Spinocerebellar Ataxia, Autosomal Recessive 32

Mendelian MONDO:0859245 Pathograph 24 Show in embeddings browser Autosomal Recessive Cerebellar Ataxia

Spinocerebellar ataxia, autosomal recessive 32 (SCAR32), also called PRDX3-associated neurodegeneration (PRAN), is the recessive cerebellar ataxia caused by biallelic loss-of-function variants in PRDX3. Peroxiredoxin 3 is the one member of the six-isoform human peroxiredoxin family that is restricted to mitochondria, where it is the thioredoxin-dependent peroxidase that clears the hydrogen peroxide generated by the respiratory chain. SCAR32 is therefore an ataxia of failed mitochondrial redox buffering rather than of a structural, channel, repeat-expansion or DNA-repair lesion, and it sits alongside TXN2 deficiency as one of two ultra-rare diseases of the mitochondrial thioredoxin system. The entity was defined in 2021 from five unrelated families in the PREPARE recessive-ataxia network. The core picture is a slowly progressive cerebellar syndrome — gait then limb ataxia, cerebellar dysarthria, nystagmus and dysmetria — with cerebellar atrophy that is present in every reported patient, frequently disproportionate to the clinical severity, and often accompanied by T2 hyperintensity of the dentate nuclei, cerebellar cortex, middle cerebellar peduncles and posterior pons. Olivary and brainstem degeneration is reported in part of the cohort. What is distinctive, and unexplained, is the range of onset. It was described in 2023 as birth to 35 years on the cases then published; a Korean report the same year, counting nine patients, put it at infantile onset to 55 years. Either way it spans both nonsense and missense alleles across a literature of roughly twenty patients, with no genotype-phenotype rule established. A second descriptive pattern proposed from the same report is a caudal-to-rostral spatial spread of the disease. The severe infantile end adds early peripheral neuropathy and rapid cerebellar volume loss; the adult end can be a nearly pure, slowly progressive cerebellar syndrome with independent ambulation preserved a decade after onset. Non-cerebellar features reported in individual patients — profound hearing impairment, dystonia, hypogonadotropic hormonal dysfunction, thyroid autoimmunity, intellectual disability — are each single-patient or few-patient observations and are curated here without frequency bands for that reason. Every PRDX3 allele characterised so far behaves as loss of function: the mutant protein is absent from patient fibroblasts, glutathione peroxidase activity and maximal mitochondrial respiratory capacity fall, and PRDX5 is co-reduced. One allele, p.Asp163Glu, adds a second mechanism on top of simple enzyme loss — an unstable protein that aggregates and triggers both the mitochondrial and the endoplasmic-reticulum unfolded protein responses — which is the current best candidate explanation for why that patient's disease began in infancy. A point this entry is deliberate about: no neuropathological study of a SCAR32 patient has been published, and the word Purkinje does not appear anywhere in the PRDX3 ataxia literature. The degeneration is therefore curated at the cerebellar-cortex level that imaging actually supports, and conformance to the `cerebellar_purkinje_degeneration` module is NOT declared. See the open discussion.

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1
Inheritance
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Pathophys.
22
Phenotypes
3
Gaps
24
Pathograph
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Genes
7
Variants
4
Medical Actions
4
Differentials
3
Models
10
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Every reported patient carries two PRDX3 alleles — homozygous in the consanguineous and founder-allele families, compound heterozygous in several non-consanguineous ones — with unaffected heterozygous parents. PRDX3 is nuclear-encoded and autosomal (10q26.11), so despite the disease being mitochondrial in its biochemistry the transmission is nuclear recessive, with a 25 percent sibling recurrence risk and no maternal transmission.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33889951 SUPPORT Human Clinical
"we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration."
Establishes recessive inheritance of PRDX3 ataxia across five unrelated families in the defining study.
PMID:35766882 SUPPORT Human Clinical
"The further segregation analysis confirmed these findings and showed that his healthy brother was carrier of the PRDX3 c.489C > G variant in heterozygosis"
Documents an unaffected heterozygous sibling, the segregation pattern expected of a recessive allele.
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Discussions and Knowledge Gaps

3
Which cerebellar cell population degenerates in SCAR32, and is the Purkinje cell the primary target?
KNOWLEDGE GAP OPEN scar32_which_cerebellar_cell_population
Attached to
pathophysiology#Cerebellar Cortical Degeneration
Every other recessive cerebellar ataxia curated here that declares conformance to the `cerebellar_purkinje_degeneration` module does so on the strength of neuropathology, a mouse or canine model with Purkinje-cell counts, or an explicit statement in the literature. SCAR32 has none of these: no autopsy or biopsy study of a SCAR32 patient has been published, no published model measures cerebellar cell populations, and the word Purkinje does not appear in any of the PRDX3 ataxia reports. The available human evidence is imaging — cerebellar cortical and vermian atrophy with dentate, cortical, peduncular and olivary T2 change — which localises the lesion to the cerebellar cortex and its connections but not to a cell type. This entry therefore stops at the cortex and does not declare module conformance. The gap matters beyond bookkeeping: the disease also involves the inferior olives and brainstem, and if the primary lesion were olivary or afferent rather than Purkinje-intrinsic, the shared Purkinje module would be the wrong causal story for it.
Proposed experiments
Cerebellar histopathology of a SCAR32 brain
exp_scar32_cerebellar_histopathology
Quantitative Purkinje-cell, granule-cell and dentate-neuron counts with calbindin immunostaining on post-mortem cerebellum from a genetically confirmed SCAR32 patient, compared with age-matched controls.
Would support
pathophysiology#Cerebellar Cortical Degeneration
Supporting outcome
  • Selective loss of Purkinje neurons with relative preservation of granule cells would localise the degeneration to the Purkinje cell and justify declaring conformance to the shared module.
Refuting outcome
  • Preserved Purkinje-cell counts with granule-cell or olivary loss would show that the shared Purkinje module is the wrong mechanism for SCAR32.
Cell-type-resolved prdx3 loss in a cerebellum-bearing model
exp_scar32_cell_type_resolved_deletion
Conditional Prdx3 deletion in mouse restricted to Purkinje cells versus to granule cells versus to inferior olivary neurons, with motor phenotyping and cerebellar histology.
Would support
pathophysiology#Cerebellar Neuronal Oxidative Injury
Supporting outcome
  • Ataxia and cerebellar degeneration following Purkinje-restricted deletion but not the other two would establish Purkinje-cell autonomy of the lesion.
Why does the same class of loss-of-function PRDX3 allele produce onset at 19 months in one patient and at 35 years in another?
KNOWLEDGE GAP OPEN scar32_age_at_onset_unexplained
Attached to
genetic#PRDX3
Age at onset in SCAR32 spans birth to the mid-thirties across roughly twenty patients, and the spread is not explained by allele class: nonsense and missense alleles both appear at both ends. Two partial explanations have been offered and neither is established. The first is positional — variants in the later part of the thioredoxin domain, near the catalytic CXXC motifs, have been observed in the earlier-onset patients. The second is compensatory — PRDX5 and glutathione peroxidase are co-regulated with PRDX3, so a residual hypomorphic allele such as p.Gly180Ser paired with a null might be buffered well enough to delay onset by decades. A third, allele-specific mechanism is documented for p.Asp163Glu, where aggregation and unfolded-protein-response activation add an insult the null alleles do not carry. Distinguishing these matters for counselling, because it determines whether a genotype predicts anything about age at onset.
Proposed experiments
Residual-activity and compensation panel across reported PRDX3 alleles
exp_scar32_allele_activity_panel
Express each reported PRDX3 allele in a PRDX3-null cell background and measure protein abundance, thioredoxin-dependent peroxidase activity, aggregation propensity, and PRDX5/GPX1 compensatory induction, then test those measures against the reported age at onset for each allele.
Would support
pathophysiology#PRDX3 Loss of Function
Supporting outcome
  • A monotonic relationship between residual peroxidase activity (or the degree of compensatory induction) and age at onset would establish a genotype-phenotype rule for the disease.
Refuting outcome
  • No relationship between any biochemical measure and age at onset would point the explanation away from the allele and towards modifiers or environment.
Would an antioxidant or thioredoxin-system-directed drug change the course of SCAR32?
KNOWLEDGE GAP OPEN scar32_antioxidant_therapy_lead
Attached to
pathophysiology#Mitochondrial Hydrogen Peroxide Accumulation treatments#
The mechanism invites the question and nothing answers it. The defining paper ends by saying its findings suggest targets for future therapeutic approaches; the only concrete datum is one patient with biallelic TXN2 variants — the partner disease of the same mitochondrial thioredoxin system, whose product recycles oxidised PRDX3 — who improved clinically on idebenone. That is a single case in a different gene, and idebenone's action is on electron transport rather than on peroxide scavenging, so the inference to PRDX3 disease is two steps long. It is recorded as a lead precisely so that it is not mistaken for a treatment: no SCAR32 patient has been given idebenone or any other antioxidant in a published report, and the entry's `treatments` block deliberately contains no such entry.
Proposed experiments
Antioxidant rescue in PRDX3-deficient cerebellar and in vivo models
exp_scar32_antioxidant_rescue_panel
Test mitochondria-targeted peroxide scavengers and thioredoxin-system agents, including idebenone as the clinically available comparator, against the established PRDX3-loss readouts: hydrogen peroxide accumulation and apoptotic sensitisation in PRDX3-depleted cerebellar cells, and locomotor output and oxidative-stress survival in the prdx3 zebrafish crispant and the Drosophila knockdown.
Would support
pathophysiology#Mitochondrial Hydrogen Peroxide Accumulation
Supporting outcome
  • Rescue of the peroxide and apoptosis readouts with a corresponding improvement in the in vivo locomotor phenotype would justify a first clinical trial and identify which arm of the redox system to target.
Refuting outcome
  • Correction of the peroxide readout without any improvement in the locomotor or survival phenotype would indicate that the neuronal injury is not reversible by scavenging alone and would redirect effort towards the proteostatic arm.
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Pathophysiology

6
PRDX3 Loss of Function
Biallelic PRDX3 variants — nonsense, frameshift, splice and missense alike — converge on absence of the peroxiredoxin 3 protein from patient cells. PRDX3 is the only one of the six human peroxiredoxins confined to mitochondria, and it functions as a homodimer packed into a decameric/dodecameric ring; the recurrent p.Asp202Asn missense allele sits at the conserved dimer interface of that ring and destroys the protein rather than merely blunting its catalysis. The mutant protein is absent in patient fibroblasts across every allele characterised to date, so the molecular lesion is enzyme loss and not a dominant-negative or neomorphic activity.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic germline PRDX3 alleles: homozygous in the consanguineous and founder-allele families and compound heterozygous in several non-consanguineous ones. Reported classes are nonsense, frameshift, noncanonical splice and missense, and all characterised alleles leave the protein absent from patient fibroblasts.
thioredoxin-dependent peroxiredoxin activity GO:0008379 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent thioredoxin-dependent peroxiredoxin activity, annotated with thioredoxin peroxidase activity (GO:0008379). GO:0008379 is a molecular function from the Gene Ontology. ∅ ABSENT
Downstream
Mitochondrial Hydrogen Peroxide Accumulation Loss of the mitochondrial thioredoxin-dependent peroxidase removes the principal matrix route for disposing of respiratory-chain hydrogen peroxide.
Misfolded PRDX3 Aggregation and Unfolded Protein Response Allele-specific: the destabilising p.Asp163Glu missense protein aggregates before it is cleared, adding a proteostatic insult to the enzyme loss.
Show evidence (4 references)
PMID:33889951 SUPPORT Other
"Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species."
Background statement in the defining paper establishing PRDX3 as the exclusively mitochondrial peroxiredoxin; graded OTHER because it reports no experiment of its own.
PMID:37553803 SUPPORT Other
"All PRDX3 variants reported to date act via loss‐of‐function, as the mutant proteins are absent in patients' fibroblasts, leading to complete loss of the enzyme."
Summarises the published functional data across alleles as uniform loss of function; graded OTHER because it restates prior results rather than a new experiment.
PMID:37553803 SUPPORT Other
"The mutation is located in the PRX_Tyrp2cys domain of the protein at a region of high conservation in the dimer interface located between two PRDX3 subunits of the dodecamer ring and causes a complete absence of the protein."
Locates the recurrent p.Asp202Asn allele at the oligomer dimer interface and states that it abolishes the protein; graded OTHER as a structural interpretation of published data.
+ 1 more reference
Mitochondrial Hydrogen Peroxide Accumulation
Superoxide produced by the respiratory chain is dismutated to hydrogen peroxide in the matrix, where peroxiredoxin 3 is the dominant scavenger. Without it the peroxide load rises: patient fibroblasts show reduced glutathione peroxidase activity and increasing mitochondrial superoxide as external hydrogen peroxide is raised, and PRDX3-depleted cerebellar cells accumulate hydrogen peroxide directly. Compensating transcripts (SOD2, GPX1, catalase, TXN2, PRDX5) are upregulated but do not restore buffering.
hydrogen peroxide catabolic process GO:0042744 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hydrogen peroxide catabolic process (GO:0042744). GO:0042744 is a biological process from the Gene Ontology. ↓ DECREASED cell redox homeostasis GO:0045454 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cell redox homeostasis (GO:0045454). GO:0045454 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Cerebellar Neuronal Oxidative Injury Unbuffered matrix peroxide is the proximate oxidative insult to cerebellar neurons.
Mitochondrial Respiratory Impairment Oxidative damage to the organelle degrades its own respiratory capacity.
Show evidence (2 references)
PMID:33889951 SUPPORT In Vitro
"Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
Couples PRDX3 protein loss to measured loss of peroxidase activity in patient cells.
PMID:33889951 SUPPORT In Vitro
"PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species."
Shows directly that removing PRDX3 from a cerebellar cell line raises hydrogen peroxide and kills the cells.
Misfolded PRDX3 Aggregation and Unfolded Protein Response
This node is allele-specific and does not apply to the null alleles. The p.Asp163Glu missense protein is unstable, forms insoluble aggregates and is routed to proteasomal degradation, and its expression activates the unfolded protein response in both the mitochondrion and the endoplasmic reticulum. Expressed exogenously it damages mitochondria far more severely than the p.Asp202Asn or p.Ala142Gly alleles do — cristae disorganisation, membrane damage and lipid-droplet accumulation — and in cultured mouse cortical neurons it distorts neurite morphology. This is the current candidate explanation for the exceptionally early, 19-month onset in that patient, and it is a proteostatic mechanism layered on top of, not instead of, the shared enzyme loss.
mitochondrial unfolded protein response GO:0034514 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mitochondrial unfolded protein response (GO:0034514). GO:0034514 is a biological process from the Gene Ontology. ↑ INCREASED endoplasmic reticulum unfolded protein response GO:0030968 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cerebellar Neuronal Oxidative Injury Proteostatic stress compounds the redox insult in the one allele where it has been demonstrated.
Show evidence (3 references)
PMID:35766882 SUPPORT In Vitro
"The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum."
States the aggregation-plus-UPR mechanism demonstrated for this allele.
PMID:35766882 SUPPORT In Vitro
"Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization."
Documents the organelle damage produced by expressing the aggregating allele.
PMID:35766882 SUPPORT In Vitro
"In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria."
Extends the aggregating-allele damage to cultured neurons, the cell class relevant to the disease.
Mitochondrial Respiratory Impairment
PRDX3-deficient cells lose respiratory reserve. Patient fibroblasts in the defining cohort had reduced maximal respiratory capacity, and prdx3-depleted zebrafish larvae show significant reductions in ATP production and maximal respiration. This is a consequence of the redox lesion rather than a primary OXPHOS subunit defect: PRDX3 is not part of any respiratory complex, and one later patient's fibroblasts showed no measurable respiratory abnormality at all, so the finding is not uniform across cell lines.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
cellular respiration GO:0045333 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular respiration (GO:0045333). GO:0045333 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
SCAR32 patient dermal fibroblasts PRIMARY CELL CULTURE In the 2024 report the patient fibroblast line reproduced none of the expected biochemistry: oxygen consumption was indistinguishable from controls and susceptibility to oxidative stress was not increased, leading the authors to conclude that the relevant PRDX3 functions are not expressed in peripheral cells.
Animal models
prdx3 F0 crispant zebrafish Zebrafish recapitulates Oxygen-consumption studies in prdx3-depleted larvae reproduce the loss of respiratory capacity measured in patient fibroblasts.
Downstream
Cerebellar Neuronal Oxidative Injury Reduced respiratory reserve leaves high-demand cerebellar neurons less able to tolerate the redox insult.
Show evidence (3 references)
PMID:33889951 SUPPORT In Vitro
"Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
Reports the reduced maximal respiratory capacity in patient fibroblasts.
PMID:38837640 SUPPORT Model Organism
"significant reductions in ATP production and maximal respiration"
Independent respiratory deficit in the prdx3-depleted zebrafish larva.
PMID:38837640 NO_EVIDENCE In Vitro
"Metabolic parameters obtained from OCR traces did not show significant changes in mitochondrial function between the patient and the controls."
A later patient's fibroblasts showed no respiratory abnormality, so this node is not uniformly demonstrable in peripheral cells.
Cerebellar Neuronal Oxidative Injury
Cerebellar neurons are the cell population in which the redox failure becomes a disease. Removing PRDX3 from cerebellar cells raises hydrogen peroxide, reduces viability and sensitises them to reactive-oxygen-species-triggered apoptosis; the same sensitisation is seen in prdx3-depleted zebrafish larvae as an increase in apoptotic cells and in apoptosis-associated transcripts. Why the cerebellum in particular is the vulnerable region, when PRDX3 is ubiquitously expressed, is not established.
cellular response to reactive oxygen species GO:0034614 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to reactive oxygen species (GO:0034614). GO:0034614 is a biological process from the Gene Ontology. ↑ INCREASED neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
prdx3 F0 crispant zebrafish Zebrafish recapitulates prdx3 depletion in vivo reproduces the ROS-sensitised apoptosis and the motor consequence that this node asserts for human cerebellar neurons.
Pan-neuronal and pan-glial Drosophila prdx3 knockdown Fruit fly partially recapitulates Reproduces the causal step from neuronal loss of the peroxiredoxin to locomotor failure and oxidative-stress vulnerability, but not the anatomy.
Downstream
Cerebellar Cortical Degeneration Sustained oxidative injury and apoptosis of cerebellar neurons is the cellular substrate of the tissue-level degeneration.
Show evidence (3 references)
PMID:33889951 SUPPORT In Vitro
"PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species."
The closest available cerebellar cell model shows peroxide accumulation and apoptotic sensitisation on PRDX3 loss.
PMID:38837640 SUPPORT Model Organism
"our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate."
In vivo confirmation that prdx3 depletion sensitises to ROS-triggered apoptosis and impairs motor output.
PMID:33889951 SUPPORT Model Organism
"Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
Neuronal and glial loss of the fly orthologue produces locomotor failure and oxidative-stress lethality.
Cerebellar Cortical Degeneration
The tissue-level lesion is a cerebellar cortical degeneration: cerebellar atrophy is present in every reported patient, is often severe and early relative to the clinical picture, and is accompanied on MRI by T2 hyperintensity of the dentate nuclei and of the cerebellar cortex itself, with variable extension to the middle cerebellar peduncles, posterior pons and inferior olives. It is curated at the cortical rather than the Purkinje-cell level on purpose: no autopsy or biopsy neuropathology of a SCAR32 patient has been published, and no paper in this literature identifies the Purkinje cell as the degenerating population. Conformance to the `cerebellar_purkinje_degeneration` module is therefore not declared here — see the open discussion.
cerebellar cortex UBERON:0002129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellar cortex (UBERON:0002129). UBERON:0002129 is an anatomical location from the Uberon multi-species anatomy ontology. dentate nucleus UBERON:0002132 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dentate nucleus (UBERON:0002132). UBERON:0002132 is an anatomical location from the Uberon multi-species anatomy ontology. inferior olivary complex UBERON:0002127 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in inferior olivary complex (UBERON:0002127). UBERON:0002127 is an anatomical location from the Uberon multi-species anatomy ontology. pons UBERON:0000988 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pons (UBERON:0000988). UBERON:0000988 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive cerebellar ataxia Loss of cerebellar cortical tissue removes the coordination signal, giving the progressive gait, limb, speech and eye-movement incoordination that defines the disease.
Cerebellar atrophy Cerebellar cortical tissue loss is what the imaging phenotype measures.
Show evidence (4 references)
PMID:37731903 SUPPORT Human Clinical
"Only a few reports have described the MRI features of PRDX3 disease, including T2 signal changes in the reticular formation, dentate nucleus and transverse stripes of the pons, which are not typically seen in other hereditary degenerative ataxia."
Adds the reticular-formation and transverse-pontine-stripe signal changes, and states that this infratentorial pattern is not typical of other hereditary degenerative ataxias.
PMID:37553803 SUPPORT Other
"The presence of cerebellar atrophy is a ubiquitous feature in patients with bi‐allelic PRDX3 mutations."
Establishes cerebellar atrophy as universal across the reported PRDX3 cohort; graded OTHER as a synthesis of published cases.
PMID:42608543 SUPPORT Human Clinical
"MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
Adds the dentate and cerebellar-cortical signal change seen in every patient of a four-patient series.
+ 1 more reference
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spinocerebellar Ataxia, Autosomal Recessive 32 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

