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Classifications

Harrison's Chapter

🔗

Mappings

MONDO

MONDO:0012166 autosomal dominant sensory ataxia 1

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Inheritance

1

Autosomal dominant HP:0000006

ADSA segregates as an autosomal dominant trait in every reported kindred: two founder-related families from Maritime Canada, a Belgian family, and an Ecuadorian family, all carrying the same heterozygous RNF170 p.Arg199Cys allele. Onset is late (fifth to seventh decade), so apparently unaffected younger relatives cannot be scored as non-penetrant; age-dependent penetrance is therefore not established and no penetrance figure is asserted.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:32943585 SUPPORT Human Clinical

"By exome-sequencing we have identified the same p.Arg199Cys RNF170 mutation in an Ecuadorian family affected by an autosomal dominant late-onset progressive sensory ganglionopathy."

An independent third kindred confirms dominant transmission of the same allele.

PMID:32943585 SUPPORT Human Clinical

"Two sisters III-2 and III-4, aged 58 and 49, are reportedly unaffected but given the late onset of the disease were not considered for segregation analysis."

Documents why apparent non-penetrance cannot be scored in this late-onset disorder.

◈

Mechanistic Hypotheses

3

p.Arg199Cys Toxic Gain-of-Function / Dominant-Negative Model

r199c_toxic_gain_of_function EMERGING

Evidence balance 3 support

The currently favoured but unproven explanation for dominance. Because heterozygous carriers of RNF170 nonsense alleles are unaffected, losing one functional copy of RNF170 cannot by itself cause sensory ataxia; the p.Arg199Cys protein must therefore do something a null allele does not. Candidate mechanisms are a toxic property of the misfolded, unstable mutant protein, or a dominant-negative action on the erlin1/2-RNF170 complex in which the destabilised mutant poisons the complex or perturbs its stoichiometry. The strongest positive evidence is the dose-dependent dominant developmental toxicity of mutant RNF170 mRNA in zebrafish embryos. This model, not simple haploinsufficiency, is what the field currently regards as plausible, but no specific toxic species or poisoned complex has been demonstrated, and the zebrafish readout is embryonic development rather than adult sensory neurodegeneration.

Pathograph links

RNF170 Protein Destabilization by Enhanced Autoubiquitination -> Dysregulated ER Calcium Release in Sensory Neurons INDIRECT UNKNOWN INTERMEDIATES Alternative routes that bypass the IP3-receptor-ERAD step: a toxic property of the unstable mutant protein, or mis-ubiquitination of an unidentified non-IP3-receptor substrate. Both are invoked because the observed patient calcium defect is demonstrably not explained by defective IP3 receptor ubiquitination.

Show evidence (3 references)

PMID:32943585 SUPPORT Human Clinical

"Although the exact mechanism remains elusive, a toxic gain of function seems plausible and is supported by the dose-dependent toxicity of RNF170 Arg199Cys in zebrafish larvae"

States the hypothesis and its supporting model-organism observation while explicitly flagging that the mechanism is unresolved.

PMID:21115467 SUPPORT Model Organism

"Microinjection of wild-type or mutant orthologous messenger RNAs into zebrafish (Danio rerio) embryos confirmed that the mutation dominantly disrupts normal embryonic development."

Direct experimental demonstration that the mutant allele acts dominantly in a model organism.

PMID:32943585 SUPPORT Human Clinical

"However, both the clinical phenotype, with primary involvement of upper motor neurons vs dorsal root ganglia sensory neurons, and the disease-causing mechanism, loss-of-function vs toxic gain-of-function, differ between RNF170 HSP and autosomal dominant sensory ataxia, respectively."

Contrasts the recessive loss-of-function disease with the proposed toxic gain-of-function mechanism of the dominant disease.

RNF170 Haploinsufficiency Model

rnf170_haploinsufficiency ALTERNATIVE

Evidence balance 1 support 1 refute

The straightforward reading of the biochemistry: p.Arg199Cys destabilises RNF170, lowering its steady-state level, and reduced RNF170 dosage impairs IP3 receptor ERAD in vulnerable sensory neurons. It is retained here because the loss-of-expression biochemistry is solid in patient-derived cells and because Rnf170-null mice reproduce proprioceptive and gait deficits. It is nevertheless disfavoured as the primary disease mechanism: heterozygous carriers of RNF170 nonsense alleles, who are unambiguously haploinsufficient, are clinically unaffected, and their biallelic relatives develop spastic paraplegia rather than sensory ataxia.

Pathograph links

RNF170 Protein Destabilization by Enhanced Autoubiquitination -> Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD DIRECT Under the reduced-dosage reading, less RNF170 means less IP3 receptor ubiquitination capacity at the ER membrane.

Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD -> Dysregulated ER Calcium Release in Sensory Neurons DIRECT

Show evidence (2 references)

PMID:25882839 SUPPORT In Vitro

"Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation."

Establishes the reduced-dosage premise of the haploinsufficiency model in patient-derived cells.

PMID:32943585 REFUTE Human Clinical

"Indeed, despite previous evidence of reduced stability and expression level of mutant Arg199Cys RNF170 haploinsufficiency is unlikely to be the primary disease since heterozygous carriers of nonsense variants in RNF170 were later shown to be unaffected"

Human genetic evidence directly against haploinsufficiency as the primary mechanism.

Non-IP3-Receptor Substrate Dysregulation Model

non_ip3r_substrate_dysregulation EMERGING

Evidence balance 2 support

Patient lymphoblasts show a genuine functional defect in agonist-evoked Ca2+ mobilisation, yet this defect cannot be attributed to aberrant IP3 receptor ubiquitination: mutant RNF170 attaches the full normal complement of ubiquitin conjugates to activated IP3 receptors, and receptor levels, store content and IP3 production are all unchanged. The authors of that work therefore proposed that the pathogenic consequence lies with other, still unidentified RNF170 substrates, or is an adaptive response to chronically reduced RNF170. Under this model the IP3 receptor is a marker of the pathway rather than the critical substrate, and identifying the true substrate is the central open problem.

Pathograph links

RNF170 Protein Destabilization by Enhanced Autoubiquitination -> Dysregulated ER Calcium Release in Sensory Neurons INDIRECT UNKNOWN INTERMEDIATES Alternative routes that bypass the IP3-receptor-ERAD step: a toxic property of the unstable mutant protein, or mis-ubiquitination of an unidentified non-IP3-receptor substrate. Both are invoked because the observed patient calcium defect is demonstrably not explained by defective IP3 receptor ubiquitination.

Show evidence (2 references)

PMID:25882839 SUPPORT In Vitro

"Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels."

The primary functional study explicitly proposes non-IP3-receptor substrates as the likely explanation.

PMID:25882839 SUPPORT In Vitro

"wild-type and mutant RNF170 have apparently identical ubiquitin ligase activities toward IP3 receptors"

Shows the mutant is not deficient in its best-characterised catalytic activity, motivating the search for another substrate.

?

Discussions and Knowledge Gaps

3

Does the Rnf170-null mouse model autosomal dominant sensory ataxia, or does it actually model the recessive RNF170 spastic paraplegia, given that human heterozygous RNF170 null carriers are unaffected?

HUMAN MODEL MISMATCH OPEN adsa_null_mouse_models_recessive_not_dominant_disease

Attached to

pathophysiology#RNF170 Protein Destabilization by Enhanced Autoubiquitination pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD

Evidence exists in the model but its translational validity is the open question, which is why this is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap. Rnf170-/- mice do develop ADSA-like proprioceptive loss and age-dependent gait abnormality, which is superficially strong support for a loss-of-function mechanism. But the human genetics point the other way: heterozygous carriers of RNF170 nonsense alleles are clinically unaffected, and individuals homozygous for such alleles develop hereditary spastic paraplegia with upper-motor-neuron involvement rather than sensory ataxia. A complete-null mouse therefore corresponds genotypically to the recessive human disease, not to the heterozygous missense state that causes ADSA. The naturally occurring canine RNF170 frameshift model has the same problem: it segregates recessively and its authors propose it as a model of SPG85. Consequently the null-mouse phenotype cannot be used as evidence that ADSA is caused by loss of RNF170 function, and the concordance of its sensory phenotype with ADSA may reflect convergence on a shared vulnerable pathway rather than mechanistic identity. A further internal inconsistency: the null mouse accumulates Itpr1 most in cerebellum and spinal cord, yet the cerebellum is precisely the structure spared in the human disease. No p.Arg199Cys knock-in animal exists, so the dominant allele has never been modelled in its native heterozygous state.

Proposed experiments

Heterozygous Rnf170 p.Arg199Cys knock-in mouse versus null littermates

exp_adsa_r199c_knockin_mouse

Generate a knock-in mouse carrying the orthologous Rnf170 p.Arg199Cys allele and phenotype it in the heterozygous state alongside heterozygous and homozygous null littermates, scoring dorsal root ganglion neuronopathy, posterior column degeneration, proprioception and gait. If the heterozygous knock-in is affected while the heterozygous null is not, the allele acts by a mechanism other than haploinsufficiency.

Would support

pathophysiology#RNF170 Protein Destabilization by Enhanced Autoubiquitination

Test for dominant-negative poisoning of the erlin1/2-RNF170 complex

exp_adsa_dominant_negative_complex_assay

Determine whether mutant RNF170 co-assembles with the erlin1/2 complex and impairs wild-type RNF170 function in a heterozygous setting, which would distinguish a dominant-negative from a purely toxic misfolding mechanism.

Would support

pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD

Dorsal-root-ganglion-specific phenotyping in null and knock-in animals

exp_adsa_drg_specific_phenotyping

Phenotype dorsal root ganglion neurons specifically, rather than whole cerebellum or cord homogenates, in both null and knock-in animals, since the human lesion is a ganglionopathy and bulk-tissue readouts may have obscured the relevant cell population.

Would support

pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy

Show evidence (3 references)

PMID:26433933 SUPPORT Model Organism

"Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established."

The authors of the null mouse study themselves flag that the functional nature of the dominant human allele was unresolved, which is precisely the gap a null genotype cannot close.

PMID:32943585 REFUTE Human Clinical

"Indeed, despite previous evidence of reduced stability and expression level of mutant Arg199Cys RNF170 haploinsufficiency is unlikely to be the primary disease since heterozygous carriers of nonsense variants in RNF170 were later shown to be unaffected"

Human genetic evidence that the loss-of-function state modelled by the null mouse does not cause the dominant disease.

PMID:39177409 SUPPORT Model Organism

"RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein."

The other available large-animal RNF170 model is likewise recessive and is proposed by its authors as a model of the recessive human disease.

Why does a ubiquitously expressed ER ubiquitin ligase, when mutated, damage large dorsal root ganglion sensory neurons and the posterior columns specifically, while sparing the cerebellum and cortex?

KNOWLEDGE GAP OPEN adsa_selective_vulnerability_of_dorsal_root_ganglion_neurons

Attached to

pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy

RNF170 is broadly expressed and the erlin1/2-RNF170-IP3 receptor module operates in all cells, yet the human disease is remarkably restricted. The only mechanistic hint is regional: in Rnf170-null mice Itpr1 protein accumulates in cerebellum and spinal cord but not cerebral cortex, showing that the consequences of losing this pathway are already region-dependent at the biochemical level. That does not explain why large sensory neurons in the dorsal root ganglia are the cells that die in humans, and it sits awkwardly with the clinical sparing of the cerebellum. Nor does it explain why the closely related recessive disease targets upper motor neurons instead. No neuropathological study of dorsal root ganglia in ADSA has been reported, so the ganglionopathy is inferred entirely from electrophysiology and imaging, and selective vulnerability is the central unexplained feature of the disorder.

Proposed experiments

Cross-cell-type comparison of the erlin1/2-RNF170-IP3 receptor module

exp_adsa_cell_type_pathway_comparison

Compare RNF170, ERLIN1/2 and ITPR1 expression levels and IP3-receptor turnover kinetics across dorsal root ganglion sensory neurons, corticospinal motor neurons and cerebellar Purkinje cells, to test whether pathway dependency tracks the disease-vulnerable cell type.

Would support

pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy

Calcium handling in patient-derived iPSC sensory neurons

exp_adsa_ipsc_sensory_neuron_calcium

Measure agonist-evoked ER calcium release in patient-derived iPSC sensory neurons carrying p.Arg199Cys alongside isogenic controls and RNF170-null lines, to test whether the sensory-neuron lineage is disproportionately sensitive.

Would support

pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons

Neuropathological examination of ADSA dorsal root ganglia

exp_adsa_human_drg_neuropathology

Perform neuropathological examination of dorsal root ganglia and spinal cord from an affected individual. No such study has been reported, so the ganglionopathy is currently inferred entirely from electrophysiology and imaging.

Would support

pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy

Show evidence (1 reference)

PMID:26433933 SUPPORT Model Organism

"Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice."

Demonstrates that loss of this pathway has region-selective biochemical consequences, the only current clue to selective vulnerability.

If mutant RNF170 ubiquitinates IP3 receptors normally, what substrate actually mediates the calcium-signalling defect and the neurodegeneration?

OPEN QUESTION OPEN adsa_true_pathogenic_substrate_of_rnf170

Attached to

pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons

The assumption that ADSA is a disease of IP3 receptor ERAD is inherited from RNF170's known biochemistry, not demonstrated in patient cells. In ADSA lymphoblasts the calcium defect is real, yet mutant RNF170 attaches the full normal set of ubiquitin conjugates to activated IP3 receptors, and receptor level, store content and IP3 production are unchanged. The original investigators therefore concluded that the defect reflects abnormal ubiquitination of other, unidentified substrates or an adaptive response to chronically low RNF170. Identifying the operative substrate would determine whether ADSA is genuinely an IP3-receptor-turnover disease or a distinct ER quality-control disease that merely shares a gene with one.

Proposed experiments

Comparative ubiquitinome profiling of ADSA patient cells

exp_adsa_ubiquitinome_profiling

Perform comparative ubiquitinome or diGly proteomics on ADSA patient cells and isogenic controls to identify substrates whose ubiquitination is altered by p.Arg199Cys.

Would support

pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons

RNF170 interactome in the mutant versus wild-type state

exp_adsa_mutant_rnf170_interactome

Define the RNF170 interactome in the mutant versus wild-type state, including the erlin1/2 and TMUB1 scaffolds, to look for a poisoned complex.

Would support

pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD

Reproduce the calcium defect in the degenerating cell type

exp_adsa_calcium_defect_in_sensory_neurons

Determine whether the lymphoblast calcium defect is cell-autonomous and reproducible in sensory neurons, the cell type that actually degenerates, rather than only in an immortalised blood-derived lineage.

Would support

pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons

Show evidence (1 reference)

PMID:25882839 SUPPORT In Vitro

"Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels."

States the unresolved substrate question in the words of the study that created it.

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Pathophysiology

11

RNF170 p.Arg199Cys Transmembrane Destabilizing Substitution

The single molecular lesion of ADSA. Arginine 199 is a charged residue in a transmembrane region of RNF170; systematic point mutagenesis showed that ionic interactions between charged transmembrane residues are what hold the protein together, so replacing this arginine with cysteine removes a stabilising charge pair. The substitution does not damage the catalytic RING function.

RNF170 hgnc:25358

endoplasmic reticulum membrane GO:0005789

Downstream

RNF170 Protein Destabilization by Enhanced Autoubiquitination

Show evidence (2 references)

PMID:25882839 SUPPORT In Vitro

"The basis for these effects was probed via additional point mutations, revealing that ionic interactions between charged residues in the transmembrane domains of RNF170 are required for protein stability."

Explains why an arginine-to-cysteine change at position 199 destabilises the protein.

PMID:21610068 SUPPORT In Vitro

"RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity."

Establishes the membrane topology and ER localisation that make a transmembrane charge pair structurally relevant.

RNF170 Protein Destabilization by Enhanced Autoubiquitination

The destabilised mutant protein autoubiquitinates more avidly and is cleared by the proteasome, so steady-state RNF170 levels fall. This is seen both in cells transfected with mutant constructs and, importantly, in lymphoblasts from ADSA patients, establishing that the reduced-dosage state exists in patient tissue and is not an overexpression artefact.

Non-IP3-Receptor Substrate Dysregulation Model p.Arg199Cys Toxic Gain-of-Function / Dominant-Negative Model RNF170 Haploinsufficiency Model

protein autoubiquitination GO:0051865 ↑ INCREASED proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 ↑ INCREASED protein destabilization GO:0031648 ↑ INCREASED

Downstream

Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD Under the reduced-dosage reading, less RNF170 means less IP3 receptor ubiquitination capacity at the ER membrane.

Dysregulated ER Calcium Release in Sensory Neurons Alternative routes that bypass the IP3-receptor-ERAD step: a toxic property of the unstable mutant protein, or mis-ubiquitination of an unidentified non-IP3-receptor substrate. Both are invoked because the observed patient calcium defect is demonstrably not explained by defective IP3 receptor ubiquitination.

Show evidence (1 reference)

PMID:25882839 SUPPORT In Vitro

"Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation."

Directly documents enhanced autoubiquitination and proteasomal clearance of the mutant protein in patient-derived cells.

Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD

RNF170 is the E3 ligase arm of the ER quality-control module that disposes of activated IP3 receptors. On receptor activation the erlin1/2 (SPFH1/2) complex binds the third intralumenal loop of IP3R1 and recruits RNF170, which then attaches the mono-, K48- and K63-linked ubiquitin conjugates that commit the receptor to ERAD. Erlin1/2 binding is the rate-limiting first step and RNF170 recruitment depends on it. Reduced RNF170 availability slows this turnover pathway. This node states the canonical pathway; the evidence that mutant RNF170 actually fails at this step is weak, which is why the causal edge into it is hypothesis-tagged and the node carries PROVISIONAL confidence.

RNF170 Haploinsufficiency Model

RNF170 hgnc:25358 ITPR1 hgnc:6180 ERLIN1 hgnc:16947 ERLIN2 hgnc:1356 TMUB1 hgnc:21709

ERAD pathway GO:0036503 ↓ DECREASED protein K48-linked ubiquitination GO:0070936 ↓ DECREASED

ubiquitin protein ligase activity GO:0061630 ↓ DECREASED

endoplasmic reticulum membrane GO:0005789

Downstream

Dysregulated ER Calcium Release in Sensory Neurons

Show evidence (7 references)

PMID:21610068 SUPPORT In Vitro

"These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP(3) receptors where it mediates IP(3) receptor ubiquitination."

Establishes the erlin1/2-RNF170 module and its substrate.

PMID:21610068 SUPPORT In Vitro

"Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP(3) receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus-induced IP(3) receptor processing."

Loss-of-function experiments show that reduced RNF170 impairs IP3 receptor ubiquitination and degradation.

PMID:35568199 SUPPORT In Vitro

"The first and rate-limiting step in this process is thought to be the association of conformationally active IP3Rs with the erlin1/2 complex, an endoplasmic reticulum-located oligomer of erlin1 and erlin2 that recruits the E3 ubiquitin ligase RNF170"

Defines the order of events and identifies erlin1/2 binding as rate limiting for RNF170 recruitment.

+ 4 more references

Dysregulated ER Calcium Release in Sensory Neurons

The convergent functional abnormality, reached by whichever upstream route is correct. Patient lymphoblasts mobilise significantly less cytosolic Ca2+ in response to platelet-activating factor, while store content, receptor level and IP3 production are all normal — localising the defect to the IP3 receptor itself. In Rnf170-null mice Itpr1 protein accumulates in the cerebellum and spinal cord but not the cerebral cortex, showing that loss of this pathway perturbs IP3 receptor homeostasis in a regionally selective way. Note that this regional pattern does not map cleanly onto the human lesion, since the cerebellum is clinically and radiologically spared in ADSA.

sensory neuron of dorsal root ganglion CL:1001451

release of sequestered calcium ion into cytosol GO:0051209 ↓ DECREASED calcium-mediated signaling GO:0019722 ↕ DYSREGULATED

Downstream

Dorsal Root Ganglion Sensory Neuronopathy How a chronic, subtle perturbation of ER calcium handling selectively kills large dorsal root ganglion sensory neurons over decades is not established; no intermediate steps have been demonstrated in human tissue.

Variable Corticospinal Tract Involvement A minor, inconstant second target of the same pathway perturbation. Included because the recessive RNF170 disease injures upper motor neurons as its primary lesion, so the corticospinal tract is demonstrably vulnerable to disruption of this module; why it is only variably affected in ADSA is unknown.

Show evidence (3 references)

PMID:25882839 SUPPORT In Vitro

"In ADSA lymphoblasts, platelet-activating factor-induced Ca(2+) mobilization was significantly impaired, whereas neither Ca(2+) store content, IP3 receptor levels, nor IP3 production were altered, indicative of a functional defect at the IP3 receptor locus, which may be the cause of neurodegeneration."

Demonstrates a calcium-signalling defect in patient-derived cells and localises it to the IP3 receptor.

PMID:26433933 SUPPORT Model Organism

"Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice."

Shows region-selective IP3 receptor accumulation when the pathway is lost in vivo.

PMID:31636353 SUPPORT Human Clinical

"Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias"

Positions dysregulated IP3/calcium signalling as the shared pathway for RNF170-related neurodegeneration.

Variable Corticospinal Tract Involvement

A minor and inconstant arm of the disease. Some affected individuals show corticospinal signs (spasticity, hyperreflexia, extensor plantar responses) alongside the dominant sensory picture, while others have none and Babinski is explicitly absent. This node is deliberately kept small and PROVISIONAL: the entire human evidence base is a single "variable findings" clause, and no imaging or neuropathological demonstration of corticospinal degeneration in ADSA exists. It is modelled rather than omitted because it is the point of clinical contact with the recessive RNF170 disease (SPG85), in which upper-motor-neuron involvement is the primary lesion, and because it is what the curated Pyramidal Signs phenotype rests on.

corticospinal tract UBERON:0002707

Downstream

Progressive Sensory Gait Ataxia Where present, pyramidal involvement compounds the gait disorder, but the gait phenotype is sensory in origin and occurs without it.

