Autosomal Recessive Spinocerebellar Ataxia 10

Mendelian MONDO:0013392 Pathograph 54 Show in embeddings browser Autosomal recessive cerebellar ataxia

Slowly progressive autosomal recessive cerebellar ataxia caused by biallelic, mostly loss-of-function, variants in ANO10 (anoctamin 10, TMEM16K) on 3p22. Onset is usually in adulthood (mean about 33 years, range from the teens to the sixth decade), earlier in Romani patients homozygous for the founder c.1150_1151del. Gait, limb and truncal ataxia with dysarthria and oculomotor signs (downbeat nystagmus, dysmetric saccades) are accompanied by corticospinal tract signs, marked cerebellar atrophy on MRI, and, variably, executive cognitive impairment, epilepsy, lower motor neuron involvement, sphincter disturbance and retinal or lens changes; peripheral neuropathy is typically absent. TMEM16K is an endoplasmic reticulum calcium-regulated phospholipid scramblase with weak non-selective channel activity; its loss impairs ER-endosome contact-site sorting and local calcium signalling, and low coenzyme Q10 has been found in muscle of some patients. How these defects lead to cerebellar degeneration is not established.

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1
Inheritance
12
Pathophys.
35
Phenotypes
54
Pathograph
1
Genes
3
Medical Actions
3
Models
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Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
Biallelic ANO10 variants (homozygous or compound heterozygous) cause disease; heterozygous parents and siblings are unaffected.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:38469933 SUPPORT BACKGROUND Human Clinical
"Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10)."
Systematic review statement of the recessive biallelic mechanism.
PMID:32319254 SUPPORT Human Clinical
"Sanger sequencing confirmed this condition and indicated that her healthy parents (III-4 and III-5) and 39-year-old brother (IV-2) were heterozygous for this mutation"
Heterozygous relatives are unaffected, consistent with recessive inheritance.
PMID:21092923 SUPPORT Human Clinical
"In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture."
Homozygosity mapping in a consanguineous sibship identified the locus.
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Pathophysiology

12
ANO10 Biallelic Loss of Function
Most disease alleles are truncating (frameshift, nonsense, canonical splice) and predicted to abolish anoctamin 10; a minority are missense or in-frame. Three tested missense disease variants are expressed and reach the ER but fail to complement TMEM16K-null cells.
cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. lower motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lower motor neuron, annotated with motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
ANO10 hgnc:25519 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANO10 (hgnc:25519). hgnc:25519 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
phospholipid scramblase activity GO:0017128 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phospholipid scramblase activity (GO:0017128). GO:0017128 is a molecular function from the Gene Ontology.
Downstream
Impaired ER Phospholipid Scrambling
Defective Endosomal Retrograde Sorting
Deranged Local Calcium Signaling
Candidate Neuronal Proteome Perturbation
Secondary Coenzyme Q10 Deficiency The link between ANO10 loss and low CoQ10 has no proposed molecular mechanism.
Corticospinal Tract Dysfunction Pyramidal involvement is a consistent clinical feature; its cellular basis is not studied.
Brainstem Involvement
Retinal degeneration No mechanism has been studied.
Cataract
Bladder sphincter dysfunction
Show evidence (2 references)
PMID:38469933 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most patients (>80%) had loss-of-function (LOF) variants."
Allelic spectrum across 94 patients is dominated by loss-of-function alleles.
PMID:32620747 SUPPORT In Vitro
"Reintroduction of wild type TMEM16K, but not human disease variants rescues the observed cellular defect."
Missense disease alleles are functionally null in a complementation assay.
Impaired ER Phospholipid Scrambling
TMEM16K is an ER-resident, calcium-regulated phospholipid scramblase with non-selective ion channel activity, structurally a TMEM16 scramblase rather than a plasma-membrane chloride channel. TMEM16K-null fibroblasts lose calcium-induced phosphatidylserine redistribution in the ER. The older description of ANO10 as a calcium-activated chloride channel is not supported by whole-cell recordings.
phospholipid scramblase activity GO:0017128 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phospholipid scramblase activity (GO:0017128). GO:0017128 is a molecular function from the Gene Ontology.
Downstream
Defective Endosomal Retrograde Sorting
Show evidence (3 references)
PMID:31477691 SUPPORT In Vitro
"Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity."
Reconstitution and localisation establish the normal function that is lost.
PMID:31217287 SUPPORT In Vitro
"This Ca2+-induced PtdSer redistribution was not observed in TMEM16K-null fibroblasts, but was recovered in these cells by reexpressing TMEM16K."
Loss of TMEM16K abolishes ER scrambling in cells.
PMID:31477691 REFUTE In Vitro
"However, the currents detected in TMEM16K-transfected cells did not differ from those seen in mock-transfected cells in either condition (Fig. 1e, f), suggesting that TMEM16K is not trafficked to PM and/or does not mediate PM Ca2+-activated currents."
Refutes the plasma-membrane calcium-activated chloride channel model of ANO10 used in early SCAR10 reports.
Defective Endosomal Retrograde Sorting
TMEM16K forms ER-endosome contact sites with RAB7-positive endosomes. TMEM16K-null mouse fibroblasts fail to return CI-MPR and cholera toxin B from endosomes to the trans-Golgi network and show impaired endolysosomal acidification, while endocytosis and the biosynthetic pathway are unaffected. This has not been examined in neurons.
retrograde transport, endosome to Golgi GO:0042147 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retrograde transport, endosome to Golgi (GO:0042147). GO:0042147 is a biological process from the Gene Ontology.
Animal models
TMEM16K knockout mouse Mus musculus recapitulates Knockout embryonic fibroblasts show the endosome-to-Golgi retrograde trafficking defect.
Downstream
Lower Motor Neuron and Neuromuscular Involvement The same knockout mice have progressive neuromuscular dysfunction, but a causal link from the fibroblast sorting defect to neurons is not shown.
Cerebellar Cortical Degeneration Proposed by analogy with endolysosomal defects in other neurodegenerations; not tested in cerebellum.
Show evidence (1 reference)
PMID:32620747 SUPPORT In Vitro
"Altogether, these data demonstrate that depletion of the ER-resident protein TMEM16K perturbs endosomal retrograde trafficking, a defect similar to that observed upon depletion of known cargo-sorting components"
Retrograde trafficking defect in knockout fibroblasts.
Deranged Local Calcium Signaling
Ano10-null epithelial cells and macrophages show deranged calcium signalling, reduced volume regulation and reduced apoptosis. Calcium dysregulation in Purkinje cells is the most often proposed SCAR10 mechanism, but it has not been measured in Purkinje cells or any neuron.
cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
intracellular calcium ion homeostasis GO:0006874 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology.
Animal models
Ano10 null mouse Mus musculus partially recapitulates Intestinal epithelial cells and peritoneal macrophages from null mice show calcium-signalling, volume-regulation and apoptosis defects.
Downstream
Cerebellar Cortical Degeneration Hypothesised; the module's calcium-to-degeneration step is not demonstrated for ANO10.
Show evidence (2 references)
PMID:27838374 SUPPORT In Vitro
"We therefore propose that mutations in ANO10 cause cellular defects and genetic disorders through deranged local Ca2+ signaling."
Calcium-signalling defect in Ano10-null cells, extrapolated by the authors to disease.
PMID:42129323 SUPPORT INDIRECT BACKGROUND Other
"While ANO10-mediated calcium dysregulation in Purkinje cells has been proposed to cause SCAR10, the precise pathogenic mechanism remains unclear."
Records the Purkinje calcium hypothesis and its unproven status.
Candidate Neuronal Proteome Perturbation
ANO10 knockout and patient-variant SH-SY5Y neuroblastoma lines show proteome changes enriched for synaptic function, cell cycle regulation, extracellular matrix remodelling and immune homeostasis. The authors present these as candidate pathways awaiting validation.
neuron (SH-SY5Y neuroblastoma line) CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (SH-SY5Y neuroblastoma line), annotated with neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
modulation of chemical synaptic transmission GO:0050804 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated modulation of chemical synaptic transmission (GO:0050804). GO:0050804 is a biological process from the Gene Ontology. extracellular matrix organization GO:0030198 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. cell cycle GO:0007049 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cell cycle (GO:0007049). GO:0007049 is a biological process from the Gene Ontology.
Experimental models
ANO10-mutant SH-SY5Y neuronal lines CELL LINE Proteome-wide differences between control and mutant lines.
Downstream
Cerebellar Cortical Degeneration Candidate contribution only; no in vivo validation.
Show evidence (1 reference)
PMID:42129323 SUPPORT In Vitro
"Comparative proteomic analysis revealed disruptions in synaptic function, cell cycle regulation, extracellular matrix remodelling, and immune homeostasis as candidate pathways potentially contributing to SCAR10 pathogenesis."
Proteomic result in engineered neuronal lines.
Secondary Coenzyme Q10 Deficiency
Low CoQ10 has been reported in skeletal muscle, and in some patients in plasma, fibroblasts or CSF, but not systematically measured across cohorts. Whether it contributes to neurodegeneration, and whether it is a consistent feature, is unresolved.
Downstream
Decreased muscle coenzyme Q10
Show evidence (2 references)
PMID:25182700 SUPPORT Human Clinical
"In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
Muscle CoQ10 deficiency in two genetically confirmed patients.
PMID:35648332 SUPPORT REVIEW SYNTHESIS Other
"However, further investigation is needed to elucidate CoQ10 contribution to SCAR10 pathology and its therapeutic potential"
Review flags the CoQ10 role as unresolved.
Cerebellar Cortical Degeneration
Marked cerebellar atrophy on MRI is reported in essentially every patient and can precede ataxia; FDG-PET shows cerebellar and frontal hypometabolism. No human neuropathology was found in the cited sources, so Purkinje cell loss is inferred from imaging and the clinical syndrome rather than shown histologically. The mode of cell loss is unstudied; the only cell-death data (Ano10-null epithelial cells and macrophages) report reduced rather than increased apoptosis, so no cell-death process is bound.
cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
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.
Downstream
Loss of Cerebellar Cortical Output
Cerebellar atrophy
Cerebellar and frontal FDG-PET hypometabolism
Cerebral Cortical Network Dysfunction Frontal hypometabolism may reflect cerebello-cerebral disconnection or primary cortical involvement; the sources do not distinguish these.
Show evidence (2 references)
PMID:25089919 SUPPORT Human Clinical
"Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy."
Imaging evidence of cerebellar degeneration in nine patients.
PMID:35648332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Brain MRI, performed on 55 patients, revealed cerebellar atrophy in all 55/55 (100%) patients, with five patients showing cortical atrophy and one patient slight brainstem atrophy, in addition to cerebellar atrophy."
Pooled imaging across published cases.
Loss of Cerebellar Cortical Output
Cerebellar dysfunction produces the core syndrome of gait, limb and truncal ataxia, dysarthria and cerebellar oculomotor signs. Severe cerebellar atrophy can be present before ataxia is detectable on examination.
cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
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.
Downstream
Progressive cerebellar ataxia
Progressive gait ataxia
Limb ataxia
Truncal ataxia
Dysarthria
Dysmetria
Intention tremor
Downbeat nystagmus
Pendular nystagmus
Dysmetric saccades
Saccadic smooth pursuit
Postural tremor
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by adulthood-onset of slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (e.g. horizontal, vertical, and/or downbeat nystagmus, hypermetric..."
Orphanet definition of the cerebellar syndrome.
Corticospinal Tract Dysfunction
Pyramidal signs (hyperreflexia, extensor plantar responses, clonus, spasticity) are frequent, giving a spastic-ataxic phenotype.
corticospinal tract UBERON:0002707 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corticospinal tract (UBERON:0002707). UBERON:0002707 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hyperreflexia
Babinski sign
Ankle clonus
Spasticity
Show evidence (1 reference)
PMID:25089919 SUPPORT Human Clinical
"Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
Corticospinal signs in the French series.
Lower Motor Neuron and Neuromuscular Involvement
Some patients have proximal leg wasting, fasciculations and EMG evidence of lower motor neuron involvement. TMEM16K knockout mice show progressive shrinkage of neuromuscular junctions.
lower motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lower motor neuron, annotated with motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
Animal models
TMEM16K knockout mouse Mus musculus partially recapitulates Progressive neuromuscular junction shrinkage, hindlimb clasping and impaired ledge walking.
Downstream
Fasciculations
EMG abnormality
Pes cavus Pes cavus usually reflects long-standing distal weakness; its origin in SCAR10 is not studied.
Show evidence (2 references)
ORPHA:284289 SUPPORT Other
"Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement."
Orphanet records EMG lower motor neuron findings.
PMID:30515630 SUPPORT BACKGROUND Human Clinical
"The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline."
Summary of the known phenotype in the introduction of a cohort study.
Brainstem Involvement
Facial muscle involvement, strabismus, ptosis, vertical gaze paresis and, rarely, vocal cord paralysis or inspiratory stridor suggest brainstem involvement in a subset of patients.
brainstem UBERON:0002298 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brainstem (UBERON:0002298). UBERON:0002298 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Strabismus
Ptosis
Vertical gaze paresis
Vocal cord paralysis
Inspiratory stridor
Show evidence (1 reference)
PMID:38469933 SUPPORT Human Clinical
"We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
Brainstem pathology is the authors' interpretation of new clinical signs.
Cerebral Cortical Network Dysfunction
Executive and attentional deficits, broader cognitive decline in some families, epilepsy, cortical reflex myoclonus physiology (giant SEPs) and bradykinesia indicate involvement beyond the cerebellum, with frontal hypometabolism on FDG-PET.
frontal lobe UBERON:0016525 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in frontal lobe (UBERON:0016525). UBERON:0016525 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired executive functioning
Cognitive impairment
Seizure
Giant somatosensory evoked potentials
Bradykinesia
Show evidence (1 reference)
PMID:35256372 SUPPORT Human Clinical
"Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans."
Frontal hypometabolism in two patients.
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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 Autosomal Recessive Spinocerebellar Ataxia 10 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