22
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37731903 SUPPORT Human Clinical
"All of these patients presented with gait ataxia, and most eventually developed upper limb ataxia, dysarthria and/or dysphagia."
Places dysphagia in the usual progression across the nine patients published to that point.
Ear 1
Profound hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365), qualified as severity severe. HP:0000365 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (2 references)
PMID:36190665 SUPPORT Human Clinical
"In addition, associated hearing impairment further delineates the PRDX3 associated gene phenotypes."
The single report that adds hearing impairment to the PRDX3 phenotype.
PMID:37553803 NO_EVIDENCE Human Clinical
"Serum immunoglobulin, AFP, eye examination and hearing assessment were all normal."
Hearing was formally normal in another paediatric SCAR32 patient, which is why no frequency band is assigned.
Endocrine 2
Goiter HP:0000853 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Goiter (HP:0000853). HP:0000853 is a phenotype from the Human Phenotype Ontology.
One patient; see the note on the antibody phenotype.
Show evidence (1 reference)
PMID:41351775 SUPPORT Human Clinical
"These findings were associated with an enlargement and heterogeneous echogenicity of the thyroid gland."
The thyroid enlargement accompanying the autoantibody findings.
Hypogonadotropic hypogonadism HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
Reported in one patient only. Do not read this as a SCAR32-associated endocrinopathy without further cases.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"An endocrinological exam showed that the patient presented with low levels of follicle‐stimulating hormone (FSH) at 1.9 mIU/mL, luteinizing hormone (LH) at 1 mIU/mL, testosterone at 0.2 mg/mL and dihydrotestosterone (DHT) at 0.01 mg/mL."
The hormone profile establishing hypogonadotropic hypogonadism in this patient.
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the note on peripheral neuropathy.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
Documents multidirectional nystagmus alongside the other cerebellar signs in a reported patient.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36190665 SUPPORT Human Clinical
"The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
Hypotonia in the same severely affected proband.
Nervous System 9
Progressive cerebellar ataxia OBLIGATE HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073), qualified as course progressive. HP:0002073 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33889951 SUPPORT Human Clinical
"The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration."
Progressive cerebellar ataxia is the presenting and defining feature in the founding cohort.
PMID:42608543 SUPPORT Human Clinical
"Age at onset was 9-30 years, with a predominantly pure cerebellar phenotype; one patient had autoimmune comorbidities."
Confirms a predominantly pure cerebellar phenotype in an independent four-patient series.
Gait ataxia HP:0002066 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait ataxia (HP:0002066). HP:0002066 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41351775 SUPPORT Human Clinical
"Consequently, the patient presented with slowly progressive gait ataxia and cerebellar vermis atrophy."
Gait ataxia as the presenting symptom in a paediatric SCAR32 patient.
Cerebellar atrophy OBLIGATE HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272), qualified as course progressive. HP:0001272 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:37553803 SUPPORT Other
"The presence of cerebellar atrophy is a ubiquitous feature in patients with bi‐allelic PRDX3 mutations."
States explicitly that cerebellar atrophy is universal in the reported PRDX3 cohort, which is the basis for the OBLIGATE band.
PMID:42608543 SUPPORT Human Clinical
"MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
Cerebellar atrophy in all four patients of an independent series.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
No frequency band is assigned. The published patients come from separate single-case and small-series reports with no pooled cohort denominator, and nerve conduction was not performed in every patient.
Show evidence (1 reference)
PMID:35766882 SUPPORT Human Clinical
"We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease."
Peripheral neuropathy early in the course of the infantile-onset case.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
Cerebellar dysarthria on examination in a reported patient.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Bound to the parent HP:0001337 rather than to `Postural tremor` (HP:0002174): the tremor is described as postural in one patient, as postural and action in another, and simply as tremor in a third, so the parent is what is true across the disease.
Show evidence (2 references)
PMID:37731903 SUPPORT Human Clinical
"Ataxic gait was prominently observed from the age of 11 years, followed by the onset of both hands tremors at age 13 and dysarthria at age 15."
Documents the sequence of gait ataxia, then hand tremor, then dysarthria in a Korean patient.
PMID:38837640 SUPPORT Human Clinical
"He also presented upper and lower limb dysmetria, slight upper limb postural tremor, and hyporeflexia."
Postural tremor on examination in an independent patient.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36190665 SUPPORT Human Clinical
"The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
Global developmental delay in a severely affected PRDX3 proband.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36190665 SUPPORT Human Clinical
"The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
Dystonia in a reported PRDX3 patient.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249), qualified as severity mild. HP:0001249 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (2 references)
PMID:41351775 SUPPORT Human Clinical
"The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) indicated mild cognitive impairment (full-scale IQ: 74)"
Formal psychometric documentation of mild cognitive impairment in a SCAR32 patient.
PMID:37553803 NO_EVIDENCE Human Clinical
"There was no evidence of cognitive impairment, extrapyramidal or pyramidal tract involvement, autonomic dysfunction, or peripheral neuropathy."
An adult SCAR32 patient with no cognitive impairment, establishing that intellectual disability is not constant.
Other 7
Abnormal dentate nucleus signal Abnormal dentate nucleus morphology HP:0100321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal dentate nucleus morphology (HP:0100321). HP:0100321 is a phenotype from the Human Phenotype Ontology.
Bound to the closest available HPO concept. HPO has no term for a T2 signal abnormality of the dentate nucleus specifically; `Abnormal dentate nucleus morphology` is broader than the imaging finding but is the accurate parent.
Show evidence (1 reference)
PMID:42608543 SUPPORT Human Clinical
"MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
Documents dentate-nucleus T2 hyperintensity in every patient of the series.
Dysmetria HP:0001310 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmetria (HP:0001310). HP:0001310 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
Four-limb dysmetria on examination in a reported patient.
Saccadic smooth pursuit interruptions HP:0001152 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Saccadic smooth pursuit interruptions (HP:0001152). HP:0001152 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37553803 SUPPORT Human Clinical
"On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
Saccadic pursuit on examination in a reported patient.
PMID:37731903 SUPPORT Human Clinical
"Most patients displayed oculomotor signs, with a few also exhibiting hypokinetic features, hyperkinetic features and muscle weakness."
Places oculomotor signs among the common features across the published cohort.
Abnormal saccadic eye movements HP:0000570 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal saccadic eye movements (HP:0000570). HP:0000570 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38837640 SUPPORT Human Clinical
"Saccades were limited in the horizontal and vertical planes and associated with gaze‐evoked nystagmus."
Documents restricted saccades with gaze-evoked nystagmus on examination.
Ophthalmoplegia HP:0000602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ophthalmoplegia (HP:0000602). HP:0000602 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38837640 SUPPORT Human Clinical
"Here, we describe a new biallelic pathogenic variant in PRDX3 occurring in two unrelated boys who presented an early onset, slowly progressive cerebellar syndrome, external ophthalmoplegia, global hypokinesia, and behavioral changes."
External ophthalmoplegia in the two patients of this series.
Hypokinesia HP:0002375 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokinesia (HP:0002375). HP:0002375 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38837640 SUPPORT Human Clinical
"Here, we describe a new biallelic pathogenic variant in PRDX3 occurring in two unrelated boys who presented an early onset, slowly progressive cerebellar syndrome, external ophthalmoplegia, global hypokinesia, and behavioral changes."
Global hypokinesia in the two patients of this series.
Anti-thyroid peroxidase antibody positivity HP:0025379 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anti-thyroid peroxidase antibody positivity (HP:0025379). HP:0025379 is a phenotype from the Human Phenotype Ontology.
Two patients across the whole literature, so no frequency band. Treat as a reported association awaiting replication rather than a feature of SCAR32.
Show evidence (2 references)
PMID:41351775 SUPPORT Human Clinical
"Comprehensive laboratory tests showed decreased levels of selenium (85.44 µg/L), increased levels of thyroid autoantibodies, including anti-thyroid peroxidase (30.54 IU/mL) and anti-thyroglobulin (238.21 IU/mL)."
The measured thyroid autoantibody titres, together with the low selenium, in this patient.
PMID:42608543 SUPPORT Human Clinical
"Age at onset was 9-30 years, with a predominantly pure cerebellar phenotype; one patient had autoimmune comorbidities."
A second, independent patient with autoimmune comorbidity, though the report does not say which.
🧬

Genetic Associations

1
PRDX3
Gene: PRDX3 hgnc:9354 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRDX3 (hgnc:9354). hgnc:9354 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:33889951 SUPPORT Human Clinical
"we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration."
Establishes PRDX3 as the causative gene across five unrelated families.
Variants (7)
PRDX3 c.604G>A (p.Asp202Asn) Pathogenic
missense LOF
Recurrent missense allele at the conserved dimer interface of the PRDX3 oligomer; abolishes the protein rather than reducing its catalytic rate. First reported in two unrelated Kurdish families, subsequently homozygous in a Brazilian patient and in a British boy with cerebellar hypoplasia found in 100,000 Genomes Project data.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"A homozygous missense variant in PRDX3 (NM_006793.5): c.604G>A, p.(Asp202Asn) residing within a 6.45 Mb region of homozygosity (Fig. 1C) was identified and confirmed by Sanger Sequencing in proband I."
Identifies the recurrent missense allele in the homozygous state in a further unrelated patient.
PRDX3 c.619C>T (p.Arg207*) Pathogenic
nonsense LOF
Nonsense allele that is comparatively frequent in East Asian population data and was carried by all four patients in the Japanese series, homozygous in one and compound heterozygous in three; also reported homozygous in a Chinese paediatric patient.
Show evidence (3 references)
PMID:42608543 SUPPORT Human Clinical
"Genetic analysis identified one homozygous and three compound heterozygous PRDX3 nonsense variants: the previously reported p.Arg207* in all patients, p.Arg170* in two, and novel p.Gln50* in one."
Documents p.Arg207* in every patient of the Japanese series.
PMID:42608543 SUPPORT Human Clinical
"The relatively high p.Arg207* allele frequency in East Asians and the 0.97% prevalence in our undiagnosed ataxia cohort support SCAR32 as an important cause of early-onset autosomal recessive cerebellar ataxia in Japan."
Establishes p.Arg207* as a comparatively common East Asian allele and gives the diagnostic yield in a repeat-negative ataxia cohort.
PMID:41351775 SUPPORT Human Clinical
"This rare variant (gnomAD allele frequency: 2/251,446; 1/18,394 East Asian) was predicted to cause premature termination and loss of protein function"
Quantifies the population rarity of the allele and its East Asian enrichment.
PRDX3 c.508C>T (p.Arg170*) Pathogenic
nonsense LOF
The most frequently reported pathogenic allele, seen homozygous in an Indian patient and compound heterozygous in two Korean patients and in two of the four Japanese patients. Reported alongside a novel p.Asp171Gly missense allele four base pairs away in one Korean proband.
Show evidence (1 reference)
PMID:37731903 SUPPORT Human Clinical
"The genetic findings identified in our study indicated that the p.Arg170Ter variant is the most frequent pathogenic hit"
Identifies p.Arg170Ter as the most frequently recurring PRDX3 allele.
PRDX3 c.496A>T (p.Lys166*) Pathogenic
nonsense LOF
Homozygous nonsense allele in a consanguineous family, and the report that first added profound hearing impairment to the PRDX3 phenotype alongside global developmental delay, hypotonia, dystonia and cerebellar atrophy.
Show evidence (1 reference)
PMID:36190665 SUPPORT Human Clinical
"a biallelic nonsense variant (c.496A > T; p.Lys166*) in the exon 5 of the PRDX3 gene that segregated perfectly within the family."
Identifies the allele and its segregation in the family.
PRDX3 c.425C>G (p.Ala142Gly) Pathogenic
missense LOF
Missense allele reported in compound heterozygosity with the p.Leu176TrpfsTer11 frameshift. Used as a comparator in the aggregation experiments, where it damaged mitochondria less severely than p.Asp163Glu.
Show evidence (1 reference)
PMID:38837640 SUPPORT Human Clinical
"Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one."
Documents the allele in a compound-heterozygous patient.
PRDX3 c.489C>G (p.Asp163Glu) Pathogenic
missense LOF
Missense allele found homozygous in the earliest-onset patient reported (19 months). Unlike the other alleles it produces an unstable protein that aggregates and activates the mitochondrial and endoplasmic-reticulum unfolded protein responses before being cleared, and damages mitochondria more severely than p.Asp202Asn or p.Ala142Gly when expressed exogenously. This allele is not simply a null: the published data show loss of the enzyme plus a gain of aggregation-driven proteostatic stress that the nonsense alleles do not produce, which is why the node-level `functional_impact_category` of LOSS_OF_FUNCTION describes the shared lesion rather than this allele in full.
Show evidence (1 reference)
PMID:35766882 SUPPORT Human Clinical
"in PRDX3 was identified in homozygosis in the proband, and in heterozygosis in each progenitor"
Establishes the homozygous state in the proband with heterozygous parents.
PRDX3 c.525_535del (p.Leu176TrpfsTer11) Pathogenic
frameshift LOF
Frameshift allele reported homozygous in one patient and compound heterozygous with p.Ala142Gly in a second, both presenting with early-onset slowly progressive cerebellar syndrome.
Show evidence (1 reference)
PMID:38837640 SUPPORT Human Clinical
"Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one."
Documents the frameshift allele in compound heterozygosity with a known missense allele.
💊

Medical Actions

4
Physiotherapy and gait/balance training
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
The mainstay of management. No disease-modifying therapy exists, so care is the general progressive-ataxia package: physiotherapy, gait and balance training, fall reduction, and mobility aids as ambulation declines. Function is tracked with SARA and, in paediatric patients, with balance and gross-motor measures.
Mechanism Target:
Progressive cerebellar ataxia — Addresses the functional consequence of the cerebellar syndrome. It does not act on the redox lesion and does not alter the degeneration. `treatment_effect` is deliberately absent: `TreatmentEffectEnum` offers INHIBITS, ACTIVATES, MODULATES, BYPASSES and RESTORES, and none of them is true of a purely symptomatic rehabilitative intervention.
Speech and language therapy
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
For the cerebellar dysarthria, and later for the dysphagia that most patients develop as the syndrome spreads rostrally.
Mechanism Target:
Dysarthria — Symptomatic management of the cerebellar speech disorder. `treatment_effect` is absent for the same reason as on the physiotherapy link: no value in the enum describes a symptomatic intervention.
Genetic counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive transmission means a 25 percent sibling recurrence risk and, for an affected person, a low risk to offspring outside consanguinity. Both Korean probands were compound heterozygotes in a non-consanguineous setting, which is the specific point the Korean report makes about diagnostic strategy; carrier and cascade testing follow once the familial alleles are known.
Show evidence (1 reference)
PMID:37731903 SUPPORT Human Clinical
"Particularly, both patients presented compound heterozygotes alleles highlighting the importance of consideration for compound heterozygote modes during diagnostic evaluation in nonconsanguineous populations."
States the counselling-relevant point about compound heterozygosity in non-consanguineous families.
Human chorionic gonadotropin replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: chorionic gonadotropin CHEBI:81570 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses chorionic gonadotropin (CHEBI:81570). CHEBI:81570 is a therapeutic agent from Chemical Entities of Biological Interest.
One reported patient had hypogonadotropic hormonal dysfunction with micropenis and received intramuscular human chorionic gonadotropin, 500 IU weekly for four weeks, after which testosterone rose. This treated a comorbidity found in a single SCAR32 patient; it is not a therapy for SCAR32, and the relationship of the endocrinopathy to PRDX3 deficiency is unestablished.
Mechanism Target:
RESTORES Hypogonadotropic hypogonadism — Gonadotropin replacement for the documented low FSH, LH and testosterone in the one patient in whom this was found.
Show evidence (1 reference)
PMID:37553803 SUPPORT Human Clinical
"Subsequent laboratory evaluations revealed an increase in testosterone levels to 6.42 mg/mL, while DHT levels remained unchanged at 0.01 mg/mL."
The biochemical response to the gonadotropin course in the single treated patient.
🔬

