Who We Are
We are a 510(c)(3) foundation dedicated to patients, families and caregivers living with the ultra rare neurodegenerative disorder CONDSIAS. We are here to foster connection, build awareness, advance research and find a cure for CONDSIAS.
What is CONDSIAS?
CONDSIAS (Childhood Onset Neurodegeneration, Stress-Induced with Variable Ataxia and Seizures) is an ultra-rare autosomal recessive neurodegenerative disorder. There are currently less than 40 known patients in the world. The disorder occurs when a child inherits two variations in the ADPRS (also known as ADPRHL2) gene, one from each of their parents. Children with CONDISAS develop typically for some time before symptoms start to appear. Symptoms vary widely, but are known to include seizures, ataxia, developmental regression, cognitive impairment, peripheral neuropathy (nerve problems), hearing loss, dystonia, musculoskeletal abnormalities (Scoliosis, foot deformities), and ocular problems, among others.
CONDSIAS is progressive and symptoms get worse over time, most often in response to illness, fever, infection or other stress on the body. Because of that, progression is often cyclic, and patients can have episodes of stability and even symptom improvement between periods of decline. More research is needed to understand why some patients deteriorate faster and die early in the disease’s progression, while others have lived into their teen and early adult years.
CONDISAS is diagnosed through genetic testing (whole exome sequencing) and identification of a monogenic pathogenic mutation in ADPRS. Many gene variants have been identified as causing CONDSIAS. More research is needed to understand what role each gene variant plays in disease severity and progression.
There is currently no established treatment or cure for CONDSIAS, but there is hope.
Have you or a loved one been diagnosed with CONDSIAS? CONTACT US
What’s does the ADPRS (ADPRHL2) gene do?
ADPRS (or ADPRHL2) refers to the ADP-ribosylserine hydrolase gene and the enzyme it encodes. It is involved in DNA repair, and gives the instructions to make an enzyme called ARH3.
When our DNA gets damaged by stress, illness, toxins, aging, etc. the cell attaches special “tags” called poly-ADP-ribose molecules (PAR) onto certain proteins. These tags act as a marker to signal where the DNA needs repair. PARylation, or poly-ADP-ribosylation, is a post-translational modification where multiple ADP-ribose (ADPr) units are covalently added to proteins by a family of enzymes called PARPs (poly(ADP-ribose) polymerases). ARH3’s job is to clear those ADP-ribose tags when they’re no longer needed. If too much PAR builds up, it confuses the cell and can trigger cell death.
Variations in the ADPRS gene affect its ability to make ARH3, causing a buildup of PAR, triggering cell death and causing CONDSIAS.
THIS IS WHERE THERE’S HOPE
Currently there are drugs on the market called PARP1 inhibitors. These drugs keep PARP1 from creating PAR, which can prevent the excessive buildup that leads to cell death in patients with CONDSIAS. PARP1 inhibitors were developed for and are used in cancer treatment, but there are some antibiotics (Doxycycline and Minocycline) that happen to also inhibit PARP and have been used off-label in patients with CONDSIAS. Research is needed to determine their efficacy and long term safety, and if a more potent PARP inhibitor might lead to better outcomes.
Our Research Roadmap
(under construction)
The current understanding of the ADPRS gene and CONDSIAS lead us to some excellent avenues for research that have potential to move us toward effective therapies and even a cure.
Prevailing theories in loss-of-function (LoF) mutation characterization show elevated ADP-ribose levels under stress conditions compared to WT, indicating that the DNA damage response mediated by ARH3 is significantly impaired in the disease state.
Priority 1 - SMALL MOLECUE REPURPOSING PROJECT:
We are looking for partners to help us build on research into existing PARP inhibitors and their potential efficacy as a treatment for CONDSIAS.
Existing research tools include a heterozygous KO mouse model and a homozygous
KO mouse model, as well as cell viability assays.
Priority 2 - GENETIC MEDICINE INTERVENTIONS: we’re exploring ASO approaches for nonsense variants.
Concurrently, we’re working on PATIENT INFORMATION COORDINATION: putting together a patient registry and finding a partner to conduct a natural history study are high priority.
Stay updated on the latest research regarding CONDSIAS
Lenny is an energetic, imaginative and determined kiddo, whose development was completely typical until about four months before his fourth birthday. He suddenly began experiencing strange attacks during which he seemed to lose control of his head and neck, affecting his overall coordination and balance. Initially diagnosed with a benign movement disorder, we knew something else was going on when he started having more severe, longer and more frequent attacks in conjunction with a strep infection. That infection was followed by deterioration in his gait, speech, behavior and cognitive skills. Genetic testing was ordered and a few months later we had the answer: CONDSIAS. Like so many rare disease families, we were told there was no treatment and no cure, and we should try to give him as normal a life as possible. But we knew we could do better than that, for him and for everyone else dealing with this awful disorder.
CONDSIAS is just one of the 10,000 distinct types of rare and genetic diseases that affect 400 million people worldwide. Half the patients diagnosed with rare diseases are children, and 3 in 10 of them will not live to see their fifth birthday. Research into rare diseases and the genes involved with them expands our knowledge of ALL diseases, and our ability to treat and cure them. Understanding of CONDSIAS and the ADPRS gene directly relates to certain cancers and other forms of neurodegeneration. This research doesn’t just benefit rare disease families; it improves medicine for everyone.
Lenny’s best friend and bedtime companion since he was a baby is his tiger lovie. The tiger symbol represents the fierceness with which we are fighting to make life better for everyone living with CONDSIAS, and our determination to find a cure.
“Life is mysterious and amazing…
but we have work to do now.”
Ponyo, Hayao Miyazaki, 2009
About Lenny
Photos by Krista Mason