes (28/36; 77.7%) were the other clues. The fatality rate and median age of death were 44.6% (n = 21) and 7 (2–34) years, respectively. ADPRHL2 variants should be considered in the context of episodic, stress-induced pediatric and adult-onset movement disorders and seizures.

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Section: Discussionmentioning

confidence: 87%

Section: Results Of the Systematic Reviewmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Adprhl2 Mutations öZ Yıldız Et Al 163mentioning

confidence: 99%

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Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature

Öz Yıldız,

Yalnızoğlu,

Şimsek Kiper

et al. 2024

Neuropediatrics

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“…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: 82%

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

Bannister,

Bray,

Aggarwal

et al. 2024

Preprint

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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.

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

Lindskov,

Karlsson,

Skovbølling

et al. 2023

Cerebellum

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An Indian child with CONDSIAS due to a novel variant in ADPRHL2 gene

Cited by 4 publications

References 8 publications

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature

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

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

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