| Domain | Established finding | Evidence type / strength | Key identifiers or quantitative facts |
|---|---|---|---|
| Disease identity | Distal myopathy 6, adult-onset is the ACTN2-related autosomal dominant distal myopathy phenotype designated MPD6 | Authoritative disease table + review-level confirmation; strong for nomenclature/assignment (pqac-00000000, pqac-00000008) | OMIM phenotype **618655**; inheritance **AD**; locus **1q43**; gene **ACTN2**; protein **actinin alpha-2** |
| Causal gene | The causal gene is **ACTN2**, a sarcomeric Z-disc gene expressed in skeletal and cardiac muscle | Authoritative gene-disease table + functional review; strong for gene assignment, moderate for mechanistic interpretation (pqac-00000000, pqac-00000009) | **ACTN2 OMIM 102573**; chromosome **1q43** |
| Key pathogenic variants | Reported MPD6-associated heterozygous missense variants are **c.1459T>C (p.Cys487Arg)** and **c.392T>C (p.Leu131Pro)** | Primary cohort abstract evidence + review synthesis; moderate-strong (pqac-00000002, pqac-00000003, pqac-00000011) | p.Cys487Arg in families 1-3; p.Leu131Pro in family 4 |
| Reported families / geography | Four families were reported: **three from the same village in northern Spain** and **one from Sweden** | Primary cohort abstract evidence; moderate (pqac-00000002, pqac-00000003) | **4 families total**; clustering suggests possible local aggregation for p.Cys487Arg but no founder study established |
| Core phenotype | Clinical presentation is **adult-onset asymmetric distal weakness**, initially with **tibialis anterior atrophy** and **ankle dorsiflexion** involvement, later spreading proximally | Primary cohort abstract evidence; moderate (pqac-00000002, pqac-00000003) | Pattern: distal lower-limb onset, **asymmetric**, then **proximal progression** |
| Pathology | Muscle biopsy showed **rimmed vacuolar pathology** | Primary cohort abstract evidence; moderate (pqac-00000002, pqac-00000003) | Histopathology: **rimmed vacuoles** |
| Penetrance / segregation | Variants **co-segregated** with disease and showed **full penetrance** in the reported families | Primary cohort abstract evidence; moderate (pqac-00000002, pqac-00000003) | **Full penetrance** reported in all 4 families |
| Protein/domain context | ACTN2 contains an **actin-binding domain (ABD)**, **4 spectrin repeats**, and **EF-hand region**; MPD6 variants map to the **ABD** (p.Leu131Pro) and **spectrin-repeat region** (p.Cys487Arg) | Functional/structural review evidence; moderate for domain mapping, indirect for MPD6 mechanism (pqac-00000009, pqac-00000011) | p.Leu131Pro: ABD; p.Cys487Arg: spectrin-like repeat region |
| Population frequency | In a 2021 ACTN2 review, both MPD6 variants were reported as **absent from gnomAD v3.1** | Review evidence; moderate (pqac-00000011) | **Absent in gnomAD v3.1**: p.Leu131Pro, p.Cys487Arg |
| Mechanistic interpretation | Best-supported mechanism is disruption of **Z-disc / sarcomere integrity** with downstream myofibrillar degeneration; exact MPD6-specific causal mechanism remains incompletely defined | Indirect functional review + gene function data; moderate/limited for MPD6-specific causality (pqac-00000009, pqac-00000011) | ACTN2 is an actin cross-linker/scaffold at the Z-disc; **direct MPD6 functional assay evidence missing** |
| Cardiac association | ACTN2 is allelic to cardiomyopathy phenotypes, but direct, quantitative cardiac-risk data for MPD6 are not established in the retrieved MPD6 evidence | Strong for allelic relationship; limited for MPD6-specific risk (pqac-00000000, pqac-00000008, pqac-00000012) | Allelic to **CMH23** and **CMD1AA**; pragmatic cardiac surveillance may be reasonable, but **MPD6-specific penetrance unknown** |
| Epidemiology | **No robust prevalence or incidence estimate** was identified for MPD6 | Evidence gap; weak/absent (pqac-00000008) | Prevalence: **not established**; incidence: **not established** |
| Natural history granularity | Adult onset and progression from distal to proximal weakness are established, but detailed age-at-onset ranges, disease duration, respiratory outcomes, and survival are not well quantified in the retrieved evidence | Limited primary evidence; weak-moderate (pqac-00000002, pqac-00000003) | Age-specific quantitative natural history: **missing/limited** |
| Diagnostics | Diagnosis currently relies on **clinical pattern recognition + muscle pathology + molecular testing** (multigene panel/WES/WGS in neuromuscular practice) rather than a disease-specific biomarker | General neuromuscular diagnostic review + direct disease genetics; moderate, partly extrapolated (pqac-00000002, pqac-00000003) | No validated MPD6-specific biomarker, screening test, or diagnostic criteria set identified |
| Treatment | **No approved disease-modifying therapy** specific to MPD6 was identified | Evidence gap; weak/absent (pqac-00000006, pqac-00000007) | Management appears supportive/rehabilitative; ACTN2-specific pharmacotherapy: **none established** |
| Trials / implementation | **No relevant clinical trial** for ACTN2-related MPD6 was identified in the retrieved searches | Trial-search negative evidence; weak/absent (pqac-00000000, pqac-00000001) | Relevant interventional trial: **none found** |
| Missing evidence summary | No robust data were found for prevalence, incidence, sex ratio, quality of life metrics, prognosis/survival, founder effect confirmation, environmental modifiers, omics biomarkers, or validated animal/natural disease models specific to MPD6 | Evidence gap statement synthesized from available sources; weak/absent (pqac-00000002, pqac-00000003, pqac-00000011) | Clearly missing: epidemiology, QoL, survival, response rates, prevention trials, MPD6-specific model system validation |


*Table: This table summarizes the strongest currently retrievable evidence for ACTN2-related Distal Myopathy 6, including disease identity, causal variants, phenotype, pathology, and major evidence gaps. It is useful as a compact curation-ready snapshot for a disease knowledge base entry.*