Diagnosis

2
Molecular genetic testing
Diagnosis rests on finding biallelic pathogenic PRDX3 variants, in practice by exome or genome sequencing after repeat-expansion testing is negative. Homozygosity mapping helps in consanguineous families. A noncanonical splice allele causing exon skipping has been reported, so RNA studies may be needed when only one clearly damaging allele is found. In East Asian patients the recurrent p.Arg207* nonsense allele is worth specific attention.
Show evidence (1 reference)
PMID:42608543 SUPPORT Human Clinical
"We report four unrelated Japanese patients with SCAR32 identified among 411 ataxia cases negative for repeat expansion disorders."
Describes the practical diagnostic route — sequencing after negative repeat-expansion testing.
Brain MRI
MRI is the key supporting investigation. Cerebellar atrophy is universal; dentate-nucleus T2 hyperintensity and cerebellar cortical T2 hyperintensity have been proposed as a characteristic SCAR32 signature, with variable involvement of the middle cerebellar peduncles, posterior pons and inferior olives. The atrophy can be striking relative to a mild examination.
Show evidence (1 reference)
PMID:42608543 SUPPORT Human Clinical
"MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
The imaging pattern proposed as characteristic of SCAR32.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate has been published for SCAR32, so the qualitative ULTRA_RARE tier is used rather than a numeric Orphanet band. About fifteen patients had been described by mid-2024 and roughly twenty by 2026. The disease is not uniformly distributed: a Japanese series found four patients among 411 repeat-expansion-negative ataxia cases, a diagnostic yield in a selected cohort that is not a population rate.
Show evidence (2 references)
PMID:38837640 SUPPORT Other
"15 individuals harboring pathogenic variants have been described with onset ages ranging from infancy to adulthood."
The published case count as of 2024; graded OTHER because it is a literature tally rather than a study result.
PMID:42608543 SUPPORT Human Clinical
"We report four unrelated Japanese patients with SCAR32 identified among 411 ataxia cases negative for repeat expansion disorders."
Gives the numerator and denominator behind the Japanese diagnostic yield quoted in the note.
Republic of Korea
Point Prevalence 0.034 per 100,000 <1 in 1,000,000
0.34 patients per million, which is 0.034 per 100,000. This is the only published population figure for SCAR32 and it is an ALLELE-FREQUENCY-DERIVED ESTIMATE, not an observed rate: it is calculated from the Korean Variant Archive 2 frequencies of the three PRDX3 alleles identified in that study, and the authors express it as at least 17 expected patients nationally against a handful diagnosed. It therefore reflects the alleles known in 2023 and should be read as a lower bound on an undiagnosed population rather than a measurement.
Show evidence (1 reference)
PMID:37731903 SUPPORT Human Clinical
"Considering the allele frequencies of the 3 identified variants reported in the KOVA2, PRDX3 disease patients are estimated to be 0.34 individuals per million (at least 17 patients in the Republic of Korea), indicating that more efforts should be made in identifying PRDX3 disease."
The allele-frequency-derived national estimate and its stated derivation.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Spinocerebellar Ataxia, Autosomal Recessive 32:

Autosomal recessive ataxia due to TXN2 deficiency
Overlapping Features The other disease of the mitochondrial thioredoxin system, and the closest mechanistic neighbour: like SCAR32 it causes early-onset neurodegeneration through increased ROS, impaired oxidative-stress defence and mitochondrial dysfunction, but through the thioredoxin rather than the peroxiredoxin.
Distinguishing Features
  • Biallelic TXN2 rather than PRDX3 variants
Friedreich ataxia
Overlapping Features The commonest recessive ataxia and a routine early consideration; also a mitochondrial, oxidative-stress-linked disease. Distinguished by the GAA repeat expansion in FXN, prominent sensory neuropathy and areflexia, cardiomyopathy and scoliosis, and by spinal cord rather than cerebellar cortical atrophy.
Distinguishing Features
  • GAA repeat expansion in FXN
  • Cardiomyopathy and marked proprioceptive loss with areflexia
Repeat-expansion spinocerebellar ataxias
Overlapping Features SCA1/2/3/6/7/10 and the late-onset FGF14 (SCA27B) GAA expansion are the first tier excluded in practice, and were negative in every SCAR32 patient reported from a screening cohort.
Distinguishing Features
  • A pathogenic repeat expansion rather than biallelic PRDX3 variants
  • Usually dominant family history
Other early-onset autosomal recessive cerebellar ataxias
Overlapping Features Ataxia with vitamin E deficiency, ataxia-telangiectasia, ARSACS, COQ8A ataxia and the recessive ataxias with cerebellar atrophy generally. Several of these are treatable, which is why they are excluded first.
Distinguishing Features
  • Distinct causal genes and biochemical markers (alpha-fetoprotein, vitamin E, coenzyme Q10)
🧫

Experimental Models

1
SCAR32 patient dermal fibroblasts PRIMARY_CELL_CULTURE
Primary dermal fibroblasts from SCAR32 patients, the workhorse model of this literature and an inconsistent one. In the defining cohort they showed absent PRDX3, reduced glutathione peroxidase activity and reduced maximal respiratory capacity; in the infantile-onset patient they showed near-absent PRDX3, raised mitochondrial superoxide and increased sensitivity to glutathione depletion; but in the 2024 pair of patients they were biochemically unremarkable.
Pathograph links
Mitochondrial Respiratory Impairment fails to recapitulate fidelity: low In the 2024 report the patient fibroblast line reproduced none of the expected biochemistry: oxygen consumption was indistinguishable from controls and susceptibility to oxidative stress was not increased, leading the authors to conclude that the relevant PRDX3 functions are not expressed in peripheral cells.
Limitations: This is a negative result in one laboratory's line and does not overturn the positive fibroblast findings of the defining cohort; genotypes differ between the reports. What it does establish is that a normal fibroblast assay cannot be used to exclude SCAR32, and that fibroblasts are an unreliable surrogate for the neuronal phenotype.
Readouts
Fibroblast oxygen consumption rate
Direction: UNCHANGED
Interpretation: Seahorse respirometry of the patient line was not different from controls — a real negative, not a missing measurement.
Show evidence (1 reference)
PMID:38837640 SUPPORT In Vitro
"Metabolic parameters obtained from OCR traces did not show significant changes in mitochondrial function between the patient and the controls."
The respirometry measurement behind this negative readout.
Show evidence (1 reference)
PMID:38837640 SUPPORT In Vitro
"While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function"
The authors' own statement that their fibroblast model did not reproduce the PRDX3 loss-of-function phenotype.
Show evidence (1 reference)
PMID:33889951 SUPPORT In Vitro
"Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
The positive fibroblast result that made this the standard model for the disease.
🐁

Animal Models

2
prdx3 F0 crispant zebrafish
An F0 "crispant" zebrafish generated to test prdx3 function during nervous system development, made because no zebrafish model of PRDX3 existed. Larvae show reduced burst activity on tail-coiling, reduced locomotor velocity and distance, increased susceptibility to oxidative stress, impaired mitochondrial bioenergetics, and increased apoptotic cells with raised apoptosis-associated transcripts.
Species
Zebrafish
Genotype
prdx3 CRISPR-Cas9 F0 crispant (somatic biallelic disruption)
Publication
PMID:38837640
Pathograph links
Cerebellar Neuronal Oxidative Injury recapitulates fidelity: moderate prdx3 depletion in vivo reproduces the ROS-sensitised apoptosis and the motor consequence that this node asserts for human cerebellar neurons.
Limitations: Species divergence, and an F0 somatic crispant is mosaic rather than a germline null, so residual prdx3 is expected. The apoptosis and motor readouts are whole-larva measurements at 24-120 hours post fertilisation: nothing localises the injury to the cerebellum, and a developing larva is not a model of the adult-onset human presentations.
Readouts
ROS-triggered apoptotic cell burden
Direction: INCREASED
Interpretation: Acridine-orange-positive cells and apoptosis-associated transcripts both rise in prdx3-depleted larvae, the in vivo counterpart of the apoptotic sensitisation seen in PRDX3-knockdown cerebellar cells.
Show evidence (1 reference)
PMID:38837640 SUPPORT Model Organism
"we observed a likely ROS‐triggered increment of acridine orange‐positive cells"
The apoptosis measurement behind this readout.
Larval locomotor burst activity
Direction: DECREASED
Interpretation: Reduced burst activity on the tail-coiling test is the motor output consequence of prdx3 depletion.
Show evidence (1 reference)
PMID:38837640 SUPPORT Model Organism
"The tail‐coiling test results showed a significant decrease in burst activity in prdx3‐F0 animals compared with controls"
The locomotor measurement behind this readout.
Mitochondrial Respiratory Impairment recapitulates fidelity: moderate Oxygen-consumption studies in prdx3-depleted larvae reproduce the loss of respiratory capacity measured in patient fibroblasts.
Limitations: Whole-larva respirometry rather than a neuronal measurement, in a mosaic F0 animal; and the corresponding human finding is itself inconsistent between patient fibroblast lines.
Readouts
Larval maximal respiration and ATP production
Direction: DECREASED
Interpretation: Seahorse respirometry of 120-hpf larvae shows reduced ATP-linked and maximal respiration on prdx3 depletion.
Show evidence (1 reference)
PMID:38837640 SUPPORT Model Organism
"oxygen consumption rate studies revealed impaired mitochondrial bioenergetics in 120‐hpf larvae compared with controls, with significant reductions in ATP production and maximal respiration"
The respirometry measurement behind this readout.
Show evidence (1 reference)
PMID:38837640 SUPPORT Model Organism
"our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate."
Establishes the crispant as an informative in vivo model of prdx3 depletion.
Pan-neuronal and pan-glial Drosophila prdx3 knockdown
In vivo knockdown of the fly PRDX3 orthologue in neurons and in glia, used in the defining paper to test whether loss of the enzyme is sufficient to cause a locomotor phenotype and oxidative-stress vulnerability in an intact nervous system.
Species
Fruit fly
Genotype
RNAi knockdown of the PRDX3 orthologue driven pan-neuronally and pan-glially
Publication
PMID:33889951
Pathograph links
Cerebellar Neuronal Oxidative Injury partially recapitulates fidelity: low Reproduces the causal step from neuronal loss of the peroxiredoxin to locomotor failure and oxidative-stress vulnerability, but not the anatomy.
Limitations: Drosophila has no cerebellum, so the model cannot address the regional selectivity that is the central unexplained feature of the human disease. Knockdown is RNAi rather than a null allele and is driven throughout neurons and glia rather than in the affected population, and the locomotor readout is not ataxia.
Readouts
Survival under oxidative stress challenge
Direction: DECREASED
Interpretation: Shortened survival on oxidative-stress exposure is the in vivo expression of the lost peroxide-buffering capacity.
Show evidence (1 reference)
PMID:33889951 SUPPORT Model Organism
"Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
The survival measurement behind this readout.
Show evidence (1 reference)
PMID:33889951 SUPPORT Model Organism
"Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
Establishes that neuronal and glial loss of the orthologue is sufficient for a locomotor and oxidative-stress phenotype.
{ }

Source YAML

click to show 
name: Spinocerebellar Ataxia, Autosomal Recessive 32
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: spinocerebellar ataxia, autosomal recessive 32
  term:
    id: MONDO:0859245
    label: spinocerebellar ataxia, autosomal recessive 32
description: >-
  Spinocerebellar ataxia, autosomal recessive 32 (SCAR32), also called
  PRDX3-associated neurodegeneration (PRAN), is the recessive cerebellar ataxia
  caused by biallelic loss-of-function variants in PRDX3. Peroxiredoxin 3 is the
  one member of the six-isoform human peroxiredoxin family that is restricted to
  mitochondria, where it is the thioredoxin-dependent peroxidase that clears the
  hydrogen peroxide generated by the respiratory chain. SCAR32 is therefore an
  ataxia of failed mitochondrial redox buffering rather than of a structural,
  channel, repeat-expansion or DNA-repair lesion, and it sits alongside TXN2
  deficiency as one of two ultra-rare diseases of the mitochondrial thioredoxin
  system.

  The entity was defined in 2021 from five unrelated families in the PREPARE
  recessive-ataxia network. The core picture is a slowly progressive cerebellar
  syndrome — gait then limb ataxia, cerebellar dysarthria, nystagmus and
  dysmetria — with cerebellar atrophy that is present in every reported patient,
  frequently disproportionate to the clinical severity, and often accompanied by
  T2 hyperintensity of the dentate nuclei, cerebellar cortex, middle cerebellar
  peduncles and posterior pons. Olivary and brainstem degeneration is reported in
  part of the cohort.

  What is distinctive, and unexplained, is the range of onset. It was described in
  2023 as birth to 35 years on the cases then published; a Korean report the same
  year, counting nine patients, put it at infantile onset to 55 years. Either way
  it spans both nonsense and missense alleles across a literature of roughly
  twenty patients, with no genotype-phenotype rule established. A second
  descriptive pattern proposed from the same report is a caudal-to-rostral spatial
  spread of the disease. The severe
  infantile end adds early peripheral neuropathy and rapid cerebellar volume loss;
  the adult end can be a nearly pure, slowly progressive cerebellar syndrome with
  independent ambulation preserved a decade after onset. Non-cerebellar features
  reported in individual patients — profound hearing impairment, dystonia,
  hypogonadotropic hormonal dysfunction, thyroid autoimmunity, intellectual
  disability — are each single-patient or few-patient observations and are curated
  here without frequency bands for that reason.

  Every PRDX3 allele characterised so far behaves as loss of function: the mutant
  protein is absent from patient fibroblasts, glutathione peroxidase activity and
  maximal mitochondrial respiratory capacity fall, and PRDX5 is co-reduced. One
  allele, p.Asp163Glu, adds a second mechanism on top of simple enzyme loss — an
  unstable protein that aggregates and triggers both the mitochondrial and the
  endoplasmic-reticulum unfolded protein responses — which is the current best
  candidate explanation for why that patient's disease began in infancy.

  A point this entry is deliberate about: no neuropathological study of a SCAR32
  patient has been published, and the word Purkinje does not appear anywhere in
  the PRDX3 ataxia literature. The degeneration is therefore curated at the
  cerebellar-cortex level that imaging actually supports, and conformance to the
  `cerebellar_purkinje_degeneration` module is NOT declared. See the open
  discussion.
parents:
- Autosomal Recessive Cerebellar Ataxia
synonyms:
- SCAR32
- PRDX3-associated neurodegeneration
- PRAN
- PRDX3-related autosomal recessive cerebellar ataxia
- spinocerebellar ataxia type 32, autosomal recessive
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Presents and is managed as a progressive cerebellar ataxia; the whole
      reported phenotype is neurological apart from isolated endocrine findings.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian recessive disorder diagnosed by exome sequencing rather than
      within one organ-system Part.
references:
- reference: PMID:33889951
  title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
- reference: PMID:35766882
  title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
- reference: PMID:36190665
  title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
- reference: PMID:37553803
  title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
- reference: PMID:37553955
  title: "Exon Skipping Caused by Noncanonical Splicing Mutation in PRDX3-Related Spinocerebellar Ataxia."
- reference: PMID:35792670
  title: "Expanding PRDX3 disease: broad range of onset age and infratentorial MRI signal changes."
- reference: PMID:37731903
  title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
- reference: PMID:38837640
  title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
- reference: PMID:41351775
  title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
- reference: PMID:42608543
  title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every reported patient carries two PRDX3 alleles — homozygous in the
    consanguineous and founder-allele families, compound heterozygous in
    several non-consanguineous ones — with unaffected heterozygous parents.
    PRDX3 is nuclear-encoded and autosomal (10q26.11), so despite the disease
    being mitochondrial in its biochemistry the transmission is nuclear
    recessive, with a 25 percent sibling recurrence risk and no maternal
    transmission.
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration."
    explanation: Establishes recessive inheritance of PRDX3 ataxia across five unrelated families in the defining study.
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The further segregation analysis confirmed these findings and showed that his healthy brother was carrier of the PRDX3 c.489C > G variant in heterozygosis"
    explanation: Documents an unaffected heterozygous sibling, the segregation pattern expected of a recessive allele.
pathophysiology:
- name: PRDX3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic PRDX3 variants — nonsense, frameshift, splice and missense alike —
    converge on absence of the peroxiredoxin 3 protein from patient cells. PRDX3
    is the only one of the six human peroxiredoxins confined to mitochondria, and
    it functions as a homodimer packed into a decameric/dodecameric ring; the
    recurrent p.Asp202Asn missense allele sits at the conserved dimer interface of
    that ring and destroys the protein rather than merely blunting its catalysis.
    The mutant protein is absent in patient fibroblasts across every allele
    characterised to date, so the molecular lesion is enzyme loss and not a
    dominant-negative or neomorphic activity.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline PRDX3 alleles: homozygous in the consanguineous and
      founder-allele families and compound heterozygous in several
      non-consanguineous ones. Reported classes are nonsense, frameshift,
      noncanonical splice and missense, and all characterised alleles leave the
      protein absent from patient fibroblasts.
  molecular_functions:
  - preferred_term: thioredoxin-dependent peroxiredoxin activity
    term:
      id: GO:0008379
      label: thioredoxin peroxidase activity
    modifier: ABSENT
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species."
    explanation: Background statement in the defining paper establishing PRDX3 as the exclusively mitochondrial peroxiredoxin; graded OTHER because it reports no experiment of its own.
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All PRDX3 variants reported to date act via loss‐of‐function, as the mutant proteins are absent in patients' fibroblasts, leading to complete loss of the enzyme."
    explanation: Summarises the published functional data across alleles as uniform loss of function; graded OTHER because it restates prior results rather than a new experiment.
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutation is located in the PRX_Tyrp2cys domain of the protein at a region of high conservation in the dimer interface located between two PRDX3 subunits of the dodecamer ring and causes a complete absence of the protein."
    explanation: Locates the recurrent p.Asp202Asn allele at the oligomer dimer interface and states that it abolishes the protein; graded OTHER as a structural interpretation of published data.
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the patient's fibroblasts, PRDX3 expression was nearly absent."
    explanation: Direct measurement of protein loss in patient-derived fibroblasts.
  downstream:
  - target: Mitochondrial Hydrogen Peroxide Accumulation
    description: >-
      Loss of the mitochondrial thioredoxin-dependent peroxidase removes the
      principal matrix route for disposing of respiratory-chain hydrogen peroxide.
  - target: Misfolded PRDX3 Aggregation and Unfolded Protein Response
    description: >-
      Allele-specific: the destabilising p.Asp163Glu missense protein aggregates
      before it is cleared, adding a proteostatic insult to the enzyme loss.

- name: Mitochondrial Hydrogen Peroxide Accumulation
  biological_scale: MOLECULAR
  description: >-
    Superoxide produced by the respiratory chain is dismutated to hydrogen
    peroxide in the matrix, where peroxiredoxin 3 is the dominant scavenger.
    Without it the peroxide load rises: patient fibroblasts show reduced
    glutathione peroxidase activity and increasing mitochondrial superoxide as
    external hydrogen peroxide is raised, and PRDX3-depleted cerebellar cells
    accumulate hydrogen peroxide directly. Compensating transcripts (SOD2, GPX1,
    catalase, TXN2, PRDX5) are upregulated but do not restore buffering.
  biological_processes:
  - preferred_term: hydrogen peroxide catabolic process
    term:
      id: GO:0042744
      label: hydrogen peroxide catabolic process
    modifier: DECREASED
  - preferred_term: cell redox homeostasis
    term:
      id: GO:0045454
      label: cell redox homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
    explanation: Couples PRDX3 protein loss to measured loss of peroxidase activity in patient cells.
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species."
    explanation: Shows directly that removing PRDX3 from a cerebellar cell line raises hydrogen peroxide and kills the cells.
  downstream:
  - target: Cerebellar Neuronal Oxidative Injury
    description: >-
      Unbuffered matrix peroxide is the proximate oxidative insult to cerebellar
      neurons.
  - target: Mitochondrial Respiratory Impairment
    description: >-
      Oxidative damage to the organelle degrades its own respiratory capacity.

