| Domain | Best-established finding | Evidence type / year | Key quantitative data | Knowledge-base ontology suggestions |
|---|---|---|---|---|
| Identity / causal gene | SCAR20 is an ultra-rare Mendelian neurodevelopmental/neurodegenerative disorder caused by biallelic loss-of-function or loss-reducing variants in **SNX14**; identifiers include **OMIM #616354** and **MONDO:0014601**. | Human disease-gene association, discovery cohort and curated disease-target evidence, 2015-2024 (pqac-00000017, pqac-00000000) | Open Targets lists **1 associated target (SNX14)** for MONDO_0014601; early human reports established **22 affected individuals** in one major cohort (pqac-00000000, pqac-00000019) | MONDO:0014601; OMIM:616354; HGNC:SNX14; NCBI Gene: SNX14; inheritance: HP:0000007 |
| Core human phenotype and frequencies | Core syndrome: developmental delay/intellectual disability, hypotonia, gait abnormality/ataxia, cerebellar atrophy, coarse facies; frequent autistic-like behavior, nystagmus, hypertrichosis/macroglossia; seizures and hearing loss occur in a subset. | Primary human cohort, 2015; expanded case reports 2020-2024 (pqac-00000019, pqac-00000002, pqac-00000004, pqac-00000006) | In **22/22**: delayed gross/fine motor development, delayed/absent language and social skills, hypotonia, gait abnormalities, cerebellar atrophy, coarse facies. Additional features: autistic-like behavior **12/22 (55%)**, nystagmus **11/22 (50%)**, hypertrichosis **12/22 (55%)**, macroglossia **12/22 (55%)**, epileptic seizures **8/22 (36%)**, hepatosplenomegaly **5/22 (23%)** (pqac-00000019) | HPO: HP:0001263 developmental delay; HP:0001249 intellectual disability; HP:0001252 hypotonia; HP:0002066 gait ataxia; HP:0001251 ataxia; HP:0001272 cerebellar atrophy; HP:0000280 coarse face; HP:0000717 autism; HP:0000639 nystagmus; HP:0000998 hypertrichosis; HP:0000158 macroglossia; HP:0001250 seizures; HP:0000407 sensorineural hearing impairment |
| Course / imaging | Typically childhood-onset, often evident in infancy with progressive cerebellar degeneration; MRI may be normal early and then become abnormal, showing progressive cerebellar atrophy/hypotrophy, sometimes delayed myelination, pontine atrophy, thin corpus callosum, or extra-axial fluid prominence. | Primary human case series, 2020-2024 (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000006) | Examples: onset by **3 months** with hypotonia/lack of head control in one family; one child had cerebellum normal on MRI at **2 years** but sibling showed progressive cerebellar atrophy by **4 years**; delayed sitting at **11 months**, ataxic gait at **1.5 years**, first words at **2 years** reported in 2023 case (pqac-00000002, pqac-00000004, pqac-00000006) | HPO: HP:0012759 neurodevelopmental delay; HP:0001317 delayed myelination; HP:0001272 cerebellar atrophy; HP:0002500 abnormal cerebral white matter morphology; HP:0002060 abnormality of cerebellar vermis; UBERON:0002037 cerebellum; UBERON:0001891 pons; UBERON:0000955 brain |
| Molecular mechanism | SNX14 localizes to ER and ER-lipid droplet contacts and is required for neutral lipid homeostasis, fatty-acid desaturation/lipid droplet biogenesis, lysosome-autophagy function, and in mouse Purkinje cells also supports spastin-dependent microtubule organization and axonal mitochondrial transport. | Human cells, engineered cell lines, mouse mechanistic studies, 2018-2024 (pqac-00000009, pqac-00000011, pqac-00000008, pqac-00000015) | SNX14-deficient Purkinje cells formed about **50% fewer oleic-acid-induced lipid droplets** than WT; spastin interaction and mitochondrial transport defects were quantified in **28-29 cells/group** in mouse neuron assays; discovery paper identified lysosome/autophagosome dysfunction in affected individuals (pqac-00000010, pqac-00000011, pqac-00000017) | GO:0005783 endoplasmic reticulum; GO:0005811 lipid droplet; GO:0005764 lysosome; GO:0016236 macroautophagy; GO:0006869 lipid transport; GO:0035357 peroxisome organization not established; GO:0007005 mitochondrion organization; GO:0007018 microtubule-based movement; CL:0000121 Purkinje cell |
