Child-Onset Cerebellar Ataxia Caused by Two Compound Heterozygous Variants in ADPRS Gene: A Case Report

Abstract

Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions.Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic.Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.

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

“…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. 11,16 Four of them showed stress-related episodic psychosis, ataxia, motor neuropathy, and pyramidal abnormalities.…”

“…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.…”

“…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.…”

“…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.…”

“…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.…”