- name: Misfolded PRDX3 Aggregation and Unfolded Protein Response
  biological_scale: CELLULAR
  description: >-
    This node is allele-specific and does not apply to the null alleles. The
    p.Asp163Glu missense protein is unstable, forms insoluble aggregates and is
    routed to proteasomal degradation, and its expression activates the
    unfolded protein response in both the mitochondrion and the endoplasmic
    reticulum. Expressed exogenously it damages mitochondria far more severely
    than the p.Asp202Asn or p.Ala142Gly alleles do — cristae disorganisation,
    membrane damage and lipid-droplet accumulation — and in cultured mouse
    cortical neurons it distorts neurite morphology. This is the current
    candidate explanation for the exceptionally early, 19-month onset in that
    patient, and it is a proteostatic mechanism layered on top of, not instead
    of, the shared enzyme loss.
  biological_processes:
  - preferred_term: mitochondrial unfolded protein response
    term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    modifier: INCREASED
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum."
    explanation: States the aggregation-plus-UPR mechanism demonstrated for this allele.
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization."
    explanation: Documents the organelle damage produced by expressing the aggregating allele.
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria."
    explanation: Extends the aggregating-allele damage to cultured neurons, the cell class relevant to the disease.
  downstream:
  - target: Cerebellar Neuronal Oxidative Injury
    description: >-
      Proteostatic stress compounds the redox insult in the one allele where it
      has been demonstrated.

- name: Mitochondrial Respiratory Impairment
  biological_scale: CELLULAR
  description: >-
    PRDX3-deficient cells lose respiratory reserve. Patient fibroblasts in the
    defining cohort had reduced maximal respiratory capacity, and prdx3-depleted
    zebrafish larvae show significant reductions in ATP production and maximal
    respiration. This is a consequence of the redox lesion rather than a primary
    OXPHOS subunit defect: PRDX3 is not part of any respiratory complex, and one
    later patient's fibroblasts showed no measurable respiratory abnormality at
    all, so the finding is not uniform across cell lines.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cellular respiration
    term:
      id: GO:0045333
      label: cellular respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
    explanation: Reports the reduced maximal respiratory capacity in patient fibroblasts.
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "significant reductions in ATP production and maximal respiration"
    explanation: Independent respiratory deficit in the prdx3-depleted zebrafish larva.
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: "Metabolic parameters obtained from OCR traces did not show significant changes in mitochondrial function between the patient and the controls."
    explanation: A later patient's fibroblasts showed no respiratory abnormality, so this node is not uniformly demonstrable in peripheral cells.
  downstream:
  - target: Cerebellar Neuronal Oxidative Injury
    description: >-
      Reduced respiratory reserve leaves high-demand cerebellar neurons less able
      to tolerate the redox insult.

- name: Cerebellar Neuronal Oxidative Injury
  biological_scale: CELLULAR
  description: >-
    Cerebellar neurons are the cell population in which the redox failure becomes
    a disease. Removing PRDX3 from cerebellar cells raises hydrogen peroxide,
    reduces viability and sensitises them to reactive-oxygen-species-triggered
    apoptosis; the same sensitisation is seen in prdx3-depleted zebrafish larvae
    as an increase in apoptotic cells and in apoptosis-associated transcripts.
    Why the cerebellum in particular is the vulnerable region, when PRDX3 is
    ubiquitously expressed, is not established.
  biological_processes:
  - preferred_term: cellular response to reactive oxygen species
    term:
      id: GO:0034614
      label: cellular response to reactive oxygen species
    modifier: INCREASED
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species."
    explanation: The closest available cerebellar cell model shows peroxide accumulation and apoptotic sensitisation on PRDX3 loss.
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate."
    explanation: In vivo confirmation that prdx3 depletion sensitises to ROS-triggered apoptosis and impairs motor output.
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
    explanation: Neuronal and glial loss of the fly orthologue produces locomotor failure and oxidative-stress lethality.
  downstream:
  - target: Cerebellar Cortical Degeneration
    description: >-
      Sustained oxidative injury and apoptosis of cerebellar neurons is the
      cellular substrate of the tissue-level degeneration.

- name: Cerebellar Cortical Degeneration
  biological_scale: TISSUE
  description: >-
    The tissue-level lesion is a cerebellar cortical degeneration: cerebellar
    atrophy is present in every reported patient, is often severe and early
    relative to the clinical picture, and is accompanied on MRI by T2
    hyperintensity of the dentate nuclei and of the cerebellar cortex itself,
    with variable extension to the middle cerebellar peduncles, posterior pons and
    inferior olives. It is curated at the cortical rather than the Purkinje-cell
    level on purpose: no autopsy or biopsy neuropathology of a SCAR32 patient has
    been published, and no paper in this literature identifies the Purkinje cell
    as the degenerating population. Conformance to the
    `cerebellar_purkinje_degeneration` module is therefore not declared here —
    see the open discussion.
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  - preferred_term: dentate nucleus
    term:
      id: UBERON:0002132
      label: dentate nucleus
  - preferred_term: inferior olivary complex
    term:
      id: UBERON:0002127
      label: inferior olivary complex
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  evidence:
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only a few reports have described the MRI features of PRDX3 disease, including T2 signal changes in the reticular formation, dentate nucleus and transverse stripes of the pons, which are not typically seen in other hereditary degenerative ataxia."
    explanation: Adds the reticular-formation and transverse-pontine-stripe signal changes, and states that this infratentorial pattern is not typical of other hereditary degenerative ataxias.
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The presence of cerebellar atrophy is a ubiquitous feature in patients with bi‐allelic PRDX3 mutations."
    explanation: Establishes cerebellar atrophy as universal across the reported PRDX3 cohort; graded OTHER as a synthesis of published cases.
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
    explanation: Adds the dentate and cerebellar-cortical signal change seen in every patient of a four-patient series.
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration."
    explanation: Documents severe early cerebellar atrophy with olivary and brainstem involvement in the defining cohort.
  downstream:
  - target: Progressive cerebellar ataxia
    description: >-
      Loss of cerebellar cortical tissue removes the coordination signal, giving
      the progressive gait, limb, speech and eye-movement incoordination that
      defines the disease.
    evidence:
    - reference: PMID:33889951
      reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration."
      explanation: Couples the cerebellar atrophy and the progressive ataxia in the same clinical characterisation.
  - target: Cerebellar atrophy
    description: >-
      Cerebellar cortical tissue loss is what the imaging phenotype measures.

phenotypes:
- name: Progressive cerebellar ataxia
  category: Nervous System
  description: >-
    The defining feature. Onset is usually with gait ataxia, followed by limb
    ataxia, cerebellar dysarthria and dysmetria; progression is typically slow,
    with ambulation often retained years to a decade after onset, though the
    infantile-onset patient lost autonomous ambulation within two weeks of onset.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration."
    explanation: Progressive cerebellar ataxia is the presenting and defining feature in the founding cohort.
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age at onset was 9-30 years, with a predominantly pure cerebellar phenotype; one patient had autoimmune comorbidities."
    explanation: Confirms a predominantly pure cerebellar phenotype in an independent four-patient series.

- name: Gait ataxia
  category: Nervous System
  description: >-
    The usual first symptom across the age range, from a toddler with acute loss
    of independent sitting and walking to an adult reporting insidious unsteadiness.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:41351775
    reference_title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, the patient presented with slowly progressive gait ataxia and cerebellar vermis atrophy."
    explanation: Gait ataxia as the presenting symptom in a paediatric SCAR32 patient.

- name: Cerebellar atrophy
  category: Nervous System
  description: >-
    Present in every reported patient and often disproportionate to the clinical
    severity; the vermis is affected early and quantitatively (one infant lost 19
    percentage points of midsagittal vermis relative diameter between 23 and 32
    months of age).
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The presence of cerebellar atrophy is a ubiquitous feature in patients with bi‐allelic PRDX3 mutations."
    explanation: States explicitly that cerebellar atrophy is universal in the reported PRDX3 cohort, which is the basis for the OBLIGATE band.
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
    explanation: Cerebellar atrophy in all four patients of an independent series.

- name: Abnormal dentate nucleus signal
  category: Nervous System
  description: >-
    T2 hyperintensity of the dentate nuclei, reported in all four patients of the
    Japanese series and, with cerebellar cortical hyperintensity, proposed there as
    a characteristic radiological signature of SCAR32.
  phenotype_term:
    preferred_term: Abnormal dentate nucleus morphology
    term:
      id: HP:0100321
      label: Abnormal dentate nucleus morphology
  evidence:
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
    explanation: Documents dentate-nucleus T2 hyperintensity in every patient of the series.
  notes: >-
    Bound to the closest available HPO concept. HPO has no term for a T2 signal
    abnormality of the dentate nucleus specifically; `Abnormal dentate nucleus
    morphology` is broader than the imaging finding but is the accurate parent.

- name: Peripheral neuropathy
  category: Nervous System
  description: >-
    Reported in the infantile-onset patient, in whom nerve conduction was normal at
    19 months and showed moderate motor and sensory neuropathy by age 4. Absent in
    several adult-onset patients with formally normal nerve conduction studies, so
    it appears to track with the severe end of the spectrum rather than being a
    constant feature.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:35766882
    reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease."
    explanation: Peripheral neuropathy early in the course of the infantile-onset case.
  notes: >-
    No frequency band is assigned. The published patients come from separate
    single-case and small-series reports with no pooled cohort denominator, and
    nerve conduction was not performed in every patient.

- name: Nystagmus
  category: Eye
  description: >-
    Multidirectional, bidirectional horizontal or gaze-evoked nystagmus, reported
    in patients across the age range.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
    explanation: Documents multidirectional nystagmus alongside the other cerebellar signs in a reported patient.
  notes: >-
    No frequency band; see the note on peripheral neuropathy.

- name: Dysarthria
  category: Nervous System
  description: Cerebellar dysarthria, generally appearing with or shortly after the gait ataxia.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
    explanation: Cerebellar dysarthria on examination in a reported patient.

- name: Dysmetria
  category: Nervous System
  description: Limb dysmetria on finger-to-nose and heel-to-shin testing, part of the appendicular cerebellar syndrome.
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
    explanation: Four-limb dysmetria on examination in a reported patient.

- name: Dysphagia
  category: Digestive
  description: >-
    Swallowing difficulty develops in most patients as part of the caudal-to-rostral
    progression of the cerebellar syndrome, alongside upper-limb ataxia and
    dysarthria. It was explicitly absent in one adult with a pure cerebellar
    phenotype who remained ambulant ten years after onset.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these patients presented with gait ataxia, and most eventually developed upper limb ataxia, dysarthria and/or dysphagia."
    explanation: Places dysphagia in the usual progression across the nine patients published to that point.

- name: Saccadic smooth pursuit interruptions
  category: Eye
  description: >-
    Oculomotor signs are reported in most patients. Saccadic pursuit was
    documented on examination alongside multidirectional nystagmus in a patient
    with an otherwise pure cerebellar syndrome.
  phenotype_term:
    preferred_term: Saccadic smooth pursuit interruptions
    term:
      id: HP:0001152
      label: Saccadic smooth pursuit interruptions
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On neurological examination, he exhibited moderate gait ataxia, cerebellar dysarthria, saccadic pursuit, multi‐directional nystagmus, four limbs dysmetria, comprising a scale for the assessment and rating of ataxia (SARA) score of 12/40."
    explanation: Saccadic pursuit on examination in a reported patient.
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients displayed oculomotor signs, with a few also exhibiting hypokinetic features, hyperkinetic features and muscle weakness."
    explanation: Places oculomotor signs among the common features across the published cohort.

- name: Tremor
  category: Nervous System
  description: >-
    Hand tremor is part of the hyperkinetic component that accompanies the ataxia
    in a subset of patients; in one Korean patient it followed the gait ataxia by
    two years.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxic gait was prominently observed from the age of 11 years, followed by the onset of both hands tremors at age 13 and dysarthria at age 15."
    explanation: Documents the sequence of gait ataxia, then hand tremor, then dysarthria in a Korean patient.
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also presented upper and lower limb dysmetria, slight upper limb postural tremor, and hyporeflexia."
    explanation: Postural tremor on examination in an independent patient.
  notes: >-
    Bound to the parent HP:0001337 rather than to `Postural tremor` (HP:0002174):
    the tremor is described as postural in one patient, as postural and action in
    another, and simply as tremor in a third, so the parent is what is true across
    the disease.

- name: Abnormal saccadic eye movements
  category: Eye
  description: >-
    Saccades limited in both horizontal and vertical planes, with gaze-evoked
    nystagmus, in one of the two patients of the 2024 series; the same series
    reports external ophthalmoplegia in its probands. This is the ocular-motor
    component that oculomotor signs in most patients refers to.
  phenotype_term:
    preferred_term: Abnormal saccadic eye movements
    term:
      id: HP:0000570
      label: Abnormal saccadic eye movements
  evidence:
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Saccades were limited in the horizontal and vertical planes and associated with gaze‐evoked nystagmus."
    explanation: Documents restricted saccades with gaze-evoked nystagmus on examination.

- name: Ophthalmoplegia
  category: Eye
  description: >-
    External ophthalmoplegia was part of the presenting syndrome in the two
    patients of the 2024 series. It is not reported in the pure cerebellar
    adult-onset patients.
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  evidence:
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a new biallelic pathogenic variant in PRDX3 occurring in two unrelated boys who presented an early onset, slowly progressive cerebellar syndrome, external ophthalmoplegia, global hypokinesia, and behavioral changes."
    explanation: External ophthalmoplegia in the two patients of this series.

- name: Hypokinesia
  category: Nervous System
  description: >-
    The hypokinetic half of the movement-disorder component the defining cohort
    describes as concomitant hyper- and hypokinetic. Global hypokinesia was
    documented on examination in the 2024 series.
  phenotype_term:
    preferred_term: Hypokinesia
    term:
      id: HP:0002375
      label: Hypokinesia
  evidence:
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a new biallelic pathogenic variant in PRDX3 occurring in two unrelated boys who presented an early onset, slowly progressive cerebellar syndrome, external ophthalmoplegia, global hypokinesia, and behavioral changes."
    explanation: Global hypokinesia in the two patients of this series.

- name: Global developmental delay
  category: Nervous System
  description: >-
    Reported at the severe, early-onset end of the spectrum — a 6-month-old who
    failed to achieve milestones, and a proband with global developmental delay,
    hypotonia, speech difficulty and dystonia. Adult-onset patients have normal
    development.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36190665
    reference_title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
    explanation: Global developmental delay in a severely affected PRDX3 proband.

- name: Hypotonia
  category: Nervous System
  description: Axial and appendicular hypotonia, reported in the paediatric patients.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36190665
    reference_title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
    explanation: Hypotonia in the same severely affected proband.

- name: Dystonia
  category: Nervous System
  description: >-
    Part of the hyperkinetic movement-disorder component that accompanies the
    ataxia in a subset of patients.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:36190665
    reference_title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment."
    explanation: Dystonia in a reported PRDX3 patient.

- name: Profound hearing impairment
  category: Ear
  description: >-
    Profound hearing impairment was reported in a single consanguineous proband
    homozygous for the nonsense allele p.Lys166*, and was the feature that report
    proposed as an extension of the PRDX3 phenotype. Hearing assessment was
    explicitly normal in another paediatric patient, so this is not a general
    feature of SCAR32.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:36190665
    reference_title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, associated hearing impairment further delineates the PRDX3 associated gene phenotypes."
    explanation: The single report that adds hearing impairment to the PRDX3 phenotype.
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum immunoglobulin, AFP, eye examination and hearing assessment were all normal."
    explanation: Hearing was formally normal in another paediatric SCAR32 patient, which is why no frequency band is assigned.

- name: Intellectual disability
  category: Nervous System
  description: >-
    Mild cognitive impairment was formally documented in one paediatric patient
    (full-scale IQ 74, with perceptual reasoning and processing speed most
    affected). Several adult patients had no cognitive impairment on examination,
    so cognition is variable and not a defining feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    severity: MILD
  evidence:
  - reference: PMID:41351775
    reference_title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) indicated mild cognitive impairment (full-scale IQ: 74)"
    explanation: Formal psychometric documentation of mild cognitive impairment in a SCAR32 patient.
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence of cognitive impairment, extrapyramidal or pyramidal tract involvement, autonomic dysfunction, or peripheral neuropathy."
    explanation: An adult SCAR32 patient with no cognitive impairment, establishing that intellectual disability is not constant.

- name: Anti-thyroid peroxidase antibody positivity
  category: Endocrine
  description: >-
    Raised anti-thyroid peroxidase and anti-thyroglobulin antibodies with an
    enlarged, heterogeneously echogenic thyroid, in one Chinese paediatric
    patient who also had a low serum selenium. One patient in the Japanese series
    is separately recorded as having autoimmune comorbidities. The reporting
    authors offer an oxidative-stress rationale for a link to PRDX3 deficiency,
    but it is a hypothesis about two patients, not an established association.
  phenotype_term:
    preferred_term: Anti-thyroid peroxidase antibody positivity
    term:
      id: HP:0025379
      label: Anti-thyroid peroxidase antibody positivity
  evidence:
  - reference: PMID:41351775
    reference_title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive laboratory tests showed decreased levels of selenium (85.44 µg/L), increased levels of thyroid autoantibodies, including anti-thyroid peroxidase (30.54 IU/mL) and anti-thyroglobulin (238.21 IU/mL)."
    explanation: The measured thyroid autoantibody titres, together with the low selenium, in this patient.
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age at onset was 9-30 years, with a predominantly pure cerebellar phenotype; one patient had autoimmune comorbidities."
    explanation: A second, independent patient with autoimmune comorbidity, though the report does not say which.
  notes: >-
    Two patients across the whole literature, so no frequency band. Treat as a
    reported association awaiting replication rather than a feature of SCAR32.

- name: Goiter
  category: Endocrine
  description: >-
    Thyroid enlargement with heterogeneous echogenicity accompanied the
    autoantibody rise in the same single patient.
  phenotype_term:
    preferred_term: Goiter
    term:
      id: HP:0000853
      label: Goiter
  evidence:
  - reference: PMID:41351775
    reference_title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings were associated with an enlargement and heterogeneous echogenicity of the thyroid gland."
    explanation: The thyroid enlargement accompanying the autoantibody findings.
  notes: One patient; see the note on the antibody phenotype.