| 2024 omics findings | 2024 mouse multi-omics/ultrastructure work linked selective cerebellar vulnerability to lipid dyshomeostasis, especially acylcarnitine accumulation and triglyceride depletion before overt Purkinje-cell loss. | Mouse lipidomics, MALDI-MS imaging, TEM, RNA-seq-associated paper, 2024 (pqac-00000008, pqac-00000010, pqac-00000014, pqac-00000022) | Lipidomics in **n=8 WT** and **n=10 KO** mice showed **significantly increased acylcarnitines only in cerebellum**; MALDI-MS showed cerebellar reduction of **PE C38:2, TG 46:1, TG 53:2** and accumulation of **L-carnitine**; TEM in **n=3 mice/genotype** showed fewer but enlarged telolysosomes; predegenerating PCs had mostly intact mitochondria, supporting a primary lipid storage/clearance defect (pqac-00000022) | CHEBI: acylcarnitine, L-carnitine, triglyceride, phosphatidylethanolamine; GO:0006631 fatty acid metabolic process; GO:0016042 lipid catabolic process; GO:0005773 vacuole/lysosomal compartment; CL:0000121 Purkinje cell; UBERON:0002037 cerebellum |
| Diagnosis | Diagnosis is gene-first plus phenotyping: WES commonly identifies biallelic SNX14 variants; WGS can solve deep intronic disease; RNA studies confirm aberrant splicing; MRI and clinical pattern support interpretation. | Human diagnostic studies, 2015-2024 (pqac-00000017, pqac-00000002, pqac-00000004, pqac-00000001, pqac-00000020) | WES enabled discovery and additional families in 2015; 2023 report identified first deep intronic variant **c.462-589A>G** by **trio WGS**, causing pseudo-exon inclusion and predicted **p.Asp155Valfs*8**; 2021 Korean family had homozygous **c.2746-2A>G**; 2024 family had **p.Arg238Ter** plus **p.Gln915Leu** with in-vitro expression reduction (pqac-00000004, pqac-00000002, pqac-00000001) | SO:0001589 frameshift_variant; SO:0001578 stop_gained; SO:0001629 splice_acceptor_variant / splice_region_variant; NCIT: whole exome sequencing, whole genome sequencing, Sanger sequencing, magnetic resonance imaging |
| Treatment status | No disease-specific human therapy or interventional SCAR20 trial identified; management is supportive/rehabilitative. **Valproate is mouse-only preclinical evidence** and should not be interpreted as established patient treatment. | Clinical-trial search plus preclinical rescue studies, 2021-2024 (pqac-00000011, pqac-00000014) | ClinicalTrials searches retrieved **no relevant SCAR20 interventional trials**. In mice, valproate/valproic acid partially rescued motor deficits or Purkinje-cell degeneration; SCD1 overexpression rescued cellular lipid phenotypes in vitro, also preclinical only (pqac-00000011, pqac-00000014) | NCIT: supportive care; physical therapy; occupational therapy; speech therapy; valproic acid **mouse-only preclinical**; genetic counseling |
| Models | Experimental and natural models converge on Purkinje-cell/cerebellar pathology and lipid-homeostasis mechanisms. | Zebrafish, mouse, dog, human cell models, 2015-2024 (pqac-00000016, pqac-00000017, pqac-00000011, pqac-00000008, pqac-00000009) | Zebrafish knockdown showed loss of neural tissue volume/reduced Purkinje-cell area; mouse KO models show selective Purkinje-cell degeneration and motor deficits; Hungarian Vizsla natural disease involved **2 affected full-sibling puppies** from a litter of 9 and carrier detection in **3/133** unaffected dogs; no epidemiologic prevalence/incidence estimate for human SCAR20 is established (**unknown**) (pqac-00000016, pqac-00000017) | NCBI Taxon: 10090 mouse, 7955 zebrafish, 9615 dog, 9606 human; CL:0000121 Purkinje cell; UBERON:0002037 cerebellum; disease frequency metadata: prevalence unknown, incidence unknown |


*Table: This table summarizes the strongest currently gathered evidence for SNX14-related autosomal recessive spinocerebellar ataxia 20 across clinical, mechanistic, diagnostic, and model-system domains. It is designed to help populate a structured knowledge base while clearly separating human-established findings from mouse-only preclinical results.*