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

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 extra-neurological and neuroimaging findings of this disorder in a female child caused by a novel frameshift variation in the ADPRHL2 gene.