35
Eye 9
Downbeat nystagmus FREQUENT HP:0010545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downbeat nystagmus (HP:0010545). HP:0010545 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:284289 SUPPORT Other
"HP:0010545 | Downbeat nystagmus | Frequent (79-30%)"
Orphanet frequency annotation.
PMID:42702636 SUPPORT Human Clinical
"Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated."
Downbeat nystagmus as an isolated early sign.
Pendular nystagmus HP:0012043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Horizontal pendular nystagmus, annotated with Pendular nystagmus (HP:0012043). HP:0012043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40128498 SUPPORT Human Clinical
"This report describes two siblings with early-onset spastic-ataxia with horizontal pendular nystagmus, ultimately diagnosed with SCAR10."
Case report of the nystagmus subtype.
Dysmetric saccades FREQUENT HP:0000641 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmetric (hypermetric) saccades, annotated with Dysmetric saccades (HP:0000641). HP:0000641 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0000641 | Dysmetric saccades | Frequent (79-30%)"
Orphanet frequency annotation.
Saccadic smooth pursuit FREQUENT Saccadic smooth pursuit interruptions HP:0001152 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Saccadic smooth pursuit, annotated with Saccadic smooth pursuit interruptions (HP:0001152). HP:0001152 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0001152 | Saccadic smooth pursuit | Frequent (79-30%)"
Orphanet frequency annotation.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38469933 SUPPORT Human Clinical
"We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
Strabismus newly recognised in the MDSGene series.
Ptosis FREQUENT HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0000508 | Ptosis | Frequent (79-30%)"
Orphanet frequency annotation.
Vertical gaze paresis FREQUENT Ophthalmoparesis HP:0000597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild vertical gaze paresis, annotated with Ophthalmoparesis (HP:0000597). HP:0000597 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30515630 SUPPORT Human Clinical
"Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
Vertical gaze paresis in 5 of 10 patients.
Retinal degeneration HP:0000546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal degeneration (HP:0000546). HP:0000546 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25182700 SUPPORT Human Clinical
"Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other."
Retinal degeneration in one patient.
ORPHA:284289 SUPPORT Other
"HP:0000608 | Macular degeneration | Frequent (79-30%)"
Orphanet annotates macular degeneration as frequent.
Cataract OCCASIONAL HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0000518 | Cataract | Occasional (29-5%)"
Orphanet frequency annotation.
Genitourinary 1
Bladder sphincter dysfunction Urinary bladder sphincter dysfunction HP:0002839 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sphincter (vesicorectal) dysfunction, annotated with Urinary bladder sphincter dysfunction (HP:0002839). HP:0002839 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30515630 SUPPORT Human Clinical
"Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
Sphincter disturbance in 3 of 10 patients.
PMID:35110481 SUPPORT BACKGROUND Human Clinical
"This disorder is characterized by slowly progressive cerebellar ataxia and pyramidal signs inconstantly associated with cognitive decline, polyneuropathy, epilepsy, and vesicorectal dysfunction."
Introductory summary of the variable features.
Limbs 2
Ankle clonus FREQUENT HP:0011448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle clonus (HP:0011448). HP:0011448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0011448 | Ankle clonus | Frequent (79-30%)"
Orphanet frequency annotation.
Pes cavus FREQUENT HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30515630 SUPPORT Human Clinical
"Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
Pes cavus in 4 of 10 patients.
Musculoskeletal 2
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity, annotated with Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35110481 SUPPORT Human Clinical
"This case presented with adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline."
Spastic ataxia phenotype.
EMG abnormality FREQUENT HP:0003457 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EMG evidence of lower motor neuron involvement, annotated with EMG abnormality (HP:0003457). HP:0003457 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0003457 | EMG abnormality | Frequent (79-30%)"
Orphanet frequency annotation.
Nervous System 17
Progressive cerebellar ataxia VERY_FREQUENT HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073), qualified as adult onset. HP:0002073 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (3 references)
ORPHA:284289 SUPPORT Other
"HP:0002073 | Progressive cerebellar ataxia | Very frequent (99-80%)"
Orphanet frequency annotation.
PMID:25089919 SUPPORT Human Clinical
"The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow."
Onset age and slow progression.
PMID:38469933 SUPPORT Human Clinical
"The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants."
Earlier onset in the Romani founder group.
Progressive gait ataxia FREQUENT HP:0007240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive gait ataxia (HP:0007240). HP:0007240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0007240 | Progressive gait ataxia | Frequent (79-30%)"
Orphanet frequency annotation.
Limb ataxia FREQUENT HP:0002070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb ataxia (HP:0002070). HP:0002070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0002070 | Limb ataxia | Frequent (79-30%)"
Orphanet frequency annotation.
Truncal ataxia FREQUENT HP:0002078 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Truncal ataxia (HP:0002078). HP:0002078 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0002078 | Truncal ataxia | Frequent (79-30%)"
Orphanet frequency annotation.
Dysarthria FREQUENT 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 (2 references)
ORPHA:284289 SUPPORT Other
"HP:0001260 | Dysarthria | Frequent (79-30%)"
Orphanet frequency annotation.
PMID:25182700 SUPPORT Human Clinical
"Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade."
Progressive dysarthria in two patients.
Dysmetria FREQUENT 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)
ORPHA:284289 SUPPORT Other
"HP:0001310 | Dysmetria | Frequent (79-30%)"
Orphanet frequency annotation.
Intention tremor OCCASIONAL HP:0002080 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intention tremor (HP:0002080). HP:0002080 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0002080 | Intention tremor | Occasional (29-5%)"
Orphanet frequency annotation.
Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28316589 SUPPORT Human Clinical
"The aim of this study is to report a patient with a marked postural tremor responding to transcranial cerebello-cerebral direct current stimulation (tCCDCS)."
Marked postural tremor in an ANO10 patient.
Cerebellar atrophy VERY_FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30515630 SUPPORT Human Clinical
"All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI."
Cerebellar atrophy in all ten patients.
PMID:42702636 SUPPORT Human Clinical
"Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy."
Atrophy can precede clinical ataxia.
Hyperreflexia FREQUENT HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0001347 | Hyperreflexia | Frequent (79-30%)"
Orphanet frequency annotation.
Babinski sign HP:0003487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Extensor plantar response, annotated with Babinski sign (HP:0003487). HP:0003487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25089919 SUPPORT Human Clinical
"Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
Extensor plantar responses among frequent corticospinal signs.
Fasciculations FREQUENT HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"HP:0002380 | Fasciculations | Frequent (79-30%)"
Orphanet frequency annotation.
Vocal cord paralysis HP:0001605 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vocal cord paralysis (HP:0001605). HP:0001605 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34969792 SUPPORT Human Clinical
"Here we report a 41-year-old man with spinocerebellar atrophy, autosomal recessive type 10 (SCAR10) due to an autosomal recessive mutation in the ANO10 gene, with VCP as the presenting symptom."
Single case report.
Impaired executive functioning HP:0033051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Executive dysfunction, annotated with Impaired executive functioning (HP:0033051). HP:0033051 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30515630 SUPPORT Human Clinical
"Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions."
Executive deficits in 6 of 10 patients.
PMID:27045840 SUPPORT Human Clinical
"We reported for the first time the neuropsychological profile of 2 ARCA3 patients showing an adult-onset executive and attentional syndrome."
Executive and attentional syndrome in two siblings.
Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive decline, annotated with Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31423897 SUPPORT Human Clinical
"Cognitive impairment seems to be a characteristic of the SCAR10 produced by this mutation, with a range from mild impairment, especially involving prefrontal systems, to a severe cognitive impairment suggesting widespread cerebral involvement."
Spectrum of cognitive impairment in three siblings.
PMID:22008874 SUPPORT Human Clinical
"Here, we describe additional patients from neighbouring Bulgaria, outlining invariable ANO10-ataxia features and confirming global intellectual decline as part of the phenotype resulting from complete Anactomin 10 deficit."
Intellectual decline in Romani founder-allele patients.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27045840 SUPPORT Human Clinical
"The objective of this study was to describe the phenotype of 2 siblings with compound heterozygous ANO10 mutations and progressive cerebellar ataxia, epilepsy, and cognitive impairment."
Epilepsy in two siblings.
ORPHA:284289 SUPPORT Other
"HP:0002197 | Generalized-onset seizure | Frequent (79-30%)"
Orphanet annotates generalized-onset seizures as frequent.
PMID:35256372 SUPPORT Human Clinical
"One of them had temporal lobe epilepsy and she also carried a heterozygous variant in CACNB4, a potential risk gene for epilepsy."
Focal epilepsy, possibly modified by a second variant.
Bradykinesia HP:0002067 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bradykinesia (HP:0002067). HP:0002067 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30515630 SUPPORT Human Clinical
"Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
Bradykinesia in 7 of 10 patients.
Respiratory 1
Inspiratory stridor HP:0010307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inspiratory stridor, annotated with Stridor (HP:0010307). HP:0010307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts."
Orphanet lists inspiratory stridor as a variable feature.
Other 3
Cerebellar and frontal FDG-PET hypometabolism Abnormal brain FDG positron emission tomography HP:0012658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar and frontal hypometabolism on FDG-PET, annotated with Abnormal brain FDG positron emission tomography (HP:0012658). HP:0012658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35256372 SUPPORT Human Clinical
"Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans."
Only two patients have been imaged with FDG-PET in the cited sources.
Giant somatosensory evoked potentials HP:0001312 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Giant somatosensory evoked potentials (HP:0001312). HP:0001312 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30515630 SUPPORT Human Clinical
"Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures."
Cortical hyperexcitability in 3 of 10 patients.
Decreased muscle coenzyme Q10 Decreased level of coenzyme Q10 in skeletal muscle HP:0034369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased muscle coenzyme Q10, annotated with Decreased level of coenzyme Q10 in skeletal muscle (HP:0034369). HP:0034369 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25182700 SUPPORT Human Clinical
"In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
Muscle CoQ10 deficiency in two patients.
PMID:31477691 SUPPORT BACKGROUND Human Clinical
"SCAR10 causes cerebellar ataxia, with cerebellar atrophy evident in magnetic resonance imaging scans of brains and coenzyme Q10 deficiency found in muscle biopsy, fibroblasts and cerebrospinal fluid"
Background summary of where low CoQ10 has been found.
🧬

Genetic Associations

1
ANO10 (Causative)
Gene: ANO10 hgnc:25519 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANO10 (hgnc:25519). hgnc:25519 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:21092923 SUPPORT Human Clinical
"This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10)."
Gene discovery in the Dutch family; Serbian and French families carried further alleles.
PMID:22008874 SUPPORT Human Clinical
"Based on the history and population genetics of the Roma/Gypsies, we hypothesised that p.Leu384fs could be another founder mutation in this population, whose identification in a larger number of genetically homogeneous patients will contribute to defining the phenotypic spectrum of the disorder."
Romani founder allele.
PMID:25089919 SUPPORT Human Clinical
"The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity."
Most frequent allele in the French series.
+ 3 more references
💊

Medical Actions

3
Coenzyme Q10 Supplementation
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: coenzyme Q10 CHEBI:46245 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses coenzyme Q10 (CHEBI:46245). CHEBI:46245 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Proposed because of secondary CoQ10 deficiency. Evidence is limited to open-label case reports with variable or no benefit; no controlled trial exists.
Mechanism Target:
Secondary Coenzyme Q10 Deficiency — Replaces the deficient cofactor.
Show evidence (1 reference)
PMID:25182700 SUPPORT INDIRECT Human Clinical
"The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation."
Rationale for supplementation, not an outcome.
Target Phenotypes: Progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology. Epilepsy HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology. Decreased muscle coenzyme Q10 HP:0034369 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Decreased muscle coenzyme Q10, annotated with Decreased level of coenzyme Q10 in skeletal muscle (HP:0034369). HP:0034369 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:36698452 SUPPORT Human Clinical
"Two years after treatment with CoQ10, her ataxia had clearly improved, but she showed mild signs of lower limb spasticity."
Uncontrolled improvement in one patient.
PMID:36698452 REFUTE BACKGROUND Human Clinical
"CoQ10 supplementation has had mixed success with at least 1 patient showing no improvement."
Benefit is inconsistent across reported patients.
PMID:35648332 SUPPORT REVIEW SYNTHESIS Human Clinical
"CoQ10 supplementation was beneficial for some patients, improving their mobility, cognition or fatigue symptoms."
Review of open-label reports.
+ 1 more reference
Cerebello-Cerebral Transcranial Direct Current Stimulation
Action: transcranial cerebello-cerebral direct current stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is transcranial cerebello-cerebral direct current stimulation, annotated with Transcranial Direct Current Stimulation (NCIT:C129862). NCIT:C129862 is a clinical intervention from the NCI Thesaurus. Ontology label: Transcranial Direct Current Stimulation NCIT:C129862
Platform: Device
Anodal cerebellar tDCS with a contralateral motor cortex return electrode markedly reduced postural tremor in one patient, compared with baseline and sham.
Target Phenotypes: Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28316589 SUPPORT Human Clinical
"A dramatic response of postural tremor was observed after tCCDCS, with a major drop of the power spectral density to 26.12% of basal values."
Single-patient response.
Rehabilitation and Supportive Care
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
Platform: Behavioral / lifestyle
No disease-modifying therapy exists; management is physiotherapy, speech therapy, antiseizure treatment where needed and genetic counselling.
Target Phenotypes: Progressive gait ataxia HP:0007240 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive gait ataxia (HP:0007240). HP:0007240 is a phenotype from the Human Phenotype Ontology. Truncal ataxia HP:0002078 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Truncal ataxia (HP:0002078). HP:0002078 is a phenotype from the Human Phenotype Ontology. Limb ataxia HP:0002070 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Limb ataxia (HP:0002070). HP:0002070 is a phenotype from the Human Phenotype Ontology. Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
🔬

Diagnosis

2
Brain MRI
Marked cerebellar atrophy is present in essentially all patients and may precede ataxia. Absence of peripheral neuropathy helps distinguish ANO10 ataxia from other recessive ataxias.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25089919 SUPPORT Human Clinical
"An ANO10 mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy."
Diagnostic profile of ANO10 ataxia.
Multigene panel or exome sequencing
Diagnosis is by sequencing ANO10, usually within an ataxia or movement-disorder gene panel or exome; ANO10 accounted for 10% of a cohort of sporadic or recessive adult-onset ataxia.
multi-gene panel sequencing NCIT:C198412 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30838263 SUPPORT Human Clinical
"A genetic diagnosis in this family was obtained through next-generation sequencing techniques after over 10 years of expensive sequencing of individual genes using the traditional Sanger approach."
Next-generation sequencing ended a long diagnostic odyssey.
PMID:25182700 SUPPORT Human Clinical
"In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
Exome sequencing identified the diagnosis.
📊

Prevalence

2
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet point-prevalence class <1 / 1 000 000.
Show evidence (1 reference)
ORPHA:284289 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25182700"
Orphanet epidemiology table.
Published and new cases (MDSGene review)
Cases In Literature Ultra Rare
82 published and 12 newly identified patients analysed in the 2024 MDSGene review.
Show evidence (1 reference)
PMID:38469933 SUPPORT REVIEW SYNTHESIS Human Clinical
"Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients."
Size of the reported patient population.
🧫

Experimental Models

1
ANO10-mutant SH-SY5Y neuronal lines CELL_LINE
CRISPR/Cas9-engineered SH-SY5Y neuroblastoma lines (one knockout and three carrying recurrent SCAR10 variants) profiled by mass-spectrometry proteomics.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:42129323
Pathograph links
Candidate Neuronal Proteome Perturbation measures fidelity: low observes: cellular Proteome-wide differences between control and mutant lines.
Limitations: A proliferating neuroblastoma line, not Purkinje cells; findings are correlative candidate pathways without functional validation.
Show evidence (1 reference)
PMID:42129323 SUPPORT In Vitro
"These findings offer a foundation for further investigation and experimental validation, with potential implications for the development of targeted therapeutic approaches."
Authors frame the results as requiring validation.
🐁

