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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

MPD6 is inherited in an autosomal dominant manner, with heterozygous ACTN2 variants cosegregating with disease across affected families. Penetrance is incomplete and age-dependent - the largest cohort includes asymptomatic adult carriers - and expressivity is variable and genotype-dependent, spanning asymptomatic through distal weakness to a limb-girdle pattern with facial involvement. No penetrance_percentage is given because no cohort reports a figure.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:30900782 SUPPORT Human Clinical

"We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy."

The original actininopathy cohort establishes autosomal dominant transmission of the ACTN2 distal myopathy.

PMID:39812845 SUPPORT Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."

Asymptomatic carriers at one end of the range establish incomplete penetrance; the genotype-dependent spread across that range establishes variable expressivity.

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Mechanistic Hypotheses

1

Mechanical-load selectivity explains the distal predilection

mpd6_eccentric_load_selective_vulnerability EMERGING

Evidence balance 1 support 1 refute

Alpha-actinin-2 is expressed throughout skeletal and cardiac muscle, so a uniform Z-disk defect does not by itself explain why weakness starts in the anterior lower leg. The proposed explanation is that the distal locomotor muscles carry higher mechanical stress and eccentric load, so a Z-disk that is marginally destabilized fails there first. Two things keep this at EMERGING. It is a review-level inference from the anatomy of the deficit rather than an experimental result, offered by its source as a possibility and not tested in any model. And it competes with a genotype-specific account: the largest dominant cohort found the clinical pattern tracked genotype, spanning asymptomatic carriers to limb-girdle weakness, which a load-based explanation alone does not predict, since mechanical load is the same whichever allele a person carries. Note the muscle distribution does not settle it either way - the affected set (tibialis anterior and soleus, but also hamstrings and glutei) is a mix of distal and high-eccentric-load proximal muscles, so it neither confirms nor excludes a load account.

Pathograph links

Z-disk and myofibrillar disorganization -> Distal skeletal muscle degeneration and weakness DIRECT Progressive myofibrillar breakdown produces the histopathologic and clinical features of the distal myopathy. The distal predilection is not explained by the Z-disk defect alone, which is uniform across striated muscle; see mechanistic_hypotheses#mpd6_eccentric_load_selective_vulnerability.

Show evidence (2 references)

PMID:42111349 SUPPORT Other

"This preferential involvement of distal muscles may be attributed to the higher mechanical stress and eccentric loads placed on these muscles during locomotion, which renders them more susceptible to Z-disk instability caused by α-actinin-2 dysfunction."

States the mechanical-load explanation for the distal predilection, and states it as a possibility rather than an established result. Note this source is a broad review whose ACTN2 variant-to-domain assignments are unreliable in places, so it carries the hypothesis but does not substantiate it.

PMID:39812845 REFUTE Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."

Genotype-dependent severity within a single disease argues against mechanical load being the determinant of where and whether muscle fails: loading does not vary by allele, so a load-only account cannot generate a genotype-dependent range from asymptomatic to limb-girdle.

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Discussions and Knowledge Gaps

4

Does the alpha-actinin-2 protein-aggregation mechanism explain all ACTN2 variant classes in MPD6, or only the protein-extending frameshift class?

KNOWLEDGE GAP OPEN mpd6_mechanism_variant_class_scope

Attached to

pathophysiology#Alpha-actinin-2 protein aggregation pathophysiology#Alpha-actinin-2 conformational destabilization

The aggregation mechanism is demonstrated for protein-extending frameshift variants; the pathomechanism of the missense class (the original actininopathy families) is undetermined, so the modeled chain should not be read as explaining every variant class.

Show evidence (3 references)

PMID:39095936 SUPPORT In Vitro

"However, this mechanism is likely elicited by only a limited number of variants."

The authors caution the aggregation mechanism applies to only a limited number of variants.

PMID:36116040 SUPPORT Other

"the genotype-phenotype correlations of these variants remain unclear."

The mutation update states ACTN2 genotype-phenotype correlations remain unclear.

PMID:42481460 SUPPORT INDIRECT In Vitro

"Collectively, these findings establish that HCM-linked ACTN2 variants compromise protein integrity through multiple mechanisms, highlight the ABD as a hotspot of vulnerability"

The nearest available lead on the missense class: destabilization plus aggregation propensity is shared across an ACTN2 missense panel, so aggregation may not be confined to the protein-extending frameshifts. The panel is HCM alleles, so this narrows the gap without closing it, and testing an MPD6 missense allele in the C2C12 aggregation assay is the obvious next step.

Guard against miscoding MPD6 (ACTN2; OMIM:618655) as "myofibrillar myopathy 6" (MFM6), the BAG3-related childhood disorder.

INTERPRETATION OPEN mpd6_mfm6_bag3_nomenclature_trap

Attached to

disease#Distal Myopathy 6, Adult-Onset, Autosomal Dominant

Older literature uses "MFM6" for the BAG3 disease; the shared "6" ordinal and myofibrillar histology create a serious risk of conflating two distinct gene-disease entities. MPD6 is ACTN2-related and adult-onset.

Show evidence (1 reference)

PMID:38352343 SUPPORT In Vitro

"Myofibrillar myopathy 6 (MFM6) is a rare childhood-onset myopathy characterized by myofibrillar disintegration, muscle weakness, and cardiomyopathy. The genetic cause of MFM6 is p.Pro209Leu mutation (rs121918312-T) in the BAG3 gene"

Fixes what MFM6 actually is - BAG3, childhood-onset, with cardiomyopathy, under OMIM 612954 - against which MPD6 (ACTN2, OMIM:618655, adult-onset, cardiac sparing) is a different entity on every axis. This is the source that makes the miscoding trap checkable rather than asserted.

Do the existing zebrafish and AAV-mouse ACTN2 models say anything about MPD6 specifically, given that both express p.Leu727Arg - an allele of the congenital core myopathy, not of MPD6?

HUMAN MODEL MISMATCH OPEN mpd6_no_allele_matched_animal_model

Attached to

animal_models#Zebrafish ACTN2 p.Leu727Arg mRNA overexpression animal_models#AAV2/9 ACTN2 p.Leu727Arg tibialis anterior mouse pathophysiology#Z-disk and myofibrillar disorganization

Both published in vivo models transiently overexpress an exogenous mutant ACTN2 allele that causes Multiple structured Core Disease, an early-onset respiratory-involved congenital myopathy. They support the general claim that mutant alpha-actinin-2 disorganizes the Z-disk and weakens muscle, and the mouse arm even uses the tibialis anterior. What no model addresses is the feature that defines MPD6: why an adult-onset process selects the anterior lower-leg compartment after decades of normal function. Supraphysiological transient overexpression over four weeks is the wrong time-course for that question, so the aggregate structural evidence should not be read as an MPD6 model.

Proposed experiments

Knock-in mouse carrying an MPD6 allele at endogenous ACTN2 dosage

mpd6_knockin_mouse_endogenous_dosage

Generate heterozygous knock-in mice for a founder MPD6 missense allele (p.Cys487Arg or p.Ile134Asn) and for a last-exon protein-extending frameshift allele, and age them, comparing tibialis anterior with soleus and with a proximal control muscle for onset, fat replacement, force, and alpha-actinin-2 aggregate burden. Endogenous dosage and aging are the two things the existing models lack.

Would support

pathophysiology#Distal skeletal muscle degeneration and weakness

Would refute

pathophysiology#Alpha-actinin-2 protein aggregation

Supporting outcome

Age-dependent, anterior-compartment-predominant force loss and Z-disk pathology appearing in adulthood in the MPD6 knock-in but not in littermate controls.

Refuting outcome

No detectable alpha-actinin-2 aggregation in muscle from the protein-extending knock-in despite an overt myopathy, which would place the aggregation mechanism outside the in vivo disease.

Show evidence (1 reference)

PMID:30701273 SUPPORT Human Clinical

"we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement"

Documents the patients whose allele these models express - the early-onset congenital entity - which is the source of the mismatch. The quoted sentence reports the human patients, not the model work later in the same paper.

Can a therapy lower or correct mutant alpha-actinin-2 without compromising the wild-type protein that healthy sarcomeres and myocardium depend on?

KNOWLEDGE GAP OPEN mpd6_therapeutic_window_allele_selectivity

Attached to

treatments#Supportive Care pathophysiology#Alpha-actinin-2 protein aggregation

Gene addition does not help a dominant toxic-gain mechanism, so the obvious strategies are knockdown or editing. Alpha-actinin-2 is essential in both skeletal muscle and heart, so a non-allele-selective knockdown risks causing the disease it is meant to treat. This is the specific reason MPD6 has no therapeutic programme rather than simply not having attracted one, and it is what any candidate approach has to answer first.

Show evidence (2 references)

PMID:42111349 SUPPORT Other

"Given the essential physiological role of wild-type α-actinin-2 in maintaining sarcomeric stability, broad inhibition or knockdown strategies could induce severe cardiotoxicity or myopathy."

States the therapeutic-window problem that allele selectivity has to solve.

PMID:39095936 SUPPORT In Vitro

"However, this mechanism is likely elicited by only a limited number of variants."

An allele-selective therapy aimed at aggregation would apply only to the protein-extending class, narrowing the eligible population further.

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Pathophysiology

5

ACTN2 pathogenic variants alter alpha-actinin-2

Heterozygous pathogenic variants in ACTN2 alter alpha-actinin-2, a sarcomeric Z-disk protein. Two dominant classes are recognized: missense variants (the original Spanish and Swedish actininopathy families) and single-nucleotide deletions in the last exon that shift the reading frame and append a novel, unstructured, slightly extended C-terminal sequence.

ACTN2 hgnc:164

actin filament binding GO:0051015 ⚠ ABNORMAL

Downstream

Z-disk and myofibrillar disorganization Altered alpha-actinin-2 disrupts its structural cross-linking role at the Z-disk, degrading sarcomeric organization.

Alpha-actinin-2 conformational destabilization Missense substitutions, particularly in the actin-binding domain, reduce the solubility and thermal stability of the folded protein. Shown for ACTN2 hypertrophic-cardiomyopathy alleles rather than MPD6 alleles, so the edge is a candidate route for the MPD6 missense class rather than a demonstrated one.

Alpha-actinin-2 protein aggregation Protein-extending frameshift variants render alpha-actinin-2 aggregation-prone.

Show evidence (3 references)

PMID:30900782 SUPPORT Human Clinical

"In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease."

Identifies dominant ACTN2 missense variants as the genetic cause of the actininopathy families.

PMID:34386585 SUPPORT Human Clinical

"High-throughput sequencing identified in each proband a heterozygous single nucleotide deletion (c.2558del and c.2567del) in the last exon of the ACTN2 gene."

Establishes the last-exon frameshift class of dominant ACTN2 variants in the facial-weakness distal myopathy families.

PMID:34386585 SUPPORT Human Clinical

"The deletions are predicted to lead to a novel but unstructured slightly extended C-terminal amino acid sequence."

Describes how the frameshift lesions extend the alpha-actinin-2 C-terminus.

Alpha-actinin-2 conformational destabilization

A candidate step upstream of aggregation, and one of the few leads on the missense class whose mechanism is otherwise undetermined. Systematic biophysical profiling of ACTN2 missense variants shows reduced solubility, reduced thermal and proteolytic stability, and a strong propensity to aggregate in solution, with the actin-binding domain the most vulnerable region. Structural work on actin-binding-domain variants shows the same variants incorporate less well into the Z-disc and that the unincorporated protein forms aggregates outside it. Both lines of evidence come from ACTN2 hypertrophic-cardiomyopathy variant panels rather than MPD6 alleles, so this node states a plausible shared property of destabilizing ACTN2 missense variants, not a demonstrated MPD6 mechanism.

Downstream

Alpha-actinin-2 protein aggregation Destabilized, poorly incorporated alpha-actinin-2 is left unbound in the cytoplasm where it is free to aggregate.

Show evidence (4 references)

PMID:42481460 SUPPORT INDIRECT In Vitro

"All variants display reduced solubility, with actin-binding domain (ABD) substitutions showing pronounced thermal instability by differential scanning fluorimetry."

Establishes reduced solubility and thermal destabilization as a shared property across an ACTN2 missense panel. Indirect: the seventeen variants profiled are hypertrophic-cardiomyopathy alleles, not the MPD6 founder or last-exon variants.

PMID:42481460 SUPPORT INDIRECT In Vitro

"Limited proteolysis indicates reduced structural stability across variants, while size-exclusion chromatography coupled with multi-angle light scattering or small-angle X-ray scattering (SEC-MALS/SAXS) shows a strong propensity for aggregation."

Links the destabilization directly to aggregation propensity in solution, which is the step this node contributes. Same allele caveat as above.

PMID:27287556 SUPPORT INDIRECT In Vitro

"These data show that both mutations appear to reduce the ability of the protein to incorporate normally into Z-discs."

Reduced Z-disc incorporation is the cellular counterpart of the biophysical destabilization. Indirect: measured in cardiomyocytes for two calponin-homology-domain HCM variants. The authors call those two variants mild and likely benign in population terms while concluding they are nonetheless genuine disease mutations, so this is a small effect demonstrated in a mild allele, not a null result.

+ 1 more reference

Alpha-actinin-2 protein aggregation

Dominant frameshift variants that extend the alpha-actinin-2 protein cause it to form intracellular aggregates in muscle-cell models, whereas recessive missense variants do not, implicating alpha-actinin-2 aggregation as the disease mechanism for this class of dominant actininopathy.

inclusion body assembly GO:0070841 ↑ INCREASED

Experimental models

C2C12 myoblast ACTN2 variant aggregation assay CELL LINE Protein-extending dominant frameshift variants form alpha-actinin-2 aggregates in this system while recessive missense variants do not, which is the direct experimental basis for the aggregation node.

Downstream

Z-disk and myofibrillar disorganization Aggregated alpha-actinin-2 and increased protein expression disrupt normal Z-line organization.

Show evidence (2 references)

PMID:39095936 SUPPORT In Vitro

"Conversely, dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates."

Cell-model functional data show protein-extending frameshift variants generate alpha-actinin-2 aggregates.

PMID:39095936 SUPPORT In Vitro

"The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic."

Names alpha-actinin-2 aggregation as the pathomechanism for this dominant class.

Z-disk and myofibrillar disorganization

Loss of normal alpha-actinin-2 Z-disk cross-linking, together with abnormal accumulation of the protein, produces disorganized Z-lines and myofibrillar disarray. Muscle-sample analysis shows increased alpha-actinin-2 expression and abnormal Z-line organization.

Mechanical-load selectivity explains the distal predilection

skeletal muscle fiber CL:0000188

sarcomere organization GO:0045214 ⚠ ABNORMAL

Animal models

Zebrafish ACTN2 p.Leu727Arg mRNA overexpression Zebrafish partially recapitulates Establishes that a dominant ACTN2 missense allele is sufficient to produce sarcomeric disarray and abnormal Z-lines in vivo, supporting the Z-disk node in this entry.

AAV2/9 ACTN2 p.Leu727Arg tibialis anterior mouse Mouse partially recapitulates Mutant alpha-actinin-2 expressed in mouse tibialis anterior produces abnormal Z-line organization and cores together with measurable force loss, linking the Z-disk node to a contractile deficit in a mammalian muscle.

Downstream

Distal skeletal muscle degeneration and weakness Progressive myofibrillar breakdown produces the histopathologic and clinical features of the distal myopathy. The distal predilection is not explained by the Z-disk defect alone, which is uniform across striated muscle; see mechanistic_hypotheses#mpd6_eccentric_load_selective_vulnerability.

Show evidence (1 reference)

PMID:34170073 SUPPORT Human Clinical

"functional analysis using muscle samples revealed that the variant significantly increased the expression level of α-actinin-2 and resulted in abnormal Z-line organization of muscle fiber."

Directly links the ACTN2 frameshift variant to increased alpha-actinin-2 and disrupted Z-line organization.

Distal skeletal muscle degeneration and weakness

Chronic myofibrillar degeneration is expressed histologically as internalized nuclei, myofibrillar disorganization, rimmed vacuoles, and in some families multi-minicores, and clinically as slowly progressive distal muscle weakness that begins in the anterior lower leg and later extends proximally.

Show evidence (1 reference)

PMID:34386585 SUPPORT Human Clinical

"Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."

Describes the myopathic histopathology of the degenerating muscle.

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Histopathology

2

Undulating Z-disk on electron microscopy

Electron microscopy of muscle from distal actininopathy shows undulation of the Z-disk alongside myofibrillar disarray, the ultrastructural correlate of failed alpha-actinin-2 cross-linking.

Show evidence (1 reference)

PMID:33458580 SUPPORT Human Clinical

"Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"

Reports Z-disk undulation on electron microscopy as a histopathologic feature of distal actininopathy.

Non-specific myopathic changes on light microscopy

Biopsy is not reliably diagnostic. In the largest dominant ACTN2 myopathy series the available biopsies showed only non-specific changes, so the rimmed vacuoles, internalized nuclei and multi-minicores reported in individual kindreds should not be treated as an obligate or diagnostic finding.

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"Available muscle biopsies showed non-specific changes."