Show evidence (2 references)

PMID:34469621 SUPPORT Human Clinical

"Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."

The sole human evidence for corticospinal involvement, and the reason this node is marked PROVISIONAL and OCCASIONAL rather than asserted as a core mechanism.

PMID:32943585 PARTIAL Human Clinical

"Babinski was absent."

The genotype-confirmed Ecuadorian index case had no corticospinal sign. This is tagged PARTIAL rather than REFUTE because the node's claim is already VARIABLE involvement, which an unaffected patient is consistent with rather than contradicting: the observation establishes the "variable" qualifier and refutes any obligate reading, while not supporting corticospinal involvement in this patient.

Dorsal Root Ganglion Sensory Neuronopathy

The primary cellular lesion is degeneration of large sensory neurons whose cell bodies lie in the dorsal root ganglia. Because the insult is at the cell body (a neuronopathy or ganglionopathy) rather than at the distal axon, both the centrally projecting branch (which forms the posterior columns) and the peripherally projecting branch degenerate. This is a non-length-dependent pattern, which is why sensory loss can involve the hands as prominently as the feet and why pseudoathetosis and areflexia dominate over distal weakness.

sensory neuron of dorsal root ganglion CL:1001451

dorsal root ganglion UBERON:0000044

Downstream

Posterior Column Degeneration

Peripheral Sensory Axon Degeneration

Vestibular Ganglion Sensory Neuron Degeneration Late and variable extension of the same sensory-neuron vulnerability to the vestibular (Scarpa's) ganglion.

Show evidence (2 references)

PMID:32943585 SUPPORT Human Clinical

"This finding, together with the MRI evidence of degeneration of posterior column, point to a primary involvement of sensory dorsal root ganglia, leading to degeneration of both central and peripheral branches of sensory neurons."

Directly infers dorsal root ganglion neuronopathy with dual-branch degeneration from combined electrophysiology and imaging in patients.

PMID:32943585 SUPPORT Human Clinical

"Sensory neuronopathy or ganglionopathy is a type of peripheral neuropathy characterized by primary and selective destruction of the dorsal root ganglia leading to degeneration of both central and peripheral neurites of sensory neurons"

Defines the neuronopathy pattern that the authors assign to RNF170 disease.

Posterior Column Degeneration

Loss of the centrally projecting branches of the degenerating dorsal root ganglion neurons produces the defining lesion of ADSA: atrophy and signal change in the dorsal columns of the spinal cord, demonstrable in life as reduced posterior-column volume with increased T2 signal on cervical cord MRI. These tracts carry proprioceptive and vibratory information, and their loss is the anatomical basis of the sensory ataxia.

spinal cord dorsal column UBERON:0005373

Downstream

Loss of Proprioceptive and Vibratory Afferent Input

Show evidence (2 references)

PMID:21115467 SUPPORT Human Clinical

"Autosomal dominant sensory ataxia is a rare genetic condition that results in a progressive ataxia that is caused by degeneration of the posterior columns of the spinal cord."

Establishes posterior-column degeneration as the defining lesion of the disease.

PMID:32943585 SUPPORT Human Clinical

"MRI of the cervical spine showed reduced volume and increased T2 signal of the posterior columns"

In vivo imaging confirmation of the posterior-column lesion.

Peripheral Sensory Axon Degeneration

Degeneration of the peripherally projecting branches of the affected dorsal root ganglion neurons, expressed electrophysiologically as reduced or absent sensory nerve action potentials with preserved motor conduction. This arm is genuinely variable across kindreds and is the main phenotypic difference between the reported families: the Maritime Canadian families had normal sensory nerve conduction (a purely central posterior-column picture), whereas the Ecuadorian family had absent sensory action potentials in all four limbs. The reason for this difference is unknown; a modifying genetic background has been proposed by the authors as a hypothesis, not demonstrated.

sensory neuron of dorsal root ganglion CL:1001451

Downstream

Loss of Proprioceptive and Vibratory Afferent Input

Show evidence (3 references)

PMID:32943585 SUPPORT Human Clinical

"Nerve conduction studies (NCS) showed absent sensory action potentials throughout. Motor nerve conduction was normal."

Documents selective peripheral sensory axon loss with motor sparing in an affected patient.

PMID:32943585 PARTIAL Human Clinical

"Affected cases showed progressive sensory loss and ataxia due to degeneration of the posterior columns, but normal sensory nerve conduction."

Shows that in the originally described families the peripheral arm was absent, so this node is variable rather than obligate.

PMID:34469621 PARTIAL Human Clinical

"Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."

Independently confirms that peripheral sensory neuropathy is a variable rather than constant feature.

Vestibular Ganglion Sensory Neuron Degeneration

In advanced disease the same vulnerability extends to the vestibular (Scarpa's) ganglion, producing bilateral vestibular hypofunction detectable as impaired vestibulo-ocular reflex gain on video head impulse testing. This was documented in one index case in whom testing three years earlier had been only borderline, indicating late and progressive involvement. Together with the sensory ganglionopathy this makes ADSA a phenocopy of RFC1-related CANVAS, and supports a shared susceptibility of sensory neurons in spinal, cranial and vestibular ganglia.

sensory neuron CL:0000101

vestibular ganglion UBERON:0002824

Downstream

Progressive Sensory Gait Ataxia Loss of vestibular afference compounds the proprioceptive deficit and worsens balance.

Show evidence (2 references)

PMID:32943585 SUPPORT Human Clinical

"Similar to RFC1 CANVAS, the vestibular system was also affected in the index case, suggesting a common susceptibility of sensory neurons in spinal, cranial and Scarpa"

States the vestibular-ganglion involvement and the shared-vulnerability interpretation.

PMID:32943585 SUPPORT Human Clinical

"Notably VOR testing only showed borderline changes when performed three years before."

Documents that vestibular involvement appeared late and progressed, supporting it as an advanced-stage feature.

Loss of Proprioceptive and Vibratory Afferent Input

The physiological consequence of losing large-fibre sensory pathways centrally and peripherally: joint position sense and vibration sense are degraded, deep tendon reflexes are lost because their afferent limb is destroyed, and the patient becomes dependent on vision to know where the limbs are. Removing vision unmasks the deficit (positive Romberg sign) and unmonitored limbs drift (pseudoathetosis).

proprioception GO:0019230 ↓ DECREASED

Downstream

Progressive Sensory Gait Ataxia

Show evidence (3 references)

PMID:32943585 SUPPORT Human Clinical

"Vibration was reduced to the metacarpal-phalangeal joints and to the anterior-superior iliac spine."

Documents the extensive loss of vibratory sensation resulting from large-fibre sensory pathway degeneration.

PMID:32943585 SUPPORT Human Clinical

"Deep-tendon reflexes were reduced in the upper limbs and absent in the lower limbs."

Areflexia reflects destruction of the afferent limb of the reflex arc.

PMID:26433933 SUPPORT Model Organism

"As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception."

Model-organism corroboration of the proprioceptive deficit, kept distinct from the human clinical evidence above.

Progressive Sensory Gait Ataxia

The clinical endpoint: a broad-based, unsteady, visually dependent gait that worsens over years, leading to falls, then reliance on a stick and eventually a walking aid, typically within a decade of onset. Cerebellar signs (dysarthria, nystagmus, appendicular cerebellar ataxia with eyes open) and cerebellar atrophy on imaging are characteristically absent, and it is this combination — severe ataxia with a normal cerebellum — that identifies the disorder clinically.

Show evidence (2 references)

PMID:34469621 SUPPORT Human Clinical

"All affected family members showed sensory ataxia on examination."

Sensory ataxia is the obligate clinical outcome.

PMID:32943585 SUPPORT Human Clinical

"Brain MRI was normal and in particular there was no cerebellar atrophy."

Confirms that the ataxia is sensory rather than cerebellar, the key distinguishing observation.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Source 'pathophysiology#Variable Corticospinal Tract Involvement' (for edge to 'Pyramidal Signs') not found in named elements

●

Phenotypes

14

Nervous System 3

Sensory Neuropathy OCCASIONAL Sensory neuropathy HP:0000763

Show evidence (2 references)

PMID:34469621 SUPPORT Human Clinical

"Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."

The qualifier "sometimes" applied to sensory neuropathy in a kindred where it was not universal supports the OCCASIONAL band.

PMID:32943585 SUPPORT Human Clinical

"However, in contrast to the two previously reported families, both our patients had reduced or absent sensory action potentials in the four limbs."

Documents the interfamilial variability of the peripheral sensory involvement.

Impaired Pain Sensation Impaired pain sensation HP:0007328

Show evidence (2 references)

PMID:32943585 SUPPORT Human Clinical

"Pinprick sensation was reduced to the elbow and to the hip."

Direct examination finding of reduced pinprick sensation.

PMID:32943585 PARTIAL Human Clinical

"without evidence of cerebellar or autonomic involvement and no significant foot ulcerations or pain"

Qualifies the sensory phenotype: pinprick is impaired but neuropathic pain and ulceration are not part of the syndrome.

Dysesthesia Dysesthesia HP:0012534

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"a 57-year old woman with onset of poor balance at the age of 47 years, followed by dysaesthesia and sensory loss in her feet and hands"

Documents dysaesthesia as part of the sensory syndrome.

Other 11

Sensory Ataxia OBLIGATE Sensory ataxia HP:0010871

Show evidence (1 reference)

PMID:34469621 SUPPORT Human Clinical

"All affected family members showed sensory ataxia on examination."

All affected individuals in the Belgian kindred had sensory ataxia, supporting the OBLIGATE frequency band.

Progressive Gait Ataxia Progressive gait ataxia HP:0007240

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Her older sister (III-1), now aged 62, reported progressive unsteadiness since the age of 50 resulting in multiple falls and a fracture of her right tibia and fibula."

Documents progressive gait ataxia with adult onset and functional consequences in an affected individual.

Impaired Proprioception Impaired proprioception HP:0010831

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Position sense was normal in the upper limbs and reduced to the knees in the lower limbs."

Direct examination finding of impaired position sense.

Impaired Vibration Sensation in the Lower Limbs Impaired vibration sensation in the lower limbs HP:0002166

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Vibration sensation was reduced in the upper limbs and absent in the lower limbs to the costal margin."

Documents severe lower-limb vibration loss extending to the trunk.

Positive Romberg Sign Positive Romberg sign HP:0002403

Show evidence (2 references)

PMID:32943585 SUPPORT Human Clinical

"Romberg’s was positive."

Primary evidence: a positive Romberg sign in the genotype-confirmed p.Arg199Cys Ecuadorian index case, anchoring this cardinal sign to a variant-confirmed patient.

PMID:42052314 SUPPORT Human Clinical

"Neurological examination revealed pendular nystagmus, slow rhythmic palatal myoclonus, broad-based gait, positive Romberg sign, and clumsy tandem gait."

Corroborating only. Records a positive Romberg sign in a patient with an unspecified heterozygous RNF170 variant; retained as a secondary item behind the genotype-confirmed source above. See entry note (6) for why the other findings in this case report are deliberately not curated as ADSA features.

Pseudoathetosis

Deliberately left without an ontology `term:` binding. HPO has no term for pseudoathetosis. The term suggested in review, HP:0011443, resolves to "Abnormality of coordination" - a very high-level parent that would be far broader than, and would not convey, this specific deafferentation sign, and HP:0002305 Athetosis would be positively misleading because pseudoathetosis is mechanistically distinct from athetosis. Per the CLAUDE.md guidance that `preferred_term` may stand alone when no suitable ontology term exists, the free-text preferred term is used rather than a misleading binding.

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Pseudo-athetotic arm movements could also be observed."

Direct examination finding of pseudoathetosis in the genotype-confirmed index case, evidencing upper-limb deafferentation.

Areflexia of Lower Limbs Areflexia of lower limbs HP:0002522

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Deep-tendon reflexes were reduced in the upper limbs and absent in the lower limbs."

Direct examination finding of lower limb areflexia.

Decreased Distal Sensory Nerve Action Potential OCCASIONAL Decreased distal sensory nerve action potential HP:0007230

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"NCS showed normal motor conduction parameters. Sensory action potentials had decreased amplitudes in the upper limbs and were absent in the lower limbs."

Direct nerve-conduction documentation of reduced sensory action potentials with motor sparing.

Vestibular Areflexia OCCASIONAL Vestibular areflexia HP:0008568

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"Also, bilateral vestibular areflexia was identified in the index case, mimicking CANVAS."

Reported in one of two examined affected individuals and explicitly described as stage-dependent, supporting the OCCASIONAL band.

Pyramidal Signs OCCASIONAL Abnormal pyramidal sign HP:0007256

Show evidence (1 reference)

PMID:34469621 SUPPORT Human Clinical

"Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."

Establishes pyramidal involvement as a variable feature, supporting the OCCASIONAL band. The cited source says "pyramidal involvement" generically rather than naming spasticity, which is why the binding is the parent term HP:0007256 rather than HP:0001257 Spasticity.

Impaired Smooth Pursuit OCCASIONAL Impaired smooth pursuit HP:0007772

Show evidence (1 reference)

PMID:34469621 SUPPORT Human Clinical

"Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."

Names slow-pursuit abnormalities among the variable findings, supporting the OCCASIONAL band.

🧬

Genetic Associations

1

RNF170

Gene: RNF170 hgnc:25358 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:21115467 SUPPORT Human Clinical

"We have identified a putative pathogenic mutation in the gene encoding ring-finger protein RNF170, a potential ubiquitin ligase."

Gene-discovery report establishing RNF170 as the ADSA gene.

PMID:21115467 SUPPORT Human Clinical

"We previously mapped both families to chromosome 8p12-8q12"

Records the linkage interval that localised the gene.

PMID:34469621 SUPPORT Human Clinical

"Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia."

Establishes the allelic-series boundary: a single missense allele underlies ADSA, distinct from the biallelic loss-of-function HSP alleles.

💊

Medical Actions

2

Physical Therapy and Balance Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

No disease-modifying therapy exists for ADSA. Management is supportive and centres on gait and balance rehabilitation, visual and tactile compensation strategies for the proprioceptive deficit, falls prevention, and provision of walking aids as ataxia progresses.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal dominant transmission implies a 50 percent recurrence risk for offspring, complicated by late and possibly age-dependent penetrance, so predictive testing in younger at-risk relatives requires careful counselling about an unquantified age-related risk. Because p.Arg199Cys is the only allele associated with sensory ataxia, while other RNF170 variants cause a recessive disease, interpretation of RNF170 findings must be variant-specific.

Show evidence (1 reference)

PMID:34469621 SUPPORT Human Clinical

"It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP."

Supports the counselling and testing recommendation for RNF170 in ataxia and HSP panels.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Sensory Ataxia 1:

CANVAS (RFC1-related cerebellar ataxia, neuropathy, vestibular areflexia syndrome)

Overlapping Features The most important differential. Both cause a late-onset sensory ganglionopathy with vestibular impairment. CANVAS is autosomal recessive, caused by a biallelic RFC1 AAGGG repeat expansion, and characteristically has cerebellar involvement, chronic cough and retained or brisk reflexes. ADSA is dominant, has no cerebellar involvement and no cough, and reflexes are reduced or absent; vestibular areflexia appears only in advanced disease.

Distinguishing Features

Autosomal dominant inheritance in ADSA versus autosomal recessive in CANVAS
Absent cerebellar involvement and normal cerebellar imaging in ADSA
Absence of the chronic cough that is characteristic of CANVAS
Reduced or absent reflexes in ADSA versus retained or brisk reflexes in CANVAS
Vestibular areflexia only in advanced ADSA, whereas it is a defining early feature of CANVAS

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"As opposed to autosomal recessive RFC1 CANVAS, cerebellar involvement, cough and retained/brisk reflexes are absent RNF170 related syndrome, mode of inheritance is autosomal dominant, and the vestibular areflexia may be observed only in more advanced disease stages."

Explicit point-by-point clinical contrast between the two disorders.

Spastic paraplegia 85, autosomal recessive (biallelic RNF170) Not Yet Curated MONDO:0030512

Overlapping Features The recessive disease at the other end of the same allelic series. Caused by biallelic RNF170 loss-of-function variants, it presents as a hereditary spastic paraplegia with primary upper-motor-neuron involvement rather than a dorsal root ganglion sensory neuronopathy, and is believed to act by simple loss of function rather than by whatever mechanism drives the dominant disease. Heterozygous carriers of these null alleles are unaffected. Keeping the two apart matters: same gene, different variant class, different inheritance, different target neuron, different mechanism.

Distinguishing Features

Biallelic loss-of-function variants versus the single recurrent p.Arg199Cys missense allele
Autosomal recessive versus autosomal dominant transmission
Primary upper motor neuron (corticospinal) involvement versus dorsal root ganglion sensory neuronopathy
Spasticity and weakness as the leading problem versus proprioceptive sensory ataxia
Generally earlier (childhood to adolescent) onset versus fifth-to-seventh-decade onset in ADSA

Show evidence (3 references)

PMID:32943585 SUPPORT Human Clinical

"However, both the clinical phenotype, with primary involvement of upper motor neurons vs dorsal root ganglia sensory neurons, and the disease-causing mechanism, loss-of-function vs toxic gain-of-function, differ between RNF170 HSP and autosomal dominant sensory ataxia, respectively."

States the clinical and mechanistic separation between the dominant and recessive RNF170 diseases.

PMID:31636353 SUPPORT Human Clinical

"We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families"

Establishes the recessive RNF170 disease as a separate entity.

PMID:33165979 SUPPORT Human Clinical

"We describe here a novel hereditary spastic paraplegia family with 4 affected members carrying a homozygous p.(Tyr114*) stop gain variant in RNF170."

Independent confirmation that biallelic truncating RNF170 variants cause spastic paraplegia, not sensory ataxia.

Friedreich ataxia

Overlapping Features The classic genetic posterior-column-plus-sensory-ganglion disorder, and the long-standing differential for any patient with sensory ataxia and areflexia. It is autosomal recessive, usually much earlier in onset, and typically accompanied by cardiomyopathy, scoliosis, diabetes and corticospinal involvement, none of which is characteristic of ADSA.

Distinguishing Features

Autosomal recessive FXN repeat expansion versus dominant RNF170 missense
Childhood or adolescent onset versus fifth-to-seventh-decade onset
Systemic features (cardiomyopathy, diabetes, scoliosis) absent in ADSA

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"toxic (cisplatin, pyridoxine) and genetic causes (Friedreich"

Lists Friedreich ataxia among the genetic causes in the sensory ganglionopathy differential.

Acquired sensory ganglionopathy (paraneoplastic, autoimmune, toxic)

Overlapping Features Non-genetic sensory neuronopathy must be excluded before pursuing a genetic diagnosis: anti-Hu paraneoplastic ganglionopathy, Sjogren syndrome and other autoimmune causes, and toxic exposures such as cisplatin and pyridoxine. In reported ADSA patients, screening for autoimmune, neoplastic, toxic and metabolic causes was negative.

Distinguishing Features

Subacute rather than decade-long progression in most acquired forms
Positive autoantibody, malignancy or exposure history
Absence of a dominant family history

Show evidence (1 reference)

PMID:32943585 SUPPORT Human Clinical

"There is a narrow differential diagnosis for a sensory ganglionopathy which includes paraneoplastic (anti-Hu antibodies), autoimmune (Sjogren Syndrome,), toxic (cisplatin, pyridoxine) and genetic causes"

Enumerates the acquired causes that must be excluded.

{ }

Source YAML

click to show

name: Autosomal Dominant Sensory Ataxia 1
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- ADSA
- SNAX1
- RNF170 hereditary ataxia
- ataxia, sensory, 1, autosomal dominant
- hereditary ataxia caused by mutation in RNF170
description: >-
  Autosomal dominant sensory ataxia 1 (ADSA, SNAX1) is an ultra-rare, adult-onset,
  slowly progressive, predominantly sensory ataxia caused by the recurrent
  heterozygous RNF170 missense variant p.Arg199Cys (c.595C>T). RNF170 is an
  endoplasmic reticulum membrane RING-finger E3 ubiquitin ligase that is
  recruited by the erlin1/2 (SPFH1/2) complex to conformationally activated
  inositol 1,4,5-trisphosphate (IP3) receptors and commits them to
  endoplasmic-reticulum-associated degradation (ERAD), thereby setting the
  turnover rate of the principal ER calcium-release channel.


  The defining anatomical lesion is degeneration of the posterior (dorsal)
  columns of the spinal cord, arising from a primary sensory neuronopathy
  (ganglionopathy) of the dorsal root ganglia that degenerates both the central
  and the peripheral branches of large sensory neurons. Patients present in the
  fifth to seventh decade with progressive unsteadiness, loss of proprioception
  and vibration sense, a positive Romberg sign and lower limb areflexia,
  progressing over years to walking-aid dependence. Cerebellar function and
  cerebellar imaging are characteristically spared, distinguishing ADSA from the
  spinocerebellar ataxias. Variable additional features include pyramidal signs,
  impaired smooth pursuit, and — in advanced disease — bilateral vestibular
  areflexia that can make ADSA a phenocopy ("mimic") of RFC1-negative CANVAS.