- name: Hypogonadotropic hypogonadism
  category: Endocrine
  description: >-
    One reported patient had micropenis with low FSH, LH, testosterone and
    dihydrotestosterone, responsive to human chorionic gonadotropin. This is a
    single-patient observation whose relationship to PRDX3 deficiency is not
    established; it is recorded because it changed that patient's management.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An endocrinological exam showed that the patient presented with low levels of follicle‐stimulating hormone (FSH) at 1.9 mIU/mL, luteinizing hormone (LH) at 1 mIU/mL, testosterone at 0.2 mg/mL and dihydrotestosterone (DHT) at 0.01 mg/mL."
    explanation: The hormone profile establishing hypogonadotropic hypogonadism in this patient.
  notes: >-
    Reported in one patient only. Do not read this as a SCAR32-associated
    endocrinopathy without further cases.

genetic:
- name: PRDX3
  notes: >-
    Biallelic variants in PRDX3 (peroxiredoxin 3, chromosome 10q26.11) cause
    SCAR32. Reported alleles span nonsense (p.Arg207*, p.Arg170*, p.Lys166*,
    p.Gln50*), frameshift (p.Leu8Cysfs*10, p.Leu176TrpfsTer11), noncanonical
    splice variants causing exon skipping, and missense (p.Asp202Asn, p.Ala142Gly,
    p.Asp163Glu). All behave as loss of function, with the mutant protein absent
    from patient fibroblasts. Two alleles recur across unrelated families:
    p.Asp202Asn, first found in Kurdish families and since in Brazilian and UK
    patients and sitting at a CpG dinucleotide, and p.Arg207*, which is
    comparatively common in East Asian population data and was present in all four
    patients of the Japanese series.
  gene_term:
    preferred_term: PRDX3
    term:
      id: hgnc:9354
      label: PRDX3
  relationship_type: CAUSATIVE
  variants:
  - name: PRDX3 c.604G>A (p.Asp202Asn)
    description: >-
      Recurrent missense allele at the conserved dimer interface of the PRDX3
      oligomer; abolishes the protein rather than reducing its catalytic rate.
      First reported in two unrelated Kurdish families, subsequently homozygous in
      a Brazilian patient and in a British boy with cerebellar hypoplasia found in
      100,000 Genomes Project data.
    type: missense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:37553803
      reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A homozygous missense variant in PRDX3 (NM_006793.5): c.604G>A, p.(Asp202Asn) residing within a 6.45 Mb region of homozygosity (Fig. 1C) was identified and confirmed by Sanger Sequencing in proband I."
      explanation: Identifies the recurrent missense allele in the homozygous state in a further unrelated patient.
  - name: PRDX3 c.619C>T (p.Arg207*)
    description: >-
      Nonsense allele that is comparatively frequent in East Asian population data
      and was carried by all four patients in the Japanese series, homozygous in
      one and compound heterozygous in three; also reported homozygous in a Chinese
      paediatric patient.
    type: nonsense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:42608543
      reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis identified one homozygous and three compound heterozygous PRDX3 nonsense variants: the previously reported p.Arg207* in all patients, p.Arg170* in two, and novel p.Gln50* in one."
      explanation: Documents p.Arg207* in every patient of the Japanese series.
    - reference: PMID:42608543
      reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The relatively high p.Arg207* allele frequency in East Asians and the 0.97% prevalence in our undiagnosed ataxia cohort support SCAR32 as an important cause of early-onset autosomal recessive cerebellar ataxia in Japan."
      explanation: Establishes p.Arg207* as a comparatively common East Asian allele and gives the diagnostic yield in a repeat-negative ataxia cohort.
    - reference: PMID:41351775
      reference_title: "A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This rare variant (gnomAD allele frequency: 2/251,446; 1/18,394 East Asian) was predicted to cause premature termination and loss of protein function"
      explanation: Quantifies the population rarity of the allele and its East Asian enrichment.
  - name: PRDX3 c.508C>T (p.Arg170*)
    description: >-
      The most frequently reported pathogenic allele, seen homozygous in an Indian
      patient and compound heterozygous in two Korean patients and in two of the
      four Japanese patients. Reported alongside a novel p.Asp171Gly missense
      allele four base pairs away in one Korean proband.
    type: nonsense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:37731903
      reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The genetic findings identified in our study indicated that the p.Arg170Ter variant is the most frequent pathogenic hit"
      explanation: Identifies p.Arg170Ter as the most frequently recurring PRDX3 allele.
  - name: PRDX3 c.496A>T (p.Lys166*)
    description: >-
      Homozygous nonsense allele in a consanguineous family, and the report that
      first added profound hearing impairment to the PRDX3 phenotype alongside
      global developmental delay, hypotonia, dystonia and cerebellar atrophy.
    type: nonsense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:36190665
      reference_title: "A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a biallelic nonsense variant (c.496A > T; p.Lys166*) in the exon 5 of the PRDX3 gene that segregated perfectly within the family."
      explanation: Identifies the allele and its segregation in the family.
  - name: PRDX3 c.425C>G (p.Ala142Gly)
    description: >-
      Missense allele reported in compound heterozygosity with the
      p.Leu176TrpfsTer11 frameshift. Used as a comparator in the aggregation
      experiments, where it damaged mitochondria less severely than p.Asp163Glu.
    type: missense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:38837640
      reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one."
      explanation: Documents the allele in a compound-heterozygous patient.
  - name: PRDX3 c.489C>G (p.Asp163Glu)
    description: >-
      Missense allele found homozygous in the earliest-onset patient reported
      (19 months). Unlike the other alleles it produces an unstable protein that
      aggregates and activates the mitochondrial and endoplasmic-reticulum unfolded
      protein responses before being cleared, and damages mitochondria more
      severely than p.Asp202Asn or p.Ala142Gly when expressed exogenously. This
      allele is not simply a null: the published data show loss of the enzyme
      plus a gain of aggregation-driven proteostatic stress that the nonsense
      alleles do not produce, which is why the node-level
      `functional_impact_category` of LOSS_OF_FUNCTION describes the shared
      lesion rather than this allele in full.
    type: missense
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:35766882
      reference_title: "Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in PRDX3 was identified in homozygosis in the proband, and in heterozygosis in each progenitor"
      explanation: Establishes the homozygous state in the proband with heterozygous parents.
  - name: PRDX3 c.525_535del (p.Leu176TrpfsTer11)
    description: >-
      Frameshift allele reported homozygous in one patient and compound
      heterozygous with p.Ala142Gly in a second, both presenting with early-onset
      slowly progressive cerebellar syndrome.
    type: frameshift
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:38837640
      reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one."
      explanation: Documents the frameshift allele in compound heterozygosity with a known missense allele.
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration."
    explanation: Establishes PRDX3 as the causative gene across five unrelated families.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate has been published for SCAR32, so the
    qualitative ULTRA_RARE tier is used rather than a numeric Orphanet band. About
    fifteen patients had been described by mid-2024 and roughly twenty by 2026.
    The disease is not uniformly distributed: a Japanese series found four
    patients among 411 repeat-expansion-negative ataxia cases, a diagnostic yield
    in a selected cohort that is not a population rate.
  evidence:
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "15 individuals harboring pathogenic variants have been described with onset ages ranging from infancy to adulthood."
    explanation: The published case count as of 2024; graded OTHER because it is a literature tally rather than a study result.
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four unrelated Japanese patients with SCAR32 identified among 411 ataxia cases negative for repeat expansion disorders."
    explanation: Gives the numerator and denominator behind the Japanese diagnostic yield quoted in the note.
- population: Republic of Korea
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.034
  notes: >-
    0.34 patients per million, which is 0.034 per 100,000. This is the only
    published population figure for SCAR32 and it is an ALLELE-FREQUENCY-DERIVED
    ESTIMATE, not an observed rate: it is calculated from the Korean Variant
    Archive 2 frequencies of the three PRDX3 alleles identified in that study, and
    the authors express it as at least 17 expected patients nationally against a
    handful diagnosed. It therefore reflects the alleles known in 2023 and should
    be read as a lower bound on an undiagnosed population rather than a
    measurement.
  evidence:
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering the allele frequencies of the 3 identified variants reported in the KOVA2, PRDX3 disease patients are estimated to be 0.34 individuals per million (at least 17 patients in the Republic of Korea), indicating that more efforts should be made in identifying PRDX3 disease."
    explanation: The allele-frequency-derived national estimate and its stated derivation.

animal_models:
- name: prdx3 F0 crispant zebrafish
  species: Zebrafish
  genotype: prdx3 CRISPR-Cas9 F0 crispant (somatic biallelic disruption)
  publication: PMID:38837640
  description: >-
    An F0 "crispant" zebrafish generated to test prdx3 function during nervous
    system development, made because no zebrafish model of PRDX3 existed. Larvae
    show reduced burst activity on tail-coiling, reduced locomotor velocity and
    distance, increased susceptibility to oxidative stress, impaired mitochondrial
    bioenergetics, and increased apoptotic cells with raised apoptosis-associated
    transcripts.
  evidence:
  - reference: PMID:38837640
    reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate."
    explanation: Establishes the crispant as an informative in vivo model of prdx3 depletion.
  modeled_mechanisms:
  - target: Cerebellar Neuronal Oxidative Injury
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      prdx3 depletion in vivo reproduces the ROS-sensitised apoptosis and the
      motor consequence that this node asserts for human cerebellar neurons.
    limitations: >-
      Species divergence, and an F0 somatic crispant is mosaic rather than a
      germline null, so residual prdx3 is expected. The apoptosis and motor
      readouts are whole-larva measurements at 24-120 hours post fertilisation:
      nothing localises the injury to the cerebellum, and a developing larva is
      not a model of the adult-onset human presentations.
    readouts:
    - name: ROS-triggered apoptotic cell burden
      target: Cerebellar Neuronal Oxidative Injury
      direction: INCREASED
      interpretation: >-
        Acridine-orange-positive cells and apoptosis-associated transcripts both
        rise in prdx3-depleted larvae, the in vivo counterpart of the apoptotic
        sensitisation seen in PRDX3-knockdown cerebellar cells.
      evidence:
      - reference: PMID:38837640
        reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we observed a likely ROS‐triggered increment of acridine orange‐positive cells"
        explanation: The apoptosis measurement behind this readout.
    - name: Larval locomotor burst activity
      target: Cerebellar Neuronal Oxidative Injury
      direction: DECREASED
      interpretation: >-
        Reduced burst activity on the tail-coiling test is the motor output
        consequence of prdx3 depletion.
      evidence:
      - reference: PMID:38837640
        reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The tail‐coiling test results showed a significant decrease in burst activity in prdx3‐F0 animals compared with controls"
        explanation: The locomotor measurement behind this readout.
  - target: Mitochondrial Respiratory Impairment
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Oxygen-consumption studies in prdx3-depleted larvae reproduce the loss of
      respiratory capacity measured in patient fibroblasts.
    limitations: >-
      Whole-larva respirometry rather than a neuronal measurement, in a mosaic F0
      animal; and the corresponding human finding is itself inconsistent between
      patient fibroblast lines.
    readouts:
    - name: Larval maximal respiration and ATP production
      target: Mitochondrial Respiratory Impairment
      direction: DECREASED
      interpretation: >-
        Seahorse respirometry of 120-hpf larvae shows reduced ATP-linked and
        maximal respiration on prdx3 depletion.
      evidence:
      - reference: PMID:38837640
        reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "oxygen consumption rate studies revealed impaired mitochondrial bioenergetics in 120‐hpf larvae compared with controls, with significant reductions in ATP production and maximal respiration"
        explanation: The respirometry measurement behind this readout.

- name: Pan-neuronal and pan-glial Drosophila prdx3 knockdown
  species: Fruit fly
  genotype: RNAi knockdown of the PRDX3 orthologue driven pan-neuronally and pan-glially
  publication: PMID:33889951
  description: >-
    In vivo knockdown of the fly PRDX3 orthologue in neurons and in glia, used in
    the defining paper to test whether loss of the enzyme is sufficient to cause a
    locomotor phenotype and oxidative-stress vulnerability in an intact nervous
    system.
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
    explanation: Establishes that neuronal and glial loss of the orthologue is sufficient for a locomotor and oxidative-stress phenotype.
  modeled_mechanisms:
  - target: Cerebellar Neuronal Oxidative Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces the causal step from neuronal loss of the peroxiredoxin to
      locomotor failure and oxidative-stress vulnerability, but not the anatomy.
    limitations: >-
      Drosophila has no cerebellum, so the model cannot address the regional
      selectivity that is the central unexplained feature of the human disease.
      Knockdown is RNAi rather than a null allele and is driven throughout neurons
      and glia rather than in the affected population, and the locomotor readout
      is not ataxia.
    readouts:
    - name: Survival under oxidative stress challenge
      target: Cerebellar Neuronal Oxidative Injury
      direction: DECREASED
      interpretation: >-
        Shortened survival on oxidative-stress exposure is the in vivo expression
        of the lost peroxide-buffering capacity.
      evidence:
      - reference: PMID:33889951
        reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress."
        explanation: The survival measurement behind this readout.

experimental_models:
- name: SCAR32 patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary dermal fibroblasts from SCAR32 patients, the workhorse model of this
    literature and an inconsistent one. In the defining cohort they showed absent
    PRDX3, reduced glutathione peroxidase activity and reduced maximal respiratory
    capacity; in the infantile-onset patient they showed near-absent PRDX3, raised
    mitochondrial superoxide and increased sensitivity to glutathione depletion;
    but in the 2024 pair of patients they were biochemically unremarkable.
  evidence:
  - reference: PMID:33889951
    reference_title: "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity."
    explanation: The positive fibroblast result that made this the standard model for the disease.
  modeled_mechanisms:
  - target: Mitochondrial Respiratory Impairment
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      In the 2024 report the patient fibroblast line reproduced none of the
      expected biochemistry: oxygen consumption was indistinguishable from
      controls and susceptibility to oxidative stress was not increased, leading
      the authors to conclude that the relevant PRDX3 functions are not expressed
      in peripheral cells.
    limitations: >-
      This is a negative result in one laboratory's line and does not overturn
      the positive fibroblast findings of the defining cohort; genotypes differ
      between the reports. What it does establish is that a normal fibroblast
      assay cannot be used to exclude SCAR32, and that fibroblasts are an
      unreliable surrogate for the neuronal phenotype.
    readouts:
    - name: Fibroblast oxygen consumption rate
      target: Mitochondrial Respiratory Impairment
      direction: UNCHANGED
      interpretation: >-
        Seahorse respirometry of the patient line was not different from controls
        — a real negative, not a missing measurement.
      evidence:
      - reference: PMID:38837640
        reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Metabolic parameters obtained from OCR traces did not show significant changes in mitochondrial function between the patient and the controls."
        explanation: The respirometry measurement behind this negative readout.
    evidence:
    - reference: PMID:38837640
      reference_title: "SCAR32: Functional characterization and expansion of the clinical-genetic spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function"
      explanation: The authors' own statement that their fibroblast model did not reproduce the PRDX3 loss-of-function phenotype.

diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis rests on finding biallelic pathogenic PRDX3 variants, in practice by
    exome or genome sequencing after repeat-expansion testing is negative.
    Homozygosity mapping helps in consanguineous families. A noncanonical splice
    allele causing exon skipping has been reported, so RNA studies may be needed
    when only one clearly damaging allele is found. In East Asian patients the
    recurrent p.Arg207* nonsense allele is worth specific attention.
  evidence:
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four unrelated Japanese patients with SCAR32 identified among 411 ataxia cases negative for repeat expansion disorders."
    explanation: Describes the practical diagnostic route — sequencing after negative repeat-expansion testing.
- name: Brain MRI
  description: >-
    MRI is the key supporting investigation. Cerebellar atrophy is universal;
    dentate-nucleus T2 hyperintensity and cerebellar cortical T2 hyperintensity
    have been proposed as a characteristic SCAR32 signature, with variable
    involvement of the middle cerebellar peduncles, posterior pons and inferior
    olives. The atrophy can be striking relative to a mild examination.
  evidence:
  - reference: PMID:42608543
    reference_title: "Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI showed cerebellar atrophy and T2 hyperintensity in dentate nuclei in all patients, and three had cerebellar cortical T2 hyperintensity, a potentially representative feature of SCAR32."
    explanation: The imaging pattern proposed as characteristic of SCAR32.

treatments:
- name: Physiotherapy and gait/balance training
  description: >-
    The mainstay of management. No disease-modifying therapy exists, so care is
    the general progressive-ataxia package: physiotherapy, gait and balance
    training, fall reduction, and mobility aids as ambulation declines. Function
    is tracked with SARA and, in paediatric patients, with balance and gross-motor
    measures.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Progressive cerebellar ataxia
    description: >-
      Addresses the functional consequence of the cerebellar syndrome. It does
      not act on the redox lesion and does not alter the degeneration.
      `treatment_effect` is deliberately absent: `TreatmentEffectEnum` offers
      INHIBITS, ACTIVATES, MODULATES, BYPASSES and RESTORES, and none of them is
      true of a purely symptomatic rehabilitative intervention.
  notes: >-
    No published trial or case series of any intervention in SCAR32, so this
    record carries no efficacy evidence. It describes standard ataxia care as
    applied to reported patients rather than an evidence-based therapy for this
    disease.

- name: Speech and language therapy
  description: >-
    For the cerebellar dysarthria, and later for the dysphagia that most patients
    develop as the syndrome spreads rostrally.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_mechanisms:
  - target: Dysarthria
    description: >-
      Symptomatic management of the cerebellar speech disorder.
      `treatment_effect` is absent for the same reason as on the physiotherapy
      link: no value in the enum describes a symptomatic intervention.
  notes: >-
    Standard-of-care inference from the curated phenotypes, not a SCAR32-specific
    published intervention; no efficacy evidence is attached because none exists.

- name: Genetic counselling
  description: >-
    Autosomal recessive transmission means a 25 percent sibling recurrence risk
    and, for an affected person, a low risk to offspring outside consanguinity.
    Both Korean probands were compound heterozygotes in a non-consanguineous
    setting, which is the specific point the Korean report makes about diagnostic
    strategy; carrier and cascade testing follow once the familial alleles are
    known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37731903
    reference_title: "Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Particularly, both patients presented compound heterozygotes alleles highlighting the importance of consideration for compound heterozygote modes during diagnostic evaluation in nonconsanguineous populations."
    explanation: States the counselling-relevant point about compound heterozygosity in non-consanguineous families.