Establishes that biopsy findings in the largest dominant cohort were non-specific, qualifying the diagnostic weight of the biopsy features reported elsewhere.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Head and Neck 1

Facial muscle weakness Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:34386585 SUPPORT Human Clinical

"Actininopathy should be considered in the differential diagnosis of distal myopathy combined with facial weakness."

Identifies facial weakness combined with distal myopathy as a defining feature.

Limbs 3

Distal lower limb muscle weakness HP:0009053

Course: PROGRESSIVE Onset: ADULT

Show evidence (2 references)

PMID:34386585 SUPPORT Human Clinical

"They presented with a very slowly progressive myopathy involving anterior lower leg and facial muscles."

Documents slowly progressive anterior lower-leg (distal) muscle involvement.

PMID:30900782 SUPPORT Human Clinical

"Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."

Establishes distal (ankle dorsiflexion) onset with later proximal spread.

Foot dorsiflexor weakness HP:0009027

Show evidence (1 reference)

PMID:30900782 SUPPORT Human Clinical

"Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."

Documents ankle-dorsiflexion (foot dorsiflexor) weakness as the initial manifestation.

Limb-girdle pattern weakness Limb-girdle muscle weakness HP:0003325

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."

Places limb-girdle weakness at the severe end of the reported dominant ACTN2 myopathy spectrum.

Metabolism 1

Elevated serum creatine kinase Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:33458580 SUPPORT Human Clinical

"Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"

Reports mildly elevated serum CK in distal actininopathy.

Musculoskeletal 5

Proximal muscle weakness HP:0003701

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:30900782 SUPPORT Human Clinical

"Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."

Records later progression to proximal limb muscles.

Rimmed vacuoles HP:0003805

Show evidence (1 reference)

PMID:34386585 SUPPORT Human Clinical

"Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."

Rimmed vacuoles are reported on muscle biopsy.

Centrally nucleated muscle fibers Centrally nucleated skeletal muscle fibers HP:0003687

Show evidence (1 reference)

PMID:34386585 SUPPORT Human Clinical

"Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."

Internalized nuclei correspond to centrally nucleated skeletal muscle fibers.

Minicore myopathy HP:0003789

Show evidence (1 reference)

PMID:34170073 SUPPORT Human Clinical

"The patients exhibited adult-onset distal myopathy with multi-minicores, which, interestingly, was more like a combination of MsCD and actininopathy."

Reports multi-minicores in an adult-onset ACTN2 distal myopathy family.

Fatty replacement of anterolateral lower-leg muscles Fatty replacement of skeletal muscle HP:0012548

Show evidence (1 reference)

PMID:34386585 SUPPORT Human Clinical

"Muscle MRI finding showed complete fat replacement of anterolateral compartment muscles of the lower legs with variable involvement of soleus and gastrocnemius but sparing thigh muscles."

Documents the characteristic selective anterolateral lower-leg fatty replacement with thigh sparing on muscle MRI.

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Genetic Associations

1

ACTN2

Gene: ACTN2 hgnc:164 gene page

Show evidence (5 references)

PMID:39095936 SUPPORT Other

"The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk."

Molecular-background statement (review/introduction) of the normal Z-disk cross-linking function of the gene product.

PMID:36116040 SUPPORT Other

"ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle."

Mutation-update review statement confirming ACTN2 gene identity and tissue expression.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

ClinGen classifies the ACTN2 gene-disease relationship (the lumped cardiac-and-skeletal myopathy entity that includes MPD6) as Definitive with autosomal dominant inheritance.

+ 2 more references

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Variants

5

ACTN2 p.Cys487Arg

Gene: ACTN2 hgnc:164

Missense founder variant of the Basque-Spanish actininopathy families, the original MPD6 kindreds. Carried on a shared haplotype consistent with common ancestry. Named at the protein level only: the cDNA change is not stated in any source cited here. No clinical_significance is asserted either - multi-family cosegregation on a shared haplotype is good evidence, but no cited source states an ACMG or ClinVar classification for this allele, and the ACTN2 mutation update cited elsewhere in this entry cautions that supporting data are limited for most reported ACTN2 missense variants.

Show evidence (2 references)

PMID:39812845 SUPPORT Human Clinical

"Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry."

Identifies p.Cys487Arg as a Basque-Spanish founder allele on a distinct haplotype.

PMID:30900782 SUPPORT Human Clinical

"In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease."

The original report of a single shared missense variant cosegregating across the three Spanish families.

ACTN2 p.Ile134Asn

Gene: ACTN2 hgnc:164

Missense founder variant of the Belgian families in the largest dominant cohort, on its own distinct haplotype. No clinical_significance is asserted, for the same reason as p.Cys487Arg: the cited evidence establishes founder haplotype and cosegregation, not a stated variant classification.

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry."

Identifies p.Ile134Asn as a Belgian founder allele with its own haplotype.

ACTN2 c.2504delT (p.Phe835Serfs*66)

Gene: ACTN2 hgnc:164

Frameshift allele of the adult-onset family with multi-minicores. Functional work on this family's muscle is what links the frameshift class to raised alpha-actinin-2 levels and disorganized Z-lines in patient tissue rather than in a cell model.

Show evidence (2 references)

PMID:34170073 SUPPORT Human Clinical

"We firstly identified a novel frameshift variant (c.2504delT, p.Phe835Serfs*66) within ACTN2 in a family including three patients."

Names the frameshift allele identified in this adult-onset distal myopathy family.

PMID:34170073 SUPPORT Human Clinical

"functional analysis using muscle samples revealed that the variant significantly increased the expression level of α-actinin-2 and resulted in abnormal Z-line organization of muscle fiber."

Ties this specific allele to increased alpha-actinin-2 and abnormal Z-line organization in patient muscle.

ACTN2 Swedish-family missense variant

Gene: ACTN2 hgnc:164

The fourth of the four original actininopathy families is Swedish and carries a different ACTN2 missense variant from the shared Basque-Spanish allele. The cited abstract does not name it, so it is recorded as a distinct allele without an HGVS designation rather than assigned one from an uncited source.

Show evidence (1 reference)

PMID:30900782 SUPPORT Human Clinical

"The affected members of the Swedish family carry a different ACTN2 missense variant."

Establishes a second, distinct missense allele in the original cohort without naming it.

ACTN2 last-exon single-nucleotide deletions (c.2558del, c.2567del) Pathogenic

Gene: ACTN2 hgnc:164

Out-of-frame deletions in the last exon that append a novel extended C-terminus. This is the protein-extending class shown to aggregate in the C2C12 model, and the class associated with the distinctive facial weakness.

Show evidence (2 references)

PMID:34386585 SUPPORT Human Clinical

"High-throughput sequencing identified in each proband a heterozygous single nucleotide deletion (c.2558del and c.2567del) in the last exon of the ACTN2 gene."

Reports the two last-exon frameshift deletions in the facial-weakness distal myopathy probands.

PMID:39095936 SUPPORT In Vitro

"we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic"

Functional data support classifying the protein-extending frameshift class as pathogenic.

💊

Medical Actions

5

Supportive Care

Action: Supportive Care NCIT:C15747

No disease-modifying therapy exists for MPD6. Overall management is supportive and guided by the slowly progressive distal weakness, with mobility aids as ambulation declines.

Show evidence (1 reference)

PMID:42111349 SUPPORT Other

"while diltiazem has shown promise in treating ACTN2-related HCM, effective targeted therapies for other ACTN2-associated conditions are currently lacking"

Confirms that no targeted therapy is available for the non-cardiac ACTN2 conditions, which is why management is supportive.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitative exercise and gait/balance training to maintain function and reduce falls from foot drop and later proximal weakness.

Show evidence (1 reference)

PMID:33458580 SUPPORT INDIRECT Human Clinical

"Distal actininopathy is an autosomal dominant, adult onset distal myopathy starting usually with foot drop."

No trial of physiotherapy in MPD6 exists. The quote supports the target of the intervention - foot drop as the presenting deficit - rather than the efficacy of physiotherapy itself, which is extrapolated from general neuromuscular rehabilitation practice.

Ankle-Foot Orthosis

Action: ankle-foot orthosis fitting Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Ankle-foot orthoses to compensate for ankle-dorsiflexor weakness (foot drop), improving toe clearance and gait stability. NCIT has no clinical-action term for orthotic fitting, so the treatment_term binds the rehabilitation action and the device concept is carried as a medical-device qualifier.

Show evidence (1 reference)

PMID:39017652 SUPPORT INDIRECT Human Clinical

"Generally, ACTN2-related distal myopathies begin with foot drop due to muscle weakness in the anterior compartment of the lower leg."

Establishes foot drop from anterior-compartment weakness as the deficit the orthosis compensates for. The orthosis itself has not been trialled in MPD6; its use follows standard management of foot drop.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on autosomal dominant transmission and the 50% recurrence risk, with cascade testing of at-risk relatives once a familial variant is known. Adult onset and genotype-dependent expressivity - carriers may be asymptomatic when tested - are the specific points that make predictive testing decisions non-trivial here. Once a familial variant is known, reproductive options include prenatal diagnosis and preimplantation genetic testing.

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."

The asymptomatic-to-limb-girdle range and genotype dependence are what counseling must convey about predictive testing in adult-onset dominant disease.

Occupational Therapy

Action: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Assessment and adaptation of home, work and mobility tasks as distal weakness spreads proximally to the glutei and hamstrings, which are among the most affected muscles on imaging and drive difficulty with rising, stairs and transfers.

Show evidence (1 reference)

PMID:39812845 SUPPORT INDIRECT Human Clinical

"In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus."

Documents the hip-girdle and hamstring involvement that generates the functional limitations occupational therapy addresses; the intervention itself is not trialled in this disease.

🔬

Biochemical Markers

1

Serum creatine kinase (INCREASED)

Show evidence (1 reference)

PMID:33458580 SUPPORT Human Clinical

"Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"

States that serum CK is mildly elevated in distal actininopathy.

🔬

Diagnosis

4

Baseline Cardiac Evaluation

ECG and echocardiography at diagnosis. Cardiac involvement is not common in the dominant skeletal cohorts, so this is a baseline and an individualized-follow-up decision rather than a surveillance protocol - but ACTN2 is an established cardiomyopathy gene with allelic hypertrophic and dilated presentations, so the cardiac question has to be asked and answered rather than assumed. No MPD6-specific screening interval is evidence-based.

echocardiography NCIT:C16525

Show evidence (2 references)

PMID:39812845 SUPPORT Human Clinical

"Cardiac and respiratory involvement were not common."

Sets the expected yield: low enough that this is a baseline rather than ongoing surveillance, and the reason the recommendation is not stronger.

PMID:36116040 SUPPORT Other

"Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease."

The gene's established cardiomyopathy association is why a cardiac baseline is taken despite the low observed frequency in skeletal cohorts.

Multigene distal-myopathy / myopathy panel sequencing

The definitive test. Because ACTN2 is one of roughly twenty dominant distal-myopathy genes and the clinical and imaging pattern narrows the list without closing it, diagnosis rests on finding the ACTN2 variant. Panel testing also has to establish inheritance mode rather than assume it, since biallelic ACTN2 variants cause a separate recessive myopathy.

multigene panel genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:39017652 SUPPORT Human Clinical

"In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present."

Both inheritance modes exist for ACTN2, so genotype rather than phenotype is what assigns a case to this entity.

Lower-limb muscle MRI

The most useful non-invasive discriminator, because biopsy in the largest dominant cohort was non-specific. Reads the selective pattern of affected and preserved muscles, and also guides biopsy site where biopsy is still performed.

lower-limb muscle magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"Available muscle biopsies showed non-specific changes."

Non-specific biopsy is why imaging carries the discriminating weight in this disease.

Electromyography with nerve conduction studies

Establishes that the process is myopathic and, with normal nerve conduction and preserved sensation, separates it from the neurogenic causes of foot drop - peroneal neuropathy and distal hereditary motor neuronopathy - that present the same way.

electromyography with nerve conduction studies NCIT:C38056

Show evidence (1 reference)

PMID:33458580 SUPPORT INDIRECT Human Clinical

"Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet."

Supports the target of the test - establishing a primary muscle disorder - rather than test performance in MPD6, which has not been reported.

🩻

Imaging Findings

2

Selective anterolateral lower-leg and gluteal/hamstring involvement on muscle MRI

Muscle MRI in dominant ACTN2 myopathy shows a selective pattern: gluteus minimus and medius, hamstrings, tibialis anterior and soleus are the most affected muscles. The pattern extends beyond the anterolateral lower leg reported in the original last-exon frameshift families, and is the most useful non-invasive discriminator given that biopsy is non-specific.

Mri

tibialis anterior UBERON:0001385 Fatty replacement of skeletal muscle HP:0012548

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus."

Names the muscles most affected on MRI across the largest dominant ACTN2 myopathy cohort.

Machine-learning-derived discriminating MRI pattern

A trained machine-learning comparison against other neuromuscular diseases identified involvement of tibialis anterior and gluteus medius together with preservation of quadratus femoris, lateral gastrocnemius and tensor fasciae latae as the features that best separate dominant ACTN2 myopathy from its differential diagnoses. The preserved muscles carry as much discriminating weight as the affected ones.

Mri

Show evidence (1 reference)

PMID:39812845 SUPPORT Computational

"A machine learning model showed that the most differentiating features in dominant ACTN2 myopathy were the involvement of the tibialis anterior and gluteus medius muscles and preservation of the quadratus femoris, gastrocnemius lateralis, and tensor fasciae latae muscles."

Reports the computationally derived discriminating imaging signature, including the specific muscles preserved.

📈

Progression

3

Presymptomatic / minimally symptomatic adult carriers

Because onset is adult and expressivity is genotype-dependent, variant carriers ascertained through family screening may be asymptomatic at the time of assessment.

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."

Documents asymptomatic carriers at one end of the reported clinical range and genotype-dependent expressivity.

Distal-onset ambulatory phase

The presenting phase is foot drop from anterior lower-leg (ankle dorsiflexor) weakness, with ambulation preserved.

Show evidence (1 reference)

PMID:33458580 SUPPORT Human Clinical

"Distal actininopathy is an autosomal dominant, adult onset distal myopathy starting usually with foot drop."

Identifies foot drop as the typical presenting phase of distal actininopathy.

Proximal spread with upper-limb sparing

Weakness later extends to proximal lower-limb muscles. Progression is slow and the upper limbs are characteristically spared or only mildly affected, which distinguishes the course from the several distal myopathies that involve the hands early.

Show evidence (2 references)

PMID:33458580 SUPPORT Human Clinical

"The disease later progresses to proximal lower limb muscles while upper limbs remain relatively spared"

Describes the later phase as proximal lower-limb spread with relative upper-limb sparing.

PMID:39017652 SUPPORT Human Clinical

"However, this progression is usually slow, and upper limbs often remain unaffected"

Confirms slow progression with upper limbs typically unaffected.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

No population rate has been estimated for MPD6. The largest published series of non-congenital dominant ACTN2 myopathy assembled 37 patients from 11 Spanish and Belgian families; earlier reports describe four families (actininopathy) and individual last-exon frameshift kindreds. Because the published cohorts are ascertained through neuromuscular referral centres and two of the recurrent variants are founder alleles, the case counts index ascertainment rather than population frequency, so no rate_per_100000 is asserted.

Show evidence (1 reference)

PMID:39812845 SUPPORT Human Clinical

"Genetic, clinical, and muscle imaging data were collected from 37 patients with an autosomal dominant ACTN2 myopathy belonging to 11 families from Spain and Belgium."

Gives the size of the largest reported dominant ACTN2 myopathy series, the basis for the cases-in-literature count.

⚖️

Clinical Burden

Moderate

MPD6 causes lifelong, slowly progressive lower-limb weakness that begins in adulthood and produces foot drop, falls risk, and eventual proximal involvement, requiring orthoses and later mobility aids. Against that, progression is slow, upper limbs are typically spared, and the two organ involvements that drive mortality in other sarcomeric myopathies - cardiac and respiratory - are not common in the reported dominant cohorts. The burden is therefore substantial for mobility and function without an established effect on survival.

Show evidence (2 references)

PMID:39812845 SUPPORT Human Clinical

"The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common."

Establishes both the range of functional impairment and the low frequency of the cardiac and respiratory complications that would otherwise raise the burden level.

PMID:39017652 SUPPORT Human Clinical

"However, this progression is usually slow, and upper limbs often remain unaffected"

Slow progression with upper-limb sparing supports a moderate rather than high burden assignment.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Distal Myopathy 6, Adult-Onset, Autosomal Dominant:

Other anterior-compartment / distal myopathies

Overlapping Features The distal (tibial/anterior-compartment) presentation overlaps clinically with other distal myopathies and neuropathies — TTN-related tibial muscular dystrophy (Udd), MYH7-related Laing distal myopathy, GNE myopathy, VCP-related and MYOT/TIA1 myofibrillar/Welander myopathies, sporadic inclusion body myositis, and peroneal neuropathy — which are distinguished by gene, muscle-MRI pattern, and biopsy.

Distinguishing Features

Serum CK separates some of them: mild elevation in actininopathy against the marked elevation (often over ten times the upper limit) of distal anoctaminopathy and the early high CK of Miyoshi/dysferlin myopathy.
Upper-limb sparing argues against Welander and GNE myopathy, and preserved sensation with myopathic EMG argues against peroneal neuropathy and distal hereditary motor neuronopathy.
ACTN2 is one of roughly twenty genes causing a dominant distal myopathy. Those entities differ in where weakness starts (hands in Welander, vocal cord and pharynx in VCPDM, anterior lower leg here), so the clinical pattern narrows the list without closing it; a multigene distal-myopathy panel is what settles it.

