This report describes 'neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures' (CONDSIAS); CONDSIAS exhibits autosomal recessive inheritance. The human gene implicated in this disease is ADPRS (previously ADPRHL2), a member of the ADP-ribosylglycohydrolase family; this family encodes proteins that participate in regulation of stress response pathways. There are multiple members of this gene family in human; there is one in Drosophila, Parg, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and a loss-of-function allele caused by imprecise excision of a TE insertion have been generated.
A UAS construct of wild-type human Hsap\ADPRS has been introduced into flies. Heterologous rescue (function complementation) of loss-of-function mutations of Dmel\Parg is observed: ubiquitous expression of Hsap\ADPRS significantly reduces premature death and climbing defect phenotypes. Pharmacological inhibition of poly(ADP-ribose) polymerase results in dose-dependent partial rescue of Dmel\Parg phenotypes.
Animals homozygous for a loss-of-function mutation of Dmel\Parg typically die in the larval stage; some survive to adulthood and exhibit poly-ADP ribose accumulation, neurodegeneration, reduced locomotion with climbing defects, and premature death. Ubiquitous knockdown of Parg effected by RNAi results in decreased survival when the animals are exposed to oxidative stress (hydrogen peroxide in their water or environmental hypoxia); knockdown of Parg specifically in neurons largely recapitulates this phenotype. A small number of genetic interactions have been described for Dmel\Parg; see the Parg gene report.
[updated Aug. 2020 by FlyBase; FBrf0222196]
[NEURODEGENERATION, CHILDHOOD-ONSET, STRESS-INDUCED, WITH VARIABLE ATAXIA AND SEIZURES; CONDSIAS](https://omim.org/entry/618170)
[ADP-RIBOSYLHYDROLASE-LIKE 2; ADPRHL2](https://omim.org/entry/610624)
Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. Patient have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy (summary by Ghosh et al., 2018; pubmed:30100084).
Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is caused by homozygous mutation in the ADPRHL2 gene.
ADP-ribosylation is a tightly regulated posttranslational modification of proteins involved in various essential physiological and pathological processes, including DNA repair, transcription, telomere function, and apoptosis. Poly-ADP-ribosylated proteins can subsequently initiate cellular stress response pathways. After resolution of the original insult, ADP-ribose polymers are rapidly removed by poly(ADP-ribose) polymerases. (FBrf0239965 and references cited therein).
This gene encodes a member of the ADP-ribosylglycohydrolase family. The encoded enzyme catalyzes the removal of ADP-ribose from ADP-ribosylated proteins. Poly(ADP-ribose) synthesized after DNA damage is present transiently; it is rapidly degraded by poly(ADP-ribose) glycohydrolase. This enzyme localizes to the mitochondria, in addition to the nucleus and cytoplasm. [Gene Cards, ADPRHL2; 2019.02.11]
No Drosophila ortholog of human ADPRS is identified by ortholog prediction algorithms. The sole poly(ADP-ribose) glycohydrolase in flies, Dmel\Parg, appears to be functionally analogous: human ADPRS is able to rescue loss-of-function phenotypes of Dmel\Parg (FBrf0239965).
Dmel\Parg is the sole poly(ADP-ribose) glycohydrolase in flies. It is identified as a moderate-scoring ortholog of human PARG and BPHL. Based on heterologous rescue (functional complementation), it is also functionally analogous to human ADPRS (FBrf0239965).