  ADSA sits at the dominant end of an RNF170 allelic series whose recessive end
  is a mechanistically and clinically distinct disease: biallelic RNF170
  loss-of-function variants cause autosomal recessive spastic paraplegia 85
  (SPG85), with primary upper-motor-neuron rather than dorsal-root-ganglion
  involvement. Because heterozygous carriers of RNF170 null alleles are
  unaffected, simple haploinsufficiency is an unlikely explanation for the
  dominant sensory ataxia, and the mechanism by which p.Arg199Cys acts remains
  genuinely unresolved.
disease_term:
  preferred_term: autosomal dominant sensory ataxia 1
  term:
    id: MONDO:0012166
    label: autosomal dominant sensory ataxia 1
parents:
- Hereditary ataxia
- Sensory ataxia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012166
      label: autosomal dominant sensory ataxia 1
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
external_assertions:
- name: OMIM ataxia, sensory, 1, autosomal dominant record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:608984
  url: https://omim.org/entry/608984
  description: >-
    OMIM record for autosomal dominant sensory ataxia 1 (SNAX1), the OMIM xref
    carried by MONDO:0012166 and one of the three identity anchors used in the NEC
    preflight for this entry. Recorded here rather than under `mappings:` because
    the schema's DiseaseMappings container provides only icd10cm, icd11f, mondo and
    ncit mapping slots - there is no OMIM mapping slot - and `external_assertions`
    is the pattern other disorder entries use for OMIM identifiers.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:21115467
      reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
        ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant sensory ataxia is a rare genetic condition that results in a progressive ataxia that is caused by degeneration of the posterior columns of the spinal cord."
      explanation: >-
        The disease is a progressive degenerative disorder of a central nervous
        system tract and belongs to the neurology chapter.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:34469621
      reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
        variable pyramidal involvement.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family."
      explanation: >-
        A monogenic disorder diagnosed by identifying a single heterozygous
        variant by exome sequencing belongs to the genetics chapter.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    ADSA segregates as an autosomal dominant trait in every reported kindred:
    two founder-related families from Maritime Canada, a Belgian family, and an
    Ecuadorian family, all carrying the same heterozygous RNF170 p.Arg199Cys
    allele. Onset is late (fifth to seventh decade), so apparently unaffected
    younger relatives cannot be scored as non-penetrant; age-dependent
    penetrance is therefore not established and no penetrance figure is asserted.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By exome-sequencing we have identified the same p.Arg199Cys RNF170 mutation in an Ecuadorian family affected by an autosomal dominant late-onset progressive sensory ganglionopathy."
    explanation: >-
      An independent third kindred confirms dominant transmission of the same
      allele.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two sisters III-2 and III-4, aged 58 and 49, are reportedly unaffected but given the late onset of the disease were not considered for segregation analysis."
    explanation: >-
      Documents why apparent non-penetrance cannot be scored in this late-onset
      disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. At gene discovery only two clinically ascertained families were
    known, both from Maritime Canada and sharing a founder haplotype; a Belgian
    family and an Ecuadorian family were subsequently reported carrying the same
    p.Arg199Cys allele. Only a few dozen affected individuals are on record, no
    population rate has ever been estimated, and a targeted screen of 404
    neuromuscular patients yielded no additional cases. No numeric
    rate_per_100000 is asserted because none has been measured.
  evidence:
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date only two families have been clinically ascertained with this condition, both from Maritime Canada."
    explanation: >-
      Establishes the case-count basis for the ultra-rare classification at the
      time of gene discovery.
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not find additional pathogenic variants in RNF170 in our in-house neuromuscular cohort."
    explanation: >-
      A targeted screen of 404 neuromuscular patients found no further RNF170
      cases, supporting extreme rarity even in an enriched clinical cohort.
genetic:
- name: RNF170
  gene_term:
    preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    RNF170 encodes an endoplasmic reticulum membrane RING-finger E3 ubiquitin
    ligase with three predicted membrane-spanning helices. The ADSA locus was
    originally mapped to chromosome 8p12-8q12 in the two Maritime Canadian
    families before the gene was identified by direct sequencing of the shared
    haplotype interval. Only one RNF170 allele, the missense p.Arg199Cys, has
    ever been associated with sensory ataxia; all other reported pathogenic
    RNF170 alleles are biallelic loss-of-function variants causing a different
    disease (autosomal recessive spastic paraplegia 85). A different RNF170
    variant found in a patient with sensory ataxia should therefore not be
    assumed causal by analogy.
  evidence:
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a putative pathogenic mutation in the gene encoding ring-finger protein RNF170, a potential ubiquitin ligase."
    explanation: Gene-discovery report establishing RNF170 as the ADSA gene.
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We previously mapped both families to chromosome 8p12-8q12"
    explanation: Records the linkage interval that localised the gene.
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia."
    explanation: >-
      Establishes the allelic-series boundary: a single missense allele underlies
      ADSA, distinct from the biallelic loss-of-function HSP alleles.
variants:
- name: RNF170 c.595C>T p.Arg199Cys
  gene:
    preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  description: >-
    The single recurrent ADSA allele. A rare non-synonymous substitution at a
    well-conserved residue, predicted deleterious by multiple in silico tools.
    Found on a shared founder haplotype in the two Maritime Canadian families and
    independently in a Belgian and an Ecuadorian family, showing it is not
    confined to the founder population. Arg199 is a charged residue in a
    transmembrane region, and functional work shows that ionic interactions
    between charged transmembrane residues are what maintain RNF170 stability, so
    the arginine-to-cysteine change destabilises the protein rather than
    abolishing its catalytic activity.
  clinical_significance: PATHOGENIC
  type: missense variant
  functional_effects:
  - function: RNF170 protein stability
    description: >-
      Reduced steady-state RNF170 protein level through enhanced
      autoubiquitination and proteasomal degradation, demonstrated both in
      transfected cells and in ADSA patient lymphoblasts.
  - function: IP3 receptor-mediated cytosolic calcium mobilisation
    description: >-
      Impaired agonist-evoked (platelet-activating-factor-stimulated) calcium
      mobilisation in patient lymphoblasts, with normal store content, receptor
      level and IP3 production.
  - function: ubiquitin ligase activity toward IP3 receptors
    description: >-
      Preserved rather than abolished. Mutant RNF170 attaches the full normal
      complement of mono-, K48- and K63-linked ubiquitin conjugates to activated
      IP3 receptors, so the calcium defect is not explained by defective IP3
      receptor ubiquitination.
  - function: dominant developmental toxicity in zebrafish
    description: >-
      Dose-dependent dominant disruption of embryonic development on
      microinjection of mutant orthologous mRNA, the principal evidence for an
      allele-specific toxic property.
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNF170 is an endoplasmic reticulum membrane ubiquitin ligase that contributes to the ubiquitination of activated inositol 1,4,5-trisphosphate (IP3) receptors, and also, when point mutated (arginine to cysteine at position 199), causes autosomal dominant sensory ataxia (ADSA), a disease characterized by neurodegeneration in the posterior columns of the spinal cord."
    explanation: >-
      Names the exact variant and ties it to the posterior-column
      neurodegeneration phenotype.
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation is a rare non-synonymous change in a well-conserved residue and is predicted to be pathogenic by SIFT, PolyPhen, PANTHER and Align-GVD."
    explanation: In silico support for pathogenicity at gene discovery.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed focused exome sequencing in III-3 which identified a c.595C>T, p.Arg199Cys variant in RNF170"
    explanation: Provides the cDNA-level description of the recurrent allele.
mechanistic_hypotheses:
- hypothesis_group_id: r199c_toxic_gain_of_function
  hypothesis_label: p.Arg199Cys Toxic Gain-of-Function / Dominant-Negative Model
  status: EMERGING
  description: >-
    The currently favoured but unproven explanation for dominance. Because
    heterozygous carriers of RNF170 nonsense alleles are unaffected, losing one
    functional copy of RNF170 cannot by itself cause sensory ataxia; the
    p.Arg199Cys protein must therefore do something a null allele does not.
    Candidate mechanisms are a toxic property of the misfolded, unstable mutant
    protein, or a dominant-negative action on the erlin1/2-RNF170 complex in
    which the destabilised mutant poisons the complex or perturbs its
    stoichiometry. The strongest positive evidence is the dose-dependent dominant
    developmental toxicity of mutant RNF170 mRNA in zebrafish embryos. This
    model, not simple haploinsufficiency, is what the field currently regards as
    plausible, but no specific toxic species or poisoned complex has been
    demonstrated, and the zebrafish readout is embryonic development rather than
    adult sensory neurodegeneration.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the exact mechanism remains elusive, a toxic gain of function seems plausible and is supported by the dose-dependent toxicity of RNF170 Arg199Cys in zebrafish larvae"
    explanation: >-
      States the hypothesis and its supporting model-organism observation while
      explicitly flagging that the mechanism is unresolved.
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Microinjection of wild-type or mutant orthologous messenger RNAs into zebrafish (Danio rerio) embryos confirmed that the mutation dominantly disrupts normal embryonic development."
    explanation: >-
      Direct experimental demonstration that the mutant allele acts dominantly in
      a model organism.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, both the clinical phenotype, with primary involvement of upper motor neurons vs dorsal root ganglia sensory neurons, and the disease-causing mechanism, loss-of-function vs toxic gain-of-function, differ between RNF170 HSP and autosomal dominant sensory ataxia, respectively."
    explanation: >-
      Contrasts the recessive loss-of-function disease with the proposed toxic
      gain-of-function mechanism of the dominant disease.
- hypothesis_group_id: rnf170_haploinsufficiency
  hypothesis_label: RNF170 Haploinsufficiency Model
  status: ALTERNATIVE
  description: >-
    The straightforward reading of the biochemistry: p.Arg199Cys destabilises
    RNF170, lowering its steady-state level, and reduced RNF170 dosage impairs
    IP3 receptor ERAD in vulnerable sensory neurons. It is retained here because
    the loss-of-expression biochemistry is solid in patient-derived cells and
    because Rnf170-null mice reproduce proprioceptive and gait deficits. It is
    nevertheless disfavoured as the primary disease mechanism: heterozygous
    carriers of RNF170 nonsense alleles, who are unambiguously haploinsufficient,
    are clinically unaffected, and their biallelic relatives develop spastic
    paraplegia rather than sensory ataxia.
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation."
    explanation: >-
      Establishes the reduced-dosage premise of the haploinsufficiency model in
      patient-derived cells.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, despite previous evidence of reduced stability and expression level of mutant Arg199Cys RNF170 haploinsufficiency is unlikely to be the primary disease since heterozygous carriers of nonsense variants in RNF170 were later shown to be unaffected"
    explanation: >-
      Human genetic evidence directly against haploinsufficiency as the primary
      mechanism.
- hypothesis_group_id: non_ip3r_substrate_dysregulation
  hypothesis_label: Non-IP3-Receptor Substrate Dysregulation Model
  status: EMERGING
  description: >-
    Patient lymphoblasts show a genuine functional defect in agonist-evoked Ca2+
    mobilisation, yet this defect cannot be attributed to aberrant IP3 receptor
    ubiquitination: mutant RNF170 attaches the full normal complement of
    ubiquitin conjugates to activated IP3 receptors, and receptor levels, store
    content and IP3 production are all unchanged. The authors of that work
    therefore proposed that the pathogenic consequence lies with other, still
    unidentified RNF170 substrates, or is an adaptive response to chronically
    reduced RNF170. Under this model the IP3 receptor is a marker of the pathway
    rather than the critical substrate, and identifying the true substrate is the
    central open problem.
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels."
    explanation: >-
      The primary functional study explicitly proposes non-IP3-receptor
      substrates as the likely explanation.
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "wild-type and mutant RNF170 have apparently identical ubiquitin ligase activities toward IP3 receptors"
    explanation: >-
      Shows the mutant is not deficient in its best-characterised catalytic
      activity, motivating the search for another substrate.
pathophysiology:
- name: RNF170 p.Arg199Cys Transmembrane Destabilizing Substitution
  biological_scale: MOLECULAR
  description: >-
    The single molecular lesion of ADSA. Arginine 199 is a charged residue in a
    transmembrane region of RNF170; systematic point mutagenesis showed that ionic
    interactions between charged transmembrane residues are what hold the protein
    together, so replacing this arginine with cysteine removes a stabilising
    charge pair. The substitution does not damage the catalytic RING function.
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The basis for these effects was probed via additional point mutations, revealing that ionic interactions between charged residues in the transmembrane domains of RNF170 are required for protein stability."
    explanation: >-
      Explains why an arginine-to-cysteine change at position 199 destabilises the
      protein.
  - reference: PMID:21610068
    reference_title: RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase,
      mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity."
    explanation: >-
      Establishes the membrane topology and ER localisation that make a
      transmembrane charge pair structurally relevant.
  downstream:
  - target: RNF170 Protein Destabilization by Enhanced Autoubiquitination
    causal_link_type: DIRECT

- name: RNF170 Protein Destabilization by Enhanced Autoubiquitination
  biological_scale: MOLECULAR
  description: >-
    The destabilised mutant protein autoubiquitinates more avidly and is cleared
    by the proteasome, so steady-state RNF170 levels fall. This is seen both in
    cells transfected with mutant constructs and, importantly, in lymphoblasts
    from ADSA patients, establishing that the reduced-dosage state exists in
    patient tissue and is not an overexpression artefact.
  biological_processes:
  - preferred_term: protein autoubiquitination
    term:
      id: GO:0051865
      label: protein autoubiquitination
    modifier: INCREASED
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  - preferred_term: protein destabilization
    term:
      id: GO:0031648
      label: protein destabilization
    modifier: INCREASED
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation."
    explanation: >-
      Directly documents enhanced autoubiquitination and proteasomal clearance of
      the mutant protein in patient-derived cells.
  downstream:
  - target: Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnf170_haploinsufficiency
    description: >-
      Under the reduced-dosage reading, less RNF170 means less IP3 receptor
      ubiquitination capacity at the ER membrane.
  - target: Dysregulated ER Calcium Release in Sensory Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - r199c_toxic_gain_of_function
    - non_ip3r_substrate_dysregulation
    description: >-
      Alternative routes that bypass the IP3-receptor-ERAD step: a toxic property
      of the unstable mutant protein, or mis-ubiquitination of an unidentified
      non-IP3-receptor substrate. Both are invoked because the observed patient
      calcium defect is demonstrably not explained by defective IP3 receptor
      ubiquitination.

- name: Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
  biological_scale: MOLECULAR
  description: >-
    RNF170 is the E3 ligase arm of the ER quality-control module that disposes of
    activated IP3 receptors. On receptor activation the erlin1/2 (SPFH1/2)
    complex binds the third intralumenal loop of IP3R1 and recruits RNF170, which
    then attaches the mono-, K48- and K63-linked ubiquitin conjugates that commit
    the receptor to ERAD. Erlin1/2 binding is the rate-limiting first step and
    RNF170 recruitment depends on it. Reduced RNF170 availability slows this
    turnover pathway. This node states the canonical pathway; the evidence that
    mutant RNF170 actually fails at this step is weak, which is why the causal
    edge into it is hypothesis-tagged and the node carries PROVISIONAL confidence.
  biological_processes:
  - preferred_term: ERAD pathway
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: DECREASED
  - preferred_term: protein K48-linked ubiquitination
    term:
      id: GO:0070936
      label: protein K48-linked ubiquitination
    modifier: DECREASED
  molecular_functions:
  - preferred_term: ubiquitin protein ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  - preferred_term: ITPR1
    term:
      id: hgnc:6180
      label: ITPR1
  - preferred_term: ERLIN1
    term:
      id: hgnc:16947
      label: ERLIN1
  - preferred_term: ERLIN2
    term:
      id: hgnc:1356
      label: ERLIN2
  - preferred_term: TMUB1
    term:
      id: hgnc:21709
      label: TMUB1
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:21610068
    reference_title: RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase,
      mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP(3) receptors where it mediates IP(3) receptor ubiquitination."
    explanation: Establishes the erlin1/2-RNF170 module and its substrate.
  - reference: PMID:21610068
    reference_title: RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase,
      mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP(3) receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus-induced IP(3) receptor processing."
    explanation: >-
      Loss-of-function experiments show that reduced RNF170 impairs IP3 receptor
      ubiquitination and degradation.
  - reference: PMID:35568199
    reference_title: Binding of the erlin1/2 complex to the third intralumenal loop
      of IP(3)R1 triggers its ubiquitin-proteasomal degradation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The first and rate-limiting step in this process is thought to be the association of conformationally active IP3Rs with the erlin1/2 complex, an endoplasmic reticulum-located oligomer of erlin1 and erlin2 that recruits the E3 ubiquitin ligase RNF170"
    explanation: >-
      Defines the order of events and identifies erlin1/2 binding as rate limiting
      for RNF170 recruitment.
  - reference: PMID:31636353
    reference_title: Bi-allelic variants in RNF170 are associated with hereditary spastic
      paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia."
    explanation: >-
      Independent human genetic evidence that this whole ER module is
      neurodegeneration-relevant, since every other component is itself a disease
      gene.
  - reference: PMID:38782601
    reference_title: ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol
      esterification to regulate the secretory pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 (transmembrane and ubiquitin-like domain-containing 1) and RNF170 (RING finger protein 170)."
    explanation: >-
      Names TMUB1 explicitly as an ERLIN-bridged partner of RNF170, evidencing its
      inclusion among this node's genes.
  - reference: PMID:38782601
    reference_title: ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol
      esterification to regulate the secretory pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia."
    explanation: >-
      Variants that prevent assembly of this ERLIN-TMUB1-RNF170 nanodomain are
      already established as disease-causing, supporting the assembled complex
      rather than RNF170 alone as the disease-relevant unit.
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Thus, the Ca(2+) mobilization defect seen in ADSA lymphoblasts is apparently not due to aberrant IP3 receptor ubiquitination."
    explanation: >-
      Important negative result: in ADSA cells the IP3 receptor ubiquitination step
      is not measurably defective, so this node is not established as the operative
      lesion in the human disease.
  downstream:
  - target: Dysregulated ER Calcium Release in Sensory Neurons
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnf170_haploinsufficiency

- name: Dysregulated ER Calcium Release in Sensory Neurons
  biological_scale: MOLECULAR
  description: >-
    The convergent functional abnormality, reached by whichever upstream route is
    correct. Patient lymphoblasts mobilise significantly less cytosolic Ca2+ in
    response to platelet-activating factor, while store content, receptor level
    and IP3 production are all normal — localising the defect to the IP3 receptor
    itself. In Rnf170-null mice Itpr1 protein accumulates in the cerebellum and
    spinal cord but not the cerebral cortex, showing that loss of this pathway
    perturbs IP3 receptor homeostasis in a regionally selective way. Note that
    this regional pattern does not map cleanly onto the human lesion, since the
    cerebellum is clinically and radiologically spared in ADSA.
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol
    term:
      id: GO:0051209
      label: release of sequestered calcium ion into cytosol
    modifier: DECREASED
  - preferred_term: calcium-mediated signaling
    term:
      id: GO:0019722
      label: calcium-mediated signaling
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: sensory neuron of dorsal root ganglion
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In ADSA lymphoblasts, platelet-activating factor-induced Ca(2+) mobilization was significantly impaired, whereas neither Ca(2+) store content, IP3 receptor levels, nor IP3 production were altered, indicative of a functional defect at the IP3 receptor locus, which may be the cause of neurodegeneration."
    explanation: >-
      Demonstrates a calcium-signalling defect in patient-derived cells and
      localises it to the IP3 receptor.
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice."
    explanation: >-
      Shows region-selective IP3 receptor accumulation when the pathway is lost in
      vivo.
  - reference: PMID:31636353
    reference_title: Bi-allelic variants in RNF170 are associated with hereditary spastic
      paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias"
    explanation: >-
      Positions dysregulated IP3/calcium signalling as the shared pathway for
      RNF170-related neurodegeneration.
  downstream:
  - target: Dorsal Root Ganglion Sensory Neuronopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      How a chronic, subtle perturbation of ER calcium handling selectively kills
      large dorsal root ganglion sensory neurons over decades is not established;
      no intermediate steps have been demonstrated in human tissue.
  - target: Variable Corticospinal Tract Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A minor, inconstant second target of the same pathway perturbation. Included
      because the recessive RNF170 disease injures upper motor neurons as its
      primary lesion, so the corticospinal tract is demonstrably vulnerable to
      disruption of this module; why it is only variably affected in ADSA is
      unknown.

- name: Variable Corticospinal Tract Involvement
  biological_scale: TISSUE
  description: >-
    A minor and inconstant arm of the disease. Some affected individuals show
    corticospinal signs (spasticity, hyperreflexia, extensor plantar responses)
    alongside the dominant sensory picture, while others have none and Babinski is
    explicitly absent. This node is deliberately kept small and PROVISIONAL: the
    entire human evidence base is a single "variable findings" clause, and no
    imaging or neuropathological demonstration of corticospinal degeneration in
    ADSA exists. It is modelled rather than omitted because it is the point of
    clinical contact with the recessive RNF170 disease (SPG85), in which
    upper-motor-neuron involvement is the primary lesion, and because it is what
    the curated Pyramidal Signs phenotype rests on.
  locations:
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  mechanism_confidence: PROVISIONAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."
    explanation: >-
      The sole human evidence for corticospinal involvement, and the reason this
      node is marked PROVISIONAL and OCCASIONAL rather than asserted as a core
      mechanism.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Babinski was absent."
    explanation: >-
      The genotype-confirmed Ecuadorian index case had no corticospinal sign. This
      is tagged PARTIAL rather than REFUTE because the node's claim is already
      VARIABLE involvement, which an unaffected patient is consistent with rather
      than contradicting: the observation establishes the "variable" qualifier and
      refutes any obligate reading, while not supporting corticospinal involvement
      in this patient.
  downstream:
  - target: Progressive Sensory Gait Ataxia
    causal_link_type: DIRECT
    description: >-
      Where present, pyramidal involvement compounds the gait disorder, but the
      gait phenotype is sensory in origin and occurs without it.

- name: Dorsal Root Ganglion Sensory Neuronopathy
  biological_scale: CELLULAR
  conforms_to: peripheral_axonal_degeneration#Insult to Peripheral Neurons and Schwann
    Cells
  description: >-
    The primary cellular lesion is degeneration of large sensory neurons whose
    cell bodies lie in the dorsal root ganglia. Because the insult is at the cell
    body (a neuronopathy or ganglionopathy) rather than at the distal axon, both
    the centrally projecting branch (which forms the posterior columns) and the
    peripherally projecting branch degenerate. This is a non-length-dependent
    pattern, which is why sensory loss can involve the hands as prominently as the
    feet and why pseudoathetosis and areflexia dominate over distal weakness.
  cell_types:
  - preferred_term: sensory neuron of dorsal root ganglion
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  locations:
  - preferred_term: dorsal root ganglion
    term:
      id: UBERON:0000044
      label: dorsal root ganglion
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding, together with the MRI evidence of degeneration of posterior column, point to a primary involvement of sensory dorsal root ganglia, leading to degeneration of both central and peripheral branches of sensory neurons."
    explanation: >-
      Directly infers dorsal root ganglion neuronopathy with dual-branch
      degeneration from combined electrophysiology and imaging in patients.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensory neuronopathy or ganglionopathy is a type of peripheral neuropathy characterized by primary and selective destruction of the dorsal root ganglia leading to degeneration of both central and peripheral neurites of sensory neurons"
    explanation: >-
      Defines the neuronopathy pattern that the authors assign to RNF170 disease.
  downstream:
  - target: Posterior Column Degeneration
    causal_link_type: DIRECT
  - target: Peripheral Sensory Axon Degeneration
    causal_link_type: DIRECT
  - target: Vestibular Ganglion Sensory Neuron Degeneration
    causal_link_type: DIRECT
    description: >-
      Late and variable extension of the same sensory-neuron vulnerability to the
      vestibular (Scarpa's) ganglion.