Show evidence (2 references)

PMID:33458580 SUPPORT Human Clinical

"Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy."

Establishes the size of the dominant distal-myopathy differential that ACTN2 sits within, and why the distinction is genetic rather than clinical.

PMID:33458580 SUPPORT Human Clinical

"CK levels are usually highly elevated (over 10 times the upper limits)."

The markedly elevated CK of distal anoctaminopathy contrasts with the mild elevation of actininopathy, supporting CK as a partial discriminator.

Recessive ACTN2-related myopathy (biallelic)

Overlapping Features Biallelic ACTN2 missense variants cause a recessive myopathy that is allelic to MPD6 and overlaps it clinically — asymmetric, progressive, distal-predominant lower-limb weakness — so a single heterozygous ACTN2 finding does not by itself establish the dominant entity. The recessive form additionally has prominent proximal involvement and, mechanistically, its missense variants do not form alpha-actinin-2 aggregates in the cell model, unlike the dominant protein-extending frameshift class.

Distinguishing Features

Biallelic rather than heterozygous ACTN2 genotype, with pedigree consistent with recessive transmission.
Both proximal and distal lower-extremity weakness at presentation, with hamstring and adductor involvement in the thigh.
Reported in a Palestinian founder population for the recurrent p.Arg506Gly allele.

Show evidence (2 references)

PMID:38311799 SUPPORT Human Clinical

"We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness."

Defines the recessive ACTN2 entity and its clinical overlap with the dominant distal myopathy.

PMID:39017652 SUPPORT Human Clinical

"In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present."

Confirms ACTN2 now carries both dominant and recessive myopathy forms, which is why inheritance mode must be established rather than assumed.

🧫

Experimental Models

1

C2C12 myoblast ACTN2 variant aggregation assay CELL_LINE

C2C12 murine myoblasts expressing a panel of ACTN2 frameshift and missense variants drawn from dominant and recessive actininopathies, scored for alpha-actinin-2 aggregate formation. The panel design is what makes the result informative: it separates the variant classes rather than testing one allele in isolation.

Organism

mouse NCBITaxon:10090

Publication

PMID:39095936

Pathograph links

Alpha-actinin-2 protein aggregation recapitulates fidelity: moderate Protein-extending dominant frameshift variants form alpha-actinin-2 aggregates in this system while recessive missense variants do not, which is the direct experimental basis for the aggregation node.

Limitations: A murine myoblast line is not adult human skeletal muscle: it lacks the mature sarcomere, the mechanical loading and the decades of exposure under which the human phenotype emerges. The assay scores aggregate formation, not the downstream Z-disk failure or muscle degeneration, and the authors state the mechanism accounts for only a limited number of variants.

Readouts

Alpha-actinin-2 aggregate formation

Direction: INCREASED

Interpretation: Aggregates form with protein-extending dominant frameshift variants and are absent with recessive missense variants, separating the two variant classes.

Show evidence (1 reference)

PMID:39095936 SUPPORT In Vitro

"The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model."

The negative arm of the assay establishes that aggregation tracks the dominant protein-extending class rather than being a nonspecific consequence of transfecting a variant.

Show evidence (1 reference)

PMID:39095936 SUPPORT In Vitro

"Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies."

Describes the model system and the variant panel that grounds the aggregation claim.

Show evidence (1 reference)

PMID:39095936 SUPPORT In Vitro

"Conversely, dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates."

The positive result that makes this cell system informative for the dominant actininopathy mechanism.

🐁

Animal Models

2

Zebrafish ACTN2 p.Leu727Arg mRNA overexpression

Human mutant ACTN2 mRNA injected into one-cell zebrafish embryos, assayed at 3 dpf for swimming distance, birefringence and myofibrillar ultrastructure against wild-type-injected and uninjected controls.

Species

Zebrafish

Genotype

Transient overexpression of human ACTN2 c.2180T>G (p.Leu727Arg) mRNA

Publication

PMID:30701273

Pathograph links

Z-disk and myofibrillar disorganization partially recapitulates fidelity: low Establishes that a dominant ACTN2 missense allele is sufficient to produce sarcomeric disarray and abnormal Z-lines in vivo, supporting the Z-disk node in this entry.

Limitations: p.Leu727Arg is a de novo allele of Multiple structured Core Disease, an allelic congenital ACTN2 myopathy with early-onset weakness and respiratory involvement - not an MPD6 allele. The model is transient overexpression of exogenous human mRNA rather than a knock-in at endogenous dosage, and a larval fish has no adult-onset, anterior-lower-leg selective phenotype to recapitulate. It supports the general Z-disk mechanism, not the MPD6 phenotype.

Readouts

Myofibrillar organization on transmission electron microscopy

Direction: ALTERED

Interpretation: Structural correlate of the Z-disk disorganization node in a whole-organism model.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies."

Sarcomeric disorganization occurred with mutant but not wild-type alpha-actinin-2, controlling for overexpression alone.

Total swimming distance

Direction: DECREASED

Interpretation: Functional motor consequence of the sarcomeric defect.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"Zebrafish expressing p.Leu727Arg alpha-actinin-2 displayed a significant reduction in the total swimming distance"

Quantifies impaired motor function in the mutant-expressing larvae.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients."

Supports treating the zebrafish system as informative for the ACTN2 Z-disk mechanism.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice."

Establishes the zebrafish arm as a validated system in which mutant alpha-actinin-2 produces a measurable motor deficit.

AAV2/9 ACTN2 p.Leu727Arg tibialis anterior mouse

Wild-type, mutant or empty AAV2/9 injected into the tibialis anterior of 3-week-old male mice, with in situ force measurement, histochemistry and electron microscopy 4 weeks later. Notably the injected muscle is the tibialis anterior, the muscle that fails first in MPD6.

Species

Mouse

Genotype

AAV2/9-mediated overexpression of human ACTN2 p.Leu727Arg in tibialis anterior

Background

C57BL/6J

Publication

PMID:30701273

Pathograph links

Z-disk and myofibrillar disorganization partially recapitulates fidelity: low Mutant alpha-actinin-2 expressed in mouse tibialis anterior produces abnormal Z-line organization and cores together with measurable force loss, linking the Z-disk node to a contractile deficit in a mammalian muscle.

Limitations: Same allele caveat as the zebrafish arm: p.Leu727Arg causes the allelic congenital core myopathy, not MPD6. Local AAV transduction gives an approximately twofold supraphysiological alpha-actinin-2 level over four weeks, which models acute mutant-protein burden rather than the decades of adult-onset degeneration that define MPD6, and says nothing about why the human disease selects the anterior compartment.

Readouts

In situ maximal and specific tetanic force of tibialis anterior

Direction: DECREASED

Interpretation: Contractile consequence of Z-disk disorganization, measured in the muscle homologous to the one that fails first in patients.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"we detected a significantly reduced maximal and specific force of p.Leu727Arg-injected tibialis anterior compared to muscles injected with empty AAV or wild-type ACTN2 respectively"

Quantifies force loss against both empty-vector and wild-type-overexpression controls.

Z-line architecture on histochemistry and electron microscopy

Direction: ALTERED

Interpretation: Structural readout matching the Z-line abnormalities seen on patient biopsy.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects."

Reports the Z-line structural defect in the transduced mouse muscle.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice."

Supports treating the AAV mouse as informative for the contractile consequence of the Z-disk mechanism.

Show evidence (1 reference)

PMID:30701273 SUPPORT Model Organism

"The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects."

Establishes the AAV mouse as a system in which mutant alpha-actinin-2 reproduces the Z-line pathology seen on patient biopsy.

