| Domain | Curated finding | Evidence type | Key source |
|---|---|---|---|
| Identity / variant | Autosomal dominant sensory ataxia 1 maps to MONDO:0012166 and is associated with RNF170; dominant disease is consistently linked to the heterozygous RNF170 c.595C>T (p.Arg199Cys) variant. Distinct disorder: biallelic RNF170 variants cause autosomal recessive hereditary spastic paraplegia (HSP), not ADSA1. | Aggregated disease-target mapping + human genetics | Open Targets disease-target association; human reports and review synthesis (pqac-00000000, pqac-00000002, pqac-00000003) |
| Phenotype / onset | Core dominant phenotype is late-onset, slowly progressive sensory ataxia with sensory loss and gait imbalance; reported onset spans ages 35, 47, 55, 64, and 68 in described families, with broader literature range in the 4th-8th decades. Variable pyramidal involvement occurs; vestibular areflexia can occur and mimic CANVAS in some patients. | Human family/case reports | Belgian family, Ecuadorian family, review of prior Canadian families (pqac-00000001, pqac-00000003, pqac-00000006) |
| Neurophysiology / MRI | Dominant RNF170 disease shows posterior-column / preganglionic sensory pathway dysfunction: impaired or absent SSEPs are common; SNAPs may be preserved in classic cases but reduced/absent in some families, indicating phenotypic variability with possible sensory ganglionopathy. Brain MRI may be normal without cerebellar atrophy; cervical spine MRI can show posterior-column T2 hyperintensity/volume loss; spine MRI may also be normal in some affected relatives. | Human clinical neurophysiology/imaging | Ecuadorian CANVAS-mimic family; Belgian family; comparative discussion (pqac-00000005, pqac-00000006, pqac-00000016) |
| Mechanism | RNF170 is an ER-membrane E3 ubiquitin ligase that, with ERLIN1/ERLIN2, mediates ubiquitination-dependent degradation of activated IP3 receptors (ITPRs) via ERAD/proteasomal turnover, thereby regulating ER Ca2+ signaling. For dominant p.Arg199Cys ADSA1, available evidence supports protein destabilization with increased auto-ubiquitination and a likely toxic gain-of-function mechanism; precise sensory-neuron selectivity remains unresolved. | Cell/mechanistic studies + pathway inference + human genetics | RNF170/ITPR pathway and dominant-vs-recessive contrast (pqac-00000003, pqac-00000008, pqac-00000009, pqac-00000010) |
| Inheritance / epidemiology | Inheritance is autosomal dominant for ADSA1. Known dominant evidence remains sparse: historically two Eastern Canadian families, later one Ecuadorian family, and one Belgian/European family. Founder haplotype was reported in Canadian families; common ancestry across all families is unclear. Reduced penetrance or de novo occurrence has been considered in one pedigree. No robust prevalence, incidence, sex ratio, or population allele-frequency estimates were identified. | Human pedigree studies; evidence gap for population metrics | Founder and family-count discussion (pqac-00000002, pqac-00000013, pqac-00000015) |
| Diagnosis | Diagnostic clues: dominant family history, progressive sensory ataxia, posterior-column signs, impaired proprioception/vibration, reduced or absent reflexes, abnormal SSEPs, and/or sensory neuronopathy with normal motor conduction. RNF170 testing should be considered in RFC1-negative CANVAS-like cases and included in ataxia gene panels, especially after excluding repeat expansions and common acquired causes. | Human case reports + expert diagnostic recommendation | CANVAS-mimic report and Belgian panel recommendation (pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000017) |
| Differential diagnosis | Important differentials include RFC1-related CANVAS, Friedreich ataxia, POLG-related mitochondrial disease, vitamin E deficiency, abetalipoproteinemia, spinocerebellar ataxias with neuropathy, Charcot-Marie-Tooth disease 4C, paraneoplastic sensory neuronopathy, autoimmune causes such as Sjögren syndrome, and toxic neuropathies (eg, cisplatin, pyridoxine). | Human report / review-level clinical differential | Differential lists from case/family reports (pqac-00000015, pqac-00000017) |
| Prognosis / disability | Disease course is chronic and progressive. Functional disability can become substantial; in the Ecuadorian index case, gait deterioration progressed over a decade and required a walking aid by age 57. No survival, mortality, or formal quality-of-life datasets specific to ADSA1 were found. | Human case report + evidence gap | Progressive disability in case report; no cohort outcomes (pqac-00000001, pqac-00000013) |
| Therapy / trials | No disease-modifying therapy, genotype-guided treatment, or disease-specific biomarker has been established for ADSA1. No relevant registered interventional clinical trials were identified in the tool search. Current care is supportive/extrapolated: rehabilitation, balance and fall-prevention strategies, mobility aids, symptomatic management, and genetic counseling/cascade testing. | Evidence gap + standard rare-neurology supportive practice extrapolation | Negative trial search and absence in case literature (pqac-00000013, pqac-00000014) |
| Models | Mouse: Rnf170-null mice develop age-dependent gait abnormalities, supporting a role in motor/sensory pathway integrity, but this is a loss-of-function model and does not fully replicate dominant p.Arg199Cys disease. Zebrafish: dominant p.Arg199Cys shows dose-dependent toxicity; separate knockdown/overexpression studies support RNF170 developmental and neuronal functions. Dog: a 2024 naturally occurring recessive RNF170 frameshift model in Miniature American Shepherds causes neuroaxonal dystrophy; 23/27 homozygotes (85%) were clinically affected, providing a large-animal model of the broader RNF170 phenotypic spectrum, not a direct ADSA1 model. | Mouse, zebrafish, canine models | Mouse/zebrafish/canine model evidence and limitations (pqac-00000007, pqac-00000008, pqac-00000011) |
| Evidence gaps | No convincing evidence was found for environmental or infectious causes, protective factors, gene-environment interactions, formal diagnostic criteria, disease-specific omics biomarkers, epigenetic signatures, prevention trials, or established targeted therapies for ADSA1. | Explicit absence of evidence | Across retrieved ADSA1 literature and searches (pqac-00000013, pqac-00000014, pqac-00000015) |


*Table: This table summarizes the main curated findings for Autosomal Dominant Sensory Ataxia 1, emphasizing that the dominant disorder is specifically linked to heterozygous RNF170 p.Arg199Cys and is distinct from biallelic RNF170 hereditary spastic paraplegia. It also highlights the strongest available clinical and mechanistic evidence while clearly labeling major evidence gaps.*