Animal Models

2
TMEM16K knockout mouse
Species
Mus musculus
Genotype
Ano10 (TMEM16K) knockout, ubiquitous and neuron-specific
Publication
PMID:32620747
Pathograph links
Defective Endosomal Retrograde Sorting recapitulates fidelity: moderate observes: cellular Knockout embryonic fibroblasts show the endosome-to-Golgi retrograde trafficking defect.
Limitations: Measured in fibroblasts, not in cerebellar neurons; the defect has not been shown in patient cells.
Show evidence (1 reference)
PMID:32620747 SUPPORT In Vitro
"Loss of TMEM16K leads to impaired endosomal retrograde trafficking and dysfunction in the endolysosomal pathway."
Cellular phenotype of knockout cells.
Lower Motor Neuron and Neuromuscular Involvement partially recapitulates fidelity: low observes: tissue Progressive neuromuscular junction shrinkage, hindlimb clasping and impaired ledge walking.
Limitations: Coordination was assessed only by hindlimb clasping and ledge walking; cerebellar histology, Purkinje cell counts and gait analysis are not reported, so the model does not establish cerebellar degeneration.
Show evidence (1 reference)
PMID:32620747 SUPPORT Model Organism
"Here, we find that TMEM16K knockout mice display defects in neuromuscular function and motor behaviors, corresponding to ataxic phenotypes observed in human patients."
Motor phenotype of the knockout mouse.
Ano10 null mouse
Species
Mus musculus
Genotype
Ano10-/-
Publication
PMID:27838374
Pathograph links
Deranged Local Calcium Signaling partially recapitulates fidelity: low observes: cellular Intestinal epithelial cells and peritoneal macrophages from null mice show calcium-signalling, volume-regulation and apoptosis defects.
Limitations: Only epithelial cells and macrophages were studied; no neuronal or neurological phenotype is reported.
Show evidence (1 reference)
PMID:27838374 SUPPORT In Vitro
"Similar defects were found in mouse peritoneal Ano10 null macrophages and in human THP1 macrophages with reduced ANO10 expression."
Ex vivo cells from null mice.
{ }