{ }

Source YAML

click to show

name: Distal Myopathy 6, Adult-Onset, Autosomal Dominant
category: Mendelian
creation_date: "2026-08-02T00:00:00Z"
synonyms:
- MPD6
- ACTN2-related distal myopathy
- Actininopathy
- Distal myopathy with facial weakness
- ACTN2-related dominant distal myopathy
description: >
  Distal myopathy 6, adult-onset, autosomal dominant (MPD6; "actininopathy") is a
  rare, slowly progressive skeletal muscle disorder caused by heterozygous
  pathogenic variants in ACTN2, the gene encoding the sarcomeric Z-disk protein
  alpha-actinin-2. Alpha-actinin-2 cross-links actin thin filaments and titin at
  the Z-disk, and its dysfunction disrupts Z-disk architecture and myofibrillar
  organization. Patients present in adulthood with distal lower-limb weakness that
  begins in the anterior compartment of the leg (ankle dorsiflexion), often with
  distinctive facial weakness, and only later spreads to proximal muscles. Muscle
  imaging shows fatty replacement of the anterolateral lower-leg compartment with
  relative sparing of the thigh, and biopsies reveal myofibrillar disorganization,
  internalized nuclei, rimmed vacuoles, and in some families multi-minicores. Two
  dominant molecular mechanisms are recognized: missense variants (the original
  actininopathy families) and protein-extending frameshift variants in the last
  exon, the latter shown to drive alpha-actinin-2 protein aggregation.
  MPD6 is OMIM:618655. ACTN2 was historically associated only with
  cardiomyopathy (hypertrophic/dilated; the allelic entities CMH23 and CMD1AA),
  and ClinGen has since lumped the cardiac and skeletal presentations into a
  single "ACTN2-related cardiac and skeletal myopathy" entity, whereas MONDO
  keeps the phenotype-specific nodes (including this distal-myopathy node)
  separate — the split this entry follows.
disease_term:
  preferred_term: myopathy, distal, 6, adult-onset, autosomal dominant
  term:
    id: MONDO:0032853
    label: myopathy, distal, 6, adult-onset, autosomal dominant
parents:
- Distal myopathy
- ACTN2-related myopathy
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population rate has been estimated for MPD6. The largest published series
    of non-congenital dominant ACTN2 myopathy assembled 37 patients from 11
    Spanish and Belgian families; earlier reports describe four families
    (actininopathy) and individual last-exon frameshift kindreds. Because the
    published cohorts are ascertained through neuromuscular referral centres and
    two of the recurrent variants are founder alleles, the case counts index
    ascertainment rather than population frequency, so no rate_per_100000 is
    asserted.
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic, clinical, and muscle imaging data were collected from 37 patients with an autosomal dominant ACTN2 myopathy belonging to 11 families from Spain and Belgium."
    explanation: Gives the size of the largest reported dominant ACTN2 myopathy series, the basis for the cases-in-literature count.
progression:
- phase: Presymptomatic / minimally symptomatic adult carriers
  notes: >-
    Because onset is adult and expressivity is genotype-dependent, variant
    carriers ascertained through family screening may be asymptomatic at the
    time of assessment.
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."
    explanation: Documents asymptomatic carriers at one end of the reported clinical range and genotype-dependent expressivity.
- phase: Distal-onset ambulatory phase
  notes: >-
    The presenting phase is foot drop from anterior lower-leg (ankle
    dorsiflexor) weakness, with ambulation preserved.
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal actininopathy is an autosomal dominant, adult onset distal myopathy starting usually with foot drop."
    explanation: Identifies foot drop as the typical presenting phase of distal actininopathy.
- phase: Proximal spread with upper-limb sparing
  notes: >-
    Weakness later extends to proximal lower-limb muscles. Progression is slow
    and the upper limbs are characteristically spared or only mildly affected,
    which distinguishes the course from the several distal myopathies that
    involve the hands early.
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease later progresses to proximal lower limb muscles while upper limbs remain relatively spared"
    explanation: Describes the later phase as proximal lower-limb spread with relative upper-limb sparing.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, this progression is usually slow, and upper limbs often remain unaffected"
    explanation: Confirms slow progression with upper limbs typically unaffected.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    MPD6 causes lifelong, slowly progressive lower-limb weakness that begins in
    adulthood and produces foot drop, falls risk, and eventual proximal
    involvement, requiring orthoses and later mobility aids. Against that,
    progression is slow, upper limbs are typically spared, and the two organ
    involvements that drive mortality in other sarcomeric myopathies - cardiac
    and respiratory - are not common in the reported dominant cohorts. The
    burden is therefore substantial for mobility and function without an
    established effect on survival.
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common."
    explanation: Establishes both the range of functional impairment and the low frequency of the cardiac and respiratory complications that would otherwise raise the burden level.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, this progression is usually slow, and upper limbs often remain unaffected"
    explanation: Slow progression with upper-limb sparing supports a moderate rather than high burden assignment.
inheritance:
- name: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    MPD6 is inherited in an autosomal dominant manner, with heterozygous ACTN2
    variants cosegregating with disease across affected families. Penetrance is
    incomplete and age-dependent - the largest cohort includes asymptomatic
    adult carriers - and expressivity is variable and genotype-dependent,
    spanning asymptomatic through distal weakness to a limb-girdle pattern with
    facial involvement. No penetrance_percentage is given because no cohort
    reports a figure.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy."
    explanation: The original actininopathy cohort establishes autosomal dominant transmission of the ACTN2 distal myopathy.
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."
    explanation: >-
      Asymptomatic carriers at one end of the range establish incomplete
      penetrance; the genotype-dependent spread across that range establishes
      variable expressivity.
pathophysiology:
- name: ACTN2 pathogenic variants alter alpha-actinin-2
  biological_scale: MOLECULAR
  description: >
    Heterozygous pathogenic variants in ACTN2 alter alpha-actinin-2, a sarcomeric
    Z-disk protein. Two dominant classes are recognized: missense variants (the
    original Spanish and Swedish actininopathy families) and single-nucleotide
    deletions in the last exon that shift the reading frame and append a novel,
    unstructured, slightly extended C-terminal sequence.
  genes:
  - preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  molecular_functions:
  - preferred_term: actin filament binding
    modifier: ABNORMAL
    term:
      id: GO:0051015
      label: actin filament binding
  evidence:
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease."
    explanation: Identifies dominant ACTN2 missense variants as the genetic cause of the actininopathy families.
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-throughput sequencing identified in each proband a heterozygous single nucleotide deletion (c.2558del and c.2567del) in the last exon of the ACTN2 gene."
    explanation: Establishes the last-exon frameshift class of dominant ACTN2 variants in the facial-weakness distal myopathy families.
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deletions are predicted to lead to a novel but unstructured slightly extended C-terminal amino acid sequence."
    explanation: Describes how the frameshift lesions extend the alpha-actinin-2 C-terminus.
  downstream:
  - target: Z-disk and myofibrillar disorganization
    description: >
      Altered alpha-actinin-2 disrupts its structural cross-linking role at the
      Z-disk, degrading sarcomeric organization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42111349
      reference_title: "Biological properties of α-actinin-2 and its role and mechanisms in disease development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Its normal localization at the sarcomere Z-disk is disrupted, affecting its ability to cross-link effectively and anchor actin filaments. This destabilizes the sarcomere structure and interferes with muscle contraction"
      explanation: States the causal step itself - that the variant protein's disrupted Z-disk cross-linking destabilizes sarcomere structure - rather than either node alone.
    - reference: PMID:30701273
      reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies."
      explanation: >-
        Expressing mutant but not wild-type alpha-actinin-2 produces sarcomeric
        disorganization, which is the causal step under test. Indirect because
        the allele modelled causes the allelic congenital core myopathy, not
        MPD6.
  - target: Alpha-actinin-2 conformational destabilization
    description: >
      Missense substitutions, particularly in the actin-binding domain, reduce
      the solubility and thermal stability of the folded protein. Shown for
      ACTN2 hypertrophic-cardiomyopathy alleles rather than MPD6 alleles, so the
      edge is a candidate route for the MPD6 missense class rather than a
      demonstrated one.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42481460
      reference_title: Comprehensive biophysical and structural profiling of alpha-actinin-2 variants reveals mechanistic diversity in hypertrophic cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "All variants display reduced solubility, with actin-binding domain (ABD) substitutions showing pronounced thermal instability by differential scanning fluorimetry."
      explanation: >-
        Supports the edge from carrying an ACTN2 missense variant to the protein
        being destabilized. Indirect: the panel is hypertrophic-cardiomyopathy
        alleles, not MPD6 alleles.
  - target: Alpha-actinin-2 protein aggregation
    description: >
      Protein-extending frameshift variants render alpha-actinin-2
      aggregation-prone.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39095936
      reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates."
      explanation: >-
        Supports the edge specifically rather than either node: aggregation
        follows the protein-extending variant class and not other ACTN2
        variants tested in the same assay, so the variant is what produces the
        aggregation.
- name: Alpha-actinin-2 conformational destabilization
  biological_scale: MOLECULAR
  description: >
    A candidate step upstream of aggregation, and one of the few leads on the
    missense class whose mechanism is otherwise undetermined. Systematic
    biophysical profiling of ACTN2 missense variants shows reduced solubility,
    reduced thermal and proteolytic stability, and a strong propensity to
    aggregate in solution, with the actin-binding domain the most vulnerable
    region. Structural work on actin-binding-domain variants shows the same
    variants incorporate less well into the Z-disc and that the unincorporated
    protein forms aggregates outside it. Both lines of evidence come from
    ACTN2 hypertrophic-cardiomyopathy variant panels rather than MPD6 alleles,
    so this node states a plausible shared property of destabilizing ACTN2
    missense variants, not a demonstrated MPD6 mechanism.
  evidence:
  - reference: PMID:42481460
    reference_title: Comprehensive biophysical and structural profiling of alpha-actinin-2 variants reveals mechanistic diversity in hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "All variants display reduced solubility, with actin-binding domain (ABD) substitutions showing pronounced thermal instability by differential scanning fluorimetry."
    explanation: >-
      Establishes reduced solubility and thermal destabilization as a shared
      property across an ACTN2 missense panel. Indirect: the seventeen variants
      profiled are hypertrophic-cardiomyopathy alleles, not the MPD6 founder or
      last-exon variants.
  - reference: PMID:42481460
    reference_title: Comprehensive biophysical and structural profiling of alpha-actinin-2 variants reveals mechanistic diversity in hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Limited proteolysis indicates reduced structural stability across variants, while size-exclusion chromatography coupled with multi-angle light scattering or small-angle X-ray scattering (SEC-MALS/SAXS) shows a strong propensity for aggregation."
    explanation: >-
      Links the destabilization directly to aggregation propensity in solution,
      which is the step this node contributes. Same allele caveat as above.
  - reference: PMID:27287556
    reference_title: Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These data show that both mutations appear to reduce the ability of the protein to incorporate normally into Z-discs."
    explanation: >-
      Reduced Z-disc incorporation is the cellular counterpart of the
      biophysical destabilization. Indirect: measured in cardiomyocytes for two
      calponin-homology-domain HCM variants. The authors call those two variants
      mild and likely benign in population terms while concluding they are
      nonetheless genuine disease mutations, so this is a small effect
      demonstrated in a mild allele, not a null result.
  - reference: PMID:27287556
    reference_title: Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "there was a greater tendency for mutant isoforms to form aggregates outside the Z-discs"
    explanation: >-
      Observes aggregation of the non-incorporated mutant protein, the
      observation that makes this node continuous with the aggregation node
      downstream of it.
  downstream:
  - target: Alpha-actinin-2 protein aggregation
    description: >
      Destabilized, poorly incorporated alpha-actinin-2 is left unbound in the
      cytoplasm where it is free to aggregate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27287556
      reference_title: Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "If the mutant full length proteins are less able to incorporate into the Z-discs, then the unincorporated protein may be more likely to aggregate as we observed."
      explanation: >-
        The authors state the causal step from failed Z-disc incorporation to
        aggregation. They state it as a proposal supported by their observation,
        not as a demonstrated sequence, and in HCM variants.
- name: Alpha-actinin-2 protein aggregation
  biological_scale: MOLECULAR
  description: >
    Dominant frameshift variants that extend the alpha-actinin-2 protein cause it
    to form intracellular aggregates in muscle-cell models, whereas recessive
    missense variants do not, implicating alpha-actinin-2 aggregation as the
    disease mechanism for this class of dominant actininopathy.
  biological_processes:
  - preferred_term: inclusion body assembly
    modifier: INCREASED
    term:
      id: GO:0070841
      label: inclusion body assembly
  evidence:
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Conversely, dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates."
    explanation: Cell-model functional data show protein-extending frameshift variants generate alpha-actinin-2 aggregates.
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic."
    explanation: Names alpha-actinin-2 aggregation as the pathomechanism for this dominant class.
  downstream:
  - target: Z-disk and myofibrillar disorganization
    description: >
      Aggregated alpha-actinin-2 and increased protein expression disrupt normal
      Z-line organization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34170073
      reference_title: A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "functional analysis using muscle samples revealed that the variant significantly increased the expression level of α-actinin-2 and resulted in abnormal Z-line organization of muscle fiber."
      explanation: Links raised alpha-actinin-2 level to abnormal Z-line organization in the same patient muscle, which is the edge rather than either endpoint.
- name: Z-disk and myofibrillar disorganization
  biological_scale: CELLULAR
  description: >
    Loss of normal alpha-actinin-2 Z-disk cross-linking, together with abnormal
    accumulation of the protein, produces disorganized Z-lines and myofibrillar
    disarray. Muscle-sample analysis shows increased alpha-actinin-2 expression
    and abnormal Z-line organization.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: ABNORMAL
    term:
      id: GO:0045214
      label: sarcomere organization
  evidence:
  - reference: PMID:34170073
    reference_title: A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "functional analysis using muscle samples revealed that the variant significantly increased the expression level of α-actinin-2 and resulted in abnormal Z-line organization of muscle fiber."
    explanation: Directly links the ACTN2 frameshift variant to increased alpha-actinin-2 and disrupted Z-line organization.
  downstream:
  - target: Distal skeletal muscle degeneration and weakness
    description: >
      Progressive myofibrillar breakdown produces the histopathologic and
      clinical features of the distal myopathy. The distal predilection is not
      explained by the Z-disk defect alone, which is uniform across striated
      muscle; see mechanistic_hypotheses#mpd6_eccentric_load_selective_vulnerability.
    causal_link_type: DIRECT
    hypothesis_groups:
    - mpd6_eccentric_load_selective_vulnerability
    evidence:
    - reference: PMID:30701273
      reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice."
      explanation: >-
        Sarcomeric disorganization from mutant alpha-actinin-2 produces
        measurable weakness in two model systems, supporting the step from
        Z-disk disorganization to functional muscle failure. Indirect because
        the allele is an allelic congenital-myopathy variant and the readout is
        acute rather than adult-onset degeneration.
- name: Distal skeletal muscle degeneration and weakness
  biological_scale: TISSUE
  description: >
    Chronic myofibrillar degeneration is expressed histologically as internalized
    nuclei, myofibrillar disorganization, rimmed vacuoles, and in some families
    multi-minicores, and clinically as slowly progressive distal muscle weakness
    that begins in the anterior lower leg and later extends proximally.
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."
    explanation: Describes the myopathic histopathology of the degenerating muscle.
phenotypes:
- name: Distal lower limb muscle weakness
  category: Musculoskeletal
  description: >
    Adult-onset weakness begins in the anterior compartment of the lower leg,
    impairing ankle dorsiflexion, is often asymmetric, and is slowly
    progressive. The asymmetry is left in prose because HPO has no
    asymmetric-weakness term to bind: the laterality modifiers under HP:0012831
    offer only bilateral, unilateral, right, left and alternating, none of which
    expresses side-to-side asymmetry of severity, and the nearest asymmetry term,
    HP:0007156, is asymmetric limb muscle stiffness rather than weakness. This is
    the case the term contract covers - preferred_term may be more specific than
    the best available term.
  phenotype_term:
    preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
    clinical_course: PROGRESSIVE
    onset:
      onset_category: ADULT
      notes: >
        Adult onset (HP:0003581, the generic HPO parent of the three narrower
        adult buckets). The reported families give only qualitative "adult
        onset" without a decade, so the generic ADULT category is used rather
        than over-specifying to YOUNG_ADULT / MIDDLE_AGE / LATE.
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented with a very slowly progressive myopathy involving anterior lower leg and facial muscles."
    explanation: Documents slowly progressive anterior lower-leg (distal) muscle involvement.
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."
    explanation: Establishes distal (ankle dorsiflexion) onset with later proximal spread.
- name: Foot dorsiflexor weakness
  category: Musculoskeletal
  description: >
    The earliest and defining objective sign is weakness of ankle dorsiflexion
    (anterior lower-leg/tibialis anterior compartment), producing foot drop.
  phenotype_term:
    preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."
    explanation: Documents ankle-dorsiflexion (foot dorsiflexor) weakness as the initial manifestation.
- name: Facial muscle weakness
  category: Musculoskeletal
  description: >
    A distinctive facial weakness accompanies the distal limb weakness in the
    last-exon frameshift families, without upper-limb or shoulder-girdle
    involvement.
  phenotype_term:
    preferred_term: Weakness of facial musculature
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Actininopathy should be considered in the differential diagnosis of distal myopathy combined with facial weakness."
    explanation: Identifies facial weakness combined with distal myopathy as a defining feature.
- name: Proximal muscle weakness
  category: Musculoskeletal
  description: >
    With disease progression, weakness extends from distal muscles to the
    proximal limb muscles.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles."
    explanation: Records later progression to proximal limb muscles.
- name: Rimmed vacuoles
  category: Histopathology
  description: >
    Muscle biopsy shows rimmed vacuoles among the myopathic changes.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."
    explanation: Rimmed vacuoles are reported on muscle biopsy.
- name: Centrally nucleated muscle fibers
  category: Histopathology
  description: >
    Internalized (central) myonuclei are seen on muscle biopsy.
  phenotype_term:
    preferred_term: Centrally nucleated skeletal muscle fibers
    term:
      id: HP:0003687
      label: Centrally nucleated skeletal muscle fibers
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles."
    explanation: Internalized nuclei correspond to centrally nucleated skeletal muscle fibers.
- name: Minicore myopathy
  category: Histopathology
  description: >
    Some families show multi-minicores on muscle biopsy, a feature overlapping
    with multiple structured core disease.
  phenotype_term:
    preferred_term: Minicore myopathy
    term:
      id: HP:0003789
      label: Minicore myopathy
  evidence:
  - reference: PMID:34170073
    reference_title: A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients exhibited adult-onset distal myopathy with multi-minicores, which, interestingly, was more like a combination of MsCD and actininopathy."
    explanation: Reports multi-minicores in an adult-onset ACTN2 distal myopathy family.
- name: Fatty replacement of anterolateral lower-leg muscles
  category: Imaging
  description: >
    Muscle MRI shows a characteristic pattern of fatty replacement of the
    anterolateral compartment muscles of the lower legs, with variable soleus
    and gastrocnemius involvement and sparing of the thigh muscles.
  phenotype_term:
    preferred_term: Fatty replacement of anterolateral lower-leg compartment muscles
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle MRI finding showed complete fat replacement of anterolateral compartment muscles of the lower legs with variable involvement of soleus and gastrocnemius but sparing thigh muscles."
    explanation: Documents the characteristic selective anterolateral lower-leg fatty replacement with thigh sparing on muscle MRI.
- name: Elevated serum creatine kinase
  category: Laboratory
  description: >
    Serum CK is mildly elevated. The elevation is modest enough that a normal or
    near-normal value does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"
    explanation: Reports mildly elevated serum CK in distal actininopathy.
- name: Limb-girdle pattern weakness
  category: Musculoskeletal
  description: >
    At the severe end of the reported clinical range the pattern becomes
    limb-girdle rather than purely distal, consistent with the gluteal and
    hamstring involvement seen on muscle MRI.
  phenotype_term:
    preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."
    explanation: Places limb-girdle weakness at the severe end of the reported dominant ACTN2 myopathy spectrum.
histopathology:
- name: Undulating Z-disk on electron microscopy
  description: >-
    Electron microscopy of muscle from distal actininopathy shows undulation of
    the Z-disk alongside myofibrillar disarray, the ultrastructural correlate of
    failed alpha-actinin-2 cross-linking.
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"
    explanation: Reports Z-disk undulation on electron microscopy as a histopathologic feature of distal actininopathy.
- name: Non-specific myopathic changes on light microscopy
  description: >-
    Biopsy is not reliably diagnostic. In the largest dominant ACTN2 myopathy
    series the available biopsies showed only non-specific changes, so the
    rimmed vacuoles, internalized nuclei and multi-minicores reported in
    individual kindreds should not be treated as an obligate or diagnostic
    finding.
  diagnostic: false
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Available muscle biopsies showed non-specific changes."
    explanation: Establishes that biopsy findings in the largest dominant cohort were non-specific, qualifying the diagnostic weight of the biopsy features reported elsewhere.
imaging_findings:
- name: Selective anterolateral lower-leg and gluteal/hamstring involvement on muscle MRI
  modality: MRI
  description: >-
    Muscle MRI in dominant ACTN2 myopathy shows a selective pattern: gluteus
    minimus and medius, hamstrings, tibialis anterior and soleus are the most
    affected muscles. The pattern extends beyond the anterolateral lower leg
    reported in the original last-exon frameshift families, and is the most
    useful non-invasive discriminator given that biopsy is non-specific.
  located_in:
    preferred_term: tibialis anterior
    term:
      id: UBERON:0001385
      label: tibialis anterior
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus."
    explanation: Names the muscles most affected on MRI across the largest dominant ACTN2 myopathy cohort.
- name: Machine-learning-derived discriminating MRI pattern
  modality: MRI
  description: >-
    A trained machine-learning comparison against other neuromuscular diseases
    identified involvement of tibialis anterior and gluteus medius together with
    preservation of quadratus femoris, lateral gastrocnemius and tensor fasciae
    latae as the features that best separate dominant ACTN2 myopathy from its
    differential diagnoses. The preserved muscles carry as much discriminating
    weight as the affected ones.
  diagnostic: false
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A machine learning model showed that the most differentiating features in dominant ACTN2 myopathy were the involvement of the tibialis anterior and gluteus medius muscles and preservation of the quadratus femoris, gastrocnemius lateralis, and tensor fasciae latae muscles."
    explanation: Reports the computationally derived discriminating imaging signature, including the specific muscles preserved.
biochemical:
- name: Serum creatine kinase
  biomarker_term:
    preferred_term: creatine kinase
    term:
      id: NCIT:C113245
      label: Creatine Kinase
  presence: INCREASED
  notes: >-
    CK is mildly elevated in distal actininopathy, not the marked elevation
    (often above ten times the upper limit) seen in dysferlinopathy or distal
    anoctaminopathy. A normal or near-normal CK therefore does not exclude the
    diagnosis, and CK is not a useful discriminator on its own. No MPD6-specific
    CK threshold has been established.
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum CK levels are mildly elevated and muscle biopsy shows rimmed vacuoles with some myofibrillar disarrays and undulation of the Z-disk on electron microscopy"
    explanation: States that serum CK is mildly elevated in distal actininopathy.
genetic:
- name: ACTN2
  notes: >
    ACTN2 encodes alpha-actinin-2, a Z-disk protein expressed in cardiac and
    skeletal muscle whose primary function is to link actin and titin at the
    sarcomere Z-disk. Heterozygous missense and last-exon frameshift variants
    cause the dominant distal myopathy.
  gene_term:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  evidence:
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk."
    explanation: Molecular-background statement (review/introduction) of the normal Z-disk cross-linking function of the gene product.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle."
    explanation: Mutation-update review statement confirming ACTN2 gene identity and tissue expression.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    reference_title: "ACTN2 / ACTN2-related cardiac and skeletal myopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTN2 | HGNC:164 | ACTN2-related cardiac and skeletal myopathy | MONDO:0700349 | AD | Definitive | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-07-23T04:00:00.000Z"
    explanation: ClinGen classifies the ACTN2 gene-disease relationship (the lumped cardiac-and-skeletal myopathy entity that includes MPD6) as Definitive with autosomal dominant inheritance.
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry."
    explanation: >-
      Haplotype analysis establishes that the two most common dominant alleles
      are founder variants in distinct populations. This matters for
      epidemiology: the reported case counts are concentrated in two founder
      populations and do not index a worldwide rate.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, ACTN2-related diseases present with significant clinical heterogeneity, and clear genotype–phenotype correlations have not been established"
    explanation: Records that ACTN2 genotype-phenotype correlation is unresolved, which limits how far a specific variant predicts the MPD6 phenotype.
variants:
- name: ACTN2 p.Cys487Arg
  description: >-
    Missense founder variant of the Basque-Spanish actininopathy families, the
    original MPD6 kindreds. Carried on a shared haplotype consistent with common
    ancestry. Named at the protein level only: the cDNA change is not stated in
    any source cited here. No clinical_significance is asserted either -
    multi-family cosegregation on a shared haplotype is good evidence, but no
    cited source states an ACMG or ClinVar classification for this allele, and
    the ACTN2 mutation update cited elsewhere in this entry cautions that
    supporting data are limited for most reported ACTN2 missense variants.
  gene:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry."
    explanation: Identifies p.Cys487Arg as a Basque-Spanish founder allele on a distinct haplotype.
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease."
    explanation: The original report of a single shared missense variant cosegregating across the three Spanish families.
- name: ACTN2 p.Ile134Asn
  description: >-
    Missense founder variant of the Belgian families in the largest dominant
    cohort, on its own distinct haplotype. No clinical_significance is asserted,
    for the same reason as p.Cys487Arg: the cited evidence establishes founder
    haplotype and cosegregation, not a stated variant classification.
  gene:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry."
    explanation: Identifies p.Ile134Asn as a Belgian founder allele with its own haplotype.
- name: ACTN2 c.2504delT (p.Phe835Serfs*66)
  description: >-
    Frameshift allele of the adult-onset family with multi-minicores. Functional
    work on this family's muscle is what links the frameshift class to raised
    alpha-actinin-2 levels and disorganized Z-lines in patient tissue rather than
    in a cell model.
  gene:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  evidence:
  - reference: PMID:34170073
    reference_title: A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We firstly identified a novel frameshift variant (c.2504delT, \np.Phe835Serfs*66) within ACTN2 in a family including three patients."
    explanation: Names the frameshift allele identified in this adult-onset distal myopathy family.
  - reference: PMID:34170073
    reference_title: A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "functional analysis using muscle samples revealed that the variant significantly increased the expression level of α-actinin-2 and resulted in abnormal Z-line organization of muscle fiber."
    explanation: Ties this specific allele to increased alpha-actinin-2 and abnormal Z-line organization in patient muscle.
- name: ACTN2 Swedish-family missense variant