- name: Posterior Column Degeneration
  biological_scale: TISSUE
  description: >-
    Loss of the centrally projecting branches of the degenerating dorsal root
    ganglion neurons produces the defining lesion of ADSA: atrophy and signal
    change in the dorsal columns of the spinal cord, demonstrable in life as
    reduced posterior-column volume with increased T2 signal on cervical cord MRI.
    These tracts carry proprioceptive and vibratory information, and their loss is
    the anatomical basis of the sensory ataxia.
  locations:
  - preferred_term: spinal cord dorsal column
    term:
      id: UBERON:0005373
      label: spinal cord dorsal column
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant sensory ataxia is a rare genetic condition that results in a progressive ataxia that is caused by degeneration of the posterior columns of the spinal cord."
    explanation: >-
      Establishes posterior-column degeneration as the defining lesion of the
      disease.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the cervical spine showed reduced volume and increased T2 signal of the posterior columns"
    explanation: In vivo imaging confirmation of the posterior-column lesion.
  downstream:
  - target: Loss of Proprioceptive and Vibratory Afferent Input
    causal_link_type: DIRECT

- name: Peripheral Sensory Axon Degeneration
  biological_scale: TISSUE
  conforms_to: peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination
  description: >-
    Degeneration of the peripherally projecting branches of the affected dorsal
    root ganglion neurons, expressed electrophysiologically as reduced or absent
    sensory nerve action potentials with preserved motor conduction. This arm is
    genuinely variable across kindreds and is the main phenotypic difference
    between the reported families: the Maritime Canadian families had normal
    sensory nerve conduction (a purely central posterior-column picture), whereas
    the Ecuadorian family had absent sensory action potentials in all four limbs.
    The reason for this difference is unknown; a modifying genetic background has
    been proposed by the authors as a hypothesis, not demonstrated.
  cell_types:
  - preferred_term: sensory neuron of dorsal root ganglion
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  mechanism_confidence: ESTABLISHED
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies (NCS) showed absent sensory action potentials throughout. Motor nerve conduction was normal."
    explanation: >-
      Documents selective peripheral sensory axon loss with motor sparing in an
      affected patient.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected cases showed progressive sensory loss and ataxia due to degeneration of the posterior columns, but normal sensory nerve conduction."
    explanation: >-
      Shows that in the originally described families the peripheral arm was
      absent, so this node is variable rather than obligate.
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."
    explanation: >-
      Independently confirms that peripheral sensory neuropathy is a variable
      rather than constant feature.
  downstream:
  - target: Loss of Proprioceptive and Vibratory Afferent Input
    causal_link_type: DIRECT

- name: Vestibular Ganglion Sensory Neuron Degeneration
  biological_scale: TISSUE
  description: >-
    In advanced disease the same vulnerability extends to the vestibular
    (Scarpa's) ganglion, producing bilateral vestibular hypofunction detectable as
    impaired vestibulo-ocular reflex gain on video head impulse testing. This was
    documented in one index case in whom testing three years earlier had been only
    borderline, indicating late and progressive involvement. Together with the
    sensory ganglionopathy this makes ADSA a phenocopy of RFC1-related CANVAS, and
    supports a shared susceptibility of sensory neurons in spinal, cranial and
    vestibular ganglia.
  locations:
  - preferred_term: vestibular ganglion
    term:
      id: UBERON:0002824
      label: vestibular ganglion
  cell_types:
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  mechanism_confidence: PROVISIONAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to RFC1 CANVAS, the vestibular system was also affected in the index case, suggesting a common susceptibility of sensory neurons in spinal, cranial and Scarpa"
    explanation: >-
      States the vestibular-ganglion involvement and the shared-vulnerability
      interpretation.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably VOR testing only showed borderline changes when performed three years before."
    explanation: >-
      Documents that vestibular involvement appeared late and progressed,
      supporting it as an advanced-stage feature.
  downstream:
  - target: Progressive Sensory Gait Ataxia
    causal_link_type: DIRECT
    description: >-
      Loss of vestibular afference compounds the proprioceptive deficit and
      worsens balance.

- name: Loss of Proprioceptive and Vibratory Afferent Input
  biological_scale: ORGANISM
  description: >-
    The physiological consequence of losing large-fibre sensory pathways centrally
    and peripherally: joint position sense and vibration sense are degraded, deep
    tendon reflexes are lost because their afferent limb is destroyed, and the
    patient becomes dependent on vision to know where the limbs are. Removing
    vision unmasks the deficit (positive Romberg sign) and unmonitored limbs drift
    (pseudoathetosis).
  biological_processes:
  - preferred_term: proprioception
    term:
      id: GO:0019230
      label: proprioception
    modifier: DECREASED
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vibration was reduced to the metacarpal-phalangeal joints and to the anterior-superior iliac spine."
    explanation: >-
      Documents the extensive loss of vibratory sensation resulting from
      large-fibre sensory pathway degeneration.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep-tendon reflexes were reduced in the upper limbs and absent in the lower limbs."
    explanation: >-
      Areflexia reflects destruction of the afferent limb of the reflex arc.
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception."
    explanation: >-
      Model-organism corroboration of the proprioceptive deficit, kept distinct
      from the human clinical evidence above.
  downstream:
  - target: Progressive Sensory Gait Ataxia
    causal_link_type: DIRECT

- name: Progressive Sensory Gait Ataxia
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint: a broad-based, unsteady, visually dependent gait that
    worsens over years, leading to falls, then reliance on a stick and eventually
    a walking aid, typically within a decade of onset. Cerebellar signs
    (dysarthria, nystagmus, appendicular cerebellar ataxia with eyes open) and
    cerebellar atrophy on imaging are characteristically absent, and it is this
    combination — severe ataxia with a normal cerebellum — that identifies the
    disorder clinically.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected family members showed sensory ataxia on examination."
    explanation: Sensory ataxia is the obligate clinical outcome.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI was normal and in particular there was no cerebellar atrophy."
    explanation: >-
      Confirms that the ataxia is sensory rather than cerebellar, the key
      distinguishing observation.
phenotypes:
- category: Neurologic
  name: Sensory Ataxia
  description: >-
    The defining and obligate feature: ataxia arising from loss of proprioceptive
    afference rather than from cerebellar dysfunction. Present in every affected
    individual reported.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected family members showed sensory ataxia on examination."
    explanation: >-
      All affected individuals in the Belgian kindred had sensory ataxia,
      supporting the OBLIGATE frequency band.

- category: Neurologic
  name: Progressive Gait Ataxia
  description: >-
    Broad-based unsteady gait beginning in the fifth to seventh decade and
    progressing over years from mild imbalance to stick dependence and then to
    walking-aid dependence, with falls and fractures.
  phenotype_term:
    preferred_term: Progressive gait ataxia
    term:
      id: HP:0007240
      label: Progressive gait ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her older sister (III-1), now aged 62, reported progressive unsteadiness since the age of 50 resulting in multiple falls and a fracture of her right tibia and fibula."
    explanation: >-
      Documents progressive gait ataxia with adult onset and functional
      consequences in an affected individual.

- category: Neurologic
  name: Impaired Proprioception
  description: >-
    Loss of joint position sense, most marked in the lower limbs, from degeneration
    of large sensory neurons and the posterior columns.
  phenotype_term:
    preferred_term: Impaired proprioception
    term:
      id: HP:0010831
      label: Impaired proprioception
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Position sense was normal in the upper limbs and reduced to the knees in the lower limbs."
    explanation: Direct examination finding of impaired position sense.

- category: Neurologic
  name: Impaired Vibration Sensation in the Lower Limbs
  description: >-
    Reduced or absent vibration sense, often extending well above the ankles and
    also involving the upper limbs, reflecting non-length-dependent large-fibre
    sensory loss.
  phenotype_term:
    preferred_term: Impaired vibration sensation in the lower limbs
    term:
      id: HP:0002166
      label: Impaired vibration sensation in the lower limbs
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vibration sensation was reduced in the upper limbs and absent in the lower limbs to the costal margin."
    explanation: >-
      Documents severe lower-limb vibration loss extending to the trunk.

- category: Neurologic
  name: Positive Romberg Sign
  description: >-
    Loss of balance on removing visual input, the classic bedside signature of a
    proprioceptive rather than cerebellar ataxia.
  phenotype_term:
    preferred_term: Positive Romberg sign
    term:
      id: HP:0002403
      label: Positive Romberg sign
  diagnostic: true
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Romberg’s was positive."
    explanation: >-
      Primary evidence: a positive Romberg sign in the genotype-confirmed
      p.Arg199Cys Ecuadorian index case, anchoring this cardinal sign to a
      variant-confirmed patient.
  - reference: PMID:42052314
    reference_title: Mutation in RNF170 Causes Unsteady Gait with Hypertrophic Olivary
      Degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination revealed pendular nystagmus, slow rhythmic palatal myoclonus, broad-based gait, positive Romberg sign, and clumsy tandem gait."
    explanation: >-
      Corroborating only. Records a positive Romberg sign in a patient with an
      unspecified heterozygous RNF170 variant; retained as a secondary item behind
      the genotype-confirmed source above. See entry note (6) for why the other
      findings in this case report are deliberately not curated as ADSA features.

- category: Neurologic
  name: Pseudoathetosis
  description: >-
    Slow, writhing, involuntary drift of the outstretched unmonitored limbs, seen
    in the arms of affected patients. Despite the name it is not athetosis: it is a
    deafferentation sign caused by loss of proprioceptive feedback rather than by
    basal-ganglia dysfunction, and it disappears under visual guidance. It is
    curated because it is direct clinical evidence of the prominent UPPER-limb
    involvement that makes this a non-length-dependent ganglionopathy, which is the
    basis for the deliberate non-conformance recorded in note (4).
  phenotype_term:
    preferred_term: Pseudoathetosis
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pseudo-athetotic arm movements could also be observed."
    explanation: >-
      Direct examination finding of pseudoathetosis in the genotype-confirmed index
      case, evidencing upper-limb deafferentation.
  notes: >-
    Deliberately left without an ontology `term:` binding. HPO has no term for
    pseudoathetosis. The term suggested in review, HP:0011443, resolves to
    "Abnormality of coordination" - a very high-level parent that would be far
    broader than, and would not convey, this specific deafferentation sign, and
    HP:0002305 Athetosis would be positively misleading because pseudoathetosis is
    mechanistically distinct from athetosis. Per the CLAUDE.md guidance that
    `preferred_term` may stand alone when no suitable ontology term exists, the
    free-text preferred term is used rather than a misleading binding.

- category: Neurologic
  name: Areflexia of Lower Limbs
  description: >-
    Absent lower limb deep tendon reflexes because the large-fibre afferent limb of
    the reflex arc is destroyed. Reflexes are typically reduced rather than absent
    in the upper limbs. Retained or brisk reflexes, characteristic of RFC1-CANVAS,
    are not a feature of RNF170 disease unless there is superimposed pyramidal
    involvement.
  phenotype_term:
    preferred_term: Areflexia of lower limbs
    term:
      id: HP:0002522
      label: Areflexia of lower limbs
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep-tendon reflexes were reduced in the upper limbs and absent in the lower limbs."
    explanation: Direct examination finding of lower limb areflexia.

- category: Neurologic
  name: Sensory Neuropathy
  description: >-
    A ganglionopathic (non-length-dependent) sensory neuropathy with reduced or
    absent sensory nerve action potentials and preserved motor conduction.
    Genuinely variable between kindreds: absent in the originally described
    Maritime Canadian families, prominent in the Ecuadorian family.
  phenotype_term:
    preferred_term: Sensory neuropathy
    term:
      id: HP:0000763
      label: Sensory neuropathy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."
    explanation: >-
      The qualifier "sometimes" applied to sensory neuropathy in a kindred where it
      was not universal supports the OCCASIONAL band.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in contrast to the two previously reported families, both our patients had reduced or absent sensory action potentials in the four limbs."
    explanation: >-
      Documents the interfamilial variability of the peripheral sensory
      involvement.

- category: Neurologic
  name: Decreased Distal Sensory Nerve Action Potential
  description: >-
    Electrophysiological correlate of the peripheral arm of the ganglionopathy:
    reduced or absent sensory nerve action potentials with normal motor nerve
    conduction.
  phenotype_term:
    preferred_term: Decreased distal sensory nerve action potential
    term:
      id: HP:0007230
      label: Decreased distal sensory nerve action potential
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NCS showed normal motor conduction parameters. Sensory action potentials had decreased amplitudes in the upper limbs and were absent in the lower limbs."
    explanation: >-
      Direct nerve-conduction documentation of reduced sensory action potentials
      with motor sparing.

- category: Neurologic
  name: Impaired Pain Sensation
  description: >-
    Reduced pinprick sensation extending proximally into the limbs, part of the
    broader sensory loss. Notably, significant neuropathic pain and foot ulceration
    are not features, distinguishing ADSA from the hereditary sensory and autonomic
    neuropathies.
  phenotype_term:
    preferred_term: Impaired pain sensation
    term:
      id: HP:0007328
      label: Impaired pain sensation
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pinprick sensation was reduced to the elbow and to the hip."
    explanation: Direct examination finding of reduced pinprick sensation.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "without evidence of cerebellar or autonomic involvement and no significant foot ulcerations or pain"
    explanation: >-
      Qualifies the sensory phenotype: pinprick is impaired but neuropathic pain
      and ulceration are not part of the syndrome.

- category: Neurologic
  name: Vestibular Areflexia
  description: >-
    Bilateral loss of vestibulo-ocular reflex gain, documented on video head
    impulse testing. A late feature that may be absent or borderline earlier in the
    course, and the finding that makes ADSA a CANVAS mimic.
  phenotype_term:
    preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Also, bilateral vestibular areflexia was identified in the index case, mimicking CANVAS."
    explanation: >-
      Reported in one of two examined affected individuals and explicitly described
      as stage-dependent, supporting the OCCASIONAL band.

- category: Neurologic
  name: Dysesthesia
  description: >-
    Unpleasant abnormal sensation in the hands and feet accompanying the sensory
    loss, frequently described by patients as a sensation of walking on cotton.
    Curated as dysesthesia rather than paresthesia because the cited source
    specifically reports "dysaesthesia"; the two were previously bundled in one
    entry, and only dysesthesia is snippet-supportable.
  phenotype_term:
    preferred_term: Dysesthesia
    term:
      id: HP:0012534
      label: Dysesthesia
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 57-year old woman with onset of poor balance at the age of 47 years, followed by dysaesthesia and sensory loss in her feet and hands"
    explanation: Documents dysaesthesia as part of the sensory syndrome.

- category: Neurologic
  name: Pyramidal Signs
  description: >-
    Corticospinal tract signs (spasticity, hyperreflexia, extensor plantar
    responses) occur in some affected individuals but are variable and are not
    required for the diagnosis. Their presence blurs the clinical boundary with the
    recessive RNF170 spastic paraplegia phenotype.
  phenotype_term:
    preferred_term: Abnormal pyramidal sign
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  frequency: OCCASIONAL
  reports_on:
  - target: pathophysiology#Variable Corticospinal Tract Involvement
    relationship: READOUT_OF
    description: >-
      This phenotype is the clinical readout of the variable corticospinal arm of
      the pathograph.
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."
    explanation: >-
      Establishes pyramidal involvement as a variable feature, supporting the
      OCCASIONAL band. The cited source says "pyramidal involvement" generically
      rather than naming spasticity, which is why the binding is the parent term
      HP:0007256 rather than HP:0001257 Spasticity.

- category: Neurologic
  name: Impaired Smooth Pursuit
  description: >-
    Slow-pursuit abnormalities on oculomotor examination in some affected
    individuals; saccades and pursuit were normal in others, so this is not a
    consistent feature.
  phenotype_term:
    preferred_term: Impaired smooth pursuit
    term:
      id: HP:0007772
      label: Impaired smooth pursuit
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings."
    explanation: >-
      Names slow-pursuit abnormalities among the variable findings, supporting the
      OCCASIONAL band.
imaging_findings:
- name: Posterior Column Signal Change and Atrophy on Spinal MRI
  modality: MRI
  description: >-
    Reduced volume and increased T2 signal of the posterior columns on cervical
    spinal cord MRI, the in vivo correlate of the defining posterior-column
    degeneration.
  located_in:
    preferred_term: spinal cord dorsal column
    term:
      id: UBERON:0005373
      label: spinal cord dorsal column
  phenotype_term:
    preferred_term: Dorsal column degeneration
    term:
      id: HP:0007006
      label: Dorsal column degeneration
  laterality: BILATERAL
  diagnostic: true
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the cervical spine showed reduced volume and increased T2 signal of the posterior columns"
    explanation: Direct imaging description of the diagnostic finding.

- name: Absence of Cerebellar Atrophy on Brain MRI
  modality: MRI
  description: >-
    A negative imaging finding with real diagnostic weight: the cerebellum is
    normal, which separates ADSA from the spinocerebellar ataxias and from
    RFC1-CANVAS, in which cerebellar atrophy is typical.
  diagnostic: true
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI was normal and in particular there was no cerebellar atrophy."
    explanation: Documents the diagnostically useful absence of cerebellar atrophy.
diagnosis:
- name: Molecular confirmation of RNF170 p.Arg199Cys
  description: >-
    Diagnosis rests on identifying the heterozygous RNF170 c.595C>T p.Arg199Cys
    variant, in practice by exome or targeted panel sequencing, in a patient with
    an adult-onset predominantly sensory ataxia. Because p.Arg199Cys is the only
    RNF170 allele reported in sensory ataxia, a different RNF170 variant in this
    clinical setting should not be assumed causal. In a patient with sensory ataxia
    plus vestibular areflexia, RFC1 expansion testing is usually performed first;
    RNF170 should be tested when RFC1 is negative, particularly if the family
    history is dominant.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, we recommend considering RNF170 in the diagnostic work-up of patients affected by sensory ataxic neuropathies and RFC1 negative CANVAS-like patients, particularly if there is a dominant family history."
    explanation: States the recommended diagnostic pathway.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the presence of sensory neuropathy and vestibular areflexia gene testing for RFC1 expansion was performed and resulted negative"
    explanation: >-
      Illustrates the practical testing order, with RFC1 excluded before RNF170 was
      found.

- name: Nerve conduction studies and vestibular testing
  description: >-
    Nerve conduction studies show reduced or absent sensory nerve action potentials
    with normal motor conduction when the peripheral arm is involved, and may be
    entirely normal in families with purely central disease. Video head impulse
    testing detects the late bilateral vestibulo-ocular reflex deficit. Cervical
    spinal MRI demonstrates the posterior-column lesion. Exclusion of acquired
    sensory ganglionopathy (paraneoplastic, autoimmune, toxic, metabolic) is a
    necessary part of the workup.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vestibular testing showed a bilateral VOR gain impairment at the video Head Impulse test"
    explanation: Documents the vestibular test used to establish the deficit.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for autoimmune, neoplastic, toxic and metabolic causes was negative."
    explanation: >-
      Documents that acquired causes were actively excluded before the genetic
      diagnosis was accepted.
differential_diagnoses:
- name: CANVAS (RFC1-related cerebellar ataxia, neuropathy, vestibular areflexia syndrome)
  description: >-
    The most important differential. Both cause a late-onset sensory ganglionopathy
    with vestibular impairment. CANVAS is autosomal recessive, caused by a biallelic
    RFC1 AAGGG repeat expansion, and characteristically has cerebellar involvement,
    chronic cough and retained or brisk reflexes. ADSA is dominant, has no
    cerebellar involvement and no cough, and reflexes are reduced or absent;
    vestibular areflexia appears only in advanced disease.
  distinguishing_features:
  - Autosomal dominant inheritance in ADSA versus autosomal recessive in CANVAS
  - Absent cerebellar involvement and normal cerebellar imaging in ADSA
  - Absence of the chronic cough that is characteristic of CANVAS
  - Reduced or absent reflexes in ADSA versus retained or brisk reflexes in CANVAS
  - Vestibular areflexia only in advanced ADSA, whereas it is a defining early
    feature of CANVAS
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As opposed to autosomal recessive RFC1 CANVAS, cerebellar involvement, cough and retained/brisk reflexes are absent RNF170 related syndrome, mode of inheritance is autosomal dominant, and the vestibular areflexia may be observed only in more advanced disease stages."
    explanation: >-
      Explicit point-by-point clinical contrast between the two disorders.

