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

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM # 618170) is a rare disorder first described in 2018 [1, 2]. The onset is often triggered by biological stress such as fever, infection, or trauma after a normal early motor and cognitive development. The presentation and the course of the disease are highly variable. Symptoms may include seizures, developmental delay, ataxia, gait and oculomotor abnormalities, cognitive regression, episodic involuntary movements, axonal sensorimotor polyneuropathy, psychiatric presentations, scoliosis, respiratory failure, and even autonomous nervous system dysfunction [1‒11]. Autosomal recessive transmission of pathogenic and likely pathogenic variants in the gene of adenosinediphosphate-ribosylserine hydrolase (ADPRS) that encodes the ADP-ribosylhydrolase 3 (ARH3) enzyme underlie the disorder [3, 11]. Along with their own patient, Lindskov et al. [11] estimated 44 reported cases with CONDSIAS, which figure might be around 50 by the time of this report. We are not aware of any histopathological evaluation of the nervous system among them, though the histology of a muscle biopsy suggesting myopathy has been presented [10]. Here we report two brothers with CONDSIAS with clinical, genetic, and neuropathological characteristics and highlight the utility of whole exome sequencing (WES) in rapidly establishing the diagnosis.

The proband is a 25-year-old white male. His prenatal, perinatal, and early postnatal development were uneventful. At 3 years of age, he had a febrile seizure followed by progressive neurological deterioration with slowed motor and cognitive development. At 5 years of age, he had ataxic movements that prompted neurological evaluation with the resultant diagnosis of hereditary ataxia. From 9 years of age, he was under the care of a pediatric neurologist for progressive spastic ataxia, speech problems, and cognitive limitations. Currently, he can walk short distances with bilateral support but need wheelchair for longer distances. His speech is limited to a small vocabulary. He has interest in music and playing games, but is unable to live independently.

MRI of the brain in 2013 showed no alteration. His regular cardiology monitoring revealed no abnormalities.

Analyses of FXN and genes of SCA1, 2, 3, 6, and 7 as well as of those of neurodegeneration with brain iron accumulation subtypes (MPAN, PLAN, and PKAN) revealed no pathogenic mutations. His blood counts, serum ions, liver and renal function, serum albumin, cholesterol, TSH, and urine analyses were normal.

The patient presented as a well-developed young man with moderate obesity and kyphoscoliosis. His vision, color vision, and visual field appeared intact. He had no double vision. Horizontal gaze in both directions was associated with horizontal nystagmus. Voluntary eye movements showed apraxia, while conducted eye movements revealed slowed pursuit and undershooting. Episodic perioral mini-myoclonus occurred. Cranial nerves were otherwise normal. Muscle tone, mass, and strength were normal in the upper extremities. Mild spasticity was detectable in the lower extremities, with a 4/5 strength in both proximal and distal muscles. Deep tendon reflexes were symmetric and 1+ throughout. Babinski’s sign could not be elicited. Both upper and lower extremities showed moderate appendicular ataxia and intention tremor. Alternating movements were slow. Standing and ambulation could only be carried out with bilateral help. His gait was paretico-ataxic. Speech was markedly dysarthric with scanning components and short sentences. Besides intellectual regression, he was alert, and grossly oriented in time and space. He had a shy, but cheerful disposition.

The supratentorial brain regions were appropriate for his age, except for subtle periventricular and deep white matter hyperintense signal abnormalities notable on axial T2/FLAIR sequences. The cerebellum, particularly the vermis, was significantly atrophied. The cerebellar foliae were very thin. No other intracerebral structural abnormality, iron deposition, or diffusion alteration could be seen (Fig. 1a, b).

Significant kyphoscoliosis with convexity to the left was observed. The myelon and the craniospinal region were without alterations (Fig. 1c, d).

In both lower extremities, axonal motor neuropathy was detected with large amplitude and polyphasic motor unit potentials in the affected muscles.

The parents are unrelated and healthy. The extended family history is negative for neurologic disorders. The proband’s older brother had similar, but more severe neurological symptoms, and died at 17 years of age.

Neuropathology workup: the Purkinje cells disappeared from most of the vermis, and the number of the cells was significantly reduced in the granular layer. In the cerebellar cortex, the changes were less pronounced, and only a few Purkinje cells were missing. Some cells of the dentate nucleus and inferior olives had undergone chromatolysis, and most of them were swollen. The cerebellar white matter showed no pathology (Fig. 2a–c). The anterior horn cells in the spinal cord were swollen due to chromatolysis, and their numbers were significantly reduced. Cell reduction could also be seen in Clark column (Fig. 2d). The dorsal columns were demyelinated, indicating the involvement of the sensory pathway. Demyelination could also be observed in the spinocerebellar tracts (Fig. 2e). The pyramidal tracts were intact. Secondary to the anterior horn cell lesions, neurogenic muscle atrophy was seen in the quadriceps muscle (Fig. 2f). The histological changes were suggestive of Friedreich’s ataxia, as was the severe degree of kyphoscoliosis.

Autopsy also revealed the immediate cause of death was acute pulmonary edema, likely caused by acute cardiac failure. Other postmortem findings included ventricular and atrial dilatation in the heart and hyperemia in all internal organs.