Source YAML

click to show 
name: Autosomal Recessive Spinocerebellar Ataxia 10
creation_date: "2026-10-15T12:30:00Z"
category: Mendelian
synonyms:
- SCAR10
- spinocerebellar ataxia, autosomal recessive 10
- autosomal recessive cerebellar ataxia type 3
- ARCA3
- ATX-ANO10
- ANO10-related ataxia
- adult-onset autosomal recessive cerebellar ataxia
description: >-
  Slowly progressive autosomal recessive cerebellar ataxia caused by biallelic,
  mostly loss-of-function, variants in ANO10 (anoctamin 10, TMEM16K) on 3p22.
  Onset is usually in adulthood (mean about 33 years, range from the teens to
  the sixth decade), earlier in Romani patients homozygous for the founder
  c.1150_1151del. Gait, limb and truncal ataxia with dysarthria and
  oculomotor signs (downbeat nystagmus, dysmetric saccades) are accompanied by
  corticospinal tract signs, marked cerebellar atrophy on MRI, and, variably,
  executive cognitive impairment, epilepsy, lower motor neuron involvement,
  sphincter disturbance and retinal or lens changes; peripheral neuropathy is
  typically absent. TMEM16K is an endoplasmic reticulum calcium-regulated
  phospholipid scramblase with weak non-selective channel activity; its loss
  impairs ER-endosome contact-site sorting and local calcium signalling, and
  low coenzyme Q10 has been found in muscle of some patients. How these
  defects lead to cerebellar degeneration is not established.
disease_term:
  preferred_term: autosomal recessive spinocerebellar ataxia 10
  term:
    id: MONDO:0013392
    label: autosomal recessive spinocerebellar ataxia 10
parents:
- Autosomal recessive cerebellar ataxia
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic ANO10 variants (homozygous or compound heterozygous) cause
    disease; heterozygous parents and siblings are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10)."
    explanation: Systematic review statement of the recessive biallelic mechanism.
  - reference: PMID:32319254
    reference_title: "Autosomal Recessive Spinocerebellar Ataxia Caused by a Novel Homozygous ANO10 Mutation in a Consanguineous Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed this condition and indicated that her healthy parents (III-4 and III-5) and 39-year-old brother (IV-2) were heterozygous for this mutation"
    explanation: Heterozygous relatives are unaffected, consistent with recessive inheritance.
  - reference: PMID:21092923
    reference_title: "Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture."
    explanation: Homozygosity mapping in a consanguineous sibship identified the locus.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet point-prevalence class <1 / 1 000 000.
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25182700"
    explanation: Orphanet epidemiology table.
- population: Published and new cases (MDSGene review)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: 82 published and 12 newly identified patients analysed in the 2024 MDSGene review.
  evidence:
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients."
    explanation: Size of the reported patient population.
pathophysiology:
- name: ANO10 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Most disease alleles are truncating (frameshift, nonsense, canonical
    splice) and predicted to abolish anoctamin 10; a minority are missense or
    in-frame. Three tested missense disease variants are expressed and reach
    the ER but fail to complement TMEM16K-null cells.
  genes:
  - preferred_term: ANO10
    term:
      id: hgnc:25519
      label: ANO10
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: lower motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  molecular_functions:
  - preferred_term: phospholipid scramblase activity
    term:
      id: GO:0017128
      label: phospholipid scramblase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most patients (>80%) had loss-of-function (LOF) variants."
    explanation: Allelic spectrum across 94 patients is dominated by loss-of-function alleles.
  - reference: PMID:32620747
    reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reintroduction of wild type TMEM16K, but not human disease variants rescues the observed cellular defect."
    explanation: Missense disease alleles are functionally null in a complementation assay.
  downstream:
  - target: Impaired ER Phospholipid Scrambling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31217287
      reference_title: "Predominant localization of phosphatidylserine at the cytoplasmic leaflet of the ER, and its TMEM16K-dependent redistribution."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This Ca2+-induced PtdSer redistribution was not observed in TMEM16K-null fibroblasts, but was recovered in these cells by reexpressing TMEM16K."
      explanation: Loss of TMEM16K abolishes calcium-induced ER scrambling in cells.
  - target: Defective Endosomal Retrograde Sorting
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32620747
      reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of TMEM16K leads to dysfunction of endosomal sorting, which could be rescued by wild type TMEM16K but not mutant TMEM16K bearing the human disease point mutations causing spinocerebellar ataxia."
      explanation: Knockout fibroblasts show the sorting defect; disease alleles cannot rescue it.
  - target: Deranged Local Calcium Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27838374
      reference_title: "Cellular defects by deletion of ANO10 are due to deregulated local calcium signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here we show that Ano10 knockout in epithelial cells leads to defective ion transport, attenuated volume regulation and deranged Ca2+ signaling."
      explanation: Ano10 loss perturbs calcium signalling, shown in non-neuronal cells.
  - target: Candidate Neuronal Proteome Perturbation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42129323
      reference_title: "Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "To investigate cellular responses to ANO10 deficiency, four ANO10-mutant neuronal cell lines - a knockout and three lines harbouring recurrent SCAR10-associated pathogenic variants - were engineered using CRISPR/Cas9 editing, expanded by clonal isolation, and characterised by flow cytometry."
      explanation: Knockout and patient-variant neuronal lines were compared with controls.
  - target: Secondary Coenzyme Q10 Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The link between ANO10 loss and low CoQ10 has no proposed molecular mechanism.
    evidence:
    - reference: PMID:25182700
      reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation."
      explanation: The causal direction is the authors' inference from two patients, not an experiment.
  - target: Corticospinal Tract Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Pyramidal involvement is a consistent clinical feature; its cellular basis is not studied.
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI."
      explanation: Pyramidal signs in all ten ANO10-positive patients.
  - target: Brainstem Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38469933
      reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
      explanation: Brainstem signs in ANO10 patients; the authors infer brainstem pathology.
  - target: Retinal degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: No mechanism has been studied.
    evidence:
    - reference: PMID:25182700
      reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other."
      explanation: Ocular involvement in a genetically confirmed patient.
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25182700
      reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other."
      explanation: Cataract in a genetically confirmed patient; mechanism unstudied.
  - target: Bladder sphincter dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
      explanation: Sphincter disturbance in 3 of 10 patients; mechanism unstudied.
- name: Impaired ER Phospholipid Scrambling
  biological_scale: MOLECULAR
  description: >-
    TMEM16K is an ER-resident, calcium-regulated phospholipid scramblase with
    non-selective ion channel activity, structurally a TMEM16 scramblase rather
    than a plasma-membrane chloride channel. TMEM16K-null fibroblasts lose
    calcium-induced phosphatidylserine redistribution in the ER. The older
    description of ANO10 as a calcium-activated chloride channel is not
    supported by whole-cell recordings.
  molecular_functions:
  - preferred_term: phospholipid scramblase activity
    term:
      id: GO:0017128
      label: phospholipid scramblase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:31477691
    reference_title: "The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity."
    explanation: Reconstitution and localisation establish the normal function that is lost.
  - reference: PMID:31217287
    reference_title: "Predominant localization of phosphatidylserine at the cytoplasmic leaflet of the ER, and its TMEM16K-dependent redistribution."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This Ca2+-induced PtdSer redistribution was not observed in TMEM16K-null fibroblasts, but was recovered in these cells by reexpressing TMEM16K."
    explanation: Loss of TMEM16K abolishes ER scrambling in cells.
  - reference: PMID:31477691
    reference_title: "The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "However, the currents detected in TMEM16K-transfected cells did not differ from those seen in mock-transfected cells in either condition (Fig. 1e, f), suggesting that TMEM16K is not trafficked to PM and/or does not mediate PM Ca2+-activated currents."
    explanation: Refutes the plasma-membrane calcium-activated chloride channel model of ANO10 used in early SCAR10 reports.
  downstream:
  - target: Defective Endosomal Retrograde Sorting
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32620747
      reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites."
      explanation: Scramblase-domain chimeras tie scrambling to the sorting function.
- name: Defective Endosomal Retrograde Sorting
  biological_scale: CELLULAR
  description: >-
    TMEM16K forms ER-endosome contact sites with RAB7-positive endosomes.
    TMEM16K-null mouse fibroblasts fail to return CI-MPR and cholera toxin B
    from endosomes to the trans-Golgi network and show impaired endolysosomal
    acidification, while endocytosis and the biosynthetic pathway are
    unaffected. This has not been examined in neurons.
  biological_processes:
  - preferred_term: retrograde transport, endosome to Golgi
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
    modifier: DECREASED
  evidence:
  - reference: PMID:32620747
    reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Altogether, these data demonstrate that depletion of the ER-resident protein TMEM16K perturbs endosomal retrograde trafficking, a defect similar to that observed upon depletion of known cargo-sorting components"
    explanation: Retrograde trafficking defect in knockout fibroblasts.
  downstream:
  - target: Lower Motor Neuron and Neuromuscular Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same knockout mice have progressive neuromuscular dysfunction, but a
      causal link from the fibroblast sorting defect to neurons is not shown.
    evidence:
    - reference: PMID:32620747
      reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10."
      explanation: Co-occurrence in one model; the authors do not test causation.
  - target: Cerebellar Cortical Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Proposed by analogy with endolysosomal defects in other neurodegenerations; not tested in cerebellum.
    evidence:
    - reference: PMID:35648332
      reference_title: "ANO10 Function in Health and Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Regulation of the endolysosomal pathway is an additional ANO10 function linked to SCAR10 aetiology."
      explanation: Review states the link as a hypothesis.
- name: Deranged Local Calcium Signaling
  biological_scale: CELLULAR
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Cell Calcium and Proteostasis Dysregulation"
  description: >-
    Ano10-null epithelial cells and macrophages show deranged calcium
    signalling, reduced volume regulation and reduced apoptosis. Calcium
    dysregulation in Purkinje cells is the most often proposed SCAR10
    mechanism, but it has not been measured in Purkinje cells or any neuron.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27838374
    reference_title: "Cellular defects by deletion of ANO10 are due to deregulated local calcium signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We therefore propose that mutations in ANO10 cause cellular defects and genetic disorders through deranged local Ca2+ signaling."
    explanation: Calcium-signalling defect in Ano10-null cells, extrapolated by the authors to disease.
  - reference: PMID:42129323
    reference_title: "Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "While ANO10-mediated calcium dysregulation in Purkinje cells has been proposed to cause SCAR10, the precise pathogenic mechanism remains unclear."
    explanation: Records the Purkinje calcium hypothesis and its unproven status.
  downstream:
  - target: Cerebellar Cortical Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesised; the module's calcium-to-degeneration step is not demonstrated for ANO10.
    evidence:
    - reference: PMID:35648332
      reference_title: "ANO10 Function in Health and Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Dysregulation of calcium signalling in Purkinje cells due to ANO10 defects is proposed as the main mechanism leading to spinocerebellar ataxia autosomal recessive type 10 (SCAR10), a rare, slowly progressive spinocerebellar ataxia."
      explanation: Review statement of the proposed causal step.
- name: Candidate Neuronal Proteome Perturbation
  biological_scale: CELLULAR
  description: >-
    ANO10 knockout and patient-variant SH-SY5Y neuroblastoma lines show
    proteome changes enriched for synaptic function, cell cycle regulation,
    extracellular matrix remodelling and immune homeostasis. The authors
    present these as candidate pathways awaiting validation.
  cell_types:
  - preferred_term: neuron (SH-SY5Y neuroblastoma line)
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    modifier: DYSREGULATED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  - preferred_term: cell cycle
    term:
      id: GO:0007049
      label: cell cycle
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:42129323
    reference_title: "Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Comparative proteomic analysis revealed disruptions in synaptic function, cell cycle regulation, extracellular matrix remodelling, and immune homeostasis as candidate pathways potentially contributing to SCAR10 pathogenesis."
    explanation: Proteomic result in engineered neuronal lines.
  downstream:
  - target: Cerebellar Cortical Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Candidate contribution only; no in vivo validation.
    evidence:
    - reference: PMID:42129323
      reference_title: "Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "All four processes are functionally linked to calcium signalling, aligning with previous reports implicating abnormal calcium homeostasis in spinocerebellar ataxias."
      explanation: Authors connect the proteomic findings to the calcium hypothesis of neurodegeneration.
- name: Secondary Coenzyme Q10 Deficiency
  biological_scale: TISSUE
  description: >-
    Low CoQ10 has been reported in skeletal muscle, and in some patients in
    plasma, fibroblasts or CSF, but not systematically measured across
    cohorts. Whether it contributes to neurodegeneration, and whether it is a
    consistent feature, is unresolved.
  chemical_entities:
  - preferred_term: coenzyme Q10
    term:
      id: CHEBI:46245
      label: coenzyme Q10
    modifier: DECREASED
  evidence:
  - reference: PMID:25182700
    reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
    explanation: Muscle CoQ10 deficiency in two genetically confirmed patients.
  - reference: PMID:35648332
    reference_title: "ANO10 Function in Health and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, further investigation is needed to elucidate CoQ10 contribution to SCAR10 pathology and its therapeutic potential"
    explanation: Review flags the CoQ10 role as unresolved.
  downstream:
  - target: Decreased muscle coenzyme Q10
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25182700
      reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
      explanation: The deficiency is measured in muscle.
- name: Cerebellar Cortical Degeneration
  biological_scale: TISSUE
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    Marked cerebellar atrophy on MRI is reported in essentially every patient
    and can precede ataxia; FDG-PET shows cerebellar and frontal
    hypometabolism. No human neuropathology was found in the cited sources, so
    Purkinje cell loss is inferred from imaging and the clinical syndrome
    rather than shown histologically. The mode of cell loss is unstudied; the
    only cell-death data (Ano10-null epithelial cells and macrophages) report
    reduced rather than increased apoptosis, so no cell-death process is bound.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy."
    explanation: Imaging evidence of cerebellar degeneration in nine patients.
  - reference: PMID:35648332
    reference_title: "ANO10 Function in Health and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Brain MRI, performed on 55 patients, revealed cerebellar atrophy in all 55/55 (100%) patients, with five patients showing cortical atrophy and one patient slight brainstem atrophy, in addition to cerebellar atrophy."
    explanation: Pooled imaging across published cases.
  downstream:
  - target: Loss of Cerebellar Cortical Output
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI."
      explanation: Cerebellar atrophy and ataxia co-occur in every patient of the series.
  - target: Cerebellar atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25089919
      reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy."
      explanation: Imaging correlate of cerebellar degeneration.
  - target: Cerebellar and frontal FDG-PET hypometabolism
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35256372
      reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Furthermore, we provide evidence for a cerebellar as well as a frontal involvement on brain (18F)FDG PET scans which has not previously been reported."
      explanation: Hypometabolism maps degeneration beyond the cerebellum.
  - target: Cerebral Cortical Network Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Frontal hypometabolism may reflect cerebello-cerebral disconnection or
      primary cortical involvement; the sources do not distinguish these.
    evidence:
    - reference: PMID:35256372
      reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans."
      explanation: Frontal hypometabolism accompanies cerebellar degeneration.
- name: Loss of Cerebellar Cortical Output
  biological_scale: ORGANISM
  conforms_to: "cerebellar_purkinje_degeneration#Loss of Cerebellar Cortical Output"
  description: >-
    Cerebellar dysfunction produces the core syndrome of gait, limb and truncal
    ataxia, dysarthria and cerebellar oculomotor signs. Severe cerebellar
    atrophy can be present before ataxia is detectable on examination.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by adulthood-onset of slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (e.g. horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), increased deep tendon reflexes and progressive cognitive decline."
    explanation: Orphanet definition of the cerebellar syndrome.
  downstream:
  - target: Progressive cerebellar ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002073 | Progressive cerebellar ataxia | Very frequent (99-80%)"
      explanation: Core cerebellar sign.
  - target: Progressive gait ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007240 | Progressive gait ataxia | Frequent (79-30%)"
      explanation: Cerebellar gait ataxia.
  - target: Limb ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002070 | Limb ataxia | Frequent (79-30%)"
      explanation: Cerebellar limb ataxia.
  - target: Truncal ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002078 | Truncal ataxia | Frequent (79-30%)"
      explanation: Cerebellar truncal ataxia.
  - target: Dysarthria
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
      explanation: Cerebellar dysarthria.
  - target: Dysmetria
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001310 | Dysmetria | Frequent (79-30%)"
      explanation: Cerebellar limb dysmetria.
  - target: Intention tremor
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002080 | Intention tremor | Occasional (29-5%)"
      explanation: Cerebellar intention tremor.
  - target: Downbeat nystagmus
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010545 | Downbeat nystagmus | Frequent (79-30%)"
      explanation: Cerebellar oculomotor sign.
  - target: Pendular nystagmus
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40128498
      reference_title: "Pendular Nystagmus: a Novel Feature of ANO10-Related Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This report describes two siblings with early-onset spastic-ataxia with horizontal pendular nystagmus, ultimately diagnosed with SCAR10."
      explanation: Nystagmus subtype in ANO10 ataxia.
  - target: Dysmetric saccades
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000641 | Dysmetric saccades | Frequent (79-30%)"
      explanation: Cerebellar saccadic dysmetria.
  - target: Saccadic smooth pursuit
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001152 | Saccadic smooth pursuit | Frequent (79-30%)"
      explanation: Cerebellar pursuit deficit.
  - target: Postural tremor
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28316589
      reference_title: "A Postural Tremor Highly Responsive to Transcranial Cerebello-Cerebral DCS in ARCA3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The postural tremor of cerebellar ataxia associated with ANO10 mutation was highly responsive to tCCDCS in our patient."
      explanation: Tremor attributed to the cerebellar syndrome and modulated by cerebellar stimulation.
- name: Corticospinal Tract Dysfunction
  biological_scale: TISSUE
  description: >-
    Pyramidal signs (hyperreflexia, extensor plantar responses, clonus,
    spasticity) are frequent, giving a spastic-ataxic phenotype.
  locations:
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  evidence:
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
    explanation: Corticospinal signs in the French series.
  downstream:
  - target: Hyperreflexia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001347 | Hyperreflexia | Frequent (79-30%)"
      explanation: Corticospinal sign.
  - target: Babinski sign
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25089919
      reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
      explanation: Extensor plantar responses as corticospinal signs.
  - target: Ankle clonus
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011448 | Ankle clonus | Frequent (79-30%)"
      explanation: Corticospinal sign.
  - target: Spasticity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25089919
      reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
      explanation: Spasticity as a corticospinal sign.
- name: Lower Motor Neuron and Neuromuscular Involvement
  biological_scale: TISSUE
  description: >-
    Some patients have proximal leg wasting, fasciculations and EMG evidence
    of lower motor neuron involvement. TMEM16K knockout mice show progressive
    shrinkage of neuromuscular junctions.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement."
    explanation: Orphanet records EMG lower motor neuron findings.
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline."
    explanation: Summary of the known phenotype in the introduction of a cohort study.
  downstream:
  - target: Fasciculations
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts."
      explanation: Wasting with fasciculations reflects lower motor neuron involvement.
  - target: EMG abnormality
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement."
      explanation: EMG shows the lower motor neuron involvement.
  - target: Pes cavus
    causal_link_type: UNKNOWN
    description: Pes cavus usually reflects long-standing distal weakness; its origin in SCAR10 is not studied.
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
      explanation: Pes cavus in 4 of 10 patients; its cause is not studied.
- name: Brainstem Involvement
  biological_scale: TISSUE
  description: >-
    Facial muscle involvement, strabismus, ptosis, vertical gaze paresis and,
    rarely, vocal cord paralysis or inspiratory stridor suggest brainstem
    involvement in a subset of patients.
  locations:
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  evidence:
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
    explanation: Brainstem pathology is the authors' interpretation of new clinical signs.
  downstream:
  - target: Strabismus
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38469933
      reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
      explanation: Strabismus is one of the signs taken to indicate brainstem pathology.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
      explanation: Ptosis is frequent; attribution to brainstem involvement is inferred.
  - target: Vertical gaze paresis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
      explanation: Vertical gaze paresis in 5 of 10 patients; attribution to brainstem involvement is inferred.
  - target: Vocal cord paralysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34969792
      reference_title: "Vocal cord paralysis as a presenting sign of autosomal recessive spinocerebellar atrophy type 10."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Here we report a 41-year-old man with spinocerebellar atrophy, autosomal recessive type 10 (SCAR10) due to an autosomal recessive mutation in the ANO10 gene, with VCP as the presenting symptom."
      explanation: >-
        Vocal cord paralysis is reported in SCAR10, but the lesion site (brainstem
        nucleus or peripheral recurrent laryngeal nerve) is not established, so
        the edge from brainstem involvement is an inference.
  - target: Inspiratory stridor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:284289
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts."
      explanation: Stridor is a variable feature; attribution to brainstem involvement is inferred.
- name: Cerebral Cortical Network Dysfunction
  biological_scale: TISSUE
  description: >-
    Executive and attentional deficits, broader cognitive decline in some
    families, epilepsy, cortical reflex myoclonus physiology (giant SEPs) and
    bradykinesia indicate involvement beyond the cerebellum, with frontal
    hypometabolism on FDG-PET.
  locations:
  - preferred_term: frontal lobe
    term:
      id: UBERON:0016525
      label: frontal lobe
  evidence:
  - reference: PMID:35256372
    reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans."
    explanation: Frontal hypometabolism in two patients.
  downstream:
  - target: Impaired executive functioning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35256372
      reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients had onset of cerebellar ataxia in adulthood with slow progression and presented corticospinal tract signs, eye movement abnormalities and cognitive executive impairment."
      explanation: Executive impairment in the patients with frontal hypometabolism.
  - target: Cognitive impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31423897
      reference_title: "Cognitive characterization of SCAR10 caused by a homozygous c.132dupA mutation in the ANO10 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cognitive impairment seems to be a characteristic of the SCAR10 produced by this mutation, with a range from mild impairment, especially involving prefrontal systems, to a severe cognitive impairment suggesting widespread cerebral involvement."
      explanation: Authors attribute the cognitive deficits to prefrontal and wider cerebral involvement.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27045840
      reference_title: "Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, epilepsy and porencephalic cysts were also described in our ARCA3 patients, the cyst thus expanding the clinical phenotype of ARCA3 patients due to ANO10 mutation."
      explanation: Epilepsy as part of the extracerebellar phenotype.
  - target: Giant somatosensory evoked potentials
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures."
      explanation: Cortical hyperexcitability.
  - target: Bradykinesia
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:30515630
      reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
      explanation: Bradykinesia in 7 of 10 patients; its substrate is not studied.
phenotypes:
- category: Neurological
  name: Progressive cerebellar ataxia
  description: >-
    Slowly progressive ataxia is present in all patients; onset is usually
    adult (mean 33 years, range 17-43 in the French series; 27-53 in the
    Italian series), about 14 years earlier in Romani c.1150_1151del
    homozygotes. Disability is severe by the sixth decade.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    onset:
      onset_category: ADULT
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002073 | Progressive cerebellar ataxia | Very frequent (99-80%)"
    explanation: Orphanet frequency annotation.
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow."
    explanation: Onset age and slow progression.
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants."
    explanation: Earlier onset in the Romani founder group.
- category: Neurological
  name: Progressive gait ataxia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive gait ataxia
    term:
      id: HP:0007240
      label: Progressive gait ataxia
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007240 | Progressive gait ataxia | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Limb ataxia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002070 | Limb ataxia | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Truncal ataxia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Truncal ataxia
    term:
      id: HP:0002078
      label: Truncal ataxia
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002078 | Truncal ataxia | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Dysarthria
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
  - reference: PMID:25182700
    reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade."
    explanation: Progressive dysarthria in two patients.
- category: Ophthalmologic
  name: Downbeat nystagmus
  description: >-
    Downbeat and gaze-evoked nystagmus are characteristic and can be the only
    examination finding at presentation, together with severe cerebellar
    atrophy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Downbeat nystagmus
    term:
      id: HP:0010545
      label: Downbeat nystagmus
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010545 | Downbeat nystagmus | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
  - reference: PMID:42702636
    reference_title: "Downbeat nystagmus without ataxia as an early manifestation of spinocerebellar ataxia, autosomal recessive type 10 (SCAR10): a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated."
    explanation: Downbeat nystagmus as an isolated early sign.
- category: Ophthalmologic
  name: Pendular nystagmus
  description: Horizontal pendular nystagmus reported in siblings with early-onset spastic ataxia.
  phenotype_term:
    preferred_term: Horizontal pendular nystagmus
    term:
      id: HP:0012043
      label: Pendular nystagmus
  evidence:
  - reference: PMID:40128498
    reference_title: "Pendular Nystagmus: a Novel Feature of ANO10-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes two siblings with early-onset spastic-ataxia with horizontal pendular nystagmus, ultimately diagnosed with SCAR10."
    explanation: Case report of the nystagmus subtype.
- category: Ophthalmologic
  name: Dysmetric saccades
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysmetric (hypermetric) saccades
    term:
      id: HP:0000641
      label: Dysmetric saccades
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000641 | Dysmetric saccades | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Ophthalmologic
  name: Saccadic smooth pursuit
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Saccadic smooth pursuit
    term:
      id: HP:0001152
      label: Saccadic smooth pursuit interruptions
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001152 | Saccadic smooth pursuit | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Dysmetria
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001310 | Dysmetria | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Intention tremor
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002080 | Intention tremor | Occasional (29-5%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Postural tremor
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:28316589
    reference_title: "A Postural Tremor Highly Responsive to Transcranial Cerebello-Cerebral DCS in ARCA3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aim of this study is to report a patient with a marked postural tremor responding to transcranial cerebello-cerebral direct current stimulation (tCCDCS)."
    explanation: Marked postural tremor in an ANO10 patient.
- category: Neurological
  name: Cerebellar atrophy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI."
    explanation: Cerebellar atrophy in all ten patients.
  - reference: PMID:42702636
    reference_title: "Downbeat nystagmus without ataxia as an early manifestation of spinocerebellar ataxia, autosomal recessive type 10 (SCAR10): a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy."
    explanation: Atrophy can precede clinical ataxia.
- category: Neurological
  name: Cerebellar and frontal FDG-PET hypometabolism
  phenotype_term:
    preferred_term: Cerebellar and frontal hypometabolism on FDG-PET
    term:
      id: HP:0012658
      label: Abnormal brain FDG positron emission tomography
  evidence:
  - reference: PMID:35256372
    reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans."
    explanation: Only two patients have been imaged with FDG-PET in the cited sources.
- category: Neurological
  name: Hyperreflexia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001347 | Hyperreflexia | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Babinski sign
  phenotype_term:
    preferred_term: Extensor plantar response
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity."
    explanation: Extensor plantar responses among frequent corticospinal signs.
- category: Neurological
  name: Ankle clonus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ankle clonus
    term:
      id: HP:0011448
      label: Ankle clonus
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011448 | Ankle clonus | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: Spasticity
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:35110481
    reference_title: "Autosomal Recessive Spinocerebellar Ataxia Type 10: A Report of a New Case in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case presented with adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline."
    explanation: Spastic ataxia phenotype.
- category: Neurological
  name: Fasciculations
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002380 | Fasciculations | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Neurological
  name: EMG abnormality
  frequency: FREQUENT
  phenotype_term:
    preferred_term: EMG evidence of lower motor neuron involvement
    term:
      id: HP:0003457
      label: EMG abnormality
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003457 | EMG abnormality | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Musculoskeletal
  name: Pes cavus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
    explanation: Pes cavus in 4 of 10 patients.
- category: Ophthalmologic
  name: Strabismus
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:38469933
    reference_title: "ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis."
    explanation: Strabismus newly recognised in the MDSGene series.
- category: Ophthalmologic
  name: Ptosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
    explanation: Orphanet frequency annotation.
- category: Ophthalmologic
  name: Vertical gaze paresis
  description: Mild vertical gaze paresis in half of an Italian cohort; supranuclear origin was not specified.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mild vertical gaze paresis
    term:
      id: HP:0000597
      label: Ophthalmoparesis
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
    explanation: Vertical gaze paresis in 5 of 10 patients.
- category: Respiratory
  name: Vocal cord paralysis
  description: Presenting sign in one 41-year-old man before ataxia developed.
  phenotype_term:
    preferred_term: Vocal cord paralysis
    term:
      id: HP:0001605
      label: Vocal cord paralysis
  evidence:
  - reference: PMID:34969792
    reference_title: "Vocal cord paralysis as a presenting sign of autosomal recessive spinocerebellar atrophy type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a 41-year-old man with spinocerebellar atrophy, autosomal recessive type 10 (SCAR10) due to an autosomal recessive mutation in the ANO10 gene, with VCP as the presenting symptom."
    explanation: Single case report.
- category: Respiratory
  name: Inspiratory stridor
  phenotype_term:
    preferred_term: Inspiratory stridor
    term:
      id: HP:0010307
      label: Stridor
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts."
    explanation: Orphanet lists inspiratory stridor as a variable feature.
- category: Neurological
  name: Impaired executive functioning
  description: >-
    Executive and attentional deficits occur even with a normal MMSE and are
    the most consistent cognitive finding.
  phenotype_term:
    preferred_term: Executive dysfunction
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions."
    explanation: Executive deficits in 6 of 10 patients.
  - reference: PMID:27045840
    reference_title: "Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We reported for the first time the neuropsychological profile of 2 ARCA3 patients showing an adult-onset executive and attentional syndrome."
    explanation: Executive and attentional syndrome in two siblings.
- category: Neurological
  name: Cognitive impairment
  description: >-
    Ranges from mild prefrontal impairment to global intellectual decline,
    the latter notably in Romani c.1150_1151del and some c.132dupA homozygotes.
  phenotype_term:
    preferred_term: Cognitive decline
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:31423897
    reference_title: "Cognitive characterization of SCAR10 caused by a homozygous c.132dupA mutation in the ANO10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive impairment seems to be a characteristic of the SCAR10 produced by this mutation, with a range from mild impairment, especially involving prefrontal systems, to a severe cognitive impairment suggesting widespread cerebral involvement."
    explanation: Spectrum of cognitive impairment in three siblings.
  - reference: PMID:22008874
    reference_title: "ANO10 c.1150_1151del is a founder mutation causing autosomal recessive cerebellar ataxia in Roma/Gypsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe additional patients from neighbouring Bulgaria, outlining invariable ANO10-ataxia features and confirming global intellectual decline as part of the phenotype resulting from complete Anactomin 10 deficit."
    explanation: Intellectual decline in Romani founder-allele patients.
- category: Neurological
  name: Seizure
  description: Generalized or focal (including temporal lobe) epilepsy in a minority of patients.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27045840
    reference_title: "Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The objective of this study was to describe the phenotype of 2 siblings with compound heterozygous ANO10 mutations and progressive cerebellar ataxia, epilepsy, and cognitive impairment."
    explanation: Epilepsy in two siblings.
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002197 | Generalized-onset seizure | Frequent (79-30%)"
    explanation: Orphanet annotates generalized-onset seizures as frequent.
  - reference: PMID:35256372
    reference_title: "Widening the spectrum of spinocerebellar ataxia autosomal recessive type 10 (SCAR10)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of them had temporal lobe epilepsy and she also carried a heterozygous variant in CACNB4, a potential risk gene for epilepsy."
    explanation: Focal epilepsy, possibly modified by a second variant.
- category: Neurological
  name: Giant somatosensory evoked potentials
  phenotype_term:
    preferred_term: Giant somatosensory evoked potentials
    term:
      id: HP:0001312
      label: Giant somatosensory evoked potentials
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures."
    explanation: Cortical hyperexcitability in 3 of 10 patients.
- category: Neurological
  name: Bradykinesia
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
    explanation: Bradykinesia in 7 of 10 patients.
- category: Genitourinary
  name: Bladder sphincter dysfunction
  description: Sphincteric (vesicorectal) disturbance in a minority of patients.
  phenotype_term:
    preferred_term: Sphincter (vesicorectal) dysfunction
    term:
      id: HP:0002839
      label: Urinary bladder sphincter dysfunction
  evidence:
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10)."
    explanation: Sphincter disturbance in 3 of 10 patients.
  - reference: PMID:35110481
    reference_title: "Autosomal Recessive Spinocerebellar Ataxia Type 10: A Report of a New Case in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This disorder is characterized by slowly progressive cerebellar ataxia and pyramidal signs inconstantly associated with cognitive decline, polyneuropathy, epilepsy, and vesicorectal dysfunction."
    explanation: Introductory summary of the variable features.
- category: Ophthalmologic
  name: Retinal degeneration
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence:
  - reference: PMID:25182700
    reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other."
    explanation: Retinal degeneration in one patient.
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000608 | Macular degeneration | Frequent (79-30%)"
    explanation: Orphanet annotates macular degeneration as frequent.
- category: Ophthalmologic
  name: Cataract
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:284289
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Occasional (29-5%)"
    explanation: Orphanet frequency annotation.
- category: Metabolic
  name: Decreased muscle coenzyme Q10
  description: >-
    Reported in some patients; not systematically measured, so its frequency
    is unknown.
  phenotype_term:
    preferred_term: Decreased muscle coenzyme Q10
    term:
      id: HP:0034369
      label: Decreased level of coenzyme Q10 in skeletal muscle
  evidence:
  - reference: PMID:25182700
    reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
    explanation: Muscle CoQ10 deficiency in two patients.
  - reference: PMID:31477691
    reference_title: "The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "SCAR10 causes cerebellar ataxia, with cerebellar atrophy evident in magnetic resonance imaging scans of brains and coenzyme Q10 deficiency found in muscle biopsy, fibroblasts and cerebrospinal fluid"
    explanation: Background summary of where low CoQ10 has been found.
genetic:
- name: ANO10
  gene_term:
    preferred_term: ANO10
    term:
      id: hgnc:25519
      label: ANO10
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Over 40 SCAR10-associated variants are reported (NM_018075.5), more than
    80% loss-of-function. Recurrent alleles: c.1150_1151del (p.Leu384fs), a
    Romani founder allele found homozygous in all Romani patients and
    associated with earlier onset and intellectual decline; c.132dupA
    (p.Asp45Argfs*9), the most frequent allele in the French series and
    described there as never homozygous, though a later sibship was
    homozygous for it. Missense and splice-altering alleles include
    p.Leu510Arg (the original Dutch family), c.1163-9A>G and p.Met622Val.
    No ClinGen gene-disease validity record for this pair was found in the
    local cache.
  evidence:
  - reference: PMID:21092923
    reference_title: "Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10)."
    explanation: Gene discovery in the Dutch family; Serbian and French families carried further alleles.
  - reference: PMID:22008874
    reference_title: "ANO10 c.1150_1151del is a founder mutation causing autosomal recessive cerebellar ataxia in Roma/Gypsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the history and population genetics of the Roma/Gypsies, we hypothesised that p.Leu384fs could be another founder mutation in this population, whose identification in a larger number of genetically homogeneous patients will contribute to defining the phenotypic spectrum of the disorder."
    explanation: Romani founder allele.
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity."
    explanation: Most frequent allele in the French series.
  - reference: PMID:31423897
    reference_title: "Cognitive characterization of SCAR10 caused by a homozygous c.132dupA mutation in the ANO10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive spinocerebellar ataxia type 10 (SCAR10) caused by a homozygous c.132dupA mutation in the anoctamin 10 gene is infrequent and little is known about its cognitive profile."
    explanation: c.132dupA does occur homozygously, contrary to the earlier French observation.
  - reference: PMID:36698452
    reference_title: "Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in ANO10 (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein."
    explanation: Intronic splice allele with absent protein.
  - reference: PMID:30515630
    reference_title: "ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel."
    explanation: Diagnostic yield of 10% among adult-onset sporadic or recessive ataxia.
animal_models:
- name: TMEM16K knockout mouse
  species: Mus musculus
  genotype: Ano10 (TMEM16K) knockout, ubiquitous and neuron-specific
  publication: PMID:32620747
  modeled_mechanisms:
  - target: Defective Endosomal Retrograde Sorting
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Knockout embryonic fibroblasts show the endosome-to-Golgi retrograde trafficking defect.
    limitations: >-
      Measured in fibroblasts, not in cerebellar neurons; the defect has not
      been shown in patient cells.
    evidence:
    - reference: PMID:32620747
      reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of TMEM16K leads to impaired endosomal retrograde trafficking and dysfunction in the endolysosomal pathway."
      explanation: Cellular phenotype of knockout cells.
  - target: Lower Motor Neuron and Neuromuscular Involvement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Progressive neuromuscular junction shrinkage, hindlimb clasping and impaired ledge walking.
    limitations: >-
      Coordination was assessed only by hindlimb clasping and ledge walking;
      cerebellar histology, Purkinje cell counts and gait analysis are not
      reported, so the model does not establish cerebellar degeneration.
    evidence:
    - reference: PMID:32620747
      reference_title: "TMEM16K is an interorganelle regulator of endosomal sorting."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we find that TMEM16K knockout mice display defects in neuromuscular function and motor behaviors, corresponding to ataxic phenotypes observed in human patients."
      explanation: Motor phenotype of the knockout mouse.
- name: Ano10 null mouse
  species: Mus musculus
  genotype: Ano10-/-
  publication: PMID:27838374
  modeled_mechanisms:
  - target: Deranged Local Calcium Signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Intestinal epithelial cells and peritoneal macrophages from null mice show calcium-signalling, volume-regulation and apoptosis defects.
    limitations: >-
      Only epithelial cells and macrophages were studied; no neuronal or
      neurological phenotype is reported.
    evidence:
    - reference: PMID:27838374
      reference_title: "Cellular defects by deletion of ANO10 are due to deregulated local calcium signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Similar defects were found in mouse peritoneal Ano10 null macrophages and in human THP1 macrophages with reduced ANO10 expression."
      explanation: Ex vivo cells from null mice.
experimental_models:
- name: ANO10-mutant SH-SY5Y neuronal lines
  experimental_model_type: CELL_LINE
  description: >-
    CRISPR/Cas9-engineered SH-SY5Y neuroblastoma lines (one knockout and three
    carrying recurrent SCAR10 variants) profiled by mass-spectrometry
    proteomics.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:42129323
  modeled_mechanisms:
  - target: Candidate Neuronal Proteome Perturbation
    relationship: MEASURES
    fidelity: LOW
    model_scale: CELLULAR
    description: Proteome-wide differences between control and mutant lines.
    limitations: >-
      A proliferating neuroblastoma line, not Purkinje cells; findings are
      correlative candidate pathways without functional validation.
    evidence:
    - reference: PMID:42129323
      reference_title: "Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings offer a foundation for further investigation and experimental validation, with potential implications for the development of targeted therapeutic approaches."
      explanation: Authors frame the results as requiring validation.
diagnosis:
- name: Brain MRI
  description: >-
    Marked cerebellar atrophy is present in essentially all patients and may
    precede ataxia. Absence of peripheral neuropathy helps distinguish ANO10
    ataxia from other recessive ataxias.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:25089919
    reference_title: "Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An ANO10 mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy."
    explanation: Diagnostic profile of ANO10 ataxia.
- name: Multigene panel or exome sequencing
  description: >-
    Diagnosis is by sequencing ANO10, usually within an ataxia or
    movement-disorder gene panel or exome; ANO10 accounted for 10% of a
    cohort of sporadic or recessive adult-onset ataxia.
  diagnosis_term:
    preferred_term: multi-gene panel sequencing
    term:
      id: NCIT:C198412
      label: Multi-gene Panel Sequencing
  evidence:
  - reference: PMID:30838263
    reference_title: "Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genetic diagnosis in this family was obtained through next-generation sequencing techniques after over 10 years of expensive sequencing of individual genes using the traditional Sanger approach."
    explanation: Next-generation sequencing ended a long diagnostic odyssey.
  - reference: PMID:25182700
    reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10"
    explanation: Exome sequencing identified the diagnosis.
treatments:
- name: Coenzyme Q10 Supplementation
  description: >-
    Proposed because of secondary CoQ10 deficiency. Evidence is limited to
    open-label case reports with variable or no benefit; no controlled trial
    exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Decreased muscle coenzyme Q10
    term:
      id: HP:0034369
      label: Decreased level of coenzyme Q10 in skeletal muscle
  target_mechanisms:
  - target: Secondary Coenzyme Q10 Deficiency
    description: Replaces the deficient cofactor.
    evidence:
    - reference: PMID:25182700
      reference_title: "ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation."
      explanation: Rationale for supplementation, not an outcome.
  evidence:
  - reference: PMID:36698452
    reference_title: "Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two years after treatment with CoQ10, her ataxia had clearly improved, but she showed mild signs of lower limb spasticity."
    explanation: Uncontrolled improvement in one patient.
  - reference: PMID:36698452
    reference_title: "Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "CoQ10 supplementation has had mixed success with at least 1 patient showing no improvement."
    explanation: Benefit is inconsistent across reported patients.
  - reference: PMID:35648332
    reference_title: "ANO10 Function in Health and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CoQ10 supplementation was beneficial for some patients, improving their mobility, cognition or fatigue symptoms."
    explanation: Review of open-label reports.
  - reference: PMID:36698452
    reference_title: "Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "CoQ10 deficiency has been reported in several patients with ANO10 variants and supplementation with CoQ10 improved patient mobility and epilepsy, supporting the possibility of an underlying mitochondrial impairment as a consequence of ANO10 dysfunction."
    explanation: Summarises reported effects on mobility and epilepsy.
- name: Cerebello-Cerebral Transcranial Direct Current Stimulation
  description: >-
    Anodal cerebellar tDCS with a contralateral motor cortex return electrode
    markedly reduced postural tremor in one patient, compared with baseline
    and sham.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: transcranial cerebello-cerebral direct current stimulation
    term:
      id: NCIT:C129862
      label: Transcranial Direct Current Stimulation
  target_phenotypes:
  - preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:28316589
    reference_title: "A Postural Tremor Highly Responsive to Transcranial Cerebello-Cerebral DCS in ARCA3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dramatic response of postural tremor was observed after tCCDCS, with a major drop of the power spectral density to 26.12% of basal values."
    explanation: Single-patient response.
- name: Rehabilitation and Supportive Care
  description: >-
    No disease-modifying therapy exists; management is physiotherapy, speech
    therapy, antiseizure treatment where needed and genetic counselling.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Progressive gait ataxia
    term:
      id: HP:0007240
      label: Progressive gait ataxia
  - preferred_term: Truncal ataxia
    term:
      id: HP:0002078
      label: Truncal ataxia
  - preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  notes: >-
    No ANO10-specific rehabilitation study was found; the recommendation
    follows general management of degenerative ataxias.
notes: >-
  MONDO:0013392 corresponds to OMIM 613728 and ORPHA:284289. Not to be
  confused with spinocerebellar ataxia 10 (SCA10), the dominant ATXN10
  pentanucleotide-repeat disorder. Peripheral neuropathy is absent in most
  series (none of nine French patients), although polyneuropathy is listed
  among inconstant features in some reports.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal_Recessive_Spinocerebellar_Ataxia_10 · 2026-10-15T13:06:16Z · View source