- name: Spastic paraplegia 85, autosomal recessive (biallelic RNF170)
  disease_term:
    preferred_term: spastic paraplegia 85, autosomal recessive
    term:
      id: MONDO:0030512
      label: spastic paraplegia 85, autosomal recessive
  description: >-
    The recessive disease at the other end of the same allelic series. Caused by
    biallelic RNF170 loss-of-function variants, it presents as a hereditary spastic
    paraplegia with primary upper-motor-neuron involvement rather than a dorsal root
    ganglion sensory neuronopathy, and is believed to act by simple loss of function
    rather than by whatever mechanism drives the dominant disease. Heterozygous
    carriers of these null alleles are unaffected. Keeping the two apart matters:
    same gene, different variant class, different inheritance, different target
    neuron, different mechanism.
  distinguishing_features:
  - Biallelic loss-of-function variants versus the single recurrent p.Arg199Cys
    missense allele
  - Autosomal recessive versus autosomal dominant transmission
  - Primary upper motor neuron (corticospinal) involvement versus dorsal root
    ganglion sensory neuronopathy
  - Spasticity and weakness as the leading problem versus proprioceptive sensory
    ataxia
  - Generally earlier (childhood to adolescent) onset versus fifth-to-seventh-decade
    onset in ADSA
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, both the clinical phenotype, with primary involvement of upper motor neurons vs dorsal root ganglia sensory neurons, and the disease-causing mechanism, loss-of-function vs toxic gain-of-function, differ between RNF170 HSP and autosomal dominant sensory ataxia, respectively."
    explanation: >-
      States the clinical and mechanistic separation between the dominant and
      recessive RNF170 diseases.
  - reference: PMID:31636353
    reference_title: Bi-allelic variants in RNF170 are associated with hereditary spastic
      paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families"
    explanation: Establishes the recessive RNF170 disease as a separate entity.
  - reference: PMID:33165979
    reference_title: 'RNF170-Related Hereditary Spastic Paraplegia: Confirmation by
      a Novel Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here a novel hereditary spastic paraplegia family with 4 affected members carrying a homozygous p.(Tyr114*) stop gain variant in RNF170."
    explanation: >-
      Independent confirmation that biallelic truncating RNF170 variants cause
      spastic paraplegia, not sensory ataxia.

- name: Friedreich ataxia
  description: >-
    The classic genetic posterior-column-plus-sensory-ganglion disorder, and the
    long-standing differential for any patient with sensory ataxia and areflexia. It
    is autosomal recessive, usually much earlier in onset, and typically accompanied
    by cardiomyopathy, scoliosis, diabetes and corticospinal involvement, none of
    which is characteristic of ADSA.
  distinguishing_features:
  - Autosomal recessive FXN repeat expansion versus dominant RNF170 missense
  - Childhood or adolescent onset versus fifth-to-seventh-decade onset
  - Systemic features (cardiomyopathy, diabetes, scoliosis) absent in ADSA
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "toxic (cisplatin, pyridoxine) and genetic causes (Friedreich"
    explanation: >-
      Lists Friedreich ataxia among the genetic causes in the sensory
      ganglionopathy differential.

- name: Acquired sensory ganglionopathy (paraneoplastic, autoimmune, toxic)
  description: >-
    Non-genetic sensory neuronopathy must be excluded before pursuing a genetic
    diagnosis: anti-Hu paraneoplastic ganglionopathy, Sjogren syndrome and other
    autoimmune causes, and toxic exposures such as cisplatin and pyridoxine. In
    reported ADSA patients, screening for autoimmune, neoplastic, toxic and
    metabolic causes was negative.
  distinguishing_features:
  - Subacute rather than decade-long progression in most acquired forms
  - Positive autoantibody, malignancy or exposure history
  - Absence of a dominant family history
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a narrow differential diagnosis for a sensory ganglionopathy which includes paraneoplastic (anti-Hu antibodies), autoimmune (Sjogren Syndrome,), toxic (cisplatin, pyridoxine) and genetic causes"
    explanation: Enumerates the acquired causes that must be excluded.
progression:
- phase: Presymptomatic adulthood
  age_range: Birth to fourth or fifth decade
  notes: >-
    Carriers are clinically normal for most of adult life. Because onset is late, an
    unaffected examination in an at-risk relative in this age range carries no
    information about carrier status.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two sisters III-2 and III-4, aged 58 and 49, are reportedly unaffected but given the late onset of the disease were not considered for segregation analysis."
    explanation: >-
      Shows that even relatives in their fifties may be presymptomatic.
- phase: Onset of imbalance and sensory symptoms
  age_range: Fifth to seventh decade
  notes: >-
    Presentation is with poor balance, then distal dysaesthesia and sensory loss in
    feet and hands. Reported onset ages include 47, 50 and about 60 years.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 57-year old woman with onset of poor balance at the age of 47 years, followed by dysaesthesia and sensory loss in her feet and hands"
    explanation: Documents the presenting sequence and age of onset.
- phase: Progressive ataxia with loss of independent mobility
  age_range: Roughly 5 to 15 years after onset
  notes: >-
    Ataxia worsens, falls and fractures occur, and patients move from a stick to a
    walking aid. Vestibular involvement, when it develops, appears at this stage and
    compounds the imbalance.
  evidence:
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has been using a stick to walk since the age of 55."
    explanation: >-
      Documents progression to aid dependence roughly five years after onset.
treatments:
- name: Physical Therapy and Balance Rehabilitation
  description: >-
    No disease-modifying therapy exists for ADSA. Management is supportive and
    centres on gait and balance rehabilitation, visual and tactile compensation
    strategies for the proprioceptive deficit, falls prevention, and provision of
    walking aids as ataxia progresses.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  notes: >-
    Deliberately uncited. No trial, cohort or guideline addressing treatment of
    RNF170-related sensory ataxia exists, and this is standard-of-care extrapolation
    from the management of sensory ataxias generally; attaching a PMID here would
    misrepresent the evidence base. Recorded as a treatment because falls prevention
    and mobility aids are the substance of real clinical management.

- name: Genetic Counseling
  description: >-
    Autosomal dominant transmission implies a 50 percent recurrence risk for
    offspring, complicated by late and possibly age-dependent penetrance, so
    predictive testing in younger at-risk relatives requires careful counselling
    about an unquantified age-related risk. Because p.Arg199Cys is the only allele
    associated with sensory ataxia, while other RNF170 variants cause a recessive
    disease, interpretation of RNF170 findings must be variant-specific.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34469621
    reference_title: RNF170 mutation causes autosomal dominant sensory ataxia with
      variable pyramidal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP."
    explanation: >-
      Supports the counselling and testing recommendation for RNF170 in ataxia and
      HSP panels.
animal_models:
- species: Mouse
  genotype: Rnf170 knockout (Rnf170-/-)
  category: Knockout
  description: >-
    Constitutive Rnf170 knockout mice develop age-dependent gait abnormalities from
    about 12 months, with asynchronous stepping between diagonal limb pairs and a
    fixed step sequence, together with reduced proprioceptive and thermal
    nociceptive sensitivity, and accumulate Itpr1 protein in cerebellum and spinal
    cord but not cerebral cortex. The model therefore reproduces ADSA-like sensory
    and gait phenotypes and demonstrates regionally selective IP3 receptor
    dysregulation. Its relationship to the human dominant disease is nonetheless
    problematic — see the HUMAN_MODEL_MISMATCH discussion — because it models
    complete loss of function, a state that in humans is either clinically silent
    (heterozygous carriers) or causes spastic paraplegia (biallelic).
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  associated_phenotypes:
  - Impaired proprioception
  - Progressive gait ataxia
  - Reduced thermal nociception
  evidence:
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Remarkably, Rnf170(-/-) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires."
    explanation: Describes the age-dependent gait phenotype of the null mouse.
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception."
    explanation: >-
      Documents the proprioceptive deficit that parallels the human sensory
      phenotype.

- species: Zebrafish
  genotype: Transient expression of wild-type versus p.Arg199Cys orthologous mRNA
  category: Transient overexpression
  description: >-
    Microinjection of mutant orthologous RNF170 mRNA into zebrafish embryos
    disrupted normal development in a dominant, dose-dependent manner, whereas
    wild-type mRNA did not. This is the principal positive experimental evidence
    that the p.Arg199Cys allele has a dominant toxic property rather than merely
    reducing gene dosage, and it is the main support for the toxic gain-of-function
    hypothesis. It is a developmental readout in a non-mammalian embryo, not a model
    of adult sensory neurodegeneration.
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  evidence:
  - reference: PMID:21115467
    reference_title: A mutation in the RNF170 gene causes autosomal dominant sensory
      ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Microinjection of wild-type or mutant orthologous messenger RNAs into zebrafish (Danio rerio) embryos confirmed that the mutation dominantly disrupts normal embryonic development."
    explanation: >-
      Demonstrates dominant action of the mutant allele in a model organism.

- species: Dog
  genotype: RNF170 c.367delG p.Ala123Glnfs*11 (homozygous, naturally occurring)
  category: Naturally occurring
  description: >-
    A naturally occurring canine RNF170 frameshift causing neuroaxonal dystrophy
    with pelvic limb weakness and ataxia, segregating in an autosomal recessive
    pattern. Included here for completeness and contrast: its authors explicitly
    propose it as a large-animal model of human autosomal recessive spastic
    paraplegia 85, NOT of ADSA. It is therefore a model of the recessive allelic
    disease and must not be treated as evidence about the dominant p.Arg199Cys
    mechanism.
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  evidence:
  - reference: PMID:39177409
    reference_title: Canine RNF170 Single Base Deletion in a Naturally Occurring Model
      for Human Neuroaxonal Dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern."
    explanation: >-
      Documents the recessive canine allele and its mode of inheritance.
  - reference: PMID:39177409
    reference_title: Canine RNF170 Single Base Deletion in a Naturally Occurring Model
      for Human Neuroaxonal Dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein."
    explanation: >-
      The authors assign this model to the recessive human disease, not to ADSA.
discussions:
- discussion_id: adsa_null_mouse_models_recessive_not_dominant_disease
  prompt: >-
    Does the Rnf170-null mouse model autosomal dominant sensory ataxia, or does it
    actually model the recessive RNF170 spastic paraplegia, given that human
    heterozygous RNF170 null carriers are unaffected?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#RNF170 Protein Destabilization by Enhanced Autoubiquitination
  - pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
  rationale: >-
    Evidence exists in the model but its translational validity is the open
    question, which is why this is a HUMAN_MODEL_MISMATCH rather than a plain
    knowledge gap. Rnf170-/- mice do develop ADSA-like proprioceptive loss and
    age-dependent gait abnormality, which is superficially strong support for a
    loss-of-function mechanism. But the human genetics point the other way:
    heterozygous carriers of RNF170 nonsense alleles are clinically unaffected, and
    individuals homozygous for such alleles develop hereditary spastic paraplegia
    with upper-motor-neuron involvement rather than sensory ataxia. A complete-null
    mouse therefore corresponds genotypically to the recessive human disease, not to
    the heterozygous missense state that causes ADSA. The naturally occurring canine
    RNF170 frameshift model has the same problem: it segregates recessively and its
    authors propose it as a model of SPG85. Consequently the null-mouse phenotype
    cannot be used as evidence that ADSA is caused by loss of RNF170 function, and
    the concordance of its sensory phenotype with ADSA may reflect convergence on a
    shared vulnerable pathway rather than mechanistic identity. A further internal
    inconsistency: the null mouse accumulates Itpr1 most in cerebellum and spinal
    cord, yet the cerebellum is precisely the structure spared in the human disease.
    No p.Arg199Cys knock-in animal exists, so the dominant allele has never been
    modelled in its native heterozygous state.
  proposed_experiments:
  - experiment_id: exp_adsa_r199c_knockin_mouse
    name: Heterozygous Rnf170 p.Arg199Cys knock-in mouse versus null littermates
    description: >-
      Generate a knock-in mouse carrying the orthologous Rnf170 p.Arg199Cys allele
      and phenotype it in the heterozygous state alongside heterozygous and
      homozygous null littermates, scoring dorsal root ganglion neuronopathy,
      posterior column degeneration, proprioception and gait. If the heterozygous
      knock-in is affected while the heterozygous null is not, the allele acts by a
      mechanism other than haploinsufficiency.
    would_support:
    - pathophysiology#RNF170 Protein Destabilization by Enhanced Autoubiquitination
  - experiment_id: exp_adsa_dominant_negative_complex_assay
    name: Test for dominant-negative poisoning of the erlin1/2-RNF170 complex
    description: >-
      Determine whether mutant RNF170 co-assembles with the erlin1/2 complex and
      impairs wild-type RNF170 function in a heterozygous setting, which would
      distinguish a dominant-negative from a purely toxic misfolding mechanism.
    would_support:
    - pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
  - experiment_id: exp_adsa_drg_specific_phenotyping
    name: Dorsal-root-ganglion-specific phenotyping in null and knock-in animals
    description: >-
      Phenotype dorsal root ganglion neurons specifically, rather than whole
      cerebellum or cord homogenates, in both null and knock-in animals, since the
      human lesion is a ganglionopathy and bulk-tissue readouts may have obscured
      the relevant cell population.
    would_support:
    - pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy
  evidence:
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established."
    explanation: >-
      The authors of the null mouse study themselves flag that the functional nature
      of the dominant human allele was unresolved, which is precisely the gap a null
      genotype cannot close.
  - reference: PMID:32943585
    reference_title: 'Mutation in RNF170 causes sensory ataxic neuropathy with vestibular
      areflexia: a CANVAS mimic.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, despite previous evidence of reduced stability and expression level of mutant Arg199Cys RNF170 haploinsufficiency is unlikely to be the primary disease since heterozygous carriers of nonsense variants in RNF170 were later shown to be unaffected"
    explanation: >-
      Human genetic evidence that the loss-of-function state modelled by the null
      mouse does not cause the dominant disease.
  - reference: PMID:39177409
    reference_title: Canine RNF170 Single Base Deletion in a Naturally Occurring Model
      for Human Neuroaxonal Dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein."
    explanation: >-
      The other available large-animal RNF170 model is likewise recessive and is
      proposed by its authors as a model of the recessive human disease.

- discussion_id: adsa_selective_vulnerability_of_dorsal_root_ganglion_neurons
  prompt: >-
    Why does a ubiquitously expressed ER ubiquitin ligase, when mutated, damage
    large dorsal root ganglion sensory neurons and the posterior columns
    specifically, while sparing the cerebellum and cortex?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons
  - pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy
  rationale: >-
    RNF170 is broadly expressed and the erlin1/2-RNF170-IP3 receptor module operates
    in all cells, yet the human disease is remarkably restricted. The only
    mechanistic hint is regional: in Rnf170-null mice Itpr1 protein accumulates in
    cerebellum and spinal cord but not cerebral cortex, showing that the
    consequences of losing this pathway are already region-dependent at the
    biochemical level. That does not explain why large sensory neurons in the dorsal
    root ganglia are the cells that die in humans, and it sits awkwardly with the
    clinical sparing of the cerebellum. Nor does it explain why the closely related
    recessive disease targets upper motor neurons instead. No neuropathological
    study of dorsal root ganglia in ADSA has been reported, so the ganglionopathy is
    inferred entirely from electrophysiology and imaging, and selective
    vulnerability is the central unexplained feature of the disorder.
  proposed_experiments:
  - experiment_id: exp_adsa_cell_type_pathway_comparison
    name: Cross-cell-type comparison of the erlin1/2-RNF170-IP3 receptor module
    description: >-
      Compare RNF170, ERLIN1/2 and ITPR1 expression levels and IP3-receptor turnover
      kinetics across dorsal root ganglion sensory neurons, corticospinal motor
      neurons and cerebellar Purkinje cells, to test whether pathway dependency
      tracks the disease-vulnerable cell type.
    would_support:
    - pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy
  - experiment_id: exp_adsa_ipsc_sensory_neuron_calcium
    name: Calcium handling in patient-derived iPSC sensory neurons
    description: >-
      Measure agonist-evoked ER calcium release in patient-derived iPSC sensory
      neurons carrying p.Arg199Cys alongside isogenic controls and RNF170-null lines,
      to test whether the sensory-neuron lineage is disproportionately sensitive.
    would_support:
    - pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons
  - experiment_id: exp_adsa_human_drg_neuropathology
    name: Neuropathological examination of ADSA dorsal root ganglia
    description: >-
      Perform neuropathological examination of dorsal root ganglia and spinal cord
      from an affected individual. No such study has been reported, so the
      ganglionopathy is currently inferred entirely from electrophysiology and
      imaging.
    would_support:
    - pathophysiology#Dorsal Root Ganglion Sensory Neuronopathy
  evidence:
  - reference: PMID:26433933
    reference_title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene
      linked to human autosomal-dominant sensory ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice."
    explanation: >-
      Demonstrates that loss of this pathway has region-selective biochemical
      consequences, the only current clue to selective vulnerability.

- discussion_id: adsa_true_pathogenic_substrate_of_rnf170
  prompt: >-
    If mutant RNF170 ubiquitinates IP3 receptors normally, what substrate actually
    mediates the calcium-signalling defect and the neurodegeneration?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
  - pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons
  rationale: >-
    The assumption that ADSA is a disease of IP3 receptor ERAD is inherited from
    RNF170's known biochemistry, not demonstrated in patient cells. In ADSA
    lymphoblasts the calcium defect is real, yet mutant RNF170 attaches the full
    normal set of ubiquitin conjugates to activated IP3 receptors, and receptor
    level, store content and IP3 production are unchanged. The original
    investigators therefore concluded that the defect reflects abnormal
    ubiquitination of other, unidentified substrates or an adaptive response to
    chronically low RNF170. Identifying the operative substrate would determine
    whether ADSA is genuinely an IP3-receptor-turnover disease or a distinct ER
    quality-control disease that merely shares a gene with one.
  proposed_experiments:
  - experiment_id: exp_adsa_ubiquitinome_profiling
    name: Comparative ubiquitinome profiling of ADSA patient cells
    description: >-
      Perform comparative ubiquitinome or diGly proteomics on ADSA patient cells and
      isogenic controls to identify substrates whose ubiquitination is altered by
      p.Arg199Cys.
    would_support:
    - pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons
  - experiment_id: exp_adsa_mutant_rnf170_interactome
    name: RNF170 interactome in the mutant versus wild-type state
    description: >-
      Define the RNF170 interactome in the mutant versus wild-type state, including
      the erlin1/2 and TMUB1 scaffolds, to look for a poisoned complex.
    would_support:
    - pathophysiology#Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD
  - experiment_id: exp_adsa_calcium_defect_in_sensory_neurons
    name: Reproduce the calcium defect in the degenerating cell type
    description: >-
      Determine whether the lymphoblast calcium defect is cell-autonomous and
      reproducible in sensory neurons, the cell type that actually degenerates,
      rather than only in an immortalised blood-derived lineage.
    would_support:
    - pathophysiology#Dysregulated ER Calcium Release in Sensory Neurons
  evidence:
  - reference: PMID:25882839
    reference_title: A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal
      Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate
      Receptor-mediated Ca2+ Signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels."
    explanation: >-
      States the unresolved substrate question in the words of the study that
      created it.
notes: >-
  Scope, provenance, module-conformance and named-entity-confusion notes for this
  entry.


  (1) No GeneReviews baseline exists. PubMed searches for a GeneReviews chapter
  covering RNF170, ADSA or sensory ataxia returned no results, so the usual
  GeneReviews phenotype baseline could not be applied. The phenotype block was
  instead built from the three primary clinical reports that together constitute
  essentially the entire clinical literature on this disorder: the gene-discovery
  paper on the two Maritime Canadian families (PMID:21115467), the Belgian family
  (PMID:34469621), and the Ecuadorian family reported in detail as a CANVAS mimic
  (PMID:32943585, whose full text is cached and supplies examination-level detail).
  Every clinical feature named in those reports is represented above.


  (2) Named-entity-confusion (NEC) preflight. This disorder sits in two
  high-NEC-risk classes at once: it belongs to a numbered ataxia series and it
  shares its gene with a differently named, differently inherited disease. The
  MONDO record for MONDO:0012166 was pulled with OAK and gave three independent
  identity anchors, all of which match this entry: the causal gene RNF170
  (relationship RO:0004003 HGNC:25358), the OMIM xref OMIM:608984, and the synonyms
  ADSA and SNAX1. The two nearest confusable entities were checked and are
  deliberately excluded: autosomal recessive spastic paraplegia 85 (SPG85,
  MONDO:0030512, OMIM:619686, biallelic RNF170 loss of function) and RFC1-related
  CANVAS. Neither is curated here as a manifestation of ADSA; both are recorded as
  differential diagnoses. Both deep-research reports were independently NEC-screened
  by gene-mention frequency and passed: falcon named RNF170 160 times against 10 for
  RFC1 (p.Arg199Cys 22 times), openscientist 71 times against 3 for RFC1
  (p.Arg199Cys 11 times).


  (3) Allelic-series discipline. Only one variant, p.Arg199Cys, has ever been linked
  to sensory ataxia; every other pathogenic RNF170 allele reported is a biallelic
  loss-of-function variant causing spastic paraplegia. Literature retrieved for
  "RNF170" is therefore dominated by the recessive HSP disease (PMID:31636353,
  PMID:33165979, PMID:35041108, PMID:36046950, PMID:38499745, PMID:42462372) and by
  basic erlin/IP3-receptor cell biology. Recessive-disease papers are cited in this
  entry only where they legitimately bear on ADSA — as differential diagnosis, as
  evidence about the shared ER module, or as the source of the crucial observation
  that heterozygous null carriers are unaffected — and never as evidence for an ADSA
  clinical feature.


  (4) Module conformance, and a deliberate non-conformance. Two nodes declare
  conformance to `peripheral_axonal_degeneration`: "Dorsal Root Ganglion Sensory
  Neuronopathy" conforms to `#Insult to Peripheral Neurons and Schwann Cells` (a
  genetic insult to peripheral sensory neurons), and "Peripheral Sensory Axon
  Degeneration" conforms to `#Distal Axonal Degeneration and Demyelination`
  (documented reduced or absent sensory nerve action potentials). Conformance is
  deliberately NOT declared for that module's `#Length-Dependent Nerve Fiber
  Dysfunction` node, because ADSA is a ganglionopathy: the insult is at the sensory
  neuron cell body, degeneration proceeds along both central and peripheral
  branches, and the resulting sensory loss is not length-dependent — the hands are
  often as affected as the feet, and pseudoathetosis and areflexia dominate over the
  distal glove-and-stocking pattern that module node describes. Conformance is also
  not declared for `#Axonal Transport Impairment and Mitochondrial Dysfunction`, for
  which there is no RNF170-specific evidence. Conformance to
  `cerebellar_purkinje_degeneration` was considered and rejected outright: cerebellar
  involvement is characteristically absent, brain MRI including the cerebellum is
  normal, and the diagnostic value of the syndrome lies precisely in severe ataxia
  with a normal cerebellum.