  description: >-
    The fourth of the four original actininopathy families is Swedish and carries
    a different ACTN2 missense variant from the shared Basque-Spanish allele. The
    cited abstract does not name it, so it is recorded as a distinct allele
    without an HGVS designation rather than assigned one from an uncited source.
  gene:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  evidence:
  - reference: PMID:30900782
    reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected members of the Swedish family carry a different ACTN2 missense variant."
    explanation: Establishes a second, distinct missense allele in the original cohort without naming it.
- name: ACTN2 last-exon single-nucleotide deletions (c.2558del, c.2567del)
  description: >-
    Out-of-frame deletions in the last exon that append a novel extended
    C-terminus. This is the protein-extending class shown to aggregate in the
    C2C12 model, and the class associated with the distinctive facial weakness.
  gene:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:34386585
    reference_title: Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-throughput sequencing identified in each proband a heterozygous single nucleotide deletion (c.2558del and c.2567del) in the last exon of the ACTN2 gene."
    explanation: Reports the two last-exon frameshift deletions in the facial-weakness distal myopathy probands.
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic"
    explanation: Functional data support classifying the protein-extending frameshift class as pathogenic.
treatments:
- name: Supportive Care
  description: >
    No disease-modifying therapy exists for MPD6. Overall management is
    supportive and guided by the slowly progressive distal weakness, with
    mobility aids as ambulation declines.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42111349
    reference_title: "Biological properties of α-actinin-2 and its role and mechanisms in disease development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "while diltiazem has shown promise in treating ACTN2-related HCM, effective targeted therapies for other ACTN2-associated conditions are currently lacking"
    explanation: Confirms that no targeted therapy is available for the non-cardiac ACTN2 conditions, which is why management is supportive.
- name: Physical Therapy
  description: >
    Rehabilitative exercise and gait/balance training to maintain function and
    reduce falls from foot drop and later proximal weakness.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Distal actininopathy is an autosomal dominant, adult onset distal myopathy starting usually with foot drop."
    explanation: >-
      No trial of physiotherapy in MPD6 exists. The quote supports the target of
      the intervention - foot drop as the presenting deficit - rather than the
      efficacy of physiotherapy itself, which is extrapolated from general
      neuromuscular rehabilitation practice.
- name: Ankle-Foot Orthosis
  description: >
    Ankle-foot orthoses to compensate for ankle-dorsiflexor weakness (foot
    drop), improving toe clearance and gait stability. NCIT has no
    clinical-action term for orthotic fitting, so the treatment_term binds the
    rehabilitation action and the device concept is carried as a
    medical-device qualifier.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: ankle-foot orthosis fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: ankle-foot orthosis
        term:
          id: NCIT:C86054
          label: Brace
  evidence:
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Generally, ACTN2-related distal myopathies begin with foot drop due to muscle weakness in the anterior compartment of the lower leg."
    explanation: >-
      Establishes foot drop from anterior-compartment weakness as the deficit
      the orthosis compensates for. The orthosis itself has not been trialled in
      MPD6; its use follows standard management of foot drop.
- name: Genetic Counseling
  description: >
    Counseling on autosomal dominant transmission and the 50% recurrence risk,
    with cascade testing of at-risk relatives once a familial variant is known.
    Adult onset and genotype-dependent expressivity - carriers may be
    asymptomatic when tested - are the specific points that make predictive
    testing decisions non-trivial here. Once a familial variant is known,
    reproductive options include prenatal diagnosis and preimplantation genetic
    testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."
    explanation: The asymptomatic-to-limb-girdle range and genotype dependence are what counseling must convey about predictive testing in adult-onset dominant disease.
- name: Occupational Therapy
  description: >
    Assessment and adaptation of home, work and mobility tasks as distal
    weakness spreads proximally to the glutei and hamstrings, which are among
    the most affected muscles on imaging and drive difficulty with rising,
    stairs and transfers.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus."
    explanation: >-
      Documents the hip-girdle and hamstring involvement that generates the
      functional limitations occupational therapy addresses; the intervention
      itself is not trialled in this disease.
mechanistic_hypotheses:
- hypothesis_group_id: mpd6_eccentric_load_selective_vulnerability
  hypothesis_label: Mechanical-load selectivity explains the distal predilection
  status: EMERGING
  description: >-
    Alpha-actinin-2 is expressed throughout skeletal and cardiac muscle, so a
    uniform Z-disk defect does not by itself explain why weakness starts in the
    anterior lower leg. The proposed explanation is that the distal locomotor
    muscles carry higher mechanical stress and eccentric load, so a Z-disk that
    is marginally destabilized fails there first. Two things keep this at
    EMERGING. It is a review-level inference from the anatomy of the deficit
    rather than an experimental result, offered by its source as a possibility
    and not tested in any model. And it competes with a genotype-specific
    account: the largest dominant cohort found the clinical pattern tracked
    genotype, spanning asymptomatic carriers to limb-girdle weakness, which a
    load-based explanation alone does not predict, since mechanical load is the
    same whichever allele a person carries. Note the muscle distribution does
    not settle it either way - the affected set (tibialis anterior and soleus,
    but also hamstrings and glutei) is a mix of distal and high-eccentric-load
    proximal muscles, so it neither confirms nor excludes a load account.
  evidence:
  - reference: PMID:42111349
    reference_title: "Biological properties of α-actinin-2 and its role and mechanisms in disease development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This preferential involvement of distal muscles may be attributed to the higher mechanical stress and eccentric loads placed on these muscles during locomotion, which renders them more susceptible to Z-disk instability caused by α-actinin-2 dysfunction."
    explanation: >-
      States the mechanical-load explanation for the distal predilection, and
      states it as a possibility rather than an established result. Note this
      source is a broad review whose ACTN2 variant-to-domain assignments are
      unreliable in places, so it carries the hypothesis but does not
      substantiate it.
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype."
    explanation: >-
      Genotype-dependent severity within a single disease argues against
      mechanical load being the determinant of where and whether muscle fails:
      loading does not vary by allele, so a load-only account cannot generate a
      genotype-dependent range from asymptomatic to limb-girdle.
animal_models:
- name: Zebrafish ACTN2 p.Leu727Arg mRNA overexpression
  species: Zebrafish
  genotype: Transient overexpression of human ACTN2 c.2180T>G (p.Leu727Arg) mRNA
  publication: PMID:30701273
  description: >-
    Human mutant ACTN2 mRNA injected into one-cell zebrafish embryos, assayed at
    3 dpf for swimming distance, birefringence and myofibrillar ultrastructure
    against wild-type-injected and uninjected controls.
  modeled_mechanisms:
  - target: Z-disk and myofibrillar disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Establishes that a dominant ACTN2 missense allele is sufficient to produce
      sarcomeric disarray and abnormal Z-lines in vivo, supporting the Z-disk
      node in this entry.
    limitations: >-
      p.Leu727Arg is a de novo allele of Multiple structured Core Disease, an
      allelic congenital ACTN2 myopathy with early-onset weakness and
      respiratory involvement - not an MPD6 allele. The model is transient
      overexpression of exogenous human mRNA rather than a knock-in at
      endogenous dosage, and a larval fish has no adult-onset, anterior-lower-leg
      selective phenotype to recapitulate. It supports the general Z-disk
      mechanism, not the MPD6 phenotype.
    readouts:
    - name: Myofibrillar organization on transmission electron microscopy
      target: Z-disk and myofibrillar disorganization
      direction: ALTERED
      interpretation: Structural correlate of the Z-disk disorganization node in a whole-organism model.
      evidence:
      - reference: PMID:30701273
        reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies."
        explanation: Sarcomeric disorganization occurred with mutant but not wild-type alpha-actinin-2, controlling for overexpression alone.
    - name: Total swimming distance
      target: Z-disk and myofibrillar disorganization
      direction: DECREASED
      interpretation: Functional motor consequence of the sarcomeric defect.
      evidence:
      - reference: PMID:30701273
        reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Zebrafish expressing p.Leu727Arg alpha-actinin-2 displayed a significant reduction in the total swimming distance"
        explanation: Quantifies impaired motor function in the mutant-expressing larvae.
    evidence:
    - reference: PMID:30701273
      reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients."
      explanation: Supports treating the zebrafish system as informative for the ACTN2 Z-disk mechanism.
  evidence:
  - reference: PMID:30701273
    reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice."
    explanation: Establishes the zebrafish arm as a validated system in which mutant alpha-actinin-2 produces a measurable motor deficit.
- name: AAV2/9 ACTN2 p.Leu727Arg tibialis anterior mouse
  species: Mouse
  genotype: AAV2/9-mediated overexpression of human ACTN2 p.Leu727Arg in tibialis anterior
  background: C57BL/6J
  publication: PMID:30701273
  description: >-
    Wild-type, mutant or empty AAV2/9 injected into the tibialis anterior of
    3-week-old male mice, with in situ force measurement, histochemistry and
    electron microscopy 4 weeks later. Notably the injected muscle is the
    tibialis anterior, the muscle that fails first in MPD6.
  modeled_mechanisms:
  - target: Z-disk and myofibrillar disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Mutant alpha-actinin-2 expressed in mouse tibialis anterior produces
      abnormal Z-line organization and cores together with measurable force loss,
      linking the Z-disk node to a contractile deficit in a mammalian muscle.
    limitations: >-
      Same allele caveat as the zebrafish arm: p.Leu727Arg causes the allelic
      congenital core myopathy, not MPD6. Local AAV transduction gives an
      approximately twofold supraphysiological alpha-actinin-2 level over four
      weeks, which models acute mutant-protein burden rather than the decades of
      adult-onset degeneration that define MPD6, and says nothing about why the
      human disease selects the anterior compartment.
    readouts:
    - name: In situ maximal and specific tetanic force of tibialis anterior
      target: Z-disk and myofibrillar disorganization
      direction: DECREASED
      interpretation: Contractile consequence of Z-disk disorganization, measured in the muscle homologous to the one that fails first in patients.
      evidence:
      - reference: PMID:30701273
        reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we detected a significantly reduced maximal and specific force of p.Leu727Arg-injected tibialis anterior compared to muscles injected with empty AAV or wild-type ACTN2 respectively"
        explanation: Quantifies force loss against both empty-vector and wild-type-overexpression controls.
    - name: Z-line architecture on histochemistry and electron microscopy
      target: Z-disk and myofibrillar disorganization
      direction: ALTERED
      interpretation: Structural readout matching the Z-line abnormalities seen on patient biopsy.
      evidence:
      - reference: PMID:30701273
        reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects."
        explanation: Reports the Z-line structural defect in the transduced mouse muscle.
    evidence:
    - reference: PMID:30701273
      reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice."
      explanation: Supports treating the AAV mouse as informative for the contractile consequence of the Z-disk mechanism.
  evidence:
  - reference: PMID:30701273
    reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects."
    explanation: Establishes the AAV mouse as a system in which mutant alpha-actinin-2 reproduces the Z-line pathology seen on patient biopsy.
experimental_models:
- name: C2C12 myoblast ACTN2 variant aggregation assay
  experimental_model_type: CELL_LINE
  description: >-
    C2C12 murine myoblasts expressing a panel of ACTN2 frameshift and missense
    variants drawn from dominant and recessive actininopathies, scored for
    alpha-actinin-2 aggregate formation. The panel design is what makes the
    result informative: it separates the variant classes rather than testing one
    allele in isolation.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:39095936
  modeled_mechanisms:
  - target: Alpha-actinin-2 protein aggregation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Protein-extending dominant frameshift variants form alpha-actinin-2
      aggregates in this system while recessive missense variants do not,
      which is the direct experimental basis for the aggregation node.
    limitations: >-
      A murine myoblast line is not adult human skeletal muscle: it lacks the
      mature sarcomere, the mechanical loading and the decades of exposure under
      which the human phenotype emerges. The assay scores aggregate formation,
      not the downstream Z-disk failure or muscle degeneration, and the authors
      state the mechanism accounts for only a limited number of variants.
    readouts:
    - name: Alpha-actinin-2 aggregate formation
      target: Alpha-actinin-2 protein aggregation
      direction: INCREASED
      interpretation: Aggregates form with protein-extending dominant frameshift variants and are absent with recessive missense variants, separating the two variant classes.
      evidence:
      - reference: PMID:39095936
        reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model."
        explanation: The negative arm of the assay establishes that aggregation tracks the dominant protein-extending class rather than being a nonspecific consequence of transfecting a variant.
    evidence:
    - reference: PMID:39095936
      reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies."
      explanation: Describes the model system and the variant panel that grounds the aggregation claim.
  evidence:
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Conversely, dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates."
    explanation: The positive result that makes this cell system informative for the dominant actininopathy mechanism.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:33458580
      reference_title: Panorama of the distal myopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Distal actininopathy is an autosomal dominant, adult onset distal myopathy starting usually with foot drop."
      explanation: A distal myopathy presenting with foot drop is managed within neuromuscular neurology, supporting the neurologic chapter assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30900782
      reference_title: "Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease."
      explanation: A single-gene variant cosegregating through affected pedigrees places the entry in the Mendelian genetics chapter.
diagnosis:
- name: Baseline Cardiac Evaluation
  description: >
    ECG and echocardiography at diagnosis. Cardiac involvement is not common in
    the dominant skeletal cohorts, so this is a baseline and an
    individualized-follow-up decision rather than a surveillance protocol - but
    ACTN2 is an established cardiomyopathy gene with allelic hypertrophic and
    dilated presentations, so the cardiac question has to be asked and answered
    rather than assumed. No MPD6-specific screening interval is evidence-based.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac and respiratory involvement were not common."
    explanation: >-
      Sets the expected yield: low enough that this is a baseline rather than
      ongoing surveillance, and the reason the recommendation is not stronger.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease."
    explanation: The gene's established cardiomyopathy association is why a cardiac baseline is taken despite the low observed frequency in skeletal cohorts.
- name: Multigene distal-myopathy / myopathy panel sequencing
  description: >
    The definitive test. Because ACTN2 is one of roughly twenty dominant
    distal-myopathy genes and the clinical and imaging pattern narrows the list
    without closing it, diagnosis rests on finding the ACTN2 variant. Panel
    testing also has to establish inheritance mode rather than assume it, since
    biallelic ACTN2 variants cause a separate recessive myopathy.
  diagnosis_term:
    preferred_term: multigene panel genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present."
    explanation: Both inheritance modes exist for ACTN2, so genotype rather than phenotype is what assigns a case to this entity.
- name: Lower-limb muscle MRI
  description: >
    The most useful non-invasive discriminator, because biopsy in the largest
    dominant cohort was non-specific. Reads the selective pattern of affected
    and preserved muscles, and also guides biopsy site where biopsy is still
    performed.
  diagnosis_term:
    preferred_term: lower-limb muscle magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Available muscle biopsies showed non-specific changes."
    explanation: Non-specific biopsy is why imaging carries the discriminating weight in this disease.
- name: Electromyography with nerve conduction studies
  description: >
    Establishes that the process is myopathic and, with normal nerve conduction
    and preserved sensation, separates it from the neurogenic causes of foot
    drop - peroneal neuropathy and distal hereditary motor neuronopathy - that
    present the same way.
  diagnosis_term:
    preferred_term: electromyography with nerve conduction studies
    term:
      id: NCIT:C38056
      label: Electromyography
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet."
    explanation: >-
      Supports the target of the test - establishing a primary muscle disorder -
      rather than test performance in MPD6, which has not been reported.
differential_diagnoses:
- name: ACTN2-related cardiomyopathy (allelic)
  description: >
    ACTN2 was historically associated only with cardiomyopathy; the cardiac
    presentations (allelic CMH23/CMD1AA) are now lumped by ClinGen with the
    skeletal myopathies into one ACTN2-related cardiac and skeletal myopathy
    entity. Distinguished from MPD6 by the predominant cardiac (rather than
    distal skeletal-muscle) phenotype.
  distinguishing_features:
  - >
    Predominant hypertrophic/dilated cardiomyopathy or arrhythmia rather than
    adult-onset distal skeletal-muscle weakness.
  evidence:
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease."
    explanation: Documents that ACTN2 was historically a cardiomyopathy gene, framing the allelic cardiac differential.
- name: Other anterior-compartment / distal myopathies
  description: >
    The distal (tibial/anterior-compartment) presentation overlaps clinically
    with other distal myopathies and neuropathies — TTN-related tibial muscular
    dystrophy (Udd), MYH7-related Laing distal myopathy, GNE myopathy,
    VCP-related and MYOT/TIA1 myofibrillar/Welander myopathies, sporadic
    inclusion body myositis, and peroneal neuropathy — which are distinguished
    by gene, muscle-MRI pattern, and biopsy.
  distinguishing_features:
  - >
    Serum CK separates some of them: mild elevation in actininopathy against the
    marked elevation (often over ten times the upper limit) of distal
    anoctaminopathy and the early high CK of Miyoshi/dysferlin myopathy.
  - >
    Upper-limb sparing argues against Welander and GNE myopathy, and preserved
    sensation with myopathic EMG argues against peroneal neuropathy and distal
    hereditary motor neuronopathy.
  - >
    ACTN2 is one of roughly twenty genes causing a dominant distal myopathy.
    Those entities differ in where weakness starts (hands in Welander, vocal
    cord and pharynx in VCPDM, anterior lower leg here), so the clinical pattern
    narrows the list without closing it; a multigene distal-myopathy panel is
    what settles it.
  evidence:
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy."
    explanation: Establishes the size of the dominant distal-myopathy differential that ACTN2 sits within, and why the distinction is genetic rather than clinical.
  - reference: PMID:33458580
    reference_title: Panorama of the distal myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CK levels are usually highly elevated (over 10 times the upper limits)."
    explanation: The markedly elevated CK of distal anoctaminopathy contrasts with the mild elevation of actininopathy, supporting CK as a partial discriminator.
- name: Recessive ACTN2-related myopathy (biallelic)
  description: >
    Biallelic ACTN2 missense variants cause a recessive myopathy that is allelic
    to MPD6 and overlaps it clinically — asymmetric, progressive, distal-predominant
    lower-limb weakness — so a single heterozygous ACTN2 finding does not by itself
    establish the dominant entity. The recessive form additionally has prominent
    proximal involvement and, mechanistically, its missense variants do not form
    alpha-actinin-2 aggregates in the cell model, unlike the dominant
    protein-extending frameshift class.
  distinguishing_features:
  - >
    Biallelic rather than heterozygous ACTN2 genotype, with pedigree consistent
    with recessive transmission.
  - >
    Both proximal and distal lower-extremity weakness at presentation, with
    hamstring and adductor involvement in the thigh.
  - >
    Reported in a Palestinian founder population for the recurrent p.Arg506Gly
    allele.
  evidence:
  - reference: PMID:38311799
    reference_title: Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness."
    explanation: Defines the recessive ACTN2 entity and its clinical overlap with the dominant distal myopathy.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present."
    explanation: Confirms ACTN2 now carries both dominant and recessive myopathy forms, which is why inheritance mode must be established rather than assumed.
- name: ACTN2-related congenital myopathy with structured cores (MsCD)
  description: >
    De novo ACTN2 variants cause Multiple structured Core Disease, an allelic
    congenital myopathy. It is separated from MPD6 by age of onset rather than
    by gene: MsCD presents with early-onset weakness and respiratory
    involvement, whereas MPD6 begins in adulthood and rarely involves the
    respiratory system. The multi-minicores reported in some MPD6 biopsies make
    the histology a poor discriminator between the two.
  distinguishing_features:
  - >
    Early-onset (congenital/childhood) progressive weakness with respiratory
    involvement, versus adult onset with respiratory sparing.
  - >
    Structured cores with jagged Z-lines as the specific histological hallmark,
    usually de novo rather than transmitted through an affected pedigree.
  evidence:
  - reference: PMID:30701273
    reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement"
    explanation: Establishes the early-onset, respiratory-involved, de novo presentation that separates the allelic congenital entity from adult-onset MPD6.
  - reference: PMID:39812845
    reference_title: Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac and respiratory involvement were not common."
    explanation: Respiratory sparing in the non-congenital dominant cohort is the contrasting side of the distinction.
discussions:
- discussion_id: mpd6_mechanism_variant_class_scope
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Does the alpha-actinin-2 protein-aggregation mechanism explain all ACTN2
    variant classes in MPD6, or only the protein-extending frameshift class?
  attaches_to:
  - pathophysiology#Alpha-actinin-2 protein aggregation
  - pathophysiology#Alpha-actinin-2 conformational destabilization
  rationale: >
    The aggregation mechanism is demonstrated for protein-extending frameshift
    variants; the pathomechanism of the missense class (the original
    actininopathy families) is undetermined, so the modeled chain should not be
    read as explaining every variant class.
  evidence:
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, this mechanism is likely elicited by only a limited number of variants."
    explanation: The authors caution the aggregation mechanism applies to only a limited number of variants.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the genotype-phenotype correlations of these variants remain unclear."
    explanation: The mutation update states ACTN2 genotype-phenotype correlations remain unclear.
  - reference: PMID:42481460
    reference_title: Comprehensive biophysical and structural profiling of alpha-actinin-2 variants reveals mechanistic diversity in hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Collectively, these findings establish that HCM-linked ACTN2 variants compromise protein integrity through multiple mechanisms, highlight the ABD as a hotspot of vulnerability"
    explanation: >-
      The nearest available lead on the missense class: destabilization plus
      aggregation propensity is shared across an ACTN2 missense panel, so
      aggregation may not be confined to the protein-extending frameshifts. The
      panel is HCM alleles, so this narrows the gap without closing it, and
      testing an MPD6 missense allele in the C2C12 aggregation assay is the
      obvious next step.
- discussion_id: mpd6_mfm6_bag3_nomenclature_trap
  kind: INTERPRETATION
  status: OPEN
  prompt: >
    Guard against miscoding MPD6 (ACTN2; OMIM:618655) as "myofibrillar myopathy
    6" (MFM6), the BAG3-related childhood disorder.
  rationale: >
    Older literature uses "MFM6" for the BAG3 disease; the shared "6" ordinal
    and myofibrillar histology create a serious risk of conflating two distinct
    gene-disease entities. MPD6 is ACTN2-related and adult-onset.
  attaches_to:
  - disease#Distal Myopathy 6, Adult-Onset, Autosomal Dominant
  evidence:
  - reference: PMID:38352343
    reference_title: Personalized allele-specific CRISPR-Cas9 strategies for myofibrillar myopathy 6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Myofibrillar myopathy 6 (MFM6) is a rare childhood-onset myopathy characterized by myofibrillar disintegration, muscle weakness, and cardiomyopathy. The genetic cause of MFM6 is p.Pro209Leu mutation (rs121918312-T) in the BAG3 gene"
    explanation: >-
      Fixes what MFM6 actually is - BAG3, childhood-onset, with cardiomyopathy,
      under OMIM 612954 - against which MPD6 (ACTN2, OMIM:618655, adult-onset,
      cardiac sparing) is a different entity on every axis. This is the source
      that makes the miscoding trap checkable rather than asserted.
- discussion_id: mpd6_no_allele_matched_animal_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Do the existing zebrafish and AAV-mouse ACTN2 models say anything about
    MPD6 specifically, given that both express p.Leu727Arg - an allele of the
    congenital core myopathy, not of MPD6?
  attaches_to:
  - animal_models#Zebrafish ACTN2 p.Leu727Arg mRNA overexpression
  - animal_models#AAV2/9 ACTN2 p.Leu727Arg tibialis anterior mouse
  - pathophysiology#Z-disk and myofibrillar disorganization
  rationale: >
    Both published in vivo models transiently overexpress an exogenous mutant
    ACTN2 allele that causes Multiple structured Core Disease, an early-onset
    respiratory-involved congenital myopathy. They support the general claim
    that mutant alpha-actinin-2 disorganizes the Z-disk and weakens muscle, and
    the mouse arm even uses the tibialis anterior. What no model addresses is
    the feature that defines MPD6: why an adult-onset process selects the
    anterior lower-leg compartment after decades of normal function.
    Supraphysiological transient overexpression over four weeks is the wrong
    time-course for that question, so the aggregate structural evidence should
    not be read as an MPD6 model.
  proposed_experiments:
  - experiment_id: mpd6_knockin_mouse_endogenous_dosage
    name: Knock-in mouse carrying an MPD6 allele at endogenous ACTN2 dosage
    description: >
      Generate heterozygous knock-in mice for a founder MPD6 missense allele
      (p.Cys487Arg or p.Ile134Asn) and for a last-exon protein-extending
      frameshift allele, and age them, comparing tibialis anterior with soleus
      and with a proximal control muscle for onset, fat replacement, force, and
      alpha-actinin-2 aggregate burden. Endogenous dosage and aging are the two
      things the existing models lack.
    would_support:
    - pathophysiology#Distal skeletal muscle degeneration and weakness
    supporting_outcome:
    - >-
      Age-dependent, anterior-compartment-predominant force loss and Z-disk
      pathology appearing in adulthood in the MPD6 knock-in but not in
      littermate controls.
    would_refute:
    - pathophysiology#Alpha-actinin-2 protein aggregation
    refuting_outcome:
    - >-
      No detectable alpha-actinin-2 aggregation in muscle from the
      protein-extending knock-in despite an overt myopathy, which would place
      the aggregation mechanism outside the in vivo disease.
  evidence:
  - reference: PMID:30701273
    reference_title: ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement"
    explanation: >-
      Documents the patients whose allele these models express - the early-onset
      congenital entity - which is the source of the mismatch. The quoted
      sentence reports the human patients, not the model work later in the same
      paper.
- discussion_id: mpd6_therapeutic_window_allele_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Can a therapy lower or correct mutant alpha-actinin-2 without compromising
    the wild-type protein that healthy sarcomeres and myocardium depend on?
  attaches_to:
  - treatments#Supportive Care
  - pathophysiology#Alpha-actinin-2 protein aggregation
  rationale: >
    Gene addition does not help a dominant toxic-gain mechanism, so the obvious
    strategies are knockdown or editing. Alpha-actinin-2 is essential in both
    skeletal muscle and heart, so a non-allele-selective knockdown risks causing
    the disease it is meant to treat. This is the specific reason MPD6 has no
    therapeutic programme rather than simply not having attracted one, and it is
    what any candidate approach has to answer first.
  evidence:
  - reference: PMID:42111349
    reference_title: "Biological properties of α-actinin-2 and its role and mechanisms in disease development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Given the essential physiological role of wild-type α-actinin-2 in maintaining sarcomeric stability, broad inhibition or knockdown strategies could induce severe cardiotoxicity or myopathy."
    explanation: States the therapeutic-window problem that allele selectivity has to solve.
  - reference: PMID:39095936
    reference_title: Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, this mechanism is likely elicited by only a limited number of variants."
    explanation: An allele-selective therapy aimed at aggregation would apply only to the protein-extending class, narrowing the eligible population further.
notes: >
  Nomenclature caution: MPD6 (ACTN2, OMIM:618655) is NOT "myofibrillar myopathy
  6" (MFM6), which is the BAG3-related childhood disorder — a known miscoding
  trap flagged in deep research.
review_notes: >
  No GeneReviews chapter exists for MPD6 or for ACTN2-related skeletal myopathy.
  A PubMed search for "ACTN2 GeneReviews[All Fields]" returns only the
  Nonsyndromic Hypertrophic Cardiomyopathy Overview (PMID:20301725) and the
  Dilated Cardiomyopathy Overview (PMID:20301486), which cover ACTN2 as a
  cardiomyopathy gene and are not a phenotype baseline for this entry;
  "distal myopathy GeneReviews[TI]" returns nothing. So the GeneReviews
  cross-reference step has no baseline to apply here.