New entry for SCAR10 (ANO10/TMEM16K). Started from the Perplexity deep-research report (research/Autosomal_Recessive_Spinocerebellar_Ataxia_10-deep-research-perplexity.md), used as a lead list only; its suggested HPO/GO CURIEs were not reused where its term-validation section flagged them, and every term was looked up in cache or OLS. Evidence comes from 23 PubMed records found via the report and NCBI esearch (gene discovery, Romani founder allele, French/Italian/MDSGene cohorts, case reports, TMEM16K scramblase structure and endosomal-sorting knockout mouse, Ano10-null calcium signalling, SH-SY5Y proteomics, ANO10 review) plus the Orphanet record ORPHA:284289 for phenotype frequencies. Pathograph: ANO10 loss of function -> ER scramblase loss, endosomal retrograde sorting defect, deranged calcium signalling, candidate proteome changes and secondary CoQ10 deficiency -> cerebellar cortical degeneration (conforms to cerebellar_purkinje_degeneration) -> loss of cerebellar output -> ataxia phenotypes; separate corticospinal, lower motor neuron, brainstem and cerebral cortical branches. Purkinje-cell involvement is recorded as proposed/inferred because no neuropathology or neuronal calcium data exist. Contested points carry REFUTE items: the plasma-membrane chloride-channel model (whole-cell recordings), CoQ10 supplementation benefit. All 33 phenotypes are causally connected. Validation: just validate, validate-terms, check-entity-refs, check-causal-targets, check-folded-hyphens, check-coarse-phenotypes and validate-disorders pass; 137/137 snippets verified. check-genereviews reports no GeneReviews chapter.