  (5) Mechanism is genuinely unresolved, and the entry is built to show that rather
  than to hide it. Three `mechanistic_hypotheses` are recorded with
  hypothesis-tagged causal edges: a toxic gain-of-function or dominant-negative
  model (EMERGING, currently favoured in the literature), simple haploinsufficiency
  (ALTERNATIVE, explicitly argued against by the unaffected heterozygous null
  carriers), and dysregulation of an unidentified non-IP3-receptor substrate
  (EMERGING). The "Impaired erlin1/2-RNF170-Mediated IP3 Receptor ERAD" node carries
  `mechanism_confidence: PROVISIONAL` and a REFUTE-tagged evidence item, because the
  canonical assumption that ADSA is an IP3-receptor-ERAD disease is not supported in
  patient cells.


  (6) A 2026 case report is deliberately not used to expand the phenotype.
  PMID:42052314 describes a 60-year-old woman with hypertrophic olivary
  degeneration, palatal myoclonus, pendular nystagmus and mild cerebellar atrophy in
  whom "genetic testing revealed a heterozygous mutation in the RNF170 gene". The
  specific variant is not stated, there was no family history of ataxia, and
  cerebellar atrophy and palatal tremor are features the established ADSA literature
  explicitly reports as absent. This report is therefore treated as an unverified
  phenotype-expansion claim of uncertain significance: only the positive Romberg
  sign, which is consistent with the established phenotype, is cited from it, and
  hypertrophic olivary degeneration, palatal myoclonus, nystagmus and cerebellar
  atrophy are NOT curated as ADSA phenotypes. If the variant is later shown to be
  p.Arg199Cys and the association replicated, this decision should be revisited.
  Following review, the Positive Romberg Sign phenotype no longer depends on this
  report: its primary evidence is now the genotype-confirmed p.Arg199Cys Ecuadorian
  index case (PMID:32943585), with this case report retained only as a secondary
  corroborating item, so the phenotype stands regardless of how PMID:42052314 is
  ultimately judged.


  (7) Treatment evidence is intentionally sparse. There is no disease-modifying
  therapy and no ADSA-specific trial, cohort or guideline; ClinicalTrials.gov
  searches performed during deep research by both providers returned no
  disease-specific trial. The rehabilitation entry is recorded without an evidence
  item and with an explanatory note rather than being supported by a citation that
  does not address this disease. No `clinical_trials` block is asserted.


  (8) Onset is not curated as a phenotype. Adult/late onset is a defining feature of
  this disorder, but the HPO onset terms (HP:0003581 Adult onset, HP:0003584 Late
  onset) live in the Clinical modifier subtree rather than the Phenotypic
  abnormality subtree and are not members of the schema's `PhenotypeTerm` dynamic
  enum. Onset is therefore carried in the `progression` phases, the `inheritance`
  description and the Progressive Gait Ataxia description instead of as a
  pseudo-phenotype with an invalid term binding.


  (8a) Ontology-term granularity decisions made in review. Two bindings were
  changed and one was deliberately declined. `Pyramidal Signs` was rebound from
  HP:0001257 Spasticity to its parent HP:0007256 Abnormal pyramidal sign, because
  the only cited source says "pyramidal involvement" generically and asserting
  spasticity specifically over-committed relative to the evidence. The bundled
  "Paresthesia and Dysesthesia" phenotype was split down to a single concept and
  rebound from HP:0003401 Paresthesia to HP:0012534 Dysesthesia, since the snippet
  reports "dysaesthesia" and only that is snippet-supportable. Conversely, the new
  `Pseudoathetosis` phenotype is deliberately left with a free-text
  `preferred_term` and NO `term:` binding: HPO has no pseudoathetosis term,
  HP:0011443 resolves to the very broad "Abnormality of coordination", and
  HP:0002305 Athetosis would be actively misleading because pseudoathetosis is a
  deafferentation sign rather than an extrapyramidal one. A missing binding is
  preferable to a wrong one.


  (9) Deep-research provenance. Two independent deep-research reports were generated
  and are committed at
  `research/Autosomal_Dominant_Sensory_Ataxia_1-deep-research-falcon.md` and
  `research/Autosomal_Dominant_Sensory_Ataxia_1-deep-research-openscientist.md`.
  They were used as lead-generation and cross-check layers only: every PMID, snippet
  and ontology term in this entry was independently fetched and verified against the
  cached reference body, and no citation was taken from either report on trust. Both
  proved concordant with the primary literature and with each other on disease
  identity, the p.Arg199Cys allele, the dorsal-root-ganglion localisation, the CANVAS
  contrast and the unresolved dominance mechanism. Notably, openscientist reached the
  same conclusion recorded in the HUMAN_MODEL_MISMATCH discussion above
  independently, stating that the existing mouse and dog models are
  loss-of-function/recessive and better model SPG85 than ADSA. falcon failed to
  recover the OMIM identifier that the MONDO record supplies directly, and cited a
  narrower source set than the primary-literature sweep performed here;
  openscientist converged on the same 13-paper evidence base identified
  independently.

📚

References & Deep Research

Deep Research

2

Falcon ▸

Autosomal Dominant Sensory Ataxia 1: Comprehensive Disease Report

Edison Scientific Literature 14 citations 2026-08-01T12:03:28.639894

Autosomal Dominant Sensory Ataxia 1: Comprehensive Disease Report

Executive summary

Autosomal dominant sensory ataxia 1 (ADSA1; also SNAX1) is an exceptionally rare, adult-onset, slowly progressive neurodegenerative disorder caused by a heterozygous RNF170 c.595C>T (p.Arg199Cys) variant. Its defining abnormality is degeneration or dysfunction of proprioceptive sensory pathways—especially dorsal-root-ganglion neurons and/or their central projections in the posterior spinal columns—producing impaired vibration and joint-position sense, sensory gait ataxia, and a positive Romberg sign. Pyramidal signs, peripheral sensory-neuronopathy, and bilateral vestibular areflexia are variable extensions of the phenotype. The disorder is not primarily a cerebellar ataxia. Published dominant cases remain limited to a few Canadian, Ecuadorian, and Belgian/European families, precluding reliable estimates of prevalence, penetrance, survival, or phenotype frequencies. (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 2-4, wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 1-2)

A crucial curation distinction is that biallelic loss-of-function RNF170 variants cause a separate, infancy-onset autosomal-recessive hereditary spastic paraplegia (HSP). Findings from that allelic disorder illuminate RNF170 biology but should not be assigned directly to ADSA1. (wagner2019biallelicvariantsin pages 8-10, wagner2019biallelicvariantsin pages 1-2, wagner2019biallelicvariantsin pages 3-4)

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 (OpenTargets Search: Autosomal dominant sensory ataxia 1, daele2022rnf170mutationcauses pages 2-4, wagner2019biallelicvariantsin pages 8-10)
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 (cortese2020mutationinrnf170 pages 1-2, wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 1-2)
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 (cortese2020mutationinrnf170 pages 1-1, daele2022rnf170mutationcauses pages 1-2, cortese2020mutationinrnf170 pages 2-2)
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 (wagner2019biallelicvariantsin pages 8-10, wagner2019biallelicvariantsin pages 10-11, wagner2019biallelicvariantsin pages 1-2, wagner2019biallelicvariantsin pages 11-12)
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 (daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-2)
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 (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 1-2, daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-1)
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 (daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-1)
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 (cortese2020mutationinrnf170 pages 1-2)
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 (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 1-2)
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 (cook2024rnf170frameshiftdeletion pages 10-12, wagner2019biallelicvariantsin pages 10-11, wagner2019biallelicvariantsin pages 8-10)
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 (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 1-2, daele2022rnf170mutationcauses pages 2-4)

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.

1. Disease information

Definition and classification

ADSA1 is a Mendelian, autosomal-dominant sensory ataxia characterized by late-onset progressive impairment of large-fiber proprioceptive pathways. The usual clinical syndrome comprises imbalance worsened by loss of visual input, sensory loss, gait ataxia, and posterior-column neurophysiological abnormalities. Sensory nerve action potentials (SNAPs) may remain preserved in the classic predominantly central/preganglionic phenotype, but some families exhibit sensory ganglionopathy with reduced or absent SNAPs. (wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 4-5, cortese2020mutationinrnf170 pages 1-1)

Identifiers and synonyms

MONDO: MONDO:0012166, autosomal dominant sensory ataxia 1.
OMIM phenotype: MIM 608984, reported in the literature as autosomal dominant sensory ataxia/ADSA.
Causal gene: RNF170, ring finger protein 170; Ensembl ENSG00000120925.
Common names: autosomal dominant sensory ataxia; autosomal dominant sensory ataxia 1; ADSA; ADSA1; sensory ataxia 1; SNAX1; RNF170-related dominant sensory ataxia.
Orphanet, MeSH, ICD-10, and ICD-11: no disease-specific codes were established from the retrieved evidence. In clinical coding, the condition will generally require broader hereditary ataxia or hereditary neuropathy categories; these are not exact semantic equivalents.

Open Targets maps MONDO:0012166 specifically to RNF170 and reports five association-evidence records, including literature linked to PMID 21115467. (OpenTargets Search: Autosomal dominant sensory ataxia 1)

Evidence provenance

The phenotype is derived primarily from individually examined members of a very small number of pedigrees, not from EHR-scale cohorts, population registries, or surveillance systems. MONDO/Open Targets and similar resources aggregate these family-level reports. Consequently, apparently precise clinical frequencies should not be generalized to the wider population.

2. Etiology, risk, and protective factors

Causal factor

The established cause is a germline heterozygous RNF170 c.595C>T (p.Arg199Cys) missense variant in a transmembrane region of RNF170. The same amino-acid substitution has been reported across geographically separated dominant families and remains the only heterozygous RNF170 variant convincingly linked to this specific phenotype in the retrieved literature. (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 2-4, daele2022rnf170mutationcauses pages 4-5)

Genetic risk

An affected heterozygote has, in principle, a 50% probability of transmitting the variant in each pregnancy. Family history is therefore the principal recognized risk factor. Two Eastern Canadian families shared a disease haplotype, supporting a founder event. Common ancestry with the Ecuadorian and Belgian families has not been demonstrated. Reduced penetrance or a de novo event was considered in the Belgian pedigree because the paternal grandparents reportedly remained asymptomatic beyond age 70. (daele2022rnf170mutationcauses pages 2-4)

Reliable age-specific penetrance, carrier frequency, population allele frequency, sex effect, germline-mosaicism rate, modifier genes, and genetic anticipation have not been established. There is no evidence of a repeat-expansion mechanism, so anticipation is not expected mechanistically, but this has not been tested in a sufficiently large cohort.

Environmental, lifestyle, infectious, and protective factors

No environmental toxin, lifestyle exposure, infection, diet, protective allele, or protective behavior has been shown to alter ADSA1 occurrence or progression. No disease-specific gene–environment interaction has been reported. Acquired toxic, autoimmune, nutritional, and paraneoplastic sensory neuronopathies are important differential diagnoses, not established modifiers of RNF170 disease. (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-1)

3. Phenotypes

Core and variable manifestations

Manifestation	Characteristics and evidence	Suggested HPO term
Sensory ataxia	Core, apparently universal among clinically affected reported cases; chronic and progressive	Sensory ataxia, HP:0002066
Gait ataxia/unsteadiness	Common presenting disability; may progress to need for a walking aid	Gait ataxia, HP:0002064; unsteady gait, HP:0002317
Impaired proprioception	Reduced joint-position and vibration sense, usually distal and lower-limb predominant	Impaired proprioception, HP:0010831; decreased vibration sense, HP:0006934
Positive Romberg sign	Reflects visual compensation for proprioceptive failure	Positive Romberg sign, HP:0002403
Sensory loss/dysesthesia	Feet and legs first; hands may become involved; pinprick can also be reduced	Distal sensory impairment, HP:0002936; paresthesia, HP:0003401
Hyporeflexia/areflexia	Variable, especially with peripheral ganglion/postganglionic involvement	Hyporeflexia, HP:0001265; areflexia, HP:0001284
Pyramidal signs	Babinski signs, hypertonia, or spastic-ataxic gait in a subset; 3/10 in an earlier summarized cohort had pyramidal signs without manifest spasticity	Babinski sign, HP:0003487; lower-limb hyperreflexia, HP:0002395; spasticity, HP:0001257
Sensory neuropathy/ganglionopathy	Variable; SNAPs can be reduced or absent despite normal motor conduction	Sensory neuropathy, HP:0000763
Vestibular areflexia	Documented bilaterally in the Ecuadorian index case; may emerge in advanced disease and mimic CANVAS	Bilateral vestibular hypofunction, HP:0031609
Upper-limb ataxia/pseudoathetosis	Usually later or milder than lower-limb gait involvement	Limb ataxia, HP:0002070; pseudoathetosis, HP:0011443
Slow-pursuit abnormality	Variable oculomotor finding; does not establish cerebellar degeneration	Abnormal smooth pursuit, HP:0000617

The Belgian family had onset at ages 35, 55, 64, and 68 years in four affected relatives. The Ecuadorian proband developed poor balance at 47 years and required a walking aid by 57; her father and grandmother reportedly began near age 60. Across earlier reports, onset ranged from the fourth through eighth decades. (cortese2020mutationinrnf170 pages 1-2, wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 1-2)

Laboratory, neurophysiological, and imaging phenotypes

Somatosensory evoked potentials: delayed, abnormal, or absent lower-extremity responses support posterior-column/preganglionic dysfunction.
Nerve conduction: motor studies are generally normal. SNAPs may be preserved in classic Canadian disease but reduced or absent in Belgian and Ecuadorian cases, demonstrating genuine phenotypic variability rather than a mandatory normal sensory NCS.
MRI: brain MRI can be normal without cerebellar atrophy. Cervical spinal MRI may show posterior-column T2 hyperintensity and volume loss, although normal spinal MRI has also been reported. Frontal atrophy was described in one Belgian evaluation but is not established as a defining feature.
Vestibular testing: video head-impulse or equivalent testing may demonstrate reduced vestibulo-ocular-reflex gain bilaterally. (cortese2020mutationinrnf170 pages 1-1, daele2022rnf170mutationcauses pages 1-2, cortese2020mutationinrnf170 pages 2-2)

Quality-of-life effect

Progressive imbalance, loss of position sense, and vestibular impairment increase falls, restrict independent mobility, and may eventually require a cane, walker, or other aid. No ADSA1-specific EQ-5D, SF-36, PROMIS, employment, caregiver-burden, or activities-of-daily-living datasets were found. The Ecuadorian case provides direct evidence of meaningful mobility disability over approximately ten years. (cortese2020mutationinrnf170 pages 1-2)

4. Genetic and molecular information

Gene and variant

Gene: RNF170, encoding an endoplasmic-reticulum membrane RING-finger E3 ubiquitin ligase.
Dominant ADSA1 variant: NM transcript-dependent notation c.595C>T; p.Arg199Cys (R199C).
Variant class: germline heterozygous missense substitution in a transmembrane region.
Population frequency: no numerical gnomAD, TOPMed, 1000 Genomes, or ExAC frequency was recovered; the familial evidence and scarcity of reports imply extreme rarity, but a database value should be checked directly before production curation.
Clinical classification: the family-level segregation and repeated phenotype association support pathogenicity for ADSA1. A current ClinVar assertion and review status were not independently recovered and should not be inferred from the papers alone.
Somatic status: no somatic disease mechanism is known.

Arg199's positive charge appears important for ionic interactions that stabilize the transmembrane region. The substitution is associated with reduced RNF170 abundance through increased autoubiquitination and proteasomal degradation, but the dominant clinical mechanism is not adequately explained by simple haploinsufficiency because heterozygous carriers of truncating variants can be unaffected. A variant-specific toxic gain of function is therefore favored, although the exact toxic species and basis of sensory-neuron selectivity remain unresolved. (daele2022rnf170mutationcauses pages 2-4, wagner2019biallelicvariantsin pages 8-10, cook2024rnf170frameshiftdeletion pages 10-12, wagner2019biallelicvariantsin pages 10-11)

Allelic-disorder warning

Biallelic RNF170 variants—including splice, missense, multiexon/genomic-deletion, and frameshift alleles—cause an autosomal-recessive HSP with onset usually before age five, progressive lower-limb spasticity, and frequent optic atrophy. Wagner et al. studied nine affected individuals from four families; seven had optic atrophy and median onset was two years. These variants and phenotypes must not be entered as ADSA1-associated dominant variants. (wagner2019biallelicvariantsin pages 8-10, wagner2019biallelicvariantsin pages 3-4)

No established ADSA1 modifier gene, chromosomal abnormality, DNA-methylation signature, histone alteration, or chromatin mechanism was identified.

5. Environmental information

ADSA1 is a monogenic inherited disorder. No evidence supports pollution, radiation, occupation, smoking, alcohol, diet, physical inactivity, or infectious agents as causal or triggering factors. Avoiding neurotoxic exposures—such as excessive pyridoxine or certain chemotherapy agents—is prudent in a person with sensory dysfunction but represents prevention of superimposed neuropathy, not prevention of RNF170 disease. (cortese2020mutationinrnf170 pages 1-2, cortese2020mutationinrnf170 pages 1-1)

6. Mechanism and pathophysiology

Normal pathway

RNF170 is an ER-membrane E3 ubiquitin ligase. Following activation of inositol 1,4,5-trisphosphate receptors (IP3Rs/ITPRs), the ERLIN1–ERLIN2 complex recruits RNF170, which ubiquitinates the activated receptors and directs them toward ER-associated degradation and proteasomal turnover. This feedback limits IP3-mediated calcium release from the ER and helps restore calcium homeostasis. (wagner2019biallelicvariantsin pages 10-11, wagner2019biallelicvariantsin pages 1-2, wagner2019biallelicvariantsin pages 11-12)

The abstract of Wagner et al. states directly: “We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families.” It further concludes that the findings “highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias.” Although this experiment concerned recessive HSP, the biochemical pathway is relevant to interpreting dominant RNF170 disease. (wagner2019biallelicvariantsin pages 1-2)

Proposed ADSA1 causal chain

Upstream genetic trigger: heterozygous p.Arg199Cys alters a critical RNF170 transmembrane residue.
Protein effect: altered intramembrane interactions and RNF170 instability, with increased autoubiquitination/proteasomal turnover.
Pathway disturbance: dysregulated RNF170–ERLIN1/2–IP3R quality control and abnormal ER calcium signaling; available data favor a p.Arg199Cys-specific toxic gain of function rather than generic dosage loss.
Cellular vulnerability: long-projecting proprioceptive sensory neurons—dorsal-root-ganglion neurons and their posterior-column axons—are preferentially impaired or lost. The reason for this selectivity is unknown.
Tissue pathology: dysfunction/degeneration of central sensory tracts, with variable ganglionic/postganglionic and vestibular involvement.
Clinical output: loss of proprioceptive input causes Romberg-positive sensory ataxia; involvement of corticospinal pathways adds pyramidal signs, and vestibular involvement can produce a CANVAS-like syndrome. (cortese2020mutationinrnf170 pages 1-2, wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 4-5, wagner2019biallelicvariantsin pages 10-11)

Suggested ontology annotations

GO biological process: protein ubiquitination (GO:0016567); ER-associated ubiquitin-dependent protein catabolic process (GO:0030433); proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161); regulation of cytosolic calcium-ion concentration (GO:0051480); inositol-1,4,5-trisphosphate-sensitive calcium-release channel activity pathway.
GO molecular function: ubiquitin-protein transferase activity (GO:0004842); ligase activity (GO:0016874).
GO cellular component: endoplasmic-reticulum membrane (GO:0005789); integral component of ER membrane.
Cell Ontology: sensory neuron (CL:0000526); peripheral sensory neuron (CL:0000101); dorsal-root-ganglion neuron; proprioceptor (CL:0000199).

No disease-specific human transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics profile was found. Immune activation, fibrosis, ischemia, primary mitochondrial failure, and a defined metabolic signature are not established components of ADSA1.

7. Anatomical structures affected

The nervous system is the primary affected system. Principal sites are bilateral and length-dependent rather than unilateral:

dorsal-root ganglia and large myelinated sensory neurons;
peripheral sensory axons in cases with ganglionopathy;
posterior/dorsal columns of the cervical and more caudal spinal cord;
proprioceptive pathways and somatosensory projections;
variably, corticospinal tracts and bilateral vestibular pathways.

The cerebellum may be structurally normal; therefore, “ataxia” should not automatically be annotated as primary cerebellar degeneration. No consistent involvement of heart, lung, kidney, endocrine, gastrointestinal, or immune organs has been established. (wagner2019biallelicvariantsin pages 8-10, cortese2020mutationinrnf170 pages 1-1, cortese2020mutationinrnf170 pages 2-2)

Suggested anatomy terms include UBERON:0000955 nervous system, UBERON:0002240 spinal cord, UBERON:0002392 dorsal root ganglion, UBERON:0002291 posterior funiculus, and UBERON:0002037 cerebellum only when documenting a normal/differential assessment rather than proven primary disease.

8. Temporal development

Onset is chronic and insidious, typically in adulthood or later life. Published individual onsets range from 35 to 68 years, while summarized historical observations extend into the eighth decade. Early disease commonly consists of fatigue, imbalance, or distal sensory symptoms; intermediate disease adds marked proprioceptive loss, Romberg positivity, and gait ataxia; advanced disease may include upper-limb sensory ataxia, sensory ganglionopathy, pyramidal signs, vestibular areflexia, and dependence on mobility aids. (cortese2020mutationinrnf170 pages 1-2, wagner2019biallelicvariantsin pages 8-10, daele2022rnf170mutationcauses pages 1-2)

The course is slowly progressive and lifelong. No relapsing-remitting pattern, spontaneous remission, disease stage system, validated progression rate, or critical therapeutic window has been defined.