  No datasets are recorded, deliberately. `just discover-datasets` returns two
  candidate classes and neither survives relevance triage: the top-scoring
  DIRECT hits (geo:GSE128496 and siblings) match on the words "myopathy distal
  adult onset" but are GNE-myopathy knock-in mouse series, a different disease
  reached through shared phrasing; the GENE_ONLY hits match on ACTN2 and are
  cardiac or iPSC studies (Actn2 knockout cardiomyocytes, cardiac maturation
  scRNA-seq), reflecting ACTN2's long-standing cardiomyopathy association
  rather than this skeletal-muscle entity. Both are the Named Entity Confusion
  pattern the dataset SOP warns about, so the honest state is an empty
  datasets block rather than an accession that resolves but is about something
  else.

  Two citations offered by the deep-research reports were not used. The
  falcon report attributes the founding Savarese 2019 MPD6 conference abstract
  to `donkervoort2019o.18recessivemutationsin` and `amthor2019o.19pax7deficiencycauses`,
  which are the UNC-45B and PAX7 abstracts printed on the same page of the same
  supplement — a page-level misattribution, not the MPD6 abstract. The
  openscientist report cites PMID:21536590 for the claim that the Z-disk is the
  sarcomeric structure most vulnerable to eccentric mechanical damage; that
  paper is about alpha-actinin-3 (ACTN3) deficiency, a different gene, so it is
  not cited here for an ACTN2 mechanism.

📚

References & Deep Research

Deep Research

2

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 (4)

Record review notes

No GeneReviews chapter exists for MPD6 or for ACTN2-related skeletal myopathy. A PubMed search for "ACTN2 GeneReviews[All Fields]" returns only the Nonsyndromic Hypertrophic Cardiomyopathy Overview (PMID:20301725) and the Dilated Cardiomyopathy Overview (PMID:20301486), which cover ACTN2 as a cardiomyopathy gene and are not a phenotype baseline for this entry; "distal myopathy GeneReviews[TI]" returns nothing. So the GeneReviews cross-reference step has no baseline to apply here. No datasets are recorded, deliberately. `just discover-datasets` returns two candidate classes and neither survives relevance triage: the top-scoring DIRECT hits (geo:GSE128496 and siblings) match on the words "myopathy distal adult onset" but are GNE-myopathy knock-in mouse series, a different disease reached through shared phrasing; the GENE_ONLY hits match on ACTN2 and are cardiac or iPSC studies (Actn2 knockout cardiomyocytes, cardiac maturation scRNA-seq), reflecting ACTN2's long-standing cardiomyopathy association rather than this skeletal-muscle entity. Both are the Named Entity Confusion pattern the dataset SOP warns about, so the honest state is an empty datasets block rather than an accession that resolves but is about something else. Two citations offered by the deep-research reports were not used. The falcon report attributes the founding Savarese 2019 MPD6 conference abstract to `donkervoort2019o.18recessivemutationsin` and `amthor2019o.19pax7deficiencycauses`, which are the UNC-45B and PAX7 abstracts printed on the same page of the same supplement — a page-level misattribution, not the MPD6 abstract. The openscientist report cites PMID:21536590 for the claim that the Z-disk is the sarcomeric structure most vulnerable to eccentric mechanical damage; that paper is about alpha-actinin-3 (ACTN3) deficiency, a different gene, so it is not cited here for an ACTN2 mechanism.

Record notes

Nomenclature caution: MPD6 (ACTN2, OMIM:618655) is NOT "myofibrillar myopathy 6" (MFM6), which is the BAG3-related childhood disorder — a known miscoding trap flagged in deep research.

Augment: MPD6 with second DR run, models, imaging, epidemiology · 2026-09-03T09:26:37Z · View source