- name: Human chorionic gonadotropin replacement
  description: >-
    One reported patient had hypogonadotropic hormonal dysfunction with micropenis
    and received intramuscular human chorionic gonadotropin, 500 IU weekly for
    four weeks, after which testosterone rose. This treated a comorbidity found in
    a single SCAR32 patient; it is not a therapy for SCAR32, and the relationship
    of the endocrinopathy to PRDX3 deficiency is unestablished.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: chorionic gonadotropin
      term:
        id: CHEBI:81570
        label: Chorionic gonadotropin
  target_mechanisms:
  - target: Hypogonadotropic hypogonadism
    treatment_effect: RESTORES
    description: >-
      Gonadotropin replacement for the documented low FSH, LH and testosterone in
      the one patient in whom this was found.
  evidence:
  - reference: PMID:37553803
    reference_title: "Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent laboratory evaluations revealed an increase in testosterone levels to 6.42 mg/mL, while DHT levels remained unchanged at 0.01 mg/mL."
    explanation: The biochemical response to the gonadotropin course in the single treated patient.
  notes: >-
    A single-patient observation. Do not read this as a SCAR32 treatment.

differential_diagnoses:
- name: Autosomal recessive ataxia due to TXN2 deficiency
  description: >-
    The other disease of the mitochondrial thioredoxin system, and the closest
    mechanistic neighbour: like SCAR32 it causes early-onset neurodegeneration
    through increased ROS, impaired oxidative-stress defence and mitochondrial
    dysfunction, but through the thioredoxin rather than the peroxiredoxin.
  distinguishing_features:
  - Biallelic TXN2 rather than PRDX3 variants
- name: Friedreich ataxia
  description: >-
    The commonest recessive ataxia and a routine early consideration; also a
    mitochondrial, oxidative-stress-linked disease. Distinguished by the GAA
    repeat expansion in FXN, prominent sensory neuropathy and areflexia,
    cardiomyopathy and scoliosis, and by spinal cord rather than cerebellar
    cortical atrophy.
  distinguishing_features:
  - GAA repeat expansion in FXN
  - Cardiomyopathy and marked proprioceptive loss with areflexia
- name: Repeat-expansion spinocerebellar ataxias
  description: >-
    SCA1/2/3/6/7/10 and the late-onset FGF14 (SCA27B) GAA expansion are the first
    tier excluded in practice, and were negative in every SCAR32 patient reported
    from a screening cohort.
  distinguishing_features:
  - A pathogenic repeat expansion rather than biallelic PRDX3 variants
  - Usually dominant family history
- name: Other early-onset autosomal recessive cerebellar ataxias
  description: >-
    Ataxia with vitamin E deficiency, ataxia-telangiectasia, ARSACS, COQ8A ataxia
    and the recessive ataxias with cerebellar atrophy generally. Several of these
    are treatable, which is why they are excluded first.
  distinguishing_features:
  - Distinct causal genes and biochemical markers (alpha-fetoprotein, vitamin E, coenzyme Q10)

discussions:
- discussion_id: scar32_which_cerebellar_cell_population
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Cerebellar Cortical Degeneration"
  prompt: >-
    Which cerebellar cell population degenerates in SCAR32, and is the
    Purkinje cell the primary target?
  rationale: >-
    Every other recessive cerebellar ataxia curated here that declares
    conformance to the `cerebellar_purkinje_degeneration` module does so on the
    strength of neuropathology, a mouse or canine model with Purkinje-cell
    counts, or an explicit statement in the literature. SCAR32 has none of these:
    no autopsy or biopsy study of a SCAR32 patient has been published, no
    published model measures cerebellar cell populations, and the word Purkinje
    does not appear in any of the PRDX3 ataxia reports. The available human
    evidence is imaging — cerebellar cortical and vermian atrophy with dentate,
    cortical, peduncular and olivary T2 change — which localises the lesion to
    the cerebellar cortex and its connections but not to a cell type. This entry
    therefore stops at the cortex and does not declare module conformance. The
    gap matters beyond bookkeeping: the disease also involves the inferior olives
    and brainstem, and if the primary lesion were olivary or afferent rather than
    Purkinje-intrinsic, the shared Purkinje module would be the wrong causal
    story for it.
  proposed_experiments:
  - experiment_id: exp_scar32_cerebellar_histopathology
    name: Cerebellar histopathology of a SCAR32 brain
    description: >-
      Quantitative Purkinje-cell, granule-cell and dentate-neuron counts with
      calbindin immunostaining on post-mortem cerebellum from a genetically
      confirmed SCAR32 patient, compared with age-matched controls.
    would_support:
    - "pathophysiology#Cerebellar Cortical Degeneration"
    supporting_outcome:
    - >-
      Selective loss of Purkinje neurons with relative preservation of granule
      cells would localise the degeneration to the Purkinje cell and justify
      declaring conformance to the shared module.
    refuting_outcome:
    - >-
      Preserved Purkinje-cell counts with granule-cell or olivary loss would
      show that the shared Purkinje module is the wrong mechanism for SCAR32.
  - experiment_id: exp_scar32_cell_type_resolved_deletion
    name: Cell-type-resolved prdx3 loss in a cerebellum-bearing model
    description: >-
      Conditional Prdx3 deletion in mouse restricted to Purkinje cells versus to
      granule cells versus to inferior olivary neurons, with motor phenotyping
      and cerebellar histology.
    would_support:
    - "pathophysiology#Cerebellar Neuronal Oxidative Injury"
    supporting_outcome:
    - >-
      Ataxia and cerebellar degeneration following Purkinje-restricted deletion
      but not the other two would establish Purkinje-cell autonomy of the lesion.

- discussion_id: scar32_age_at_onset_unexplained
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "genetic#PRDX3"
  prompt: >-
    Why does the same class of loss-of-function PRDX3 allele produce onset at 19
    months in one patient and at 35 years in another?
  rationale: >-
    Age at onset in SCAR32 spans birth to the mid-thirties across roughly twenty
    patients, and the spread is not explained by allele class: nonsense and
    missense alleles both appear at both ends. Two partial explanations have been
    offered and neither is established. The first is positional — variants in the
    later part of the thioredoxin domain, near the catalytic CXXC motifs, have
    been observed in the earlier-onset patients. The second is compensatory —
    PRDX5 and glutathione peroxidase are co-regulated with PRDX3, so a residual
    hypomorphic allele such as p.Gly180Ser paired with a null might be buffered
    well enough to delay onset by decades. A third, allele-specific mechanism is
    documented for p.Asp163Glu, where aggregation and unfolded-protein-response
    activation add an insult the null alleles do not carry. Distinguishing these
    matters for counselling, because it determines whether a genotype predicts
    anything about age at onset.
  proposed_experiments:
  - experiment_id: exp_scar32_allele_activity_panel
    name: Residual-activity and compensation panel across reported PRDX3 alleles
    description: >-
      Express each reported PRDX3 allele in a PRDX3-null cell background and
      measure protein abundance, thioredoxin-dependent peroxidase activity,
      aggregation propensity, and PRDX5/GPX1 compensatory induction, then test
      those measures against the reported age at onset for each allele.
    would_support:
    - "pathophysiology#PRDX3 Loss of Function"
    supporting_outcome:
    - >-
      A monotonic relationship between residual peroxidase activity (or the
      degree of compensatory induction) and age at onset would establish a
      genotype-phenotype rule for the disease.
    refuting_outcome:
    - >-
      No relationship between any biochemical measure and age at onset would
      point the explanation away from the allele and towards modifiers or
      environment.

- discussion_id: scar32_antioxidant_therapy_lead
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Mitochondrial Hydrogen Peroxide Accumulation"
  - "treatments#"
  prompt: >-
    Would an antioxidant or thioredoxin-system-directed drug change the course of
    SCAR32?
  rationale: >-
    The mechanism invites the question and nothing answers it. The defining paper
    ends by saying its findings suggest targets for future therapeutic approaches;
    the only concrete datum is one patient with biallelic TXN2 variants — the
    partner disease of the same mitochondrial thioredoxin system, whose product
    recycles oxidised PRDX3 — who improved clinically on idebenone. That is a
    single case in a different gene, and idebenone's action is on electron
    transport rather than on peroxide scavenging, so the inference to PRDX3
    disease is two steps long. It is recorded as a lead precisely so that it is
    not mistaken for a treatment: no SCAR32 patient has been given idebenone or
    any other antioxidant in a published report, and the entry's `treatments`
    block deliberately contains no such entry.
  proposed_experiments:
  - experiment_id: exp_scar32_antioxidant_rescue_panel
    name: Antioxidant rescue in PRDX3-deficient cerebellar and in vivo models
    description: >-
      Test mitochondria-targeted peroxide scavengers and thioredoxin-system
      agents, including idebenone as the clinically available comparator, against
      the established PRDX3-loss readouts: hydrogen peroxide accumulation and
      apoptotic sensitisation in PRDX3-depleted cerebellar cells, and locomotor
      output and oxidative-stress survival in the prdx3 zebrafish crispant and the
      Drosophila knockdown.
    would_support:
    - "pathophysiology#Mitochondrial Hydrogen Peroxide Accumulation"
    supporting_outcome:
    - >-
      Rescue of the peroxide and apoptosis readouts with a corresponding
      improvement in the in vivo locomotor phenotype would justify a first
      clinical trial and identify which arm of the redox system to target.
    refuting_outcome:
    - >-
      Correction of the peroxide readout without any improvement in the locomotor
      or survival phenotype would indicate that the neuronal injury is not
      reversible by scavenging alone and would redirect effort towards the
      proteostatic arm.

notes: >-
  Curation decisions worth knowing about.

  Frequency bands are used only where a source states the denominator. Cerebellar
  atrophy and progressive cerebellar ataxia are banded OBLIGATE because the
  literature says explicitly that atrophy is ubiquitous and because ataxia is the
  defining feature. Everything else — neuropathy, hearing loss, dystonia,
  cognitive impairment, endocrine findings — is left with no band, because the
  published patients are scattered across single-case reports and small series
  with no pooled denominator, and two of these features are explicitly recorded as
  absent in other patients.

  The Japanese figure of 0.97% is a diagnostic yield in a selected cohort of
  repeat-expansion-negative ataxia patients, not a population prevalence, and is
  deliberately kept out of the `prevalence` block for that reason; it is recorded
  against the p.Arg207* allele and in the prevalence note instead.

  The OMIM identity is quoted two different ways in the literature. MONDO's exact
  match for `MONDO:0859245` is OMIM 619862, and the Korean report gives
  `[SCAR32; Online Mendelian Inheritance in Man (OMIM) #619862]`; the 2025
  Chinese case report writes `#619648` instead, which appears to be a typographic
  error. 619862 is used here. There is no `omim_mappings` slot in this schema, so
  this is recorded as a note rather than as a structured mapping.

  Four alleles reported in the literature are NOT promoted to structured
  `variants` records: c.340dupG (p.Ala114Glyfs*3), c.43C>T (p.Arg15*), c.658C>T
  (p.Gln220*) and the splice alleles c.37-2A>G and c.311+5G>T. They appear only
  inside a whitespace-collapsed summary table in the cached full text of
  PMID:41351775, from which no quotable propositional snippet can be extracted,
  and their primary reports are either uncited here or have unavailable caches.
  Curating them would mean asserting genotypes with no verifiable evidence item.

  HPO carries per-feature frequencies for OMIM:619862 as n/5 fractions over the
  founding cohort — hypermetric saccades, saccadic pursuit and dysphagia at 4/5,
  and abnormal nerve conduction velocity and somatic sensory dysfunction at 0/5.
  Those are not used as `frequency` bands here, because the cohort paper is
  abstract-only in the reference cache and none of those counts can be quoted or
  verified against it. The 0/5 entries are the more interesting half — they are
  the evidence that this is a cerebellar rather than a genuinely spinocerebellar
  ataxia despite the name — and the same point is carried instead by the curated
  NO_EVIDENCE items and by the peripheral-neuropathy note.

  Two cited papers carry no evidence item because their reference caches are
  `content_type: unavailable`, so nothing in them can be quoted or verified:
  `Exon Skipping Caused by Noncanonical Splicing Mutation in PRDX3-Related
  Spinocerebellar Ataxia` (PMID:37553955), kept in the reference list so the
  splice-allele class is not invisible, and `Expanding PRDX3 disease: broad range
  of onset age and infratentorial MRI signal changes` (PMID:35792670), the
  >3,500-exome screen that first stretched the onset range and that later reports
  cite for it.

  Not curated: `biochemical`, because no laboratory marker of SCAR32 has been
  described. The two laboratory abnormalities in the literature - the thyroid
  autoantibody titres and the low selenium in one Chinese patient - are curated as
  phenotypes rather than as biomarkers, because a single patient does not
  establish either as a marker OF the disease, and the research assays (glutathione
  peroxidase activity, mitochondrial superoxide, respirometry) belong to the
  experimental models that measured them;
  `progression`, because no staged natural-history study exists and the
  onset-to-severity relationship is exactly what the second open discussion says
  is unexplained; `clinical_trials` and `datasets`, because there are none.
📚

References & Deep Research

References

10
PMID:33889951
Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.
No top-level findings curated for this source.
PMID:35766882
Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3.
No top-level findings curated for this source.
PMID:36190665
A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia.
No top-level findings curated for this source.
PMID:37553803
Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn.
No top-level findings curated for this source.
PMID:37553955
Exon Skipping Caused by Noncanonical Splicing Mutation in PRDX3-Related Spinocerebellar Ataxia.
No top-level findings curated for this source.
PMID:35792670
Expanding PRDX3 disease: broad range of onset age and infratentorial MRI signal changes.
No top-level findings curated for this source.
PMID:37731903
Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases.
No top-level findings curated for this source.
PMID:38837640
SCAR32: Functional characterization and expansion of the clinical-genetic spectrum.
No top-level findings curated for this source.
PMID:41351775
A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32.
No top-level findings curated for this source.
PMID:42608543
Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 18 citations 2026-09-02T10:40:32.709077

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Spinocerebellar ataxia, autosomal recessive 32 (SCAR32), caused by biallelic variants in PRDX3 encoding mitochondrial peroxiredoxin 3, the thioredoxin-dependent peroxidase that clears mitochondrial matrix hydrogen peroxide
  • MONDO ID: MONDO:0859245 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Spinocerebellar ataxia, autosomal recessive 32 (SCAR32), caused by biallelic variants in PRDX3 encoding mitochondrial peroxiredoxin 3, the thioredoxin-dependent peroxidase that clears mitochondrial matrix hydrogen peroxide covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

SCAR32 / PRDX3-related cerebellar ataxia: disease-characteristics report

Executive summary

Spinocerebellar ataxia, autosomal recessive 32 (SCAR32) is an ultra-rare Mendelian neurologic disorder caused by biallelic germline variants in PRDX3, which encodes the mitochondrial-matrix antioxidant enzyme peroxiredoxin 3. The replicated phenotype is cerebellar ataxia with cerebellar atrophy, but onset ranges from infancy to adulthood and the broader spectrum includes ocular-motor abnormalities, tremor or myoclonus, hypokinetic features, neuropathy, dysphagia, and cognitive or behavioral manifestations. Evidence remains based on small case series and individual patients rather than population cohorts. No disease-specific prevalence, survival estimate, validated biomarker, treatment guideline, or interventional trial is available. The best-supported mechanism is failure of the PRDX3–TXN2 peroxide-detoxification system, followed by mitochondrial oxidative stress, impaired bioenergetics and proteostasis, and increased neuronal vulnerability. Open Targets lists a replicated PRDX3–SCAR32 association based on five evidence records and identifies MONDO:0859245 and ENSG00000165672. (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3, rebelo2021bialleliclossoffunctionvariations pages 1-2)

