| Domain | Best-supported SCA43-specific finding | Evidence strength/limitations |
|---|---|---|
| Disease identity | Spinocerebellar ataxia type 43; MONDO:0014867; Open Targets also maps the disease to EFO:0009060 and MME as the associated target (pqac-00000000) | Disease ontology support exists, but disease-target evidence is sparse and ultimately anchored to the original family report (pqac-00000000, pqac-00000007) |
| Ascertainment | Evidence comes from one five-generation Belgian family with 28 sampled relatives and 7 living affected individuals (pqac-00000002, pqac-00000007) | Very small sample size; single-family ascertainment strongly limits generalizability, penetrance estimation, phenotype frequencies, and epidemiology (pqac-00000002, pqac-00000007) |
| Causal gene/variant | Heterozygous MME variant p.Cys143Tyr / p.C143Y identified as the disease-segregating variant (pqac-00000001, pqac-00000010) | Best current causal evidence is cosegregation plus rarity/prediction; no independent SCA43 family replication in the retrieved evidence (pqac-00000010) |
| Inheritance | Autosomal dominant transmission in the reported pedigree (pqac-00000002, pqac-00000009) | Inheritance is well supported for this family, but broader penetrance and expressivity across populations remain unknown (pqac-00000009, pqac-00000010) |
| Age at onset | Late onset, reported between 42 and 68 years in affected family members (pqac-00000003, pqac-00000009) | Based only on the index family; no natural-history cohort available (pqac-00000003) |
| Core phenotype | Sensorimotor axonal polyneuropathy in 7/7 affected individuals; cerebellar ataxia in 6/7 (pqac-00000002, pqac-00000007) | Strongest phenotype data are family-specific; frequencies may reflect ascertainment rather than true disease spectrum (pqac-00000002) |
| Additional neurologic features | Reported features include gait/balance problems, dysarthria, hypometric saccades, cerebellar nystagmus, areflexia, distal amyotrophy, pes cavus, and hypoesthesia (pqac-00000003, pqac-00000004, pqac-00000006) | Clinical detail is useful but derives from a handful of examined relatives; not all features were present in all patients (pqac-00000003, pqac-00000004) |
| Imaging | Brain MRI showed cerebellar vermis atrophy (pqac-00000003) | Imaging evidence is disease-specific but limited to reported family members; no longitudinal imaging dataset (pqac-00000003) |
| Electrophysiology/pathology | Electrophysiology showed progressive severe motor axonal neuropathy with increased F-response latency, preserved sensory responses, and normal conduction velocities; one nerve biopsy showed CMT2-type axonal pathology (pqac-00000003, pqac-00000009) | Strong for neuropathy characterization in this family; limited pathology data and no disease biomarker validation (pqac-00000003) |
| Variant rarity | p.Cys143Tyr was absent from dbSNP, EVS, and ExAC at the time of publication; not found in 96 additional unrelated dominant ataxia cases screened by the authors (pqac-00000005, pqac-00000010) | Supports rarity, but database status may change over time; absence in another 96 cases underscores rarity rather than prevalence (pqac-00000005) |
| Mechanistic interpretation | MME encodes neprilysin, a zinc-dependent metalloprotease; dominant p.Cys143Tyr likely acts through a mechanism other than simple haploinsufficiency because recessive loss-of-function MME disease usually lacks cerebellar involvement (pqac-00000001, pqac-00000004, pqac-00000008) | Mechanism remains unresolved; functional studies were explicitly called for by the authors (pqac-00000001, pqac-00000008) |
| Epidemiology | No robust prevalence or incidence estimates identified for SCA43 (pqac-00000007, pqac-00000010) | Major evidence gap due to rarity and single-family basis (pqac-00000007) |
| Diagnostics | Best-supported diagnosis is clinical suspicion of dominant late-onset ataxia with axonal neuropathy followed by sequencing-based confirmation of MME (pqac-00000009, pqac-00000010) | No SCA43-specific diagnostic guideline or validated biomarker panel identified (pqac-00000009) |
| Treatment/trials | No SCA43-specific disease-modifying treatment, interventional trial, or gene-targeted therapy identified in retrieved sources (pqac-00000007, pqac-00000008) | Management is therefore extrapolated from broader hereditary ataxia/neuropathy supportive care, not direct SCA43 evidence (pqac-00000008) |
| Omics/biomarkers | No SCA43-specific transcriptomic, proteomic, metabolomic, or validated fluid biomarker study identified (pqac-00000007, pqac-00000008) | Major evidence gap limiting mechanism and trial-readiness work (pqac-00000008) |
| Models | No validated SCA43 p.Cys143Tyr model identified; Mme knockout mice do not recapitulate severe human axonal neuropathy and are not an established SCA43 model (pqac-00000008) | Important translational limitation; model-organism support is weak for this specific disease entity (pqac-00000008) |


*Table: This table summarizes the strongest disease-specific evidence currently available for spinocerebellar ataxia type 43. It highlights the core clinical-genetic findings and the major limitations created by single-family ascertainment and lack of replication, epidemiology, treatment trials, omics, and validated models.*