Perplexity ▸
Autosomal Recessive Spinocerebellar Ataxia 10 (SCAR10): Comprehensive Disease Characteristics Report
sonar-deep-research 21 citations 2026-10-15T12:41:51.628229

Autosomal Recessive Spinocerebellar Ataxia 10 (SCAR10): Comprehensive Disease Characteristics Report

Autosomal recessive spinocerebellar ataxia 10 (SCAR10), also known as adult-onset autosomal recessive cerebellar ataxia associated with ANO10, is a very rare monogenic neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, pyramidal signs, oculomotor abnormalities, and variable cognitive decline, peripheral neuropathy, epilepsy, and bladder or bowel dysfunction.[4][5][9] At the molecular level, SCAR10 is caused by biallelic loss-of-function variants in the ANO10 gene, which encodes anoctamin 10 (TMEM16K), a broadly expressed member of the calcium-activated chloride channel family with particularly high expression in the cerebellum and cerebral cortex.[14][18] Clinical series and case reports since the first description in 2010 have refined the phenotype, highlighted coenzyme Q10 (CoQ10) deficiency as a potentially treatable biochemical feature, and increasingly documented extracebellar involvement including corticospinal tract signs, frontal lobe hypometabolism, and motor neuron involvement.[10][15][19] Recent in vitro work using CRISPR/Cas9-engineered ANO10-deficient neuronal cell lines has provided the first proteomic map of SCAR10-related cellular perturbations, implicating disrupted synaptic function, cell cycle regulation, extracellular matrix remodeling, and immune homeostasis as calcium-linked pathways that may drive neurodegeneration.[7] This report synthesizes current knowledge across clinical, genetic, mechanistic, and translational domains to support structured representation of SCAR10 in a disease knowledge base, with explicit attention to ontology mapping (MONDO, HPO, GO, CL, UBERON, NCIT), evidence types, and remaining knowledge gaps.

1. Disease Information

1.1 Definition and Clinical Overview

Autosomal recessive spinocerebellar ataxia 10 (SCAR10) is an inherited neurodegenerative ataxia that primarily affects the cerebellum and corticospinal tracts, leading to progressive impairment of gait, limb coordination, speech, and eye movements.[5][10][12] OMIM describes SCAR10 (MIM #613728) as “an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging,” based on the original multi-family description by Vermeer et al. in 2010 (Am J Hum Genet 87:813–819, PMID: 21092923).[10][14] Orphanet similarly defines “adult-onset autosomal recessive cerebellar ataxia” under ORPHA:284289—explicitly equating it with SCAR10—as a rare cerebellar ataxia presenting in adulthood with slowly progressive spinocerebellar ataxia, gait and appendicular ataxia, dysarthria, ocular movement anomalies, increased deep tendon reflexes, and progressive cognitive decline, with additional variable features such as proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration, cataracts, and lower motor neuron involvement on EMG.[9] MedGen (Concept ID C3150998) echoes this definition and emphasizes the autosomal recessive inheritance and ANO10 locus on chromosome 3p22.1–p21.33.[3][5]

Clinically, SCAR10 belongs to the broader category of autosomal recessive cerebellar ataxias (ARCA) and autosomal recessive spinocerebellar ataxias (SCAR), which are characterized by progressive cerebellar degeneration often accompanied by involvement of corticospinal tracts, peripheral nerves, and sometimes extra-neurological systems.[4][12][17] SCAR10 is among the better-defined but still extremely rare subtypes, with prevalence estimated by Orphanet at less than 1 per 1,000,000 in the general population.[9] The disorder typically begins in late adolescence or early adulthood, although reported onset ages range from early teens to the fourth decade, and progression is generally slow over many years.[4][5][10] Neuroimaging consistently shows marked cerebellar atrophy, and newer functional imaging data reveal hypometabolism not only in the cerebellum but also in the frontal lobes, suggesting broader network involvement.[1][19]

It is important to distinguish SCAR10 from spinocerebellar ataxia 10 (SCA10), an autosomal dominant repeat expansion disorder caused by ATTCT pentanucleotide expansion in the ATXN10 gene on chromosome 22q13.31 (OMIM #603516), which has a different inheritance pattern, genetic mechanism, and phenotype.[2][6] The use of “spinocerebellar ataxia 10” in older literature without explicit reference to autosomal recessive inheritance or ANO10 can cause confusion; current classifications (OMIM, Orphanet, MedGen, GeneReviews) consistently reserve “SCAR10” or “autosomal recessive spinocerebellar ataxia 10” for the ANO10-linked recessive disorder.[5][9][10][12]

1.2 Key Identifiers and Ontology Mapping

SCAR10 is referenced across multiple biomedical databases with a fairly consistent set of identifiers and synonyms, which facilitates ontology alignment for knowledge-base representation. OMIM assigns phenotype entry #613728 to “Spinocerebellar ataxia, autosomal recessive 10” and links it to the ANO10 gene (MIM #613726) at 3p22.1–p21.33.[10][14] Orphanet lists “Adult-onset autosomal recessive cerebellar ataxia” with ORPHA:284289 and explicitly notes “Autosomal recessive spinocerebellar ataxia type 10; SCAR10” as synonyms.[9] MedGen maps the concept “Autosomal recessive spinocerebellar ataxia 10” to UMLS C3150998 with ANO10 as the associated gene and cross-references OMIM 613728.[3][5]

The disease is included in the Mondo Disease Ontology as MONDO:0013392 (“autosomal recessive spinocerebellar ataxia 10”), as noted in ClinGen’s Gene Curation Coalition (GenCC) submissions confirming the gene–disease relationship.[11][16] SNOMED CT includes terms such as “SCAR10 - autosomal recessive spinocerebellar ataxia type 10” and “Adult-onset autosomal recessive cerebellar ataxia” under codes like 785302009.[3][9] ICD-10 coding generally uses G11.2 (“hereditary ataxia”) as the most appropriate category, consistent with Orphanet’s mapping.[9] There is not yet an ICD-11-specific code uniquely dedicated to SCAR10; instead, it would fall under hereditary or degenerative ataxia groupings. In Human Phenotype Ontology (HPO), SCAR10 is associated with terms such as “Ataxia” (HP:0001251), “Gait ataxia” (HP:0002066), “Cerebellar atrophy” (HP:0001272), “Dysarthria” (HP:0001260), “Nystagmus” (HP:0000639), “Hyperreflexia” (HP:0001347), and “Coenzyme Q10 deficiency” (HP:0004311).[5][12][15]

From a gene standpoint, ANO10 is recorded in HGNC as “ANO10” (HGNC ID corresponding to gene symbol ANO10) and in NCBI Gene as Gene ID 55129 (“anoctamin 10”), described as encoding a transmembrane protein in the TMEM16/anoctamin family of calcium-activated chloride channels.[18][14] This gene is directly associated with SCAR10 in ClinGen/GenCC, OMIM, MedGen, Orphanet, and GeneReviews.[5][10][12][16] Collectively, these identifiers provide a coherent ontology backbone for SCAR10 that can be mapped to MONDO, UMLS, SNOMED CT, ICD-10, HPO, HGNC, and other vocabularies.

1.3 Synonyms and Alternative Names

SCAR10 has accumulated several synonyms reflecting its discovery history and evolving nosology. OMIM notes that “autosomal recessive spinocerebellar ataxia-10 (SCAR10) is also known as autosomal recessive cerebellar ataxia type 3 (ARCA3).”[4][10] Orphanet lists “Autosomal recessive spinocerebellar ataxia type 10” and “SCAR10” as synonyms for “Adult-onset autosomal recessive cerebellar ataxia.”[9] MedGen similarly enumerates “Autosomal recessive spinocerebellar ataxia type 10; autosomal recessive spinocerebellar ataxia type 10 (SCAR10); Spinocerebellar ataxia, autosomal recessive 10” under a single concept ID.[3][5]

Early genetic reports also refer to “autosomal recessive cerebellar ataxia type 3 (ARCA3)” and “autosomal recessive spinocerebellar ataxia type 10” as essentially synonymous entities linked to ANO10 mutations.[4][10][19] GeneReviews includes SCAR10 within the broader category of autosomal recessive cerebellar ataxias and abbreviates it as “SCAR10 (ANO10-related ARCA).”[12][17] In clinical practice, “ANO10-related ataxia” or “ANO10-associated autosomal recessive cerebellar ataxia” are sometimes used to emphasize the genetic basis. All of these terms refer to the same ANO10-driven disorder and should be harmonized in a knowledge base to avoid duplication.

1.4 Nature of Information Sources

Current knowledge about SCAR10 is derived almost entirely from aggregated analyses of individual patients, including family-based linkage studies, case reports, small case series, and a few gene-focused screening cohorts, rather than large registries or population-level datasets. The foundational description by Vermeer et al. (2010, Am J Hum Genet, PMID: 21092923) involved linkage analysis and targeted next-generation sequencing in a few consanguineous families, culminating in the identification of ANO10 mutations as the cause of autosomal recessive cerebellar ataxia.[10][14][16] Subsequent reports such as Balreira et al. (2014, J Neurol, PMID: 25182700) and Nanetti et al. (2019, J Neurol, PMID: 30515630) add additional families and refine phenotypic details, but each involves relatively small numbers of affected individuals.[15][18][19]

Orphanet and MedGen synthesize data from these published cases and expert-curated resources into disease-level summaries, and ClinGen/GenCC provides structured gene–disease validity assessments based on the same underlying body of literature.[3][5][11][16] The rare nature of SCAR10 means that large-scale epidemiological studies, randomized clinical trials, and longitudinal registries have not yet been reported. Thus, most clinical statistics (such as prevalence, age of onset distributions, and phenotype frequencies) are inferred from a small number of patients and should be considered approximations. Mechanistic data, by contrast, increasingly include in vitro experimental results, particularly the recent proteomic profiling of ANO10-deficient neuronal cell lines, but still lack extensive in vivo animal model characterization in the provided sources.[7]

2. Etiology

2.1 Primary Causal Factors: ANO10 Variants

SCAR10 is fundamentally a Mendelian monogenic disorder caused by biallelic pathogenic variants in the ANO10 gene, encoding the anoctamin 10 / TMEM16K protein.[4][5][10] OMIM states explicitly that “autosomal recessive spinocerebellar ataxia-10 (SCAR10) is caused by homozygous or compound heterozygous mutation in the ANO10 gene (613726) on chromosome 3p22,” based on genetic linkage and sequencing data from three unrelated families in which affected individuals carried such variants.[10][14] Vermeer et al. demonstrated that, in a remotely consanguineous Dutch family with autosomal recessive cerebellar ataxia, homozygosity mapping identified a 12.5 Mb region on chromosome 3p, and targeted next-generation sequencing within this interval revealed homozygous or compound heterozygous ANO10 mutations segregating with disease.[10][14][16] In additional consanguineous families of Romani origin, similar homozygous ANO10 variants were found in affected siblings with cerebellar ataxia, confirming the causal relationship.[10][14]

Subsequent studies have consistently linked ANO10 mutations to SCAR10 phenotypes. Balreira et al. identified compound heterozygous ANO10 variants in two adults with cerebellar ataxia and CoQ10 deficiency, noting that “mutations in ANO10… [are] the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10)” and that the variants segregated with disease in their families.[15][18] Nanetti et al. performed mutational screening in recessive ataxia cohorts and confirmed that ANO10 mutations account for a subset of unexplained ataxia cases, helping refine the clinical phenotype.[18][19] ClinGen’s GenCC curation summarizes that there is “definitive evidence supporting the relationship between ANO10 and autosomal recessive cerebellar ataxia,” based on replicated findings in both research and diagnostic settings over time.[16][11]

At the molecular level, the ANO10 protein is a member of the anoctamin (TMEM16) family of presumed calcium-activated chloride channels, with eight transmembrane domains and cytosolic N- and C-termini.[14][18] Quantitative expression analyses show that ANO10 is highly expressed in adult brain, especially cerebellum and frontal and occipital cortices, with lower expression in fetal brain, and is also found in retina and heart, consistent with the neurological and sometimes ophthalmologic manifestations of SCAR10.[14] The causal factor in SCAR10 is therefore a germline, biallelic loss-of-function in ANO10 leading to disruption of calcium-dependent membrane transport functions in neurons and possibly other cell types, as expanded in the mechanistic section.

2.2 Genetic Risk Factors and Variant Spectrum

Within the monogenic etiologic framework, the main genetic risk factor is carrying two pathogenic ANO10 alleles, either in the homozygous or compound heterozygous state. OMIM and associated literature describe multiple variant types, including splice-site mutations, nonsense mutations, frameshift insertions or deletions, and possibly some missense variants that severely impair protein function.[10][14][18] For example, Vermeer et al. reported a G-to-T transversion in intron 9 (1476+1G>T) predicted to disrupt splicing, and a deletion at nucleotide 1604 leading to premature termination at codon 535 (L535X), in affected individuals from one of the original families.[10][14] Balreira et al. found compound heterozygous mutations c.132_133insT (p.Asp45Argfs53) in exon 2 and c.1315G>T (p.Glu382) in exon 6 in two unrelated patients with ataxia and CoQ10 deficiency.[15][18]

More recent case reports continue to expand the mutational spectrum. A Japanese patient was found to harbor a novel homozygous deletion c.616delG (p.Glu206Lysfs*17), causing a frameshift and early truncation; the authors note that this variant leads to adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline.[4] Another study reports SCAR10 associated with a c.289delA ANO10 variant, illustrating that small frameshift deletions are recurring loss-of-function mechanisms.[8] Widening phenotype series describe additional ANO10 variants, some novel, in compound heterozygous configurations in adults with ataxia, corticospinal signs, and executive cognitive dysfunction.[1][19] ClinVar includes at least one splice-site variant, NM_018075.5(ANO10):c.1219-1G>T, classified as pathogenic based on ACMG guidelines and clinical testing, further reinforcing that canonical splice disruption is a recognized disease mechanism.[13]

At present, there is no evidence from the provided sources that heterozygous ANO10 variants alone confer an increased risk of ataxia or related phenotypes; heterozygous carriers in families appear clinically unaffected, consistent with the autosomal recessive inheritance pattern.[10][15][16] Nor are there reports of common susceptibility alleles, modifier polymorphisms, or GWAS-identified risk loci specific to SCAR10 in population-based studies. Thus, ANO10 loss-of-function variants act as necessary and sufficient genetic causal factors when biallelic, with carrier status being the primary genetic risk factor at the family-planning level but not for clinical disease in a single generation.

2.3 Environmental and Lifestyle Risk Factors

Available SCAR10 literature and curated resources do not identify any specific environmental, occupational, or lifestyle exposures that increase the risk of developing the disease beyond the genetic requirement of biallelic ANO10 mutation. Orphanet notes autosomal recessive inheritance and adult onset but does not list environmental risk modifiers such as toxins, diet, or physical activity.[9] OMIM, MedGen, ClinGen, and GeneReviews focus entirely on the genetic basis and clinical phenotype, without implicating particular environmental exposures.[5][10][12][16] Unlike multifactorial neurodegenerative disorders such as sporadic ataxias or Parkinson disease, SCAR10 does not appear to have a significant non-genetic component in its etiology.