DNA was extracted from peripheral blood leukocytes by using the QIAamp^® DNA Mini Kit (Qiagen, Hilden, Germany). Whole exome libraries were prepared by using the xGen DNA Library Prep Kit (Integrated DNA Technologies Inc. [IDT], Coralville, IA, USA). DNA was enzymatically fragmented and the ends treated to allow adapter ligation and PCR amplification. The xGen Exome v2 Panel probes (IDT) were applied for exome capture. The libraries were then quality checked by TapeStation 4200 (Agilent Technologies, Santa Clara, CA, USA) and quantified by Qubit 3.0 (Invitrogen, Waltham, MA, USA) followed by sequencing on a NovaSeq 6000 machine (Illumina Inc., San Diego, CA, USA) for 2 × 150 paired end reads.

Bioinformatic analysis was carried out by using the VarSeq software (Golden Helix Inc., Bozeman, MT 59715, USA). A homozygous pathogenic missense variant was detected in the 6/6 exon of the ADPRS gene on chromosome 1 at position 36,558,899, NM_017825.3: c.1004T>G, NP_060295.1: p.V335G (PM2_Moderate, PP3_Supporting, PS3_Strong, PM3_Moderate, PP1_Strong, PP4_Supporting). The two unrelated parents (as defined by analyzing 25,000 SNPs) were heterozygous carriers of the same variant.

Clinical (ataxia, corticospinal signs, peripheral neuropathy, kyphoscoliosis) and histopathological characteristics (neurodegeneration affecting the Clark and dorsal columns, spinocerebellar tracts, dentate nuclei) of CONDSIAS in our patients resemble those of Friedreich’s ataxia. Prior to the description of CONDSIAS, the clinical work up primarily intended to place the observed condition within the spectrum of autosomal recessive ataxias, and the differential diagnosis often involved many years of futile pursuit, as in our case too. WES allowed us to rapidly identify the c.1004T>G, p.V335G missense pathogenic variant in both alleles of ADPRS gene in the proband and in heterozygous state in the unrelated parents. This variant has also been described in homozygous state in several other patients with CONDSIAS from various ethnic backgrounds [1, 2, 5, 11]. In addition to pathogenic missense variants, splice site, frameshift, and nonsense variants as well as in-frame deletions also have been detected in ADPRS, causing loss of function in the gene product, ARH3. This enzyme cleaves poly-ADP-ribose from serine residues. ADP ribosylation is a posttranslational modification of proteins in various pathways including DNA repair, transcription, translation, and histone modification [11, 12]. Upon DNA damage, poly-ADP-polymerases (PARP) bind to the site of damage and modify themselves as well as other proteins by the addition of mono- and poly-ADP ribose, which elicits DNA repair. Several enzymes, including ARH3, participate in the removal of excessive mono- and poly-ADP-ribose to reestablish cellular physiology. In the context of biological stress, loss of ARH3 function contributes to a harmful accumulation of poly-ADP-ribose leading to neuronal death, the cellular mechanism underlying CONDSIAS [2, 11]. While restoration of the lost ARH3 function would require molecular or gene therapy, counterbalancing the harmful accumulation of poly-ADP-ribose by the means of PARP inhibitors has been considered to treat neurodegenerative disorders [2, 11, 13]. PARP inhibitors are approved for the treatment of various cancers [13, 14], and their benefit in preclinical models of ARH3-deficient neurodegenerative disorders has been suggested [2, 15]. Repurposing a PARP inhibitor, minocycline, in a patient with CONDSIAS was recently reported, but the outcome remains to be seen as there are no consistent data on its possible clinical benefits in human patients [11]. Nevertheless, these efforts give some hope for the development of a pathway and disease-modifying drug in the near future.

We presented clinical, genetic, and pathological characteristics of CONDSIAS in two Hungarian brothers. This is the first report including histopathological signs of the disease. The detected ADPRS pathogenic variant is rare, yet it was found in heterozygous states in the unrelated parents and in homozygous state in the proband, just as in several other patients of various ethnic backgrounds. As the biological role of the affected ARH3 enzyme is well understood, therapeutic correction of its functional loss and restoration of cell biology in an early stage of the disease may not be beyond unrealistic expectations. Care Checklist: the CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539954).

Whole exome sequencing and bioinformatic analyses were performed in collaboration with iBioScience Ltd. and the Hungarian Centre for Genomics and Bioinformatics (GenBio) at the Szentagothai Research Centre of the University of Pecs. The authors thankfully acknowledge the internal funding of whole exome sequencing provided by the Markusovszky University Teaching Hospital.

The study and the manuscript submission were approved by the Director and the Regional Ethics Committee of the Markusovszky University Teaching Hospital, Szombathely, Hungary (No. 6/2024). We certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Since the proband is incapable of giving consent, and his brother passed away long time ago, the proband’s mother provided consent for the clinical and genetic studies. Written informed consent was obtained from the proband’s mother for publication of the details of their medical case and any accompanying images.

All authors have no conflicts of interest to declare.

This study was not supported by any sponsor or external funder. The Markusovszky University Teaching Hospital, Szombathely, Hungary, provided internal financial support for the work involved in whole exome sequencing.

Conceptualization: Bernadette Kalman; methodology: Balazs Tolvaj, Marton Tompa, Arpad Vadvari, Nora Feher, and Zsuzsanna Kiss; formal analysis and investigation: Marton Tompa and Bernadette Kalman; writing – original draft preparation, resources, and supervision: Bernadette Kalman; writing – review and editing: Marton Tompa and all authors; and funding acquisition: NA.

All data generated and analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.