Novel imaging and clinical phenotypes of CONDSIAS disorder caused by a homozygous frameshift variant of ADPRHL2: a case report

Abstract

Background: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive disorder caused by defects in the ADP-Ribosylhydrolase Like 2 (ADPRHL2; OMIM: 618170) gene. This gene encodes the ADP-ribosylhydrolase enzyme (ARH3) that eliminates the addition of poly-ADP ribose (PAR) in the cellular stress onto proteins in the ADP-ribosylation process in which adding one or more ADP-ribose moieties onto the target proteins in the post-translational modification have occurred. In this study, we report a new case of CONDSIAS in the Iranian population. A literature review of CONDSIAS is also included. Case presentation: A four-year-old female patient, born to a consanguineous Iranian family, was referred with various clinical symptoms including impaired speech, variable ataxia, infrequent seizures, and gradual onset of truncal hypotonia. Over time, she developed complete motor and speech regression, bilateral sensorineural hearing loss, infrequent seizures, abdominal distension and gastrointestinal (GI) intolerance, and loss of consciousness. To better molecularly diagnose, trio-whole-exome sequencing (WES) was performed on the proband and her parents. Sanger sequencing was also applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ADPRHL2 protein were predicted. All basic metabolic tests were normal, while serial coronal magnetic resonance imaging (MRI) showed progressive cerebral and cerebellar atrophy in addition to cerebral white matter signal changes as a novel neuroimaging finding. GI intolerance was another novelty of clinical scenarios in the patient. An auditory brainstem response test showed a severe bilateral sensorineural hearing loss. An electroencephalogram also confirmed focal seizures. From the molecular perspective, a novel homozygous frameshift variant in the ADPRHL2 gene (NM_017825.2; c.636_639del, p.(Leu212fs)) was identified by WES. Conclusions: CONDSIAS is an ultra-rare neurodegenerative disorder. In the present study, we introduced extraneurological and neuroimaging findings of this disorder in a female child caused by a novel frameshift variation in the ADPRHL2 gene.

Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response

“…In addition, we observed similar increased panADPr in V335G fibroblast after H 2 O 2 exposure as previously shown (Figs 3C and E and 5A and C) (Danhauser et al, 2018). All mutations presented thus far seem to cause at least a severe reduction of ARH3 protein levels; however, it is these (potentially) hypomorphic alleles such as V335G and possibly T79P, for which there is some protein detected that might also rely on a different underlying pathomechanism (Danhauser et al, 2018;Ghosh et al, 2018;Aryan et al, 2020).…”

“…Recently, recessive ADPRHL2 (ADPRS) mutations, encoding the ARH3 protein, were shown to cause a congenital-onset neurodegenerative stress-induced (epileptic) ataxia syndrome with early pediatric onset (CONDSIAS) (Danhauser et al, 2018;Ghosh et al, 2018;Aryan et al, 2020). The neuronal vulnerability in humans is mirrored in model organisms where knockouts of a Parg homolog in Drosophila melanogaster leads to larval-stage lethality but when grown at permissive temperatures show reduced locomotion, PAR accumulation, global neurodegeneration, and premature death (Hanai et al, 2004).…”

ADP-ribosylation of RNA and DNA: fromin vitrocharacterization toin vivofunction

“…Besides PAR, ARH3 efficiently uses O AADPr as a substrate ( 98 , 101 ). Various inactivating mutations in the ADPRHL2 gene have been identified in individuals with neurodegenerative disease ( 102–104 ), hinting at the importance of ARH3. It is not understood yet how loss of functional ARH3 would lead to this phenotype.…”

New Imaging and Clinical Manifestations of NDMSBA Disorder Caused by a Novel Homozygous Missense Variant of PLAA

“…The DNA sample was sequenced on an Illumina HiSeq 4000 to obtain an average coverage depth of ~ 100×. Bioinformatics analyses and ltering steps were taken forward according to the previous studies [47,54].…”