Domain High-confidence finding Evidence type/strength Suggested ontology terms Key source/date/DOI/PMID if known
Disease identity Spinocerebellar ataxia, autosomal recessive 32 (SCAR32) is a rare PRDX3-related cerebellar ataxia/neurodegenerative disorder. MONDO records the entity as MONDO:0859245. Published reports use inconsistent OMIM numbers (#619862 and #619648), so the current OMIM record should be verified directly before database ingestion. Strong disease-level genetic association; replicated human families MONDO:0859245; cerebellar ataxia; autosomal recessive inheritance Open Targets association (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3); Rebelo et al., 2021, DOI: 10.1093/brain/awab071, PMID: 33889951 (rebelo2021bialleliclossoffunctionvariations pages 1-2)
Causal gene and inheritance Biallelic germline variants in PRDX3 cause disease; unaffected parents commonly carry one variant. PRDX3 is Ensembl ENSG00000165672 and encodes mitochondrial peroxiredoxin 3. Strong human segregation plus functional evidence; autosomal recessive PRDX3; ENSG00000165672; loss of function; germline variant Five simplex families in the discovery study and later independent cases (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3, rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)
Core motor phenotype Gait and limb ataxia, dysmetria and cerebellar dysarthria constitute the core syndrome. Severity is variable and usually mild-to-moderate but may be severe in infantile disease; SARA scores reported include 7/40, 10/40, 19/40 and, in the original adult series, 8.5–21.5. Strong but small human case series; exact pooled frequencies remain unreliable HP:0001251 Ataxia; HP:0002072 Chorea is not core and should not be assigned routinely; cerebellar dysarthria; dysmetria; unsteady gait Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 6-7); Martínez-Rubio et al., 2022, DOI: 10.1093/hmg/ddac146, PMID: 35766882 (martinezrubio2022proteinmisfoldingand pages 1-2); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3)
Onset and course Reported onset extends from infancy/birth to approximately 35 years. Most cases show chronic, slowly progressive ataxia; the p.Asp163Glu case began acutely at 19 months, progressed rapidly initially, and then remained comparatively stable from ages 4–6.5 years. Moderate human evidence; heterogeneous alleles and short follow-up HP:0003593 Infantile onset; HP:0011463 Childhood onset; HP:0003581 Adult onset; progressive neurologic deterioration Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2); comparative case summary (yang2025ahomozygousprdx3 pages 4-5)
Oculomotor and movement findings Gaze-evoked nystagmus, saccadic pursuit, hypermetric or slow saccades and ophthalmoplegia occur variably. Myoclonus, postural tremor, cervical dystonia, bradykinesia, hypomimia, rigidity and global hypokinesia expand the movement-disorder spectrum. Moderate human evidence; variable and not universal HP:0000639 Nystagmus; abnormal ocular motility; ophthalmoplegia; myoclonus; tremor; dystonia; bradykinesia; rigidity Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 6-7); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3)
Additional neurologic phenotype Dysphagia, peripheral motor-sensory neuropathy, learning difficulty, cognitive/academic decline, mood or behavioral disturbance and occasional hearing impairment have been reported. Cognition can remain normal. Limited-to-moderate human evidence; mostly individual observations HP:0002015 Dysphagia; HP:0009830 Peripheral neuropathy; learning disability; mild cognitive impairment; behavioral abnormality; hearing impairment Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3, naef2024scar32functionalcharacterization pages 3-5); comparative cases (yang2025ahomozygousprdx3 pages 4-5)
MRI and anatomy Cerebellar atrophy is the defining imaging abnormality and was universal in the later comparative case table. Severe early atrophy, vermian involvement, cerebellar cortical or middle-cerebellar-peduncle T2 hyperintensity, and occasional olivary, brainstem or mild parietal degeneration are described. Strong human imaging evidence for cerebellar atrophy; ancillary findings less consistent HP:0001272 Cerebellar atrophy; cerebellar vermis; cerebellar cortex; middle cerebellar peduncle; brainstem; inferior olivary nucleus; UBERON terms should be verified before ingestion Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 6-7); Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3)
Pathogenic-variant spectrum Reported variants include nonsense, frameshift, splice-altering and missense alleles. Examples include c.340dupG (p.Ala114GlyfsTer3), c.425C>G (p.Ala142Gly), c.489C>G (p.Asp163Glu), c.525_535del (p.Leu176TrpfsTer11), c.604G>A (p.Asp202Asn), and c.619C>T (p.Arg207Ter). Classification must be performed per allele rather than assuming every published missense allele is pathogenic. Strong for segregating truncating alleles; moderate and functional-data-dependent for missense alleles Sequence variant; frameshift variant; stop-gained variant; missense variant; splice-region variant Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 6-7, rebelo2021bialleliclossoffunctionvariations pages 14-15); Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3); Yang et al., 2025 (yang2025ahomozygousprdx3 pages 1-2)
Population frequency and founder effects Causal alleles are rare. Naef et al. reported p.Ala142Gly below 0.01% in gnomAD; Yang et al. reported p.Arg207Ter in 2/251,446 alleles overall and 1/18,394 East Asian alleles. Recurrence of p.Asp202Asn across ancestries is documented, but a founder effect has not been established. Limited population-database evidence; no validated carrier-frequency estimate Rare variant; carrier state; founder effect—not established Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3); Yang et al., 2025 (yang2025ahomozygousprdx3 pages 1-2, yang2025ahomozygousprdx3 pages 4-5)
Molecular mechanism PRDX3 is a mitochondrial matrix, thioredoxin-dependent peroxidase that reduces hydrogen peroxide; oxidized PRDX3 is regenerated by TXN2. Biallelic damaging variants can cause absent or unstable protein, weakening mitochondrial peroxide detoxification. Strong biochemical knowledge plus patient-fibroblast evidence GO:0005739 mitochondrion; mitochondrial matrix; hydrogen peroxide catabolic process; cellular oxidant detoxification; peroxidase activity; thioredoxin-dependent peroxiredoxin activity Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15, rebelo2021bialleliclossoffunctionvariations pages 2-3)
Downstream pathophysiology Deficient PRDX3 leads to increased mitochondrial H2O2/ROS and can result in reduced maximal respiration or respiratory reserve, mitochondrial membrane/cristae injury, protein instability or aggregation, unfolded-protein responses and greater apoptosis susceptibility. Selective cerebellar-neuronal degeneration then produces ataxia; the final cell-type-selectivity step is inferred, not demonstrated in human neuropathology. Mixed: human fibroblasts support protein loss and redox/bioenergetic abnormalities; structural injury, neuronal degeneration and apoptosis rely substantially on cell and animal models GO:0006979 response to oxidative stress; mitochondrial organization; cellular respiration; protein folding; response to unfolded protein; intrinsic apoptotic signaling; Purkinje cell and cerebellar neuron CL terms should be verified Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15); Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2)
Functional-assay heterogeneity Fibroblasts in the original and p.Asp163Glu studies showed PRDX3 depletion, oxidative-stress abnormalities and/or impaired respiration. In contrast, fibroblasts from a 2024 patient showed normal respiration and ROS responses despite reduced PRDX3 transcript, indicating that fibroblast assays are allele-, protocol- or tissue-dependent and are not validated diagnostic biomarkers. Direct but discordant human-cell evidence Skin fibroblast; oxygen-consumption rate; reactive oxygen species; mitochondrial respiratory capacity Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2); Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 3-5)
Diagnostic approach Diagnosis requires a compatible cerebellar syndrome/MRI plus identification of pathogenic or likely pathogenic biallelic PRDX3 variants in trans. Ataxia panels or WES are practical first-line approaches; WGS or RNA studies may resolve structural, intronic or splice-altering alleles. Segregation and allele-specific functional studies are especially important for missense or splice-region VUS. Strong genomic-diagnostic rationale; no SCAR32-specific consensus guideline Genetic testing; WES; WGS; multigene panel; RNA sequencing; segregation analysis Trio exome sequencing identified recent cases after exclusion of common dominant and recessive ataxias (naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)
Ancillary testing and differential diagnosis Brain MRI, SARA, ocular-motor examination, neuropsychology, swallowing assessment and nerve-conduction studies characterize extent and progression. Routine biochemical, neurometabolic and conduction studies may be normal. Differential diagnosis includes other recessive/mitochondrial ataxias and repeat-expansion disorders; PRDX3 sequencing does not replace repeat-expansion testing. Moderate clinical-practice inference; individual-case support Magnetic resonance imaging; SARA; nerve-conduction study; neuropsychological assessment; swallowing evaluation Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 6-7); Naef et al., 2024 (naef2024scar32functionalcharacterization pages 2-3)
Epidemiology Prevalence, incidence, sex ratio and population carrier frequency are unavailable. Published evidence consists of very small, geographically diverse families; therefore case proportions must not be treated as population frequencies. Major evidence gap Rare disease; prevalence unknown; incidence unknown Five unrelated discovery families plus subsequent isolated cases (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 1-2, yang2025ahomozygousprdx3 pages 4-5)
Prognosis and quality of life The disease is lifelong and commonly progressive, with mobility, falls, speech, swallowing, school/work and psychosocial consequences. Formal survival, mortality, life-expectancy, EQ-5D, SF-36 and validated SCAR32-specific natural-history data are unavailable. Some affected adults retain moderate function, while infantile disease may require assisted walking. Limited longitudinal human evidence; no survival or formal QoL cohort Mobility impairment; fall risk; speech impairment; activity limitation; quality of life—data unavailable Adult severity data (rebelo2021bialleliclossoffunctionvariations pages 6-7); infantile follow-up (martinezrubio2022proteinmisfoldingand pages 2-2); 2024 cases (naef2024scar32functionalcharacterization pages 2-3)
Treatment No approved disease-modifying treatment and no PRDX3/SCAR32-specific interventional trial were identified. Physical, occupational and speech/swallowing therapy; fall prevention; mobility aids; educational and psychosocial support; and symptom-directed management are reasonable supportive interventions. Antioxidants, ferroptosis modifiers and PRDX3 gene replacement remain experimental hypotheses, without demonstrated SCAR32 clinical efficacy. Supportive-care extrapolation; disease-modifying evidence unavailable Physical therapy; occupational therapy; speech therapy; rehabilitation; assistive device; genetic therapy—experimental; NCIT identifiers should be verified Mechanistic studies identify potential targets but do not establish treatment efficacy (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15, yang2025ahomozygousprdx3 pages 4-5)
Prevention and counseling Acquired primary prevention is not applicable to a Mendelian disorder. Genetic counseling, parental testing, cascade carrier testing, and—when familial pathogenic variants are known—prenatal or preimplantation genetic testing can prevent recurrence or enable informed reproductive decisions. Each pregnancy of two heterozygous parents has the standard autosomal-recessive 25% affected, 50% carrier and 25% unaffected/non-carrier probabilities. High-confidence Mendelian inference Genetic counseling; carrier testing; cascade screening; prenatal diagnosis; preimplantation genetic testing Segregation in multiple families supports recessive counseling (yang2025ahomozygousprdx3 pages 1-2, naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)
Drosophila model Pan-neuronal or pan-glial Prdx3 depletion causes abnormal locomotion and reduced survival, especially under oxidative stress; brain degeneration has also been described. This supports redox-sensitive neural vulnerability but does not reproduce the complete human phenotype. Moderate model-organism evidence; inferred relevance to humans NCBI Taxon:7227; locomotory behavior; response to oxidative stress; neuron; glial cell Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15)
Zebrafish model CRISPR/Cas9 prdx3 F0 crispants show reduced touch/burst responses, swim distance and velocity, impaired ATP production/maximal respiration, and increased oxidative-stress-associated apoptosis. Mosaic F0 knockdown and early developmental assays limit direct natural-history translation. Moderate model-organism evidence; inferred disease mechanism NCBI Taxon:7955; locomotory behavior; mitochondrial respiration; ATP metabolic process; apoptotic process Naef et al., 2024 (naef2024scar32functionalcharacterization pages 3-5)
Mouse and cellular models Prdx3-deficient mice show reduced strength, reduced skeletal-muscle mitochondrial DNA copy number and oxidative-stress-associated hippocampal cell loss. PRDX3 knockdown in cerebellar medulloblastoma cells increases H2O2, reduces viability and sensitizes cells to ROS-triggered apoptosis; mutant expression in primary mouse neurons disrupts neurites and mitochondria. These are mechanistic models, not proof of human Purkinje-cell pathology. Moderate preclinical evidence; inferred relevance to SCAR32 NCBI Taxon:10090; neuron; mitochondrial DNA maintenance; cell death; neurite morphology; oxidative stress Rebelo et al., 2021 (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15); Martínez-Rubio et al., 2022 (martinezrubio2022proteinmisfoldingand pages 2-2, martinezrubio2022proteinmisfoldingand pages 1-2)
Other species/natural disease No naturally occurring PRDX3-associated veterinary SCAR32 analogue or zoonotic/transmissible component was identified. Experimental models should not be entered as natural animal disease. Data unavailable/not applicable Natural disease—not established; zoonosis—not applicable Available evidence describes induced laboratory models only (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 3-5, rebelo2021bialleliclossoffunctionvariations pages 14-15)

Table: Compact evidence map for PRDX3-related SCAR32, separating replicated human findings from model-based inference and major knowledge gaps. Ontology labels are suggested conservatively, with uncertain identifiers explicitly left for verification.

1. Disease information

Definition. SCAR32 is an autosomal-recessive cerebellar ataxia/neurodegenerative disorder produced by biallelic damaging variants in PRDX3. The discovery study identified affected individuals in five unrelated families and described “mild-to-moderate progressive cerebellar ataxia,” movement disorders, severe early cerebellar atrophy, and occasional olivary or brainstem degeneration. (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 2-3)

Identifiers and synonyms. The preferred ontology identifier is MONDO:0859245. Synonyms include spinocerebellar ataxia, autosomal recessive 32, SCAR32, PRDX3-related cerebellar ataxia, and PRDX3-associated neurodegeneration/PRAN. Open Targets maps the disease to PRDX3, Ensembl ENSG00000165672. Retrieved publications inconsistently cite OMIM #619862 and #619648; consequently, the live OMIM entry should be checked before knowledge-base ingestion. No disease-specific ICD-10, ICD-11, or MeSH code was established in the retrieved literature; broader hereditary/cerebellar ataxia coding is required. (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3, yang2025ahomozygousprdx3 pages 1-2, naef2024scar32functionalcharacterization pages 1-2)

The evidence is principally aggregated disease-level literature derived from individually described patients and families, not EHR-scale or registry-derived data.

2. Etiology, risk, protection, and environment

The cause is genetic: pathogenic or likely pathogenic biallelic germline PRDX3 variants inherited in an autosomal-recessive pattern. Truncating, frameshift, splice-altering, and functionally damaging missense alleles have been reported. Heterozygous parents and siblings are generally clinically unaffected carriers. (naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2, yang2025ahomozygousprdx3 pages 4-5)

There are no validated susceptibility loci, modifier genes, protective alleles, environmental causes, infectious triggers, or lifestyle risk factors. Consanguinity increases the probability that both parents carry the same rare allele but is not required: compound-heterozygous disease occurred in a patient born to unrelated parents. Oxidative exposure worsens phenotypes in experimental systems, suggesting that cellular redox load can modify disease expression; this is a model-based gene–environment inference, not a demonstrated human exposure association. (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 2-3, rebelo2021bialleliclossoffunctionvariations pages 14-15)

No diet, antioxidant, exercise regimen, or avoidance strategy has been shown to prevent onset. Ordinary health-promoting behaviors may support general function but should not be represented as SCAR32-specific protective factors.

3. Phenotypes

The small and incompletely ascertained cohort precludes reliable percentages. A later comparative table described gait ataxia, limb ataxia, and cerebellar atrophy across all tabulated cases, but this is a published-case proportion subject to ascertainment bias—not a population frequency. (yang2025ahomozygousprdx3 pages 4-5)

  • Core cerebellar syndrome: gait/truncal ataxia, wide-based gait, limb dysmetria/ataxia, impaired finger-to-nose testing, dysarthria, falls, and loss of independent mobility. Suggested terms include HP:0001251 Ataxia, cerebellar dysarthria, dysmetria, unsteady gait, and frequent falls. Adult SARA scores in the original series ranged from 8.5–21.5; later patients scored 7/40 and 10/40, while the infantile case stabilized at 19/40 at ages five and 6.5 years. (rebelo2021bialleliclossoffunctionvariations pages 6-7, martinezrubio2022proteinmisfoldingand pages 1-2, naef2024scar32functionalcharacterization pages 2-3)
  • Ocular motor findings: gaze-evoked nystagmus, saccadic pursuit, hypermetric or slow saccades, and ophthalmoplegia. Suggested terms: HP:0000639 Nystagmus, abnormal saccadic eye movements, and ophthalmoplegia. (rebelo2021bialleliclossoffunctionvariations pages 6-7, naef2024scar32functionalcharacterization pages 2-3)
  • Other movement abnormalities: postural tremor, myoclonus, cervical dystonia, bradykinesia, hypomimia, rigidity, and global hypokinesia occur variably. These are associated features rather than diagnostic requirements. (rebelo2021bialleliclossoffunctionvariations pages 6-7, naef2024scar32functionalcharacterization pages 2-3)
  • Neuropathy: the severe infantile p.Asp163Glu case developed lower-limb-predominant motor-sensory neuropathy; nerve-conduction studies were initially normal at 19 months and became moderately abnormal later. Suggested term: peripheral sensorimotor neuropathy. (martinezrubio2022proteinmisfoldingand pages 2-2)
  • Neurodevelopmental/psychiatric: learning or language delay, academic decline, mild cognitive impairment, introversion/social isolation, and mood disorder have been reported, although other patients had normal cognition. A 2025 patient had WISC-IV full-scale IQ 74, perceptual reasoning 60, and processing speed 71. (yang2025ahomozygousprdx3 pages 1-2, naef2024scar32functionalcharacterization pages 2-3, naef2024scar32functionalcharacterization pages 3-5)
  • Additional findings: dysphagia, ptosis, exercise intolerance, and occasional hearing impairment have been described. Thyroid enlargement, thyroid autoantibodies, and low selenium occurred in one 2025 patient but are not established components of SCAR32. (yang2025ahomozygousprdx3 pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 6-7, yang2025ahomozygousprdx3 pages 4-5)

Quality-of-life effects likely include impaired ambulation, falls, communication and swallowing difficulties, reduced school/work participation, and psychosocial burden. No SCAR32 cohort has reported EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life measurements.

4. Genetic and molecular information

Gene. PRDX3 encodes mitochondrial peroxiredoxin 3, the organelle-specific, thioredoxin-dependent peroxide scavenger. Reported pathogenic mechanisms are predominantly loss of protein abundance or function. The disease variants are constitutional/germline; somatic causation has not been reported. (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 2-3)

Representative alleles include:

  • c.340dupG (p.Ala114GlyfsTer3)—frameshift;
  • c.425C>G (p.Ala142Gly)—missense, reported at below 0.01% in gnomAD and classified as a VUS in the 2024 study; interpretation depended on its occurrence in trans with a likely pathogenic frameshift and functional/phenotypic evidence;
  • c.489C>G (p.Asp163Glu)—homozygous missense causing protein instability/aggregation in experimental assays;
  • c.525_535delGTTAGAAGGTT (p.Leu176TrpfsTer11)—novel frameshift, homozygous or in trans with p.Ala142Gly;
  • c.604G>A (p.Asp202Asn)—recurrent homozygous missense allele at the dimer interface, associated with marked protein depletion;
  • c.619C>T (p.Arg207Ter)—homozygous nonsense allele, ACMG pathogenic in the 2025 report; observed in 2/251,446 gnomAD alleles overall and 1/18,394 East Asian alleles. (yang2025ahomozygousprdx3 pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 6-7, rebelo2021bialleliclossoffunctionvariations pages 14-15, naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)

Other published alleles include p.Arg170Ter, p.Gln220Ter, p.Lys166Ter, early frameshift/nonsense alleles, and splice-site changes. HGVS should be normalized against NM_006793.5 before ingestion because typographical inconsistencies appear in secondary tables. Variant classification must be allele-specific; publication as a disease candidate does not automatically establish ACMG pathogenicity. (yang2025ahomozygousprdx3 pages 4-5)

No validated modifier gene, epigenetic signature, recurrent copy-number abnormality, translocation, or other chromosomal lesion is known. No disease-specific methylomic, histone, single-cell, or spatial-omics dataset was identified.

5. Environmental information

No toxin, radiation, pollution, occupational exposure, smoking, alcohol, diet, exercise pattern, or infectious agent is known to cause SCAR32. Experimental oxidative challenge increases cellular, fly, and zebrafish vulnerability, but clinical avoidance thresholds and human exposure-response data do not exist. The disorder is neither infectious nor transmissible. (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 3-5)

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic damaging PRDX3 variants lead to absent, unstable, misfolded, or functionally impaired mitochondrial PRDX3 protein. (rebelo2021bialleliclossoffunctionvariations pages 14-15, martinezrubio2022proteinmisfoldingand pages 2-2)
  2. Reduced PRDX3 activity leads to impaired TXN2-dependent reduction of mitochondrial-matrix hydrogen peroxide to water. (rebelo2021bialleliclossoffunctionvariations pages 14-15, rebelo2021bialleliclossoffunctionvariations pages 2-3)
  3. Impaired peroxide clearance leads to increased mitochondrial H₂O₂/ROS and reduced oxidative-stress resilience. (rebelo2021bialleliclossoffunctionvariations pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2)
  4. Redox imbalance leads to mitochondrial membrane-potential, morphology, cristae, and respiratory abnormalities; patient fibroblasts demonstrated reduced maximal respiratory capacity in the discovery cohort, although a 2024 fibroblast line had normal respiration and ROS responses. (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 3-5)
  5. A mechanistic branch leads to protein instability/aggregation and mitochondrial plus ER unfolded-protein responses, demonstrated particularly for p.Asp163Glu in cell systems. (martinezrubio2022proteinmisfoldingand pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2)
  6. A second branch leads to reduced ATP production/respiratory reserve and increased ROS-triggered apoptosis, demonstrated in cerebellar cells and zebrafish. (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 3-5)
  7. These disturbances are inferred to lead to selective vulnerability and dysfunction/loss of cerebellar neurons—probably including Purkinje-system circuitry—plus occasional brainstem, olivary, peripheral-nerve, or broader CNS involvement. Direct human neuropathologic proof of the responsible cell population is lacking.
  8. Cerebellar circuit degeneration leads to ataxia, dysmetria, dysarthria, ocular-motor abnormalities, tremor, falls, and progressive disability. (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 6-7)

Relevant annotations include GO:0005739 mitochondrion, mitochondrial matrix, hydrogen-peroxide catabolic process, cellular oxidant detoxification, peroxidase activity, response to oxidative stress (GO:0006979), cellular respiration, mitochondrial organization, response to unfolded protein, and intrinsic apoptotic signaling. Candidate cell terms are cerebellar neuron, Purkinje neuron, neuron, astrocyte/glial cell, peripheral motor neuron, and sensory neuron; Purkinje-cell involvement should be flagged as biologically plausible rather than directly established in human tissue.

No canonical Wnt, PI3K–AKT, mTOR, or MAPK cascade has been established as the primary SCAR32 pathway. Ferroptosis and cystine-uptake effects have been proposed from broader PRDX3 cell biology, but are not demonstrated in patient nervous tissue. (yang2025ahomozygousprdx3 pages 4-5)

7. Anatomical structures affected

The central nervous system, especially the cerebellum, is primary. MRI demonstrates diffuse or vermian cerebellar atrophy; reported secondary sites include the cerebellar cortex, middle cerebellar peduncles, inferior olives, brainstem, and occasionally parietal regions. Peripheral nerves are involved in some severe cases. Changes are generally bilateral/diffuse rather than unilateral. Suggested anatomy terms include cerebellum, cerebellar vermis, cerebellar cortex, middle cerebellar peduncle, brainstem, inferior olivary nucleus, and peripheral nerve; exact UBERON identifiers should be validated before import. (rebelo2021bialleliclossoffunctionvariations pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2, naef2024scar32functionalcharacterization pages 2-3)

The relevant subcellular site is the mitochondrial matrix, with downstream effects on mitochondrial membranes and cristae. No human biopsy has established a definitive cell-selective histopathologic lesion; one original patient’s muscle biopsy showed some COX-negative fibers. (rebelo2021bialleliclossoffunctionvariations pages 6-7, martinezrubio2022proteinmisfoldingand pages 2-2)

8. Temporal development

Onset ranges from birth/infancy to approximately 35 years; earlier literature suggested a median near 21 years, but this estimate predates recognition of severe pediatric disease. Typical onset is insidious and chronic, followed by slow progression. The p.Asp163Glu patient was atypical: acute gait ataxia at 19 months, rapid development of cerebellar syndrome and atrophy, then relative stability between ages four and 6.5 years. (martinezrubio2022proteinmisfoldingand pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2, yang2025ahomozygousprdx3 pages 4-5)

There is no validated staging system. Pragmatic stages are: early imbalance/ocular-motor or school difficulties; intermediate established limb and gait ataxia with falls; and advanced mobility, speech, swallowing, or neuropathic disability. The disease is lifelong. Spontaneous remission has not been demonstrated, although plateaus can occur. No critical therapeutic window has been defined; early genetic diagnosis is nevertheless important for rehabilitation, monitoring, and counseling.