Nevertheless, as with other hereditary ataxias, general factors such as age and sex may influence disease expression or progression. SCAR10 typically manifests in teenage years or young adulthood, implying an age-dependent penetrance associated with neurodevelopmental or neurodegenerative processes.[5][10] There is no clear sex predilection described, and case series include both male and female patients.[4][10][19] Lifestyle factors such as alcohol consumption, smoking, and physical activity levels may modulate symptom severity or progression in a nonspecific manner, but this has not been systematically studied or reported for SCAR10. In the absence of disease-specific data, environmental risk factors are best considered unknown or negligible relative to the overriding genetic cause.

2.4 Protective Factors and Gene–Environment Interactions

No genetic protective variants specifically mitigating SCAR10 risk have been reported in the ANO10 locus or elsewhere. The rarity of the disease and the small size of reported cohorts make it difficult to detect protective alleles or modifier loci, and no GWAS or candidate-gene studies aimed at SCAR10 susceptibility or severity have been conducted in the literature represented by the provided sources.[5][10][16] Similarly, there is no evidence of environmental exposures that reduce the risk of SCAR10 in individuals with biallelic ANO10 mutations.

However, there is emerging evidence that metabolic supplementation—specifically coenzyme Q10—may exert a protective or disease-modifying effect in individuals with SCAR10 who exhibit CoQ10 deficiency. Balreira et al. observed that “in two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10,” and they further reported that “some patients have low levels of CoQ10 in muscle and may show some clinical improvement with CoQ10 treatment.”[5][15] This suggests that CoQ10 supplementation could partially compensate for mitochondrial dysfunction secondary to ANO10 loss, thereby modifying disease course. Such an effect would be categorized as a tertiary preventive or therapeutic protective factor rather than a primary etiologic modifier.

Gene–environment interactions specific to SCAR10 have not been characterized. One illustrative but possibly incidental finding from the 2022 case series is that one SCAR10 patient with temporal lobe epilepsy carried a heterozygous variant in CACNB4, a gene associated with epilepsy risk, suggesting a potential genetic interaction influencing seizure propensity.[1][19] The authors treat CACNB4 as a potential risk gene for epilepsy superimposed on SCAR10, but the causal relationship remains speculative. Beyond this, no systematic gene–environment interaction studies (e.g., CTD, PheGenI, GxE analyses) are available for SCAR10. For the purposes of knowledge-base modeling, SCAR10 should therefore be represented as a primarily monogenic disorder with minimal known environmental etiologic contribution, while allowing room for future discovery of modifiers.

3. Phenotypes

3.1 Core Neurological Phenotype

SCAR10 is defined clinically by a triad of gait and limb ataxia, dysarthria, and nystagmus, all associated with marked cerebellar atrophy on brain imaging.[5][9][10] Vermeer et al. reported that affected siblings in Dutch and Romani families developed “spinocerebellar ataxia between ages 20 and 35 years,” with features including “impaired coordination of limbs and gait, dysarthria, hyperreflexia, and gaze-evoked downbeat nystagmus with hypermetric saccades.”[10][14] Orphanet similarly describes adult-onset “slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (e.g. horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), [and] increased deep tendon reflexes.”[9] These neurological manifestations fall under HPO categories such as Ataxia (HP:0001251), Gait ataxia (HP:0002066), Limb ataxia (HP:0003390), Dysarthria (HP:0001260), Nystagmus (HP:0000639), Hyperreflexia (HP:0001347), and Pyramidal signs (e.g., Spasticity, HP:0001257).

The progression of motor symptoms is typically slow but inexorable. Balreira et al. note that their two patients “presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade,” indicating several decades of symptom evolution.[15] The Japanese case described adult-onset “slowly progressive spastic ataxia” with cerebellar atrophy and mild cognitive decline.[4] Nanetti et al., in a mutational screening cohort, report that ANO10 mutations are associated with cerebellar ataxia with variable additional features, but consistently involve progressive gait and limb coordination impairment.[18][19] Functionally, these core phenotypes severely affect daily activities including walking, balance, fine motor tasks, and speech, and map to quality-of-life domains such as mobility, self-care, and usual activities in tools like EQ-5D or SF-36, although formal QOL studies specific to SCAR10 have not been published in the provided sources.

From a pathophysiological standpoint, these core symptoms reflect degeneration and dysfunction of cerebellar Purkinje cells and circuits, as supported by imaging and mechanistic data. Brain MRI universally shows marked cerebellar atrophy, often with relative sparing of supratentorial structures, particularly early in disease.[4][5][10] HPO terms “Cerebellar atrophy” (HP:0001272) and “Cerebellar degeneration” (HP:0007033) are therefore integral to SCAR10’s phenotype ontology. The pyramidal signs (spasticity, hyperreflexia) suggest additional involvement of corticospinal tracts, consistent with the “spinocerebellar” designation.[4][9][10] Collectively, these features define SCAR10 as a mixed cerebellar–pyramidal ataxia syndrome with slow progression.

3.2 Oculomotor, Cognitive, and Motor Neuron Features

Beyond core ataxia, SCAR10 frequently involves oculomotor abnormalities, cognitive changes, and lower motor neuron signs. Oculomotor anomalies, including horizontal, vertical, and downbeat nystagmus and hypermetric saccades, are reported in the original OMIM summary and in Orphanet’s description.[9][10] GeneReviews lists ANO10-related ataxia among hereditary ataxias characterized by downbeat nystagmus and fasciculations.[12][17] These manifestations can be represented by HPO terms such as “Downbeat nystagmus” (HP:0000646), “Saccadic eye movements” (HP:0000519), and “Abnormal ocular motility” (HP:0000496), and they contribute to visual instability, reading difficulties, and dizziness, impacting daily functioning.

Cognitive impairment, particularly executive dysfunction, is increasingly recognized in SCAR10. Orphanet notes “progressive cognitive decline” as part of the core description.[9] The 2022 case series explicitly states that both reported patients “presented corticospinal tract signs, eye movement abnormalities and cognitive executive impairment” and that FDG-PET demonstrated reduced metabolic activity in the cerebellum and frontal lobes.[1][19] The Japanese case had “mild cognitive decline,” while Balreira et al. mention that some SCAR10 patients in the literature exhibit cognitive deficits.[4][15] These findings align with the concept of cerebellar cognitive affective syndrome, wherein cerebellar pathology leads to frontal-executive and affective disturbances via cerebrocerebellar circuits. HPO terms such as “Cognitive impairment” (HP:0100543), “Executive dysfunction” (HP:0006887), and “Frontal lobe dysfunction” (HP:0006956) are appropriate mappings.

Lower motor neuron involvement is documented by Orphanet and OMIM. Orphanet notes that EMG “shows evidence of lower motor neuron involvement,” and OMIM reports that two siblings in Vermeer’s Dutch family had “mild atrophy of the upper part of the lower limbs with fasciculations and EMG evidence of lower motor neuron involvement.”[9][10] These features correspond to HPO terms “Muscle weakness” (HP:0001324), “Muscle atrophy” (HP:0003202), and “Fasciculations” (HP:0003408), and they contribute to functional decline in walking, standing, and fine motor control. Their presence underscores that SCAR10 is not purely a cerebellar disorder but involves broader motor system degeneration.

3.3 Additional Neurological and Systemic Features

SCAR10 can present with a range of additional, variably penetrant features involving peripheral nerves, bladder and bowel function, sensory systems, and seizure propensity. Orphanet lists “proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts” as additional variable features in adult-onset autosomal recessive cerebellar ataxia/SCAR10.[9] The OMIM summary and Balreira’s report mention that some patients have bladder and bowel dysfunction, including vesicorectal disturbances.[4][5][15] Polyneuropathy is also noted as a possible manifestation in SCAR10 patients, implying peripheral nerve degeneration.[4][9]

Epilepsy appears to be an occasional but noteworthy feature. Orphanet lists epilepsy among variable manifestations, and the 2022 case series describes a woman with SCAR10 who had temporal lobe epilepsy and carried a heterozygous CACNB4 variant, which the authors considered a potential epilepsy risk gene.[1][9][19] The Japanese case report notes that epilepsy is part of the broader SCAR10 phenotype spectrum.[4] HPO terms such as “Seizure” (HP:0001250), “Epilepsy” (HP:0001250), and more specific descriptors (e.g., “Temporal lobe epilepsy,” HP:0002269) can be applied where detailed seizure types are known.

Non-neurological features, though less common, may include retinal degeneration and cataracts, as noted by Orphanet, suggesting ocular involvement beyond oculomotor symptoms.[9] Autonomic dysfunction manifesting as bladder and bowel disturbances, inspiratory stridor, and vesicorectal problems indicates involvement of autonomic pathways or muscles of respiration and pelvic floor.[4][5][9][15] These can be mapped to HPO terms such as “Neurogenic bladder” (HP:0000011), “Constipation” (HP:0002019), “Stridor” (HP:0001605), and “Retinal degeneration” (HP:0000558). While not present in all patients, these features expand SCAR10 from a purely motor ataxia to a multisystem neurodegenerative syndrome.

3.4 Age of Onset, Severity, Progression, and Quality-of-Life Impact

SCAR10 typically begins in adolescence or young adulthood, but onset can range from early teens to mid-adulthood. OMIM summarizes that onset is “in the teenage or young adult years,” with ages 13–15 in Romani siblings and 20–35 in the Dutch family.[10] Orphanet defines adult onset by noting that the disorder appears in adulthood and progresses slowly.[9] Case reports confirm variability: the Japanese patient had adult-onset spastic ataxia, while Balreira’s patients developed symptoms in adulthood and became severely disabled in their sixth decade.[4][15] Thus, the typical age-of-onset category for HPO mapping is “Young adult onset” (HP:0001750) or “Adult onset” (HP:0003581), with possible “Adolescent onset” (HP:0003621) in some cases.

Severity varies but tends to progress to substantial disability, particularly in motor domains. Balreira et al. explicitly state that their patients’ slowly progressive ataxia and dysarthria led to “severe disability in the sixth decade,” implying dependence on aids or caregivers for mobility and communication.[15] The Japanese case was described as slowly progressive but had accumulating spasticity and ataxia.[4] Long-term natural history data are limited, but the progressive nature of cerebellar atrophy and core symptoms is clear across case series.[4][5][10][15][19] Disease progression is best characterized as chronic and slowly progressive rather than relapsing or episodic, fitting HPO “Progressive” (HP:0003677) disease course.

Quality-of-life impact is profound, although detailed quantitative studies using established QOL instruments are not available in the provided sources. Impairments in gait, coordination, speech, and vision directly interfere with mobility, communication, employment, and social participation. Cognitive decline and executive dysfunction further affect decision-making, planning, and independence.[1][9][19] Autonomic and motor neuron features contribute to difficulties with continence, breathing, and muscle function, adding to overall disability. In a knowledge base, SCAR10 should be linked to generic QOL terms reflecting severe limitations in mobility, self-care, and usual activities, similar to other progressive hereditary ataxias described in GeneReviews.[12][17] Clinically, comprehensive assessment of functional status using scales like the Scale for the Assessment and Rating of Ataxia (SARA) or modified Rankin Scale would be valuable, though SCAR10-specific data have not been systematically reported.

4. Genetic and Molecular Information

4.1 ANO10 Gene Structure, Function, and Expression

ANO10 (anoctamin 10; TMEM16K) is the sole causal gene for SCAR10 in current knowledge. OMIM locates ANO10 at chromosome 3p22.1–p21.33 and notes that the protein belongs to the family of calcium-activated chloride channels reviewed by Hartzell et al. (2009).[14] NCBI Gene describes ANO10 as encoding a transmembrane protein with eight membrane-spanning domains and cytosolic N- and C-termini, belonging to the anoctamin/transmembrane 16 family.[18] These channels typically mediate calcium-dependent chloride conduction across membranes, influencing processes such as membrane excitability, secretion, and cell volume regulation.

Expression studies cited by OMIM indicate that ANO10 is broadly expressed, with highest levels in adult brain, followed by retina and heart, and lower expression in fetal brain.[14] Within adult brain, ANO10 expression peaks in frontal and occipital cortices and in the cerebellum, which aligns with SCAR10’s characteristic cerebellar atrophy, frontal lobe hypometabolism on FDG-PET, and potential visual pathway involvement.[1][14][19] This spatial expression pattern helps explain why ANO10 loss-of-function manifests predominantly as cerebellar ataxia with corticospinal and cognitive involvement, and supports the use of anatomical ontology terms such as UBERON “cerebellum,” “frontal lobe,” and “occipital cortex” in disease modeling.

At the functional level, ANO10 is hypothesized to act as an intracellular or plasma-membrane Ca(^{2+})-dependent Cl(^{-}) transporter in neurons, particularly Purkinje cells, contributing to calcium homeostasis and synaptic function.[7][14][18] GeneReviews and OMIM cite previous work proposing ANO10-mediated calcium dysregulation in Purkinje cells as a key pathogenic mechanism in SCAR10.[7][12][14] Although detailed electrophysiological characterization of ANO10 channels is limited in the provided sources, the protein’s membership in the TMEM16 family and the association of SCAR10 with calcium-linked pathways in proteomic studies support the assignment of GO molecular function terms such as “calcium-activated chloride channel activity” (GO:0005227) and biological process terms like “regulation of calcium ion transport” (GO:0051924) and “synaptic transmission” (GO:0007268).

4.2 Spectrum and Classification of Pathogenic Variants

SCAR10-related ANO10 variants span multiple classes, predominantly loss-of-function changes. Vermeer et al. reported four different mutations across three families, including a splice-site mutation (1476+1G>T) and a frameshift leading to truncation at codon 535 (L535X), both predicted to abolish normal protein function.[10][14] Balreira et al. found c.132_133insT (p.Asp45Argfs53), a frameshift insertion in exon 2, and c.1315G>T (p.Glu382), a nonsense mutation in exon 6, again producing truncated proteins.[15][18] The Japanese case featured c.616delG (p.Glu206Lysfs*17), a novel homozygous deletion causing early truncation.[4] A separate report associated SCAR10 with c.289delA, another frameshift deletion.[8] These variants fall into ACMG classes “pathogenic” or “likely pathogenic” based on predicted loss-of-function in a gene where such variants are a known disease mechanism, segregation with disease, and absence or rarity in population databases.[10][13][15][18]

ClinVar provides an example of a splice-site variant, NM_018075.5(ANO10):c.1219-1G>T, classified as pathogenic by a single clinical laboratory using ACMG criteria.[13] GenCC’s ClinGen curation, drawing on multiple reports, concludes that evidence for ANO10’s association with autosomal recessive cerebellar ataxia is “definitive,” emphasizing that numerous pathogenic variants have been identified across independent families and research cohorts.[16][11] NCBI Gene’s bibliographic references include Nanetti et al. (2019), who performed mutational screening in AR ataxia and found ANO10 variants in approximately 5% of a particular cohort, suggesting that while ANO10 mutations are rare overall, they are a noteworthy cause among unexplained recessive ataxias.[18][19]

Allele frequency data for specific ANO10 variants are not detailed in the provided sources. However, the nature of the mutations—frameshift, nonsense, and canonical splice-site changes—combined with the extreme rarity of SCAR10 and the observation that these variants are absent or extremely rare in population databases (e.g., gnomAD) in the original publications strongly supports their classification as loss-of-function, disease-causing variants.[10][15][18] For knowledge-base purposes, ANO10 variants should be mapped to HGNC “ANO10,” OMIM 613726, and classified as germline, autosomal recessive, loss-of-function pathogenic variants, with variant types annotated as frameshift, nonsense, splice-site, and sometimes missense where functional data confirm pathogenicity.