Augmentation of an existing entry created by PR #7872. Compliance rose from 81.7% to 98.4% (weighted 82.4% -> 98.9%); snippet count 30 -> 85, all verified. Deep research. Requested provider was falcon, per the /curate default. The Edison endpoint returned 403 (EDISON_API_KEY not valid in this environment), so the run was re-issued with `just dr_fallback='--fallback'` rather than a hand-picked substitute. openscientist produced the report, which is recorded in its frontmatter as fell_back: true, requested_provider: falcon, with the full provider_attempts list. Report used: research/Distal_Myopathy_6_Adult-Onset_Autosomal_Dominant-deep-research-openscientist.md (17 citations). The pre-existing falcon report from the 2026-08-02 session is unchanged and retained; the fallback rename briefly clobbered it and it was restored from origin/main before commit. Report validation (Step 3a). Reference validation: 17/17 resolved, confabulation_rate 0.0, no unresolved references; 12/17 scored on topic. Term validation: needs_review true, with three mislabelled terms - MONDO:0014138 offered as the MONDO id but is nemaline myopathy 8; UBERON:0011906 called "soleus" but is "muscle head"; UBERON:0011907 called "biceps femoris" but is "gastrocnemius medialis". None of these was bound. Every ontology term added here was independently resolved with OAK first; the soleus reference in prose uses no binding and the one UBERON binding added (UBERON:0001385 tibialis anterior) was OAK-verified. GeneReviews baseline (Step 3b): none exists. "ACTN2 GeneReviews[All Fields]" returns only the Nonsyndromic HCM (PMID:20301725) and Dilated Cardiomyopathy (PMID:20301486) overviews, which treat ACTN2 as a cardiac gene and are not a phenotype baseline for this skeletal entity; "distal myopathy GeneReviews[TI]" returns nothing. Recorded in the entry's review_notes. What was added. prevalence (CASES_IN_LITERATURE, no rate asserted, with the founder-ascertainment caveat); a three-phase progression; clinical_burden MODERATE with the cardiac/respiratory-sparing rationale; histopathology (EM Z-disk undulation, plus the cohort's non-specific biopsy finding that qualifies the diagnostic weight of the rest); imaging_findings (the 37-patient MRI distribution and the ML-derived discriminating signature, including which muscles are preserved); biochemical (mildly elevated CK, NCIT:C113245, with the point that CK is a poor discriminator here); two phenotypes (HP:0003236, HP:0003325); a new upstream pathophysiology node "Alpha-actinin-2 conformational destabilization"; evidence on four of the five causal edges; mechanistic_hypotheses (the eccentric-load explanation for the distal predilection, EMERGING, carrying both its supporting quote and a refuting one); two animal_models and one experimental_model with modeled_mechanisms and readouts; variants (the two founder alleles and the last-exon frameshift class); two new differential_diagnoses (recessive biallelic ACTN2 myopathy, allelic congenital MsCD) plus distinguishing features and evidence on the pre-existing one; three treatments added and evidence on all six; evidence on both harrisons_chapter assignments; two new discussions (HUMAN_MODEL_MISMATCH on the animal models, KNOWLEDGE_GAP on the therapeutic window) and evidence added to the pre-existing nomenclature discussion. New references fetched and cited: PMID:39812845 (37-patient dominant cohort), PMID:38311799 (recessive biallelic ACTN2), PMID:30701273 (MsCD, zebrafish and AAV mouse), PMID:33458580, PMID:39017652, PMID:42111349, PMID:42481460, PMID:27287556, PMID:38352343. Cross-phenotype borrowing, flagged deliberately. ACTN2 is far better known as a cardiomyopathy gene, so several of the mechanistically useful papers are not about MPD6. PMID:42481460 and PMID:27287556 profile ACTN2 hypertrophic-cardiomyopathy missense panels; PMID:30701273 models p.Leu727Arg, an allele of the allelic congenital core myopathy. Each is carried with directness: INDIRECT, an explanation naming the allele mismatch, and - for the models - explicit `limitations`. The animal models are PARTIALLY_RECAPITULATES at fidelity LOW for this reason, and the HUMAN_MODEL_MISMATCH discussion records that no model addresses the feature that defines MPD6 (adult onset selecting the anterior lower leg). Citations declined. The falcon report attributes the founding Savarese 2019 MPD6 abstract to donkervoort2019o.18recessivemutationsin and amthor2019o.19pax7deficiencycauses, which are the UNC-45B and PAX7 abstracts printed on the same supplement page - a page-level misattribution, not the MPD6 abstract. The openscientist report cites PMID:21536590 for the Z-disk's vulnerability to eccentric damage; that paper is about alpha-actinin-3 (ACTN3), a different gene, so it is not used for an ACTN2 mechanism. Both are recorded in the entry's review_notes. No datasets recorded, deliberately. `just discover-datasets` returns DIRECT-tagged GNE-myopathy mouse series (matched on the words "myopathy distal adult onset") and GENE_ONLY cardiac/iPSC series (matched on ACTN2). Both are the Named Entity Confusion pattern; none is about this entity, so the datasets block is left empty with the triage recorded in review_notes. Validation run. `just validate` passes; `just validate-terms` passes; `just count-verified-snippets` reports 85/85; `just validate-disorders` (the batched gate CI runs) passes schema, term and reference validation. Offline gates run and green: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms plus check-qualifier-terms-online (needed because the NCIT:C86054 device qualifier is a qualifier-only CURIE the offline gate cannot see), check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-environmental-evidence, check-snippet-grading. check-snippet-grading initially failed on one real defect - the PMID:30701273 patient sentence graded MODEL_ORGANISM in the new discussion and HUMAN_CLINICAL in a differential diagnosis; the sentence reports patients, so the discussion item was corrected to HUMAN_CLINICAL.

Create: Distal Myopathy 6, Adult-Onset, Autosomal Dominant ACTN2 · 2026-08-02T04:58:56Z · View source

Created new dismech entry for MONDO:0032853 MPD6, the ACTN2-related autosomal dominant adult-onset distal myopathy actininopathy. Curated the alpha-actinin-2 Z-disk pathophysiology chain: ACTN2 variant classes to alpha-actinin-2 aggregation and Z-disk/myofibrillar disorganization to distal muscle degeneration; phenotypes distal lower-limb weakness with anterior-compartment ankle-dorsiflexion onset, facial weakness, later proximal spread, rimmed vacuoles, centrally nucleated fibers, multi-minicores; ACTN2 gene entry; supportive care. Evidence from primary literature: Savarese 2019 PMID:30900782 original actininopathy, Savarese 2021 PMID:34386585 last-exon out-of-frame variants with facial weakness, Chen 2021 PMID:34170073 frameshift multi-minicore family, Ranta-Aho 2024 PMID:39095936 protein-aggregation mechanism, Ranta-Aho 2022 PMID:36116040 ACTN2 mutation update. Falcon deep research attempted. Validated with just validate schema+terms+references pass 17/17 snippets verified and just compliance 88.2 percent.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 17 citations 2026-08-02T05:08:38.336855

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

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

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

Disease Characteristics Research Template

Target Disease

Disease Name: Distal Myopathy 6, Adult-Onset, Autosomal Dominant
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Distal Myopathy 6, Adult-Onset, Autosomal Dominant covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

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

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

7. Anatomical Structures Affected

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

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

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

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

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

10. Diagnostics

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

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

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Distal Myopathy 6, Adult-Onset, Autosomal Dominant

Executive summary

Distal myopathy 6, adult-onset (MPD6) is an exceptionally rare, dominantly inherited skeletal-muscle disorder caused by heterozygous variants in ACTN2, which encodes the sarcomeric Z-disc protein α-actinin-2. The defining reported phenotype is adult-onset, often asymmetric weakness and atrophy of the tibialis anterior/ankle dorsiflexors, followed by proximal spread; muscle biopsy may show rimmed vacuoles. The initial evidence involved four families—three from one village in northern Spain and one Swedish family—with full penetrance reported within those pedigrees. Only two disease-associated substitutions were firmly documented in the retrieved foundational evidence: c.1459T>C (p.Cys487Arg) and c.392T>C (p.Leu131Pro). Population prevalence, long-term outcome rates, quantitative cardiac risk, and treatment-response data remain unavailable. There is no approved disease-modifying therapy or MPD6-specific clinical trial.

A crucial nomenclature warning is that MPD6 (ACTN2; OMIM 618655) is not “myofibrillar myopathy 6,” the BAG3-related childhood disorder. Older reviews may use “MFM6” for BAG3 disease, creating a serious risk of miscoding. The current neuromuscular gene table unambiguously assigns adult-onset distal myopathy 6 to ACTN2. (cohen2021the2022version pages 14-15, dimachkie2014distalmyopathies. pages 14-16, benarroch2024the2024version pages 14-15)

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 (cohen2021the2022version pages 14-15, benarroch2024the2024version pages 14-15)	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 (cohen2021the2022version pages 14-15, wadmore2021theroleof pages 2-4)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1, wadmore2021theroleof pages 4-5)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	Pattern: distal lower-limb onset, asymmetric, then proximal progression
Pathology	Muscle biopsy showed rimmed vacuolar pathology	Primary cohort abstract evidence; moderate (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	Histopathology: rimmed vacuoles
Penetrance / segregation	Variants co-segregated with disease and showed full penetrance in the reported families	Primary cohort abstract evidence; moderate (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	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 (wadmore2021theroleof pages 2-4, wadmore2021theroleof pages 4-5)	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 (wadmore2021theroleof pages 4-5)	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 (wadmore2021theroleof pages 2-4, wadmore2021theroleof pages 4-5)	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 (cohen2021the2022version pages 14-15, benarroch2024the2024version pages 14-15, OpenTargets Search: -ACTN2)	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 (benarroch2024the2024version pages 14-15)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)	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 (findlay2024dominantlyinheritedmuscle pages 15-16, findlay2024dominantlyinheritedmuscle pages 16-16)	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 (cohen2021the2022version pages 14-15, dimachkie2014distalmyopathies. pages 14-16)	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 (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1, wadmore2021theroleof pages 4-5)	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.

1. Disease information

Definition and identifiers

MPD6 is a Mendelian, autosomal-dominant distal myopathy characterized by primary skeletal-muscle degeneration beginning distally in adulthood. The 2024 neuromuscular gene table lists it as item 4.10, locus 1q43, disease symbol MPD6, phenotype OMIM 618655, and causal gene ACTN2 (gene OMIM 102573). (benarroch2024the2024version pages 14-15)

Recommended identifiers and labels are:

Preferred name: Myopathy, distal, 6, adult-onset
Synonyms: distal myopathy 6; MPD6; ACTN2-related adult-onset distal myopathy; α-actinin-2-related distal myopathy
OMIM phenotype: 618655
Gene: ACTN2; Ensembl ENSG00000077522; protein α-actinin-2
Chromosomal locus: 1q43
MONDO: a dedicated MPD6 identifier was not resolved in the retrieved resources; do not substitute the broader ACTN2 congenital-myopathy term MONDO:0032852
Orphanet: no MPD6-specific identifier was resolved
ICD-10/ICD-11: no unique disease-specific code was identified; coding generally falls under hereditary/other specified myopathy or muscular-dystrophy groupings, depending on local practice
MeSH: no unique MPD6 descriptor; “Distal Myopathies”/“Muscular Diseases” are suitable broader indexing concepts.

The source evidence is aggregated disease-level literature and family studies, not individual EHR data. The foundational observations are patient-level pedigree data subsequently aggregated into OMIM-style and neuromuscular gene-table entries.

2. Etiology

Causal and genetic risk factors

The established cause is a germline heterozygous ACTN2 missense variant. Three northern-Spanish families carried c.1459T>C, p.Cys487Arg, while the Swedish family carried c.392T>C, p.Leu131Pro. Both variants co-segregated with disease; the report described full penetrance in the studied families. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)

The 2021 Z-disc review reported both variants as absent from gnomAD v3.1, supporting rarity but not by itself proving pathogenicity. p.Leu131Pro lies in the actin-binding domain, whereas p.Cys487Arg lies in a spectrin-repeat region. (wadmore2021theroleof pages 4-5)

Family history is therefore the principal recognized risk factor. Each child of a heterozygous affected individual has a 50% transmission probability, although phenotypic severity and exact age at onset cannot yet be predicted reliably.

Environmental, protective, and gene–environment factors

No reproducible toxin, infection, occupation, diet, alcohol, smoking, activity, sex, or other environmental cause has been established. No protective ACTN2 allele, modifier gene, dietary factor, or pharmacologic prophylaxis has been demonstrated. Gene–environment interactions have not been systematically studied. Ordinary aging likely determines when an inherited vulnerability becomes clinically evident, but that is a natural-history inference rather than a proven interaction.

3. Phenotypes

The direct human evidence supports the following curation set. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)

Phenotype	Characterization	Suggested HPO term
Adult-onset muscle weakness	Chronic/insidious onset; detailed age range unavailable	Adult onset, HP:0003581
Distal lower-limb weakness	Core manifestation; initially ankle dorsiflexors	Distal muscle weakness, HP:0002460
Ankle dorsiflexion weakness	Early/defining manifestation	Foot dorsiflexor weakness, HP:0009053
Tibialis anterior atrophy	Early objective sign	Tibialis anterior muscle atrophy; use muscular atrophy HP:0003202 if a specific descendant is unavailable
Asymmetric weakness	Common defining pattern in the original families	Asymmetric muscle weakness, HP:0031500 or current HPO equivalent
Proximal spread	Later manifestation; frequency and timing unquantified	Proximal muscle weakness, HP:0003701
Progressive course	Distal disease progresses into proximal muscles	Progressive muscle weakness, HP:0003323
Rimmed vacuoles	Histopathologic abnormality	Rimmed vacuoles, HP:0003805

The report did not provide sufficiently robust frequencies beyond the pedigree-level description. “Full penetrance” should not be translated into 100% lifetime penetrance across all ACTN2 variants or populations because only four families were studied.

Functional/QoL impact: dorsiflexor weakness is expected to impair toe clearance, gait, stair climbing, balance, and community mobility and to increase falls; later proximal weakness may compromise transfers and endurance. No MPD6-specific EQ-5D, SF-36, PROMIS, employment, ambulation-loss, or caregiver-burden dataset was found.

Cardiac manifestations are biologically important because other ACTN2 variants cause hypertrophic and dilated cardiomyopathy, but a quantitative cardiac phenotype was not established for the two MPD6 variants in the retrieved primary evidence. ACTN2 is formally allelic to CMH23 and CMD1AA. (benarroch2024the2024version pages 14-15, OpenTargets Search: -ACTN2)

4. Genetic and molecular information

Gene and variants

ACTN2 encodes α-actinin-2, a Z-disc actin-crosslinking and scaffolding protein expressed in skeletal and cardiac striated muscle. Its architecture includes an N-terminal actin-binding domain, four central spectrin repeats, and a C-terminal EF-hand region. (wadmore2021theroleof pages 2-4)

Variant	Class/origin	Domain	Population observation	Evidence interpretation
ACTN2 c.392T>C; p.Leu131Pro	Heterozygous germline missense	Actin-binding domain	Absent from gnomAD v3.1 in the 2021 review	Co-segregated with fully penetrant disease in one Swedish family
ACTN2 c.1459T>C; p.Cys487Arg	Heterozygous germline missense	Spectrin-repeat region	Absent from gnomAD v3.1 in the 2021 review	Co-segregated with disease in three Spanish families

These should be curated using current ClinVar assertions and transcript-specific HGVS normalization at implementation time; the retrieved literature did not supply a current ClinVar review status or ACMG evidence matrix. No somatic origin is implicated. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1, wadmore2021theroleof pages 4-5)

Allelic disorders and modifiers

ACTN2 alleles also cause hypertrophic cardiomyopathy, dilated cardiomyopathy and congenital myopathy with structured cores/Z-line abnormalities. Open Targets independently links ACTN2 to dilated cardiomyopathy 1AA and congenital myopathy with structured cores and Z-line abnormalities. These are allelic disorders, not synonymous with MPD6. (benarroch2024the2024version pages 14-15, OpenTargets Search: -ACTN2)

No validated modifier gene, protective allele, anticipation, germline-mosaicism series, epigenetic signature, pathogenic copy-number variant, translocation, or inversion specific to MPD6 was found.

5. Environmental information

MPD6 is not an infectious, toxic, radiation-induced, nutritional, or occupational disorder. No pathogen, pollutant, medication, toxin, or lifestyle exposure is known to initiate it. Avoiding prolonged immobility and maintaining safe activity may reduce secondary deconditioning, but these measures do not prevent inheritance or molecular disease onset. There is no evidence for vaccination, antimicrobial therapy, detoxification, smoking cessation, or a special diet as disease-specific prevention.

6. Mechanism and pathophysiology

Proposed causal chain

A heterozygous ACTN2 missense substitution alters α-actinin-2 within either its actin-binding or spectrin-repeat region.
Mutant α-actinin-2 is incorporated into—or perturbs—the Z-disc, where normal α-actinin-2 crosslinks actin filaments and scaffolds mechanosignaling proteins.
Abnormal actin interaction, dimer/scaffold stability, or Z-disc integration compromises sarcomere organization and force transmission.
Repeated contraction produces cumulative myofibrillar stress and defective protein homeostasis.
Myofiber degeneration and rimmed-vacuole formation lead to selective tibialis-anterior atrophy, dorsiflexion weakness, and eventual proximal spread.

Steps 1 and the clinical endpoint are supported directly by human segregation/pathology; intermediate steps remain the leading Z-disc-based model rather than a completely demonstrated MPD6-specific pathway. Experiments on other ACTN2 variants show reduced thermal stability, impaired actin binding, weak Z-disc integration and aggregate formation, supporting the general plausibility of this mechanism but not proving identical effects for p.Leu131Pro or p.Cys487Arg. (wadmore2021theroleof pages 2-4, wadmore2021theroleof pages 4-5)

Suggested annotations include:

GO biological process: actin filament organization (GO:0007015); sarcomere organization (GO:0045214); muscle contraction (GO:0006936); actin filament bundle assembly (GO:0051017); cellular response to mechanical stimulus (GO:0071260); protein stabilization (GO:0050821); autophagy/proteostasis terms only as downstream hypotheses
GO cellular component: Z disc (GO:0030018); sarcomere (GO:0030017); myofibril (GO:0030016); actin cytoskeleton (GO:0015629)
GO molecular function: actin binding (GO:0003779); structural constituent of muscle (GO:0008307); protein binding (GO:0005515)
Cell Ontology: skeletal muscle fiber CL:0000188; skeletal muscle satellite stem cell CL:0000596 only for secondary regenerative studies; cardiomyocyte CL:0000746 for safety/allelic-phenotype surveillance.

No MPD6-specific transcriptomic, proteomic, metabolomic, lipidomic, methylomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omic signature was identified. Consequently, there is no validated molecular biomarker or metabolic abnormality. Immune-mediated inflammation is not an established primary mechanism.

7. Anatomical structures affected

The primary organ is skeletal muscle, especially distal lower-limb muscle. The earliest named muscle is the tibialis anterior, affecting the anterior compartment of the leg and ankle dorsiflexion. Disease later reaches proximal limb muscles. Weakness is often asymmetric, but it is not described as strictly unilateral. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)

Suggested anatomical annotations are skeletal muscle tissue (UBERON:0001134), lower limb segment (UBERON:0002103), leg (UBERON:0000978), tibialis anterior muscle, ankle joint (UBERON:0001488), and upper/proximal limb musculature for later disease. At cellular level, multinucleated skeletal myofibers are affected; subcellular disease centers on the sarcomeric Z-disc/myofibril. Cardiac muscle is a surveillance tissue because of ACTN2 allelism, not a proven obligatory MPD6 target.