9. Inheritance and population

Inheritance is autosomal dominant. Available reports support vertical transmission in both sexes, without evidence for sex limitation. The Canadian founder haplotype indicates a regional founder effect, but ADSA1 has also been detected in Ecuadorian and Belgian/European families. By 2022, the literature described two Canadian families, one Ecuadorian family, and one Belgian family; this is case ascertainment, not a population prevalence estimate. (daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-2)

No defensible incidence per 100,000, prevalence per 100,000, carrier frequency, sex ratio, ethnic-risk estimate, or geographic burden is available. Penetrance is probably age-dependent but cannot be quantified. Expressivity is clearly variable: central posterior-column disease predominates in some families, whereas sensory ganglionopathy, pyramidal findings, or vestibular areflexia occur in others. Consanguinity is not relevant to the dominant disorder, though it is relevant to recessive RNF170-HSP.

10. Diagnostics

Clinical and physiological work-up

A practical diagnostic sequence is:

Document sensory rather than primary cerebellar ataxia: Romberg testing, vibration and joint-position sensation, reflexes, pinprick, pseudoathetosis, eye movements, and pyramidal signs.
Obtain motor and sensory NCS/EMG. Normal motor conduction with preserved or reduced/absent SNAPs is compatible with the spectrum.
Perform tibial/median SSEPs to identify central or preganglionic sensory-pathway dysfunction.
Obtain brain and cervical-spine MRI, looking for posterior-column signal/atrophy and assessing cerebellar structure.
If oscillopsia or a CANVAS-like presentation is present, assess vestibulo-ocular reflexes using video head-impulse testing, calorics, or rotational testing.
Exclude acquired sensory neuronopathy: nutritional deficiencies, paraproteinemia, Sjögren/autoimmune disease, paraneoplastic anti-Hu disease, infection where indicated, and medication/toxin exposure.
Conduct genetic testing. (cortese2020mutationinrnf170 pages 1-2, cortese2020mutationinrnf170 pages 2-2, cortese2020mutationinrnf170 pages 1-1)

Genetic testing

Targeted sequencing of RNF170, including direct testing for c.595C>T, is appropriate when the phenotype and dominant pedigree are compelling. More commonly, RNF170 should be included in a hereditary ataxia, sensory-neuropathy, or combined ataxia/HSP panel. The Belgian authors specifically recommended RNF170 inclusion in ataxia panels, while the Ecuadorian report recommended RNF170 testing in RFC1-negative CANVAS-like disease with dominant family history. (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 1-2, daele2022rnf170mutationcauses pages 2-4)

Testing should usually first or concurrently address common repeat expansions because standard WES may miss them, especially biallelic RFC1 AAGGG expansions and dominant spinocerebellar-ataxia expansions. WES is useful when panel testing is negative; WGS may identify sequence and structural variants and improve repeat analysis if the validated pipeline supports it. CMA, karyotyping, FISH, mitochondrial testing, and RNA sequencing are not first-line ADSA1 tests unless other clinical or variant-specific evidence warrants them.

No formal society diagnostic criteria, biochemical biomarker, enzyme assay, liquid biopsy, epigenomic test, or validated prognostic biomarker exists.

Differential diagnosis

Key alternatives are RFC1-related CANVAS; Friedreich ataxia; dominant spinocerebellar ataxias; POLG-related mitochondrial sensory ataxia; vitamin-E deficiency; abetalipoproteinemia; CMT4C and other inherited neuropathies; Sjögren sensory neuronopathy; anti-Hu/paraneoplastic ganglionopathy; and pyridoxine-, cisplatin-, or other toxin-associated neuropathy. Absence of cerebellar atrophy, a dominant pedigree, prominent posterior-column physiology, and RNF170 p.Arg199Cys distinguish ADSA1, but no single clinical sign is pathognomonic. (daele2022rnf170mutationcauses pages 2-4, cortese2020mutationinrnf170 pages 1-1)

11. Outcome and prognosis

ADSA1 causes chronic progressive neurological disability, principally impaired balance, falls, and declining independent ambulation. One Ecuadorian patient progressed from initial imbalance at 47 to requiring a walking aid by 57. The late onset and absence of reported systemic organ failure suggest that morbidity rather than early mortality is the dominant concern, but available studies are too small to conclude that life expectancy is normal. (cortese2020mutationinrnf170 pages 1-2)

No five- or ten-year survival rate, standardized disability trajectory, mortality rate, recovery rate, or quality-of-life score is available. Neurological recovery is not documented; stabilization with supportive care has not been quantified. Potential adverse prognostic features—earlier onset, ganglionopathy, pyramidal involvement, or vestibular areflexia—are plausible but unvalidated.

12. Treatment and current implementation

No disease-modifying pharmacotherapy, approved RNF170-targeted therapy, gene therapy, ASO, siRNA, cell therapy, immunotherapy, surgical treatment, pharmacogenomic rule, or genotype-specific treatment algorithm exists. The ClinicalTrials.gov search retrieved no relevant disease-specific interventional trial. Published human reports do not provide response rates or controlled treatment outcomes. (cortese2020mutationinrnf170 pages 1-2, daele2022rnf170mutationcauses pages 1-2)

Current care is supportive and should be individualized:

neurologic and rehabilitation follow-up;
physical therapy for balance, strength, gait, and safe transfers;
occupational therapy and home-safety modification;
cane, trekking poles, walker, orthoses, or wheelchair as needed;
vestibular rehabilitation when bilateral hypofunction is present;
fall prevention, footwear and foot inspection where sensation is reduced;
treatment of neuropathic pain or dysesthesia using standard agents when present;
correction of superimposed nutritional deficiencies and avoidance of sensory neurotoxins;
genetic counseling and family cascade testing.

Suggested NCIt intervention concepts include Physical Therapy (NCIT:C15308), Occupational Therapy, Rehabilitation Therapy, Genetic Counseling (NCIT:C15241), and Assistive Device. These are supportive interventions extrapolated from neurological rehabilitation practice, not ADSA1-tested treatments.

The RNF170–ERLIN–IP3R pathway is a biologically plausible therapeutic target, but indiscriminate inhibition or enhancement could disrupt calcium homeostasis. Expert interpretation should therefore treat pathway modulation as preclinical, not clinically actionable. (wagner2019biallelicvariantsin pages 10-11, wagner2019biallelicvariantsin pages 1-2)

13. Prevention

Primary prevention through lifestyle modification or immunization is not possible for a germline dominant disorder. Secondary prevention consists of early molecular diagnosis, cascade testing of adult relatives who choose testing, baseline neurological assessment, and early fall-risk intervention. Tertiary prevention includes rehabilitation, mobility aids, home modification, vestibular therapy, prevention of injury, and avoidance of additional neuropathic insults.

After identification of a familial pathogenic variant, prenatal diagnosis and preimplantation genetic testing are technically feasible. Predictive testing of asymptomatic adults requires counseling about uncertain age-specific penetrance and the absence of preventive disease-modifying therapy. Testing minors for a usually adult-onset disorder should follow established ethics guidance and generally be deferred unless a clear childhood medical benefit emerges.

14. Other species and natural disease

A 2024 study/preprint reported naturally occurring autosomal-recessive neuroaxonal dystrophy in Miniature American Shepherd dogs (Canis lupus familiaris; NCBI Taxon 9615) caused by RNF170 c.367delG, p.Ala123Glnfs*11. Affected young-adult dogs developed pelvic-limb weakness and ataxia; 23/27 homozygotes (85%) were clinically affected, and linkage reached LOD 9.70. The abstract states that the deletion “perfectly segregates in an autosomal recessive pattern” and describes the dogs as an opportunity for therapeutic trials because of their relatively long lifespan. (cook2024rnf170frameshiftdeletion pages 10-12)

This is a valuable large-animal model of RNF170-associated neurodegeneration, but it models recessive truncating loss of function and neuroaxonal dystrophy—not human dominant p.Arg199Cys ADSA1. No zoonotic transmission is applicable, and no naturally occurring nonhuman disease with the exact dominant human variant was identified.

15. Model organisms

Mouse

Rnf170-null mice develop age-dependent gait abnormalities at approximately 12 months, involving interlimb coupling and step-sequence organization. They support a role for RNF170 in long-term nervous-system integrity but are loss-of-function models and do not reproduce the human heterozygous p.Arg199Cys mechanism exactly. (cook2024rnf170frameshiftdeletion pages 10-12, wagner2019biallelicvariantsin pages 10-11)

Zebrafish

Zebrafish knockdown and RNF170-expression experiments demonstrate developmental and neuronal consequences of disturbed RNF170 function, including abnormal body axis, eye/brain development, and impaired neurogenesis in loss-of-function paradigms. Separate expression work found dose-dependent toxicity from Arg199Cys, supporting a variant-specific toxic effect. These assays are mechanistically informative but cannot model decades-long human sensory tract degeneration. (cortese2020mutationinrnf170 pages 1-2, wagner2019biallelicvariantsin pages 10-11, wagner2019biallelicvariantsin pages 8-10)

Cellular systems

Patient fibroblasts and engineered SH-SY5Y neuroblastoma cells have been used to measure RNF170 abundance and IP3R degradation. Recessive loss-of-function variants increase basal IP3R levels and impair ligand-stimulated receptor degradation, supporting the RNF170–ERLIN–IP3R–ERAD mechanism. These systems lack mature proprioceptive-neuron architecture and therefore do not explain selective posterior-column vulnerability. (wagner2019biallelicvariantsin pages 1-2, wagner2019biallelicvariantsin pages 11-12, wagner2019biallelicvariantsin pages 8-10)

No validated ADSA1 patient-derived iPSC proprioceptor, sensory organoid, conditional p.Arg199Cys knock-in mouse, or humanized large-animal model was identified. Developing such models is a major research priority.

Recent developments and evidence gaps

The most relevant recent development in 2023–2024 was the 2024 canine RNF170 frameshift model, which broadens comparative understanding and may provide a practical platform for longitudinal biomarker and treatment studies. It does not, however, resolve the dominant p.Arg199Cys mechanism. No 2023–2024 human ADSA1 natural-history cohort, therapeutic trial, molecular biomarker study, or multi-omics analysis was identified. The most recent directly informative human dominant-family study retrieved was published online in 2021/print 2022 and expanded the phenotype to variable pyramidal involvement. (daele2022rnf170mutationcauses pages 2-4, daele2022rnf170mutationcauses pages 1-2, cook2024rnf170frameshiftdeletion pages 10-12)

Highest-priority research needs are: international case aggregation; standardized NCS/SSEP/vestibular phenotyping; direct population-frequency and ClinVar curation; longitudinal disability and quality-of-life measurement; p.Arg199Cys knock-in and patient-iPSC sensory-neuron models; and experiments distinguishing altered IP3R regulation from other toxic RNF170 substrates.

Key publications

Foundational RNF170 association, literature indexed as PMID 21115467; linked by Open Targets to MONDO:0012166. (OpenTargets Search: Autosomal dominant sensory ataxia 1)
Cortese et al. “Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic.” Journal of Neurology, Neurosurgery & Psychiatry. Published September 2020. DOI/URL: https://doi.org/10.1136/jnnp-2020-323719. (cortese2020mutationinrnf170 pages 1-2)
Van Daele et al. “RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement.” European Journal of Neurology 29:345–349. Online September 2021/2022 volume. DOI/URL: https://doi.org/10.1111/ene.15091. (daele2022rnf170mutationcauses pages 2-4, daele2022rnf170mutationcauses pages 1-2)
Wagner et al. “Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.” Nature Communications. Published October 2019. DOI/URL: https://doi.org/10.1038/s41467-019-12620-9. This is mechanistic/allelic-disorder evidence, not a dominant ADSA1 cohort. (wagner2019biallelicvariantsin pages 1-2, wagner2019biallelicvariantsin pages 3-4)
Kim et al. “Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia.” Human Molecular Genetics 24:7196–7206. Published December 2015. DOI/URL: https://doi.org/10.1093/hmg/ddv417. (cook2024rnf170frameshiftdeletion pages 10-12)
Cook et al. “RNF170 frameshift deletion in Miniature American Shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human RNF170 phenotypic spectrum.” Posted February 2024. DOI/URL: https://doi.org/10.21203/rs.3.rs-3914204/v1. Its preprint/publication status should be checked before assigning the highest evidence grade. (cook2024rnf170frameshiftdeletion pages 10-12)

Overall evidence assessment: strong evidence links heterozygous RNF170 p.Arg199Cys to a recognizable autosomal-dominant sensory-ataxia syndrome, but virtually all clinical knowledge comes from a handful of families. Mechanistic evidence firmly places RNF170 in ER-associated IP3R ubiquitination and calcium regulation; the exact p.Arg199Cys dominant-toxic mechanism, neuronal selectivity, epidemiology, prognosis, and treatment remain incompletely defined.

References

(cortese2020mutationinrnf170 pages 1-2): Andrea Cortese, Ilaria Callegari, Riccardo Currò, Elisa Vegezzi, Silvia Colnaghi, Maurizio Versino, Enrico Alfonsi, Giuseppe Cosentino, Enzamaria Valente, Simone Gana, Cristina Tassorelli, Anna Pichiecchio, Alexander M Rossor, Enrico Bugiardini, Antonio Biroli, Daniela Di Capua, Henry Houlden, and Mary M Reilly. Mutation in rnf170 causes sensory ataxic neuropathy with vestibular areflexia: a canvas mimic. Journal of Neurology, Neurosurgery, and Psychiatry, 91:1237-1238, Sep 2020. URL: https://doi.org/10.1136/jnnp-2020-323719, doi:10.1136/jnnp-2020-323719. This article has 24 citations.
(daele2022rnf170mutationcauses pages 2-4): Sien H. Van Daele, Matthieu Moisse, Valérie Race, Amélie Van Eesbeeck, Liesbeth Keldermans, Sascha Vermeer, Hilde Van Esch, Kristl G. Claeys, and Philip Van Damme. rnf170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement. European Journal of Neurology, 29:345-349, Sep 2022. URL: https://doi.org/10.1111/ene.15091, doi:10.1111/ene.15091. This article has 9 citations and is from a domain leading peer-reviewed journal.
(wagner2019biallelicvariantsin pages 8-10): Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, and Rebecca Schüle. Bi-allelic variants in rnf170 are associated with hereditary spastic paraplegia. Nature Communications, Oct 2019. URL: https://doi.org/10.1038/s41467-019-12620-9, doi:10.1038/s41467-019-12620-9. This article has 62 citations and is from a highest quality peer-reviewed journal.
(daele2022rnf170mutationcauses pages 1-2): Sien H. Van Daele, Matthieu Moisse, Valérie Race, Amélie Van Eesbeeck, Liesbeth Keldermans, Sascha Vermeer, Hilde Van Esch, Kristl G. Claeys, and Philip Van Damme. rnf170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement. European Journal of Neurology, 29:345-349, Sep 2022. URL: https://doi.org/10.1111/ene.15091, doi:10.1111/ene.15091. This article has 9 citations and is from a domain leading peer-reviewed journal.
(wagner2019biallelicvariantsin pages 1-2): Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, and Rebecca Schüle. Bi-allelic variants in rnf170 are associated with hereditary spastic paraplegia. Nature Communications, Oct 2019. URL: https://doi.org/10.1038/s41467-019-12620-9, doi:10.1038/s41467-019-12620-9. This article has 62 citations and is from a highest quality peer-reviewed journal.
(wagner2019biallelicvariantsin pages 3-4): Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, and Rebecca Schüle. Bi-allelic variants in rnf170 are associated with hereditary spastic paraplegia. Nature Communications, Oct 2019. URL: https://doi.org/10.1038/s41467-019-12620-9, doi:10.1038/s41467-019-12620-9. This article has 62 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: Autosomal dominant sensory ataxia 1): Open Targets Query (Autosomal dominant sensory ataxia 1, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(cortese2020mutationinrnf170 pages 1-1): Andrea Cortese, Ilaria Callegari, Riccardo Currò, Elisa Vegezzi, Silvia Colnaghi, Maurizio Versino, Enrico Alfonsi, Giuseppe Cosentino, Enzamaria Valente, Simone Gana, Cristina Tassorelli, Anna Pichiecchio, Alexander M Rossor, Enrico Bugiardini, Antonio Biroli, Daniela Di Capua, Henry Houlden, and Mary M Reilly. Mutation in rnf170 causes sensory ataxic neuropathy with vestibular areflexia: a canvas mimic. Journal of Neurology, Neurosurgery, and Psychiatry, 91:1237-1238, Sep 2020. URL: https://doi.org/10.1136/jnnp-2020-323719, doi:10.1136/jnnp-2020-323719. This article has 24 citations.
(cortese2020mutationinrnf170 pages 2-2): Andrea Cortese, Ilaria Callegari, Riccardo Currò, Elisa Vegezzi, Silvia Colnaghi, Maurizio Versino, Enrico Alfonsi, Giuseppe Cosentino, Enzamaria Valente, Simone Gana, Cristina Tassorelli, Anna Pichiecchio, Alexander M Rossor, Enrico Bugiardini, Antonio Biroli, Daniela Di Capua, Henry Houlden, and Mary M Reilly. Mutation in rnf170 causes sensory ataxic neuropathy with vestibular areflexia: a canvas mimic. Journal of Neurology, Neurosurgery, and Psychiatry, 91:1237-1238, Sep 2020. URL: https://doi.org/10.1136/jnnp-2020-323719, doi:10.1136/jnnp-2020-323719. This article has 24 citations.
(wagner2019biallelicvariantsin pages 10-11): Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, and Rebecca Schüle. Bi-allelic variants in rnf170 are associated with hereditary spastic paraplegia. Nature Communications, Oct 2019. URL: https://doi.org/10.1038/s41467-019-12620-9, doi:10.1038/s41467-019-12620-9. This article has 62 citations and is from a highest quality peer-reviewed journal.
(wagner2019biallelicvariantsin pages 11-12): Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, and Rebecca Schüle. Bi-allelic variants in rnf170 are associated with hereditary spastic paraplegia. Nature Communications, Oct 2019. URL: https://doi.org/10.1038/s41467-019-12620-9, doi:10.1038/s41467-019-12620-9. This article has 62 citations and is from a highest quality peer-reviewed journal.
(cook2024rnf170frameshiftdeletion pages 10-12): Shawna R. Cook, Cleo Schwarz, Julien Guevar, Charles-Antoine Assenmacher, Maeve Sheehy, Nathan Fanzone, Molly E. Church, Leonardo Murgiano, Margret L. Casal, Vidhya Jagannathan, Rodrigo Gutierrez-Quintana, Mark Lowrie, Frank Steffen, Tosso Leeb, and Kari J. Ekenstedt. Rnf170 frameshift deletion in miniature american shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human rnf170 phenotypic spectrum. Unknown journal, Feb 2024. URL: https://doi.org/10.21203/rs.3.rs-3914204/v1, doi:10.21203/rs.3.rs-3914204/v1.
(daele2022rnf170mutationcauses pages 4-5): Sien H. Van Daele, Matthieu Moisse, Valérie Race, Amélie Van Eesbeeck, Liesbeth Keldermans, Sascha Vermeer, Hilde Van Esch, Kristl G. Claeys, and Philip Van Damme. rnf170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement. European Journal of Neurology, 29:345-349, Sep 2022. URL: https://doi.org/10.1111/ene.15091, doi:10.1111/ene.15091. This article has 9 citations and is from a domain leading peer-reviewed journal.

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Autosomal Dominant Sensory Ataxia 1 (ADSA1): Comprehensive Disease Characterization Report

openscientist-autonomous 13 citations 2026-08-01T12:13:13.073292

Autosomal Dominant Sensory Ataxia 1 (ADSA1): Comprehensive Disease Characterization Report

Disease: Autosomal Dominant Sensory Ataxia 1 (ADSA1) Primary identifiers: MONDO:0012166 · OMIM #608984 · DOID:0111170 · GARD:0024850 · MedGen:332346 · UMLS:C1837015 Causal gene: RNF170 (OMIM 614649; HGNC:25358; NCBI Gene 81790; Ensembl ENSG00000120925; locus 8p11.21) Category:* Mendelian, monogenic, autosomal dominant

Summary

Autosomal Dominant Sensory Ataxia 1 (ADSA1; also SNAX1, ADSA, "RNF170 hereditary ataxia") is an ultra-rare, adult/middle-age–onset, slowly progressive hereditary sensory (proprioceptive) ataxia. It is caused by a single recurrent heterozygous missense mutation in RNF170, c.595C>T p.(Arg199Cys), and results clinically from degeneration of the posterior (dorsal) columns of the spinal cord and a length-dependent sensory neuronopathy/neuropathy. It was originally described in two large founder families from Maritime Canada PMID: 21115467 and has since been independently replicated in a Belgian family PMID: 34469621 and reported as a CANVAS mimic (sensory ataxic neuropathy with vestibular areflexia) PMID: 32943585. The disease is exceedingly rare, reported in only a handful of families/individuals worldwide.

Mechanistically, RNF170 is an endoplasmic reticulum (ER)–membrane RING-type E3 ubiquitin ligase that, together with the ERLIN1/2 (SPFH-family) scaffold and TMUB1, forms an ERAD "nanodomain" that ubiquitinates activated type-1 inositol 1,4,5-trisphosphate receptors (IP3R/ITPR1) and targets them for proteasomal degradation PMID: 21610068; PMID: 38782601. The Arg199Cys mutation destabilizes RNF170 by enhancing its autoubiquitination and proteasomal turnover, and functionally impairs IP3R-mediated Ca²⁺ mobilization in patient cells despite normal ER store content, IP3R levels, and IP3 production — pinpointing a defect at the IP3R signaling locus PMID: 25882839. Rnf170-knockout mice recapitulate age-dependent gait abnormalities, reduced proprioception and thermal nociception, and elevated ITPR1 protein in cerebellum and spinal cord PMID: 26433933.

Notably, RNF170 exhibits a clear allelic series: the dominant p.Arg199Cys missense allele causes ADSA1, whereas biallelic loss-of-function RNF170 variants cause a distinct autosomal recessive complicated hereditary spastic paraplegia, SPG85 (MONDO:0030512; OMIM #619686) PMID: 31636353; PMID: 36046950; PMID: 35041108. There is no disease-specific therapy; management is supportive (physiotherapy, gait/balance aids, sensory rehabilitation, fall prevention).