4.3 Germline Origin, Penetrance, and Somatic Considerations

All SCAR10-causal ANO10 variants described in the literature and curated resources are germline, inherited in an autosomal recessive fashion. Vermeer et al.’s linkage analysis in consanguineous families, the segregation of variants with disease in Balreira’s families, and the consanguineous context of the Japanese and Romani families all support germline inheritance.[4][10][15] ClinVar’s pathogenic ANO10 variants are noted as germline in origin.[13] There is no indication of somatic ANO10 mutations contributing to SCAR10 or other neurologic phenotypes in the provided data, and databases like COSMIC or TCGA are not referenced in relation to ANO10 in these contexts.[13][18]

Penetrance appears to be high for individuals with biallelic loss-of-function ANO10 variants, as virtually all reported homozygous or compound heterozygous individuals have developed ataxia and related symptoms by early or mid-adulthood.[4][5][10][15][19] Age-dependent penetrance is implicit in the typical teenage–young adult onset. Heterozygous carriers, including parents and siblings in affected families, are described as clinically unaffected, consistent with recessive inheritance and near-complete penetrance among biallelic carriers.[10][15][16] Germline mosaicism has not been reported, likely due to the rarity of SCAR10 and the scarcity of large multigenerational pedigrees.

4.4 Modifier Genes, Epigenetics, and Structural Genomic Features

Specific modifier genes that alter SCAR10 severity or presentation have not been identified in the provided sources. The heterozygous CACNB4 variant in a SCAR10 patient with temporal lobe epilepsy suggests a potential genetic interaction influencing seizure susceptibility, but evidence is anecdotal and insufficient to classify CACNB4 as a formal modifier gene for SCAR10.[1][19] Other genes with co-occurring variants in Balreira’s exome analysis were considered but rejected because only ANO10 segregated with disease and was a known ataxia gene.[15] Thus, no established modifier loci exist for SCAR10, and the phenotypic variability is likely driven by variant-specific effects within ANO10, general genetic background, and environmental factors that remain poorly characterized.

Epigenetic mechanisms such as DNA methylation, histone modification, or chromatin changes altering ANO10 expression have not been studied in SCAR10 according to the provided data. OMIM, GeneReviews, and NCBI Gene do not mention epigenetic regulation as a contributor to SCAR10.[12][14][18] Structural genomic abnormalities, such as large deletions, duplications, translocations, or inversions involving ANO10 or chromosome 3p, are also not described. All reported ANO10 variants are single-nucleotide or small indel changes, not copy-number variants.[10][14][15][18] DECIPHER or dbVar entries linking structural variation to SCAR10 are not referenced in MedGen or OMIM.[3][5][10] For now, SCAR10 should be modeled as arising from sequence-level loss-of-function mutations in ANO10 without known structural genomic or epigenetic contributions.

5. Mechanism / Pathophysiology

5.1 Causal Chain from ANO10 Loss to Clinical Manifestation

In individuals with SCAR10, biallelic loss-of-function variants in the ANO10 gene lead to reduction or absence of functional anoctamin 10 protein in neurons and other ANO10-expressing cells.[10][14][18] This deficit in ANO10 impairs calcium-activated chloride channel activity and associated calcium-dependent signaling processes, particularly in cerebellar Purkinje cells and other neurons where ANO10 expression is high.[7][14][18] Disrupted calcium homeostasis in these neurons results in downstream alterations in synaptic function, cell cycle regulation, extracellular matrix remodeling, and immune homeostasis, as demonstrated by proteomic changes in ANO10-deficient SH-SY5Y neuronal cell lines.[7] These cellular perturbations, together with secondary mitochondrial dysfunction and CoQ10 deficiency observed in some patients, lead over time to progressive neuronal dysfunction and degeneration in cerebellar and frontal cortical circuits.[5][7][15] The cumulative tissue damage manifests clinically as slowly progressive cerebellar ataxia, pyramidal signs, oculomotor abnormalities, cognitive decline, peripheral neuropathy, epilepsy, and autonomic dysfunction, with marked cerebellar atrophy and frontal hypometabolism visible on MRI and FDG-PET imaging.[1][4][5][10][19]

This causal chain integrates upstream molecular events (ANO10 loss-of-function), mid-level cellular and metabolic consequences (calcium signaling disruption, synaptic and cell-cycle changes, CoQ10 deficiency), and downstream tissue and clinical outcomes (cerebellar and frontal neurodegeneration leading to ataxia and cognitive impairment). Some steps, especially the precise mechanisms linking ANO10 deficiency to CoQ10 depletion and immune/ECM alterations, are inferred from correlative data rather than fully demonstrated causal experiments and should be marked as hypotheses to be tested.

5.2 Molecular Pathways: Calcium Signaling, Synaptic Function, and CoQ10 Metabolism

At the molecular level, ANO10’s function as a putative calcium-activated chloride channel situates SCAR10 within calcium signaling and synaptic regulation pathways. OMIM notes that ANO10 belongs to the anoctamin family of calcium-activated chloride channels and that expression is highest in brain regions critical for motor coordination and cognition.[14] The recent proteomic profiling study by ANO10-deficient SH-SY5Y neuronal cell lines provides direct evidence that ANO10 loss perturbs calcium-linked pathways. The authors report that “comparative proteomic analysis revealed disruptions in synaptic function, cell cycle regulation, extracellular matrix remodelling, and immune homeostasis as candidate pathways potentially contributing to SCAR10 pathogenesis,” and emphasize that “all four processes are functionally linked to calcium signalling, aligning with previous reports implicating abnormal calcium homeostasis in spinocerebellar ataxias.”[7] These findings support the assignment of GO biological process terms such as “regulation of synaptic transmission” (GO:0050804), “cell cycle” (GO:0007049), “extracellular matrix organization” (GO:0030198), and “immune system process” (GO:0002376) to SCAR10 pathophysiology.

CoQ10 metabolism appears as a metabolic pathway linked to SCAR10. Balreira et al. discovered that their SCAR10 patients had skeletal muscle CoQ10 deficiency and concluded that “ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.”[15][18] MedGen references Balreira’s observations and notes that “some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment.”[5] This suggests that ANO10-mediated calcium or membrane transport may influence mitochondrial function or CoQ10 biosynthesis or turnover, although the mechanistic details remain unclear. Relevant GO terms include “ubiquinone biosynthetic process” (GO:0006744) and “mitochondrial electron transport, ubiquinol to cytochrome c” (GO:0006122), and chemical ontology mapping can use CHEBI “coenzyme Q10” (CHEBI:1709).

Given the evidence, SCAR10’s molecular pathophysiology can be summarized as loss of ANO10-mediated calcium-activated chloride transport leading to dysregulated intracellular calcium signaling, altered synaptic protein composition, disturbed cell cycle and ECM dynamics, perturbed immune-related pathways, and secondary mitochondrial CoQ10 deficiency. These molecular disturbances predispose neurons—especially Purkinje cells and frontal cortical neurons—to dysfunction and death under physiological and environmental stress.

5.3 Cellular Processes: Neuronal Dysfunction, Cell Cycle, ECM, and Immune Homeostasis

The proteomic study in ANO10-deficient SH-SY5Y cells offers the most detailed window into cellular processes affected by ANO10 loss.[7] Using CRISPR/Cas9 editing, the investigators generated a knockout line and three lines harboring recurrent SCAR10-associated pathogenic ANO10 variants, then performed mass spectrometry-based proteomics and bioinformatic analyses to identify differentially expressed proteins and pathways.[7] They found that ANO10 deficiency leads to disturbances in proteins associated with synaptic function, including those that modulate neurotransmitter release and receptor trafficking, suggesting altered synaptic vesicle dynamics and signal transduction at neuronal synapses. This aligns with the cerebellar ataxia phenotype, which is often driven by impaired Purkinje cell synaptic integration of afferent signals.

Cell cycle regulation emerged as another affected process. While mature neurons are post-mitotic, aberrant activation of cell cycle pathways in neurons is a known mechanism of neurodegeneration, leading to apoptotic or necrotic cell death when neurons attempt unscheduled cell-cycle re-entry.[7] ANO10-deficient cells displayed altered abundance of cell cycle-associated proteins, indicating dysregulated cell cycle control that may predispose neuronal precursor cells or glial cells to abnormal proliferation or death. GO terms like “regulation of cell cycle” (GO:0051726) and “neuronal apoptotic process” (GO:0051402) are appropriate.

Extracellular matrix remodeling is another category highlighted by the proteomic data. Changes in ECM components and remodeling enzymes can alter synaptic architecture, axon guidance, and neurovascular interactions.[7] Disrupted ECM could contribute to cerebellar circuit disorganization and eventually to neuronal degeneration, mapping to GO:0030198 “extracellular matrix organization” and related processes. Immune homeostasis perturbations, reflected by changes in immune-related proteins, suggest altered neuroimmune interactions—possibly microglial activation, cytokine signaling, or complement pathways—that can influence neurodegeneration and repair.[7] GO terms such as “immune response” (GO:0006955) and “microglial cell activation” (GO:0001774) may be relevant, though direct cell-type data are lacking in the provided study.

Taken together, these cellular processes—synaptic dysfunction, aberrant cell cycle regulation, ECM remodeling, and immune dysregulation—form mid-level steps between ANO10 molecular dysfunction and tissue-level neurodegeneration in SCAR10. While the proteomic data are in vitro and require validation in vivo, they provide plausible mechanistic links that can be captured in a knowledge base as experimental (cell-line) evidence.

5.4 Tissue Damage Mechanisms: Cerebellar and Frontal Neurodegeneration

At the tissue level, SCAR10 causes marked cerebellar atrophy, and increasingly recognized frontal lobe involvement, culminating in the clinical phenotype. OMIM and MedGen repeatedly emphasize “marked cerebellar atrophy on brain imaging” as a defining feature.[5][10] Vermeer et al. reported MRI evidence of “marked cerebellar atrophy” in all affected siblings.[10][14] Orphanet notes brain imaging “reveals marked cerebellar atrophy,” consistent with adult-onset autosomal recessive cerebellar ataxia.[9] The Japanese and other case reports confirm cerebellar volume loss, particularly affecting the vermis and hemispheres.[4][19]

The 2022 case series extends tissue-level understanding by reporting FDG-PET findings: both SCAR10 patients had “pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (FDG PET) scans,” indicating hypometabolism and likely neurodegeneration in frontal cortices.[1][19] These imaging data align with cognitive executive impairments observed clinically and further support the concept of cerebrocerebellar network involvement. Tissue damage mechanisms likely include chronic excitotoxicity, oxidative stress from mitochondrial dysfunction, and neuroinflammation, although these specific processes are not detailed in the provided sources.

HPO terms such as “Cerebellar atrophy” (HP:0001272) and “Cerebral cortical atrophy” (HP:0002059) can be used to represent structural changes, while imaging ontology terms (e.g., RadLex classes for “cerebellar volume loss” and “hypometabolic frontal cortex”) can capture radiologic phenotypes. The underlying biological processes include “neuronal death” (GO:0070997), “axonal degeneration” (GO:0032839), and “glial activation” (GO:0014002), though direct evidence in SCAR10 is inferred rather than empirically shown in the literature.

5.5 Biochemical Abnormalities: CoQ10 Deficiency and Mitochondrial Dysfunction

The key biochemical abnormality documented in SCAR10 is coenzyme Q10 deficiency in skeletal muscle biopsies of some patients. Balreira et al. report that in two adults with cerebellar ataxia, muscle CoQ10 levels were significantly reduced, and whole-exome sequencing revealed ANO10 mutations, leading them to conclude that “ANO10

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 8
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 49
Resolved 44
Unresolved (possible confabulation) 1
Obsolete 3
Unverifiable 1
Terms whose name was checked 44
Terms named correctly 21
Terms named as a different term 11
Terms whose name is worth a second look 12

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:

  • HP:0004311 (1 mention) - the report calls it "Coenzyme Q10 deficiency"; HP calls it Abnormal macrophage morphology
  • HP:0000646 (1 mention) - the report calls it "Downbeat nystagmus"; HP calls it Amblyopia
  • HP:0000519 (1 mention) - the report calls it "Saccadic eye movements"; HP calls it Developmental cataract
  • HP:0006887 (1 mention) - the report calls it "Executive dysfunction"; HP calls it obsolete Intellectual disability, progressive
  • HP:0006956 (1 mention) - the report calls it "Frontal lobe dysfunction"; HP calls it Lateral ventricle dilatation
  • HP:0001605 (1 mention) - the report calls it "Stridor"; HP calls it Vocal cord paralysis
  • HP:0000558 (1 mention) - the report calls it "Retinal degeneration"; HP calls it Rieger anomaly
  • HP:0001750 (1 mention) - the report calls it "Young adult onset"; HP calls it Single ventricle
  • CHEBI:1709 (1 mention) - the report calls it "coenzyme Q10"; CHEBI calls it CHEBI_1709
  • GO:0032839 (1 mention) - the report calls it "axonal degeneration"; GO calls it dendrite cytoplasm
  • GO:0014002 (1 mention) - the report calls it "glial activation"; GO calls it astrocyte development

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0003408 (1 mention), reported as "Fasciculations" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0006887 (obsolete Intellectual disability, progressive) (1 mention) - replaced by HP:0001249
  • CHEBI:1709 (CHEBI_1709) (1 mention) - replaced by CHEBI:15494
  • GO:0070997 (obsolete neuron death) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0007033 (1 mention) - the report calls it "Cerebellar degeneration"; HP calls it Cerebellar dysplasia
  • HP:0000496 (1 mention) - the report calls it "Abnormal ocular motility"; HP calls it Abnormality of eye movement, and lists "Abnormal eye motility" among its other names
  • HP:0003202 (1 mention) - the report calls it "Muscle atrophy"; HP calls it Skeletal muscle atrophy, and lists "Muscle atrophy" among its other names
  • HP:0001250 (2 mentions) - the report calls it "Seizure", "Epilepsy"; HP calls it Seizure, and lists "Epilepsy" among its other names
  • HP:0003621 (1 mention) - the report calls it "Adolescent onset"; HP calls it Juvenile onset
  • HP:0003677 (1 mention) - the report calls it "Progressive"; HP calls it Slowly progressive
  • GO:0005227 (1 mention) - the report calls it "calcium-activated chloride channel activity"; GO calls it calcium-activated cation channel activity
  • GO:0007268 (1 mention) - the report calls it "synaptic transmission"; GO calls it chemical synaptic transmission, and lists "synaptic transmission" among its other names
  • GO:0050804 (1 mention) - the report calls it "regulation of synaptic transmission"; GO calls it modulation of chemical synaptic transmission, and lists "regulation of synaptic transmission" among its other names
  • GO:0051402 (1 mention) - the report calls it "neuronal apoptotic process"; GO calls it neuron apoptotic process
  • HP:0002059 (1 mention) - the report calls it "Cerebral cortical atrophy"; HP calls it Cerebral atrophy
  • GO:0070997 (1 mention) - the report calls it "neuronal death"; GO calls it obsolete neuron death, and lists "neuronal cell death" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0001250 - called "Seizure", "Epilepsy"

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: ORPHA.