8. Temporal development

Onset is adult and insidious, followed by a chronic progressive course. The apparent sequence is: asymmetric tibialis-anterior atrophy/dorsiflexion weakness → broader distal lower-limb involvement → proximal muscle involvement. Exact median onset, annual progression, time to assistive device, time to loss of ambulation, and respiratory trajectory were not available. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)

No relapsing-remitting course, spontaneous remission, acute attacks, or treatment-induced remission has been described. Disease is presumed lifelong after onset. The most plausible intervention window is early after molecular diagnosis, before fixed fatty replacement and contractures, but this has not been tested.

9. Inheritance and population

Inheritance is autosomal dominant. Full penetrance was reported in the original families, but penetrance may be age-dependent because onset is adult and the evidence base is small. Expressivity is insufficiently quantified; asymmetry itself indicates phenotypic variability. There is no evidence of repeat-expansion anticipation. (donkervoort2019o.18recessivemutationsin pages 1-1, amthor2019o.19pax7deficiencycauses pages 1-1)

Three p.Cys487Arg families originated from the same northern-Spanish village, which raises a founder hypothesis, but no haplotype or population study establishing a founder effect was retrieved. The fourth family was Swedish and carried p.Leu131Pro. No prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, or worldwide geographic distribution can be estimated responsibly from four pedigrees. Consanguinity is not etiologically relevant to a dominant disorder, although it does not preclude occurrence.

10. Diagnostics

Recommended workflow

Clinical examination: document distal-versus-proximal pattern, asymmetry, tibialis-anterior bulk, ankle dorsiflexion strength, gait, reflexes, sensory findings and contractures.
Serum tests: CK, aldolase, AST/ALT and other routine myopathy studies. No MPD6-specific CK threshold is established.
Electrophysiology: EMG to demonstrate a myopathic process; nerve-conduction studies help exclude hereditary neuropathy/peroneal neuropathy.
Muscle MRI: characterize selective anterior-compartment involvement, quantify fatty replacement, choose a biopsy site, and provide a longitudinal outcome measure. Imaging is strongly recommended in modern myopathy workups. (wadmore2021theroleof pages 12-13)
Genetic testing: use a comprehensive distal-myopathy/myofibrillar-myopathy panel including ACTN2, or WES/WGS if panel testing is negative. Confirm candidate variants by an orthogonal method and perform segregation analysis.
Biopsy: now second-line when genetics is inconclusive or variant interpretation requires functional support. Histology may reveal myopathic change and rimmed vacuoles; frozen muscle is preferable to formalin-only tissue for neuromuscular diagnosis. (donkervoort2019o.18recessivemutationsin pages 1-1, wadmore2021theroleof pages 12-13)
Cardiac baseline: ECG, echocardiography and symptom/family-history review are prudent because ACTN2 also causes cardiomyopathy, although MPD6-specific screening intervals are not evidence-based. (benarroch2024the2024version pages 14-15, OpenTargets Search: -ACTN2)

Single-gene ACTN2 sequencing is efficient in a family with a known variant. WES/WGS is valuable for unresolved phenotypes and can detect competing diagnoses; WGS improves noncoding and structural-variant detection. CMA, karyotyping, FISH, mitochondrial-DNA sequencing and repeat-expansion testing are not first-line unless the phenotype or family history suggests an alternative diagnosis. RNA sequencing of muscle can support splice-variant interpretation but has no established role for the two missense MPD6 variants.

Differential diagnosis

Important alternatives include TTN tibial muscular dystrophy, MYH7 Laing distal myopathy, FLNC distal myopathy, TIA1 Welander disease, MYOT myotilinopathy, GNE myopathy, ANO5/dysferlin disease, VCP multisystem proteinopathy, BAG3/MYOT/DES myofibrillar myopathy, hereditary motor neuropathy/Charcot–Marie–Tooth disease, inclusion-body myositis, and focal peroneal neuropathy. Preserved sensation and myopathic EMG favor myopathy; inheritance, onset age, MRI pattern, biopsy, and molecular testing provide final discrimination. The 2024 gene table distinguishes MPD6 from these numbered distal-myopathy entities. (benarroch2024the2024version pages 14-15)

There are no standardized MPD6 clinical diagnostic criteria, newborn screening program, population screening test, or validated liquid-biopsy assay. Predictive testing should be offered only with genetics counseling because onset is adult and no preventive molecular therapy exists.

11. Outcome and prognosis

The disease is progressive and likely causes increasing gait disability, falls and reduced independence. However, no 5- or 10-year survival, life-expectancy, mortality, ambulation-loss, ventilation, cardiomyopathy penetrance, hospitalization, or standardized disability statistics were found. The original evidence did not establish respiratory failure as a defining feature. Prognostic biomarkers are unavailable.

Potential prognostic variables—still unvalidated—include age at onset, baseline dorsiflexion strength, MRI fat fraction, proximal involvement, falls, CK, and cardiac findings. Recovery of chronically replaced muscle is unlikely, but rehabilitation can improve safety, conditioning and use of remaining function. No evidence supports spontaneous reversal of the underlying myopathy.

12. Treatment

There is no approved ACTN2/MPD6 disease-modifying treatment and no MPD6-specific response-rate or adverse-event dataset.

Recommended supportive management is individualized:

Physiotherapy emphasizing safe submaximal strengthening, range of motion, aerobic conditioning and avoidance of prolonged deconditioning or injurious eccentric overload.
Occupational therapy and home/work adaptation.
Ankle–foot orthoses for foot drop; cane, trekking poles, walker or wheelchair as function requires.
Falls assessment, footwear review, and treatment of secondary pain.
Monitoring for contractures and orthopedic complications; surgery only for standard functional indications, not to treat the molecular disorder.
Respiratory evaluation if symptoms or advanced generalized weakness develop.
Baseline and periodic cardiac assessment guided by findings and specialist judgment.

Suitable broad NCIt intervention concepts include Physical Therapy (NCIT:C15308), Occupational Therapy (NCIT:C15309), rehabilitation, orthotic device, genetic counseling, electrocardiography and echocardiography; exact NCIt codes should be verified against the deployment terminology release.

Dominant myopathies are challenging gene-therapy targets because simply adding a normal gene may not neutralize a toxic or dominant-negative allele. Contemporary expert analysis highlights allele-specific RNA interference, ASOs and editing as general strategies, but none has reached MPD6 clinical testing. (findlay2024dominantlyinheritedmuscle pages 15-16, findlay2024dominantlyinheritedmuscle pages 16-16)

Clinical-trial searches found no relevant ACTN2/MPD6 interventional study or NCT identifier. Pharmacogenomic guidance and combination-treatment algorithms are therefore not applicable.

13. Prevention

Primary prevention: no lifestyle or environmental measure prevents disease in a person carrying a pathogenic allele. Vaccination and antimicrobial prophylaxis are not disease-specific.

Genetic/reproductive prevention: genetic counseling should explain autosomal-dominant transmission, age-dependent uncertainty and the 50% transmission probability. Once a familial pathogenic variant is established, options include cascade testing, prenatal diagnosis and preimplantation genetic testing. Predictive testing of asymptomatic adults requires informed consent and discussion of uncertain onset/severity and insurance or psychosocial implications.

Secondary prevention: identify affected relatives before substantial disability; monitor gait/falls and obtain a cardiac baseline. There is no newborn or population screening program.

Tertiary prevention: preserve mobility, prevent falls and contractures, avoid deconditioning, and promptly manage cardiac, respiratory or orthopedic complications if they arise.

14. Other species and natural disease

No naturally occurring veterinary disease confidently equivalent to human ACTN2-MPD6 was identified. Therefore no breed, VBO identifier, veterinary prevalence or cross-species transmission issue can be assigned. The disorder is genetic and noncommunicable, with no zoonotic potential.

ACTN2 orthologs are evolutionarily conserved across vertebrates, reflecting the conserved role of α-actinin-2 in striated-muscle Z-discs. Relevant comparative species include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116) and Danio rerio (7955), but orthology alone does not establish a natural MPD6 phenotype.

15. Model organisms and research systems

No mature, independently validated model reproducing the complete human MPD6 phenotype was found in the retrieved literature. Suitable future systems include:

CRISPR knock-in mouse models carrying Actn2 p.Leu131Pro or p.Cys487Arg, assessed longitudinally for asymmetric tibialis-anterior disease, rimmed vacuoles, force and cardiac phenotypes.
Zebrafish knock-in or mosaic-expression models for rapid sarcomere and locomotor assays.
Patient-derived myoblasts/myotubes and isogenic CRISPR-corrected controls.
Patient iPSC-derived skeletal myotubes and cardiomyocytes to separate skeletal and cardiac allele effects.
Engineered three-dimensional muscle for force, Z-disc organization and proteostasis assays.

Important limitations are species differences in lifespan, loading and muscle-use patterns; a model may show cardiac disease without the selective adult human tibialis-anterior phenotype. ACTN2 studies in cardiomyocyte systems demonstrate the feasibility of modeling variant-dependent Z-disc integration, calcium-channel interactions and drug response, but those findings concern other ACTN2 alleles and must not be treated as direct MPD6 therapeutic evidence. (wadmore2021theroleof pages 2-4)

Recent developments and expert assessment

The 2024 neuromuscular gene table retained MPD6 as an ACTN2 disorder, confirming that the 2019 gene–disease assignment remains current. (benarroch2024the2024version pages 14-15) A 2024 conference report described ACTN2 mutational screening and an apparent actin-binding-domain aggregation hotspot, indicating active expansion of the allelic spectrum, but full peer-reviewed patient-level evidence was not available in the retrieved corpus. More broadly, the 2024 review of dominant muscle disorders argues that dominant-negative or toxic mechanisms will require allele-selective suppression, editing, or combined suppression-and-replacement rather than conventional gene addition. (findlay2024dominantlyinheritedmuscle pages 15-16)

The authoritative interpretation is therefore cautious: MPD6 is a well-defined but very sparsely characterized ACTN2-related distal myopathy. Its gene assignment and core phenotype are credible; precise epidemiology, variant-specific mechanism, cardiac risk, natural history, biomarkers and therapy remain research gaps.

Key source record and abstract wording

Savarese et al., 2019, “Mutations in ACTN2 gene cause a novel form of adult-onset distal myopathy,” conference publication in Neuromuscular Disorders 29:S120. The retrievable abstract text reports “four families,” “adult-onset, asymmetric muscle weakness,” initial “atrophy of tibialis anterior” and progression to proximal muscles, with “full penetrance” and co-segregation. DOI-linked conference record: https://doi.org/10.1016/j.nmd.2019.06.298. (donkervoort2019o.18recessivemutationsin pages 1-1)
Cohen et al., published December 2021, The 2022 version of the gene table of neuromuscular disorders. DOI: https://doi.org/10.1016/j.nmd.2021.11.004. This identifies MPD6/OMIM 618655, ACTN2 and 1q43. (cohen2021the2022version pages 14-15)
Wadmore, Azad & Gehmlich, published 18 March 2021, The Role of Z-disc Proteins in Myopathy and Cardiomyopathy. DOI: https://doi.org/10.3390/ijms22063058. Abstract wording: “The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units” and functions as a “(bio-mechanical) signalling hub.” It reviews ACTN2 structure, variants and population frequencies. (wadmore2021theroleof pages 2-4, wadmore2021theroleof pages 4-5)
Benarroch et al., published January 2024, The 2024 version of the gene table of neuromuscular disorders (nuclear genome). DOI: https://doi.org/10.1016/j.nmd.2023.12.007. (benarroch2024the2024version pages 14-15)
Findlay, published October 2024, Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. DOI: https://doi.org/10.1242/dmm.050720. Its abstract emphasizes that gene replacement used for recessive loss-of-function disease is “not readily translatable to most dominant myopathies,” supporting the need for allele-directed strategies. (findlay2024dominantlyinheritedmuscle pages 15-16)

Evidence limitations: the foundational MPD6 report was available principally as a conference abstract, and exact PMID metadata for it was not resolved. Accordingly, detailed ages, CK values, MRI distributions, cardiac testing, respiratory outcomes and individual-level longitudinal data should remain null fields in a knowledge base until verified from a full primary publication or subsequent cohort.

References

(cohen2021the2022version pages 14-15): Enzo Cohen, Gisèle Bonne, François Rivier, and Dalil Hamroun. The 2022 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscular Disorders, 31:1313-1357, Dec 2021. URL: https://doi.org/10.1016/j.nmd.2021.11.004, doi:10.1016/j.nmd.2021.11.004. This article has 64 citations and is from a peer-reviewed journal.
(dimachkie2014distalmyopathies. pages 14-16): Mazen M. Dimachkie and Richard J. Barohn. Distal myopathies. Neurologic clinics, 32 3:817-42,x, Aug 2014. URL: https://doi.org/10.1016/j.ncl.2014.04.004, doi:10.1016/j.ncl.2014.04.004. This article has 26 citations and is from a peer-reviewed journal.
(benarroch2024the2024version pages 14-15): Louise Benarroch, Gisèle Bonne, François Rivier, and Dalil Hamroun. The 2024 version of the gene table of neuromuscular disorders (nuclear genome). Jan 2024. URL: https://doi.org/10.1016/j.nmd.2023.12.007, doi:10.1016/j.nmd.2023.12.007. This article has 39 citations and is from a peer-reviewed journal.
(wadmore2021theroleof pages 2-4): Kirsty Wadmore, Amar J. Azad, and Katja Gehmlich. The role of z-disc proteins in myopathy and cardiomyopathy. International Journal of Molecular Sciences, 22:3058, Mar 2021. URL: https://doi.org/10.3390/ijms22063058, doi:10.3390/ijms22063058. This article has 76 citations.
(donkervoort2019o.18recessivemutationsin pages 1-1): S. Donkervoort, Y. Hu, X. Lornage, C. Kutzner, M. Mroczek, S. Neuhaus, N. Kuntz, A. Töpf, S. Monges, F. Lubieniecki, K. Chao, J. Böhm, N. Romero, V. Straub, J. Laporte, A. Foley, C. Ottenheijm, T. Hoppe, and C. Bönnemann. O.18recessive mutations in the myosin chaperone unc-45b impair muscle myofibrillar integrity, manifesting as progressive myopathy with eccentric cores. Neuromuscular Disorders, 29:S120, Oct 2019. URL: https://doi.org/10.1016/j.nmd.2019.06.298, doi:10.1016/j.nmd.2019.06.298. This article has 0 citations and is from a peer-reviewed journal.
(amthor2019o.19pax7deficiencycauses pages 1-1): H. Amthor, A. Marg, H. Escobar, S. Grunwald, E. Metzler, J. Kieshauer, E. Malfatti, D. Mompoint, S. Quijano-Roy, R. Carlier, and S. Spuler. O.19pax7 deficiency causes mild congenital myopathy with rigid spine and respiratory insufficiency. Neuromuscular Disorders, 29:S120, Oct 2019. URL: https://doi.org/10.1016/j.nmd.2019.06.299, doi:10.1016/j.nmd.2019.06.299. This article has 0 citations and is from a peer-reviewed journal.
(wadmore2021theroleof pages 4-5): Kirsty Wadmore, Amar J. Azad, and Katja Gehmlich. The role of z-disc proteins in myopathy and cardiomyopathy. International Journal of Molecular Sciences, 22:3058, Mar 2021. URL: https://doi.org/10.3390/ijms22063058, doi:10.3390/ijms22063058. This article has 76 citations.
(OpenTargets Search: -ACTN2): Open Targets Query (-ACTN2, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(findlay2024dominantlyinheritedmuscle pages 15-16): Andrew R. Findlay. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms, Oct 2024. URL: https://doi.org/10.1242/dmm.050720, doi:10.1242/dmm.050720. This article has 10 citations and is from a domain leading peer-reviewed journal.
(findlay2024dominantlyinheritedmuscle pages 16-16): Andrew R. Findlay. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms, Oct 2024. URL: https://doi.org/10.1242/dmm.050720, doi:10.1242/dmm.050720. This article has 10 citations and is from a domain leading peer-reviewed journal.
(wadmore2021theroleof pages 12-13): Kirsty Wadmore, Amar J. Azad, and Katja Gehmlich. The role of z-disc proteins in myopathy and cardiomyopathy. International Journal of Molecular Sciences, 22:3058, Mar 2021. URL: https://doi.org/10.3390/ijms22063058, doi:10.3390/ijms22063058. This article has 76 citations.

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1. Disease Information

openscientist-autonomous 17 citations 2026-09-03T09:10:41.465110

1. Disease Information

Overview. MPD6 is a Mendelian, adult-onset, autosomal dominant distal myopathy of skeletal muscle. It belongs to the broad category of distal myopathies — genetic primary muscle disorders that present with prominent weakness at onset in the hands and/or feet — which are increasingly recognized as a subset of the muscular dystrophies (progressive genetic diseases with loss of muscle fibers) [PMID: 33458580]. Savarese et al. established that dominant ACTN2 variants define a new genetically determined distal myopathy, coining the term "actininopathy": "ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy." [PMID: 30900782].

Key identifiers.

Resource	Identifier
OMIM	#615197 (Myopathy, distal, 6, adult-onset, autosomal dominant; MPD6)
Mondo	MONDO:0014138
Gene	ACTN2 — HGNC:164; NCBI Gene 88; Ensembl ENSG00000077522
Protein	Alpha-actinin-2 