9. Inheritance and population

Inheritance is autosomal recessive. When both parents are heterozygous carriers, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier, and 25% probability of an unaffected non-carrier. Penetrance for confirmed biallelic pathogenic loss-of-function genotypes appears high in reported families, but cannot be estimated formally; expressivity and age at onset are clearly variable. Anticipation is not expected because this is not a repeat-expansion disease. Germline mosaicism has not been documented. (yang2025ahomozygousprdx3 pages 1-2, naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)

Prevalence, incidence, carrier frequency, sex ratio, and population-attributable risk are unknown. Cases have arisen in geographically and ancestrally diverse families. Recurrence of p.Asp202Asn is documented, but a founder effect has not been established. Consanguinity occurs in some families but is not necessary. Published sex or ancestry distributions must not be interpreted epidemiologically because the denominator is extremely small and publication-biased. (naef2024scar32functionalcharacterization pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15, yang2025ahomozygousprdx3 pages 4-5)

10. Diagnostics

Diagnosis rests on: (1) a compatible cerebellar syndrome; (2) MRI showing cerebellar atrophy; and (3) pathogenic/likely pathogenic biallelic PRDX3 variants shown to be in trans. A practical workflow is neurological and ocular-motor examination, SARA scoring, brain MRI, then a hereditary-ataxia panel or WES that includes PRDX3. WGS is useful when exome/panel testing is negative or a structural/deep-intronic allele is suspected. RNA analysis can resolve abnormal splicing. Segregation, population frequency, conservation, protein consequence, and—where needed—functional evidence should be integrated for VUS interpretation. (naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)

Ancillary evaluation should include neuropsychology, hearing assessment when indicated, swallowing evaluation, nerve-conduction studies/EMG, and rehabilitation assessment. Routine biochemical and neurometabolic testing may be normal. PRDX3 protein, fibroblast ROS, and oxygen-consumption assays are research tools rather than validated clinical biomarkers, especially because 2024 fibroblasts showed normal bioenergetics despite a disease genotype. (naef2024scar32functionalcharacterization pages 3-5, naef2024scar32functionalcharacterization pages 2-3)

Differential diagnosis includes Friedreich ataxia, RFC1-related disease, ataxia with vitamin E deficiency, POLG and other mitochondrial ataxias, SETX-related ataxia with oculomotor apraxia, PNKP/APTX-related disorders, SPG7, SYNE1, COQ8A/ADCK3 disease, recessive spastic ataxias, and dominant or repeat-expansion SCAs. Repeat expansions require dedicated testing and can be missed by conventional WES. CMA, karyotyping, FISH, and mitochondrial-DNA testing are not first-line tests for isolated PRDX3 suspicion unless the wider phenotype indicates them.

Population newborn screening is unavailable. Targeted cascade and carrier testing are appropriate after a familial variant is established.

11. Outcome and prognosis

Available observations indicate chronic neurologic morbidity with variable progression. Some adults retain moderate function, whereas early-onset disease can require assisted walking. Dysphagia, falls, neuropathy, communication impairment, and neuropsychiatric or educational difficulties may add morbidity. (martinezrubio2022proteinmisfoldingand pages 2-2, rebelo2021bialleliclossoffunctionvariations pages 6-7, naef2024scar32functionalcharacterization pages 2-3)

There are no reliable 5- or 10-year survival rates, mortality rates, life-expectancy estimates, prognostic calculators, or validated prognostic biomarkers. Severe early onset, neuropathy, extensive atrophy, and higher SARA score may plausibly indicate greater disability, but none is validated as an independent prognostic factor. Recovery of established neurodegeneration has not been demonstrated.

12. Treatment

No approved disease-modifying pharmacotherapy, PRDX3-targeted treatment, pharmacogenomic recommendation, surgery, gene therapy, cell therapy, ASO/siRNA therapy, or SCAR32-specific clinical trial was identified. Mechanistic proposals—including mitochondria-targeted antioxidants, ferroptosis modulation, restoration of thioredoxin/peroxide detoxification, or PRDX3 gene replacement—remain preclinical hypotheses and should not be represented as effective treatments. (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15, yang2025ahomozygousprdx3 pages 4-5)

Current care is supportive and individualized:

  • physical therapy, balance/gait training, exercise within safe tolerance, fall prevention, and mobility aids;
  • occupational therapy and home/school/work adaptation;
  • speech therapy and augmentative communication where needed;
  • swallowing assessment, dietetic support, and aspiration prevention;
  • management of tremor, dystonia, rigidity, mood symptoms, pain, and sleep according to standard symptomatic practice;
  • hearing, cognition, education, and psychosocial support;
  • periodic SARA, mobility, nutrition, respiratory/aspiration-risk, and neurologic reassessment.

Suggested NCIT concepts are Physical Therapy, Occupational Therapy, Speech Therapy, Rehabilitation Therapy, Assistive Device, Genetic Counseling, and Gene Therapy—Experimental. No SCAR32-specific response rate or adverse-event dataset exists.

13. Prevention

Primary prevention through lifestyle modification, vaccination, environmental control, or prophylactic medication is not applicable. Genetic prevention and informed reproductive choice are possible through counseling, parental confirmation, cascade carrier testing, prenatal diagnosis, and preimplantation genetic testing when familial pathogenic variants are known. Secondary prevention consists of early recognition and molecular diagnosis, allowing earlier rehabilitation and surveillance. Tertiary prevention comprises fall reduction, contracture/deconditioning prevention, swallowing and aspiration management, and educational/psychosocial intervention. (yang2025ahomozygousprdx3 pages 1-2, naef2024scar32functionalcharacterization pages 2-3, martinezrubio2022proteinmisfoldingand pages 2-2)

14. Other species and natural disease

No naturally occurring PRDX3-associated SCAR32 analogue was identified in companion animals, livestock, or wildlife. There is no zoonotic potential or cross-species transmission. Orthologous PRDX3 systems are evolutionarily conserved and provide experimental models, but induced knockdown/knockout phenotypes should not be classified as natural veterinary disease.

15. Model organisms and research applications

  • Drosophila melanogaster (NCBI Taxon 7227): pan-neuronal or pan-glial Prdx3 depletion caused abnormal locomotion and shortened survival under oxidative stress; brain degeneration and oxidative susceptibility were also described. The model supports neural redox vulnerability but does not reproduce the complete human syndrome. (rebelo2021bialleliclossoffunctionvariations pages 1-2, rebelo2021bialleliclossoffunctionvariations pages 14-15)
  • Danio rerio (NCBI Taxon 7955): CRISPR/Cas9 F0 prdx3 crispants showed diminished burst/touch responses, reduced swimming distance and velocity, reduced ATP production and maximal respiration, and increased oxidative-stress-associated apoptosis. Limitations include mosaic F0 disruption and early developmental endpoints. (naef2024scar32functionalcharacterization pages 3-5)
  • Mus musculus (NCBI Taxon 10090): Prdx3 deficiency has been associated with reduced strength, reduced skeletal-muscle mitochondrial DNA copy number, and oxidative-stress-associated hippocampal cell loss. These models do not yet constitute a fully characterized SCAR32 knock-in natural-history model. (rebelo2021bialleliclossoffunctionvariations pages 14-15)
  • Human fibroblasts: original disease lines showed absent PRDX3, reduced glutathione-peroxidase activity, and reduced maximal respiratory capacity; p.Asp163Glu fibroblasts showed increased mitochondrial oxidative stress. A later line had reduced transcript but normal respiration and ROS responses, demonstrating assay and allele heterogeneity. (rebelo2021bialleliclossoffunctionvariations pages 1-2, naef2024scar32functionalcharacterization pages 3-5, martinezrubio2022proteinmisfoldingand pages 2-2)
  • Cellular neuronal/cerebellar systems: PRDX3 knockdown in cerebellar medulloblastoma cells increased H₂O₂, reduced viability, and sensitized cells to ROS-triggered apoptosis. Mutant expression in mouse primary neurons altered neurites and mitochondria; HeLa experiments demonstrated protein aggregation, damaged membranes/cristae, lipid-droplet-like structures, and mitochondrial/ER unfolded-protein responses. (rebelo2021bialleliclossoffunctionvariations pages 1-2, martinezrubio2022proteinmisfoldingand pages 2-2, martinezrubio2022proteinmisfoldingand pages 1-2)

These systems are suitable for allele-function studies, mitochondrial redox and respiration assays, modifier screens, and testing gene replacement or mitochondria-directed compounds. Major unmet needs are stable patient-derived neuronal/iPSC models, Purkinje-cell systems, allele-specific knock-in animals, longitudinal natural-history cohorts, standardized biomarkers, and genotype-stratified therapeutic studies.

Key literature and dates

  1. Rebelo AP et al. “Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.” Brain. Published April 2021; 144:1467–1481. PMID 33889951. DOI/URL: https://doi.org/10.1093/brain/awab071. The abstract states that the investigators identified recessive PRDX3 mutations in five unrelated families and that patient fibroblasts lacked PRDX3 protein. (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3, rebelo2021bialleliclossoffunctionvariations pages 1-2)
  2. Martínez-Rubio D et al. “Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3.” Human Molecular Genetics. Published June 2022; 31:3897–3913. PMID 35766882. DOI/URL: https://doi.org/10.1093/hmg/ddac146. The report’s abstract describes onset at 19 months, severe cerebellar atrophy, early neuropathy, and nearly absent PRDX3 in fibroblasts. (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3, martinezrubio2022proteinmisfoldingand pages 1-2)
  3. Naef V et al. “SCAR32: Functional characterization and expansion of the clinical-genetic spectrum.” Annals of Clinical and Translational Neurology. Published June 2024; 11:1879–1886. DOI/URL: https://doi.org/10.1002/acn3.52094. Two additional unrelated patients and a zebrafish crispant model expanded the phenotype and functional evidence. (naef2024scar32functionalcharacterization pages 1-2, naef2024scar32functionalcharacterization pages 2-3, naef2024scar32functionalcharacterization pages 3-5)
  4. Yang J et al. “A homozygous PRDX3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32.” Neurogenetics. Published online 6 December 2025. DOI/URL: https://doi.org/10.1007/s10048-025-00869-w. This post-2024 case added p.Arg207Ter, quantitative cognitive findings, and thyroid observations whose disease relationship remains uncertain. (yang2025ahomozygousprdx3 pages 1-2)

Evidence limitations

The literature consists of very small, heterogeneous, largely cross-sectional family reports. Published-case frequencies cannot be converted into prevalence or penetrance estimates. Functional evidence is compelling but sometimes discordant across fibroblast lines, and much of the downstream causal chain rests on induced cell or animal models rather than human nervous tissue. Absence of disease-specific trials, longitudinal cohorts, neuropathology, validated fluid biomarkers, single-cell data, and formal quality-of-life or survival studies should be encoded explicitly as missing evidence rather than negative biological findings.

References

  1. (OpenTargets Search: spinocerebellar ataxia autosomal recessive 32-PRDX3): Open Targets Query (spinocerebellar ataxia autosomal recessive 32-PRDX3, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (rebelo2021bialleliclossoffunctionvariations pages 1-2): Adriana P Rebelo, Ilse Eidhof, Vivian P Cintra, Léna Guillot-Noel, Claudia V Pereira, Dagmar Timmann, Andreas Traschütz, Ludger Schöls, Giulia Coarelli, Alexandra Durr, Mathieu Anheim, Christine Tranchant, Bart van de Warrenburg, Claire Guissart, Michel Koenig, Jack Howell, Carlos T Moraes, Annette Schenck, Giovanni Stevanin, Stephan Züchner, and Matthis Synofzik. Biallelic loss-of-function variations in prdx3 cause cerebellar ataxia. Brain : a journal of neurology, 144:1467-1481, Apr 2021. URL: https://doi.org/10.1093/brain/awab071, doi:10.1093/brain/awab071. This article has 46 citations.

  3. (naef2024scar32functionalcharacterization pages 2-3): Valentina Naef, Maria Lieto, Sara Satolli, Rosa De Micco, Martina Troisi, Rosa Pasquariello, Stefano Doccini, Flavia Privitera, Alessandro Filla, Alessandro Tessitore, and Filippo Maria Santorelli. Scar32: functional characterization and expansion of the clinical‐genetic spectrum. Annals of Clinical and Translational Neurology, 11:1879-1886, Jun 2024. URL: https://doi.org/10.1002/acn3.52094, doi:10.1002/acn3.52094. This article has 4 citations and is from a peer-reviewed journal.

  4. (martinezrubio2022proteinmisfoldingand pages 2-2): Dolores Martínez-Rubio, Ángela Rodríguez-Prieto, Paula Sancho, Carmen Navarro-González, Nerea Gorría-Redondo, Javier Miquel-Leal, Clara Marco-Marín, Alison Jenkins, Mario Soriano-Navarro, Alberto Hernández, Belén Pérez-Dueñas, Pietro Fazzari, Sergio Aguilera-Albesa, and Carmen Espinós. Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in prdx3. Human Molecular Genetics, 31:3897-3913, Jun 2022. URL: https://doi.org/10.1093/hmg/ddac146, doi:10.1093/hmg/ddac146. This article has 20 citations and is from a domain leading peer-reviewed journal.

  5. (rebelo2021bialleliclossoffunctionvariations pages 6-7): Adriana P Rebelo, Ilse Eidhof, Vivian P Cintra, Léna Guillot-Noel, Claudia V Pereira, Dagmar Timmann, Andreas Traschütz, Ludger Schöls, Giulia Coarelli, Alexandra Durr, Mathieu Anheim, Christine Tranchant, Bart van de Warrenburg, Claire Guissart, Michel Koenig, Jack Howell, Carlos T Moraes, Annette Schenck, Giovanni Stevanin, Stephan Züchner, and Matthis Synofzik. Biallelic loss-of-function variations in prdx3 cause cerebellar ataxia. Brain : a journal of neurology, 144:1467-1481, Apr 2021. URL: https://doi.org/10.1093/brain/awab071, doi:10.1093/brain/awab071. This article has 46 citations.

  6. (martinezrubio2022proteinmisfoldingand pages 1-2): Dolores Martínez-Rubio, Ángela Rodríguez-Prieto, Paula Sancho, Carmen Navarro-González, Nerea Gorría-Redondo, Javier Miquel-Leal, Clara Marco-Marín, Alison Jenkins, Mario Soriano-Navarro, Alberto Hernández, Belén Pérez-Dueñas, Pietro Fazzari, Sergio Aguilera-Albesa, and Carmen Espinós. Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in prdx3. Human Molecular Genetics, 31:3897-3913, Jun 2022. URL: https://doi.org/10.1093/hmg/ddac146, doi:10.1093/hmg/ddac146. This article has 20 citations and is from a domain leading peer-reviewed journal.

  7. (yang2025ahomozygousprdx3 pages 4-5): Jiaxuan Yang, Yonglin Yu, Hongfang Jiang, Yueping Che, Dingwen Wu, Haifeng Li, Yaoqin Hu, Jinpiao Zhu, and Daqing Ma. A homozygous prdx3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32. Neurogenetics, Dec 2025. URL: https://doi.org/10.1007/s10048-025-00869-w, doi:10.1007/s10048-025-00869-w. This article has 1 citations and is from a peer-reviewed journal.

  8. (naef2024scar32functionalcharacterization pages 3-5): Valentina Naef, Maria Lieto, Sara Satolli, Rosa De Micco, Martina Troisi, Rosa Pasquariello, Stefano Doccini, Flavia Privitera, Alessandro Filla, Alessandro Tessitore, and Filippo Maria Santorelli. Scar32: functional characterization and expansion of the clinical‐genetic spectrum. Annals of Clinical and Translational Neurology, 11:1879-1886, Jun 2024. URL: https://doi.org/10.1002/acn3.52094, doi:10.1002/acn3.52094. This article has 4 citations and is from a peer-reviewed journal.

  9. (rebelo2021bialleliclossoffunctionvariations pages 14-15): Adriana P Rebelo, Ilse Eidhof, Vivian P Cintra, Léna Guillot-Noel, Claudia V Pereira, Dagmar Timmann, Andreas Traschütz, Ludger Schöls, Giulia Coarelli, Alexandra Durr, Mathieu Anheim, Christine Tranchant, Bart van de Warrenburg, Claire Guissart, Michel Koenig, Jack Howell, Carlos T Moraes, Annette Schenck, Giovanni Stevanin, Stephan Züchner, and Matthis Synofzik. Biallelic loss-of-function variations in prdx3 cause cerebellar ataxia. Brain : a journal of neurology, 144:1467-1481, Apr 2021. URL: https://doi.org/10.1093/brain/awab071, doi:10.1093/brain/awab071. This article has 46 citations.

  10. (yang2025ahomozygousprdx3 pages 1-2): Jiaxuan Yang, Yonglin Yu, Hongfang Jiang, Yueping Che, Dingwen Wu, Haifeng Li, Yaoqin Hu, Jinpiao Zhu, and Daqing Ma. A homozygous prdx3 pathogenic variant in a paediatric case of spinocerebellar ataxia type 32. Neurogenetics, Dec 2025. URL: https://doi.org/10.1007/s10048-025-00869-w, doi:10.1007/s10048-025-00869-w. This article has 1 citations and is from a peer-reviewed journal.

  11. (rebelo2021bialleliclossoffunctionvariations pages 2-3): Adriana P Rebelo, Ilse Eidhof, Vivian P Cintra, Léna Guillot-Noel, Claudia V Pereira, Dagmar Timmann, Andreas Traschütz, Ludger Schöls, Giulia Coarelli, Alexandra Durr, Mathieu Anheim, Christine Tranchant, Bart van de Warrenburg, Claire Guissart, Michel Koenig, Jack Howell, Carlos T Moraes, Annette Schenck, Giovanni Stevanin, Stephan Züchner, and Matthis Synofzik. Biallelic loss-of-function variations in prdx3 cause cerebellar ataxia. Brain : a journal of neurology, 144:1467-1481, Apr 2021. URL: https://doi.org/10.1093/brain/awab071, doi:10.1093/brain/awab071. This article has 46 citations.

  12. (naef2024scar32functionalcharacterization pages 1-2): Valentina Naef, Maria Lieto, Sara Satolli, Rosa De Micco, Martina Troisi, Rosa Pasquariello, Stefano Doccini, Flavia Privitera, Alessandro Filla, Alessandro Tessitore, and Filippo Maria Santorelli. Scar32: functional characterization and expansion of the clinical‐genetic spectrum. Annals of Clinical and Translational Neurology, 11:1879-1886, Jun 2024. URL: https://doi.org/10.1002/acn3.52094, doi:10.1002/acn3.52094. This article has 4 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 15
Resolved 12
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0859245 (5 mentions) - the report calls it "if available"; MONDO calls it spinocerebellar ataxia, autosomal recessive 32

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.