Section 1 — Disease Information

Overview. ADSA1 is a monogenic, autosomal dominant, adult-onset sensory ataxia — an inability to coordinate movement due to loss of proprioceptive (position/vibration) sensation rather than primary cerebellar disease. Patients develop insidious, slowly progressive gait instability that is characteristically worse in the dark or with eyes closed (loss of visual compensation for absent proprioception), a positive Romberg sign, distal sensory loss, and areflexia; cerebellar imaging is typically normal.

Key identifiers. - MONDO: MONDO:0012166 — "Any hereditary ataxia in which the cause of the disease is a mutation in the RNF170 gene." - OMIM: #608984 (phenotype); 614649 (gene RNF170, allelic variant 614649.0001) - DOID: 0111170 · GARD: 0024850 · MedGen: 332346 · UMLS: C1837015 - Orphanet: no dedicated code cross-referenced to ADSA1 - ICD-10/ICD-11 / MeSH:* no ADSA1-specific code; classified under hereditary/spinocerebellar ataxia categories

Synonyms: SNAX1; ADSA; "ataxia, sensory, 1, autosomal dominant"; "RNF170 hereditary ataxia"; "sensory ataxic neuropathy with vestibular areflexia (CANVAS mimic)."

Information source type: Aggregated disease-level resources (OMIM, MONDO, HPO) plus individual patient reports from a small number of published families (Maritime-Canada founder families; Belgian family; scattered single cases).

Section 2 — Etiology

Primary cause — genetic. ADSA1 is entirely genetic and monogenic, caused by the heterozygous RNF170 missense variant c.595C>T p.(Arg199Cys). No environmental or infectious cause is implicated.

Genetic risk factors. The single causal allele is the dominant R199C variant; inheritance of one copy is sufficient to cause disease. Reported penetrance in pedigrees is high. There are no established susceptibility loci or GWAS signals (the disease is Mendelian, not complex).

Environmental risk factors / protective factors / gene–environment interactions. None identified. As a fully penetrant dominant Mendelian disorder, no dietary, occupational, or lifestyle risk or protective factors are known, and no gene–environment interactions have been reported.

Section 3 — Phenotypes (with HPO terms)

Frequencies below derive largely from the HPO/OMIM:608984 annotation set (Cortese et al. 2020, n=2 affected) supplemented by OMIM clinical synopsis and case reports. Given the tiny sample, frequencies are indicative.

HPO term	Phenotype	Type	Frequency
HP:0010871	Sensory ataxia	Clinical sign	2/2
HP:0002066	Gait ataxia	Clinical sign	2/2
HP:0003596	Middle-age onset	Onset	2/2
HP:0001265	Hyporeflexia	Clinical sign	2/2
HP:0003409	Distal sensory impairment (all modalities)	Clinical sign	2/2
HP:0006858	Impaired distal proprioception	Clinical sign	1/2
HP:0006886	Impaired distal vibration sensation	Clinical sign	1/2
HP:0007078	Decreased amplitude of sensory action potentials	Electrophysiology	1/2
HP:0002403	Positive Romberg sign	Clinical sign	reported
HP:0006962	Gait instability worse in the dark	Symptom	OMIM
HP:0001284	Areflexia	Clinical sign	OMIM
HP:0012534	Dysesthesia	Symptom	reported
HP:0001260	Dysarthria	Clinical sign	reported
HP:0007670	Abnormal vestibulo-ocular reflex / vestibular areflexia	Clinical sign	1/2
HP:0002359	Frequent falls	Symptom	reported
HP:0001317	Abnormal cerebellar morphology	Imaging	0/1 (usually normal)
HP:0003487	Babinski sign	Clinical sign	0/1 (usually absent)

Characteristics. Age of onset: adult/middle age (HP:0003596). Severity: mild-to-moderate initially, progressing to significant gait disability. Progression: slowly progressive over years to decades. The Belgian family additionally showed variable pyramidal involvement PMID: 34469621, and one atypical case presented with hypertrophic olivary degeneration PMID: 42052314.

Quality-of-life impact. Progressive gait instability, frequent falls, and dependence on assistive devices impair mobility, independence, and safety; sensory dysesthesia may add discomfort. No formal EQ-5D/SF-36 data exist for this ultra-rare disease.

Section 4 — Genetic / Molecular Information

Causal gene: RNF170 (RING finger protein 170), locus 8p11.21; OMIM *614649; HGNC:25358; NCBI Gene 81790; Ensembl ENSG00000120925; UniProt Q96K19.

Pathogenic variant (ADSA1): - NM_030954.4(RNF170):c.595C>T (p.Arg199Cys); GRCh38 chr8:42,856,340 G>A - ClinVar: Pathogenic, 2-star ("criteria provided, multiple submitters, no conflicts") - dbSNP: rs397514478 · ClinGen: CA129827 · UniProt variant: VAR_068219 · OMIM allelic variant: 614649.0001 - Variant type: missense (single-nucleotide substitution), germline - Allele frequency: absent from gnomAD v4 (ACMG PM2 supporting) - Functional consequence: destabilizes RNF170 (enhanced autoubiquitination/proteasomal degradation) with impaired IP3R-mediated Ca²⁺ signaling — behaving as a dominant allele; distinct from recessive LoF

Allelic series / other RNF170 variants (SPG85, recessive): p.Arg64* PMID: 36046950; p.Cys107Trp (homozygous) PMID: 35041108; additional biallelic variants in HSP cohorts PMID: 31636353; PMID: 38499745.

Modifier genes / epigenetics / chromosomal abnormalities: None specifically established for ADSA1. RNF170 functions within the ERLIN1/2–TMUB1–RNF170 ERAD complex, so those partner genes are mechanistically relevant PMID: 38782601.

Section 5 — Environmental Information

No environmental, lifestyle, or infectious factors are implicated in ADSA1. It is a purely genetic Mendelian disorder. Not applicable.

Section 6 — Mechanism / Pathophysiology

Molecular function of RNF170. RNF170 is an ER-membrane RING E3 ubiquitin ligase that binds activated IP3 receptors — recruited via the erlin1/2 SPFH complex — and mediates their ubiquitination and ER-associated degradation (ERAD): "RNF170 plays an essential role in IP3 receptor processing via the ubiquitin-proteasome pathway" PMID: 21610068. It operates within an ERLIN1/2–TMUB1–RNF170 ERAD nanodomain: "ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 ... and RNF170" PMID: 38782601.

Protein dysfunction. The Arg199Cys mutation destabilizes RNF170: "Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation" PMID: 25882839. Arg199 sits at the C-terminal end of the large cytoplasmic loop, immediately N-terminal to TM2 (residues 202–222), consistent with disruption of stabilizing transmembrane ionic interactions.

Metabolic / signaling change. The proximal downstream consequence is dysregulated ER Ca²⁺ signaling: "In ADSA lymphoblasts, platelet-activating factor-induced Ca²⁺ mobilization was significantly impaired" — despite normal ER store content, IP3R levels, and IP3 production, localizing the defect to the IP3R response PMID: 25882839. In Rnf170-null mice, ITPR1 protein accumulates selectively in cerebellum and spinal cord (not cerebral cortex) PMID: 26433933.

Causal chain (upstream → downstream):

RNF170 c.595C>T (p.Arg199Cys)  [germline, heterozygous]
│  Arg199 at TM2 boundary → loss of stabilizing ionic interactions
▼
Enhanced RNF170 autoubiquitination → proteasomal degradation (↓ functional RNF170)
▼
Impaired ERLIN1/2–TMUB1–RNF170 ERAD nanodomain → defective ITPR1 turnover
▼
Dysregulated ER Ca²⁺ signaling (↓ agonist-evoked Ca²⁺ mobilization; ITPR1 accumulation)
▼
Chronic sensory-neuron / dorsal-column dysfunction & degeneration
▼
Adult-onset, slowly progressive SENSORY (proprioceptive) ATAXIA

GO / CL terms. Biological process: GO:0070936 (protein K48-linked ubiquitination), GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process), GO:0006816 (calcium ion transport). Molecular function: GO:0061630 (ubiquitin protein ligase activity), GO:0008270 (zinc ion binding). Cellular component: GO:0005789 (ER membrane). Cell types: CL:0000101 (sensory neuron), CL:0000209 (dorsal root ganglion neuron), CL:0000121 (Purkinje cell — secondary).

Immune involvement. RNF170 has a described role in negative regulation of TLR3 signaling (GO:0034140), but immune dysfunction is not part of the ADSA1 phenotype.

Section 7 — Anatomical Structures Affected

Organ/system level: Nervous system — specifically the posterior (dorsal) columns of the spinal cord (UBERON:0002240 spinal cord) and peripheral sensory nerves / dorsal root ganglia. Vestibular pathways in CANVAS-mimic cases. Cerebellum (UBERON:0002037) is typically spared morphologically.
Tissue/cell level: Nervous tissue; large proprioceptive sensory neurons (CL:0000101, CL:0000209).
Subcellular level: Endoplasmic reticulum membrane (GO:0005789).
Localization/lateralization: Bilateral, symmetric, length-dependent sensory involvement. One atypical case showed bilateral inferior olivary hypertrophy (hypertrophic olivary degeneration) with mild cerebellar atrophy PMID: 42052314.

Section 8 — Temporal Development

Onset: Adult/middle age (HP:0003596); insidious/chronic.
Progression: Slowly progressive over years-to-decades; disease course is progressive, not episodic or relapsing–remitting.
Duration: Chronic, lifelong.
Remission: None (no spontaneous or treatment-induced remission).
Critical periods: The slow tempo provides a broad window for supportive/rehabilitative intervention.

Section 9 — Inheritance and Population

Inheritance pattern: Autosomal dominant (OMIM #608984).
Penetrance / expressivity: Apparently high penetrance in reported pedigrees; variable expressivity (e.g., variable pyramidal involvement) PMID: 34469621.
Founder effect: The two Maritime-Canada families share a disease haplotype, indicating a founder allele PMID: 21115467.
Carrier frequency: R199C is absent from gnomAD — effectively zero in general populations.
Anticipation / mosaicism / consanguinity: No anticipation (not a repeat expansion); consanguinity is irrelevant for a dominant disorder (it is relevant only for recessive SPG85).
Epidemiology: No formal prevalence/incidence; ultra-rare (<1/1,000,000), reported in only ~3 families plus scattered single cases.
Sex ratio / demographics: No sex bias reported; reported cases are of European (Canadian, Belgian) ancestry, reflecting ascertainment.

Section 10 — Diagnostics

Clinical/electrophysiology: Sensory nerve conduction studies show reduced/absent SNAPs (HP:0007078) with preserved motor conduction — the signature of a sensory neuronopathy/neuropathy. Bedside: positive Romberg, areflexia, distal sensory loss.
Imaging: MRI typically normal cerebellum (helps distinguish from cerebellar ataxias); rare HOD on MRI PMID: 42052314.
Genetic testing (diagnostic gold standard): Detection of RNF170 c.595C>T p.(Arg199Cys) by single-gene testing, hereditary-ataxia/HSP gene panels, or whole-exome/whole-genome sequencing. WES/WGS are high-yield given phenotypic overlap with other ataxias.
Clinical criteria / differential diagnosis: Differentiate from CANVAS/RFC1 disease (exclude RFC1 biallelic AAGGG expansion), paraneoplastic sensory neuronopathy (anti-Hu), Sjögren-associated ganglionopathy, vitamin E/B12 deficiency, chemotherapy (cisplatin) toxicity, and Friedreich ataxia. The CANVAS-mimic framing makes RNF170 testing important in adult sensory ataxic neuropathy PMID: 32943585.
Screening: Cascade genetic testing of at-risk relatives once a familial variant is known.

Section 11 — Outcome / Prognosis

Survival/mortality: Not life-shortening in reported families; no disease-specific mortality documented.
Morbidity/function: Progressive gait disability, falls, and eventual dependence on assistive devices are the main morbidities. Long-term functional impairment centers on mobility and balance (ICF domains).
Complications: Fall-related injury; secondary deconditioning.
Recovery: No spontaneous recovery; supportive care can maintain function.
Prognostic factors: Genotype (R199C) defines the disease; no validated molecular prognostic biomarkers beyond the causal variant.

Section 12 — Treatment

Disease-modifying therapy: None available.
Supportive/rehabilitative (mainstay): Physical therapy and balance/gait training (NCIT: Physical Therapy), occupational therapy, assistive devices (cane/walker), fall-prevention strategies, and management of neuropathic dysesthesia.
Pharmacotherapy / advanced therapeutics: No approved drugs, gene, cell, or RNA therapies. Mechanistically rational but unproven concepts include proteostasis modulation (given enhanced RNF170 degradation) and IP3R/ER-Ca²⁺-signaling–targeted approaches.
Pharmacogenomics / experimental trials: None specific to ADSA1.
NCIT intervention terms: Physical Therapy; Occupational Therapy; Supportive Care.

Section 13 — Prevention

Primary/secondary/tertiary prevention: No primary prevention (fully genetic). Tertiary prevention = fall-prevention and rehabilitation.
Genetic counseling: Central — 50% offspring transmission risk for a heterozygous parent; cascade testing for at-risk relatives.
Reproductive options: Prenatal and preimplantation genetic testing are feasible given the defined pathogenic variant.
Immunization / behavioral / public-health interventions: Not applicable.

Section 14 — Other Species / Natural Disease

Orthologs (NCBI Gene): mouse Rnf170 (77733; MGI:1924983; ENSMUSG00000013878); zebrafish rnf170 (406612; ENSDARG00000104069); dog RNF170 (475568).
Natural disease (dog): A naturally occurring Miniature American Shepherd neuroaxonal dystrophy is caused by an RNF170 1-bp deletion: "The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 ... which perfectly segregates in an autosomal recessive pattern" PMID: 39177409. This is a recessive LoF model (comparative to SPG85 more than to dominant ADSA1) but demonstrates conserved neurodegenerative consequences of RNF170 dysfunction.
Evolutionary conservation: RNF170's IP3R-ERAD function is conserved, supporting cross-species mechanistic relevance.

Section 15 — Model Organisms

Model	Type	Key features	Recapitulation	Reference
Rnf170⁻/⁻ mouse	Mammalian knockout (LoF)	Age-dependent gait abnormality; reduced proprioception & thermal nociception; ITPR1 accumulation in cerebellum/spinal cord	Reproduces sensory/gait phenotype and pathway; but LoF (models SPG85 mechanism more than dominant R199C)	PMID: 26433933
Zebrafish (rnf170)	Vertebrate	Mutant orthologous mRNA dominantly disrupts development	Supports dominant action of the mutant allele	PMID: 21115467
Miniature American Shepherd dog	Natural, mammalian	Recessive frameshift → neuroaxonal dystrophy	Comparative neurodegeneration model	PMID: 39177409
Patient lymphoblasts / transfected cells	In vitro	Destabilized mutant RNF170; impaired PAF-induced Ca²⁺	Direct human mechanistic model	PMID: 25882839

Model limitation: No R199C knock-in animal exists; the available in-vivo models are loss-of-function/recessive and therefore incompletely capture the dominant ADSA1 allele.

Mechanistic Model / Interpretation (Synthesis)

ADSA1 is best understood as a dominant, protein-destabilizing disruption of ER quality control over calcium signaling in sensory neurons. The upstream molecular lesion is destabilization of the E3 ligase RNF170; the proximal downstream consequence is failure of IP3R (ITPR1) ubiquitin/ERAD turnover and consequent Ca²⁺-signaling dysregulation; the distal, tissue-level outcome is selective vulnerability of large proprioceptive neurons and dorsal-column pathways, producing adult-onset sensory ataxia.

A central conceptual puzzle: R199C lowers mutant-protein levels (a loss-of-function–like biochemical signature), yet the disease is dominant and distinct from the recessive complete-LoF disorder SPG85 (spasticity). This argues that R199C acts through a dominant-negative or dosage-sensitive mechanism within the multiprotein ERLIN1/2–TMUB1–RNF170 nanodomain — i.e., the destabilized mutant "poisons" the complex or perturbs stoichiometry — rather than through simple haploinsufficiency. Resolving this remains the key open mechanistic question.

Allelic-series comparison:

Feature	ADSA1	SPG85
RNF170 allele	Dominant missense p.Arg199Cys	Biallelic loss-of-function (nonsense/frameshift/missense)
Inheritance	Autosomal dominant	Autosomal recessive
Onset	Adult/middle age	Infancy/childhood
Core phenotype	Sensory (proprioceptive) ataxia	Spastic paraplegia (± complex features)
IDs	MONDO:0012166; OMIM #608984	MONDO:0030512; OMIM #619686; Orphanet:631082

Evidence Base

PMID	Title (abbrev.)	Evidence type	Role
21115467	RNF170 mutation causes ADSA	Human genetics + zebrafish	Original discovery; establishes RNF170 R199C as causal
34469621	RNF170 ADSA with variable pyramidal involvement	Human genetics	Independent replication (Belgian family)
32943585	RNF170 CANVAS mimic	Human clinical	Vestibular-areflexia/CANVAS-mimic phenotype; HPO source
25882839	R199C destabilizes RNF170; impairs IP3R Ca²⁺ signaling	In vitro/biochemistry	Core mechanistic study
21610068	RNF170 mediates IP3R ubiquitination/degradation	In vitro	Establishes RNF170 molecular function
26433933	Rnf170⁻/⁻ mice, age-dependent gait	Mouse model	In-vivo pathway validation; ITPR1 accumulation
38782601	ERLIN1/2–TMUB1–RNF170 ERAD nanodomain	In vitro	Places RNF170 in ERAD complex
31636353	Bi-allelic RNF170 → HSP	Human genetics	Recessive allelic disorder (SPG85)
36046950	Stop-gain RNF170 → HSP (p.R64)*	Human genetics	Recessive LoF → SPG85
35041108	Homozygous RNF170 p.Cys107Trp → HSP	Human genetics	Recessive missense → SPG85
39177409	Canine RNF170 model of neuroaxonal dystrophy	Animal (natural)	Comparative model
42052314	RNF170 with hypertrophic olivary degeneration	Human clinical	Phenotype expansion
38499745	WES in Serbian HSP	Human genetics	RNF170 in HSP cohort

Consistency: All human genetic reports converge on RNF170 c.595C>T p.(Arg199Cys) as the recurrent ADSA1 allele; in-vitro and mouse-model data coherently support IP3R/Ca²⁺ dysregulation via impaired ERAD. The apparent tension — a "destabilizing" (LoF-like) mutation causing a dominant disease distinct from recessive LoF SPG85 — points to a dominant-negative/dosage mechanism rather than haploinsufficiency.

Limitations and Knowledge Gaps

Extreme rarity / small n: Phenotype frequencies derive from very few affected individuals (HPO annotations largely n=2); percentages are indicative, not epidemiologic.
Unresolved dominance mechanism: Whether R199C is dominant-negative, a toxic gain of function, or dosage-sensitive nanodomain poisoning is not definitively established. No R199C knock-in animal exists; existing mouse/dog models are LoF/recessive and better model SPG85.
No formal epidemiology: Prevalence, incidence, penetrance, and sex/age distributions are not rigorously quantified.
No dedicated Orphanet code for ADSA1; nosology overlaps with CANVAS and other sensory neuronopathies.
No therapeutics or biomarkers: No disease-modifying treatment, prognostic biomarker, or ADSA1-specific clinical trial.
Limited human neuropathology: Direct human confirmation of dorsal-column/DRG degeneration and ITPR1 accumulation is sparse; most molecular evidence is from patient lymphoblasts, transfected cells, and mouse tissue.

Proposed Follow-up Experiments / Actions

Generate a knock-in Rnf170^R199C/+ mouse (and iPSC-derived sensory neurons) to test dominant-negative vs. dosage mechanisms and directly model ADSA1 rather than SPG85.
Structural/biophysical study of Arg199Cys at the TM2 boundary (cryo-EM/AlphaFold-guided mutagenesis) to define how the mutation destabilizes RNF170 and perturbs the ERLIN1/2–TMUB1–RNF170 nanodomain.
Quantify ITPR1 turnover and ER Ca²⁺ dynamics in patient-derived DRG-like neurons; test whether restoring RNF170 levels or modulating proteasomal degradation rescues Ca²⁺ signaling.
International case ascertainment/registry (GeneMatcher, ataxia consortia) to refine phenotype frequencies, penetrance, progression rate, and identify additional alleles/founder haplotypes.
Systematic differential-diagnosis workflow: pair RNF170 testing with RFC1 CANVAS exclusion in adult sensory ataxic neuropathy cohorts to estimate ADSA1's diagnostic yield.
Proof-of-concept therapeutics: evaluate proteostasis modulators or IP3R/Ca²⁺-signaling agents in cellular and knock-in models.

Evidence-source legend: human clinical/genetic (family and case reports); in-vitro (patient lymphoblasts, transfected cells, biochemistry); model organism (mouse, zebrafish, dog); computational/ontology (MONDO, HPO, UniProt, ClinVar, gnomAD).

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Autosomal Dominant Sensory Ataxia 1: Comprehensive Disease Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

Evidence provenance

2. Etiology, risk, and protective factors

Causal factor

Genetic risk

Environmental, lifestyle, infectious, and protective factors

3. Phenotypes

Core and variable manifestations

Laboratory, neurophysiological, and imaging phenotypes

Quality-of-life effect

4. Genetic and molecular information

Gene and variant

Allelic-disorder warning

5. Environmental information

6. Mechanism and pathophysiology

Normal pathway

Proposed ADSA1 causal chain

Suggested ontology annotations

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and physiological work-up

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current implementation

13. Prevention

14. Other species and natural disease

15. Model organisms

Mouse

Zebrafish

Cellular systems

Recent developments and evidence gaps

Key publications

Artifacts

Autosomal Dominant Sensory Ataxia 1 (ADSA1): Comprehensive Disease Characterization Report

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes (with HPO terms)

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model / Interpretation (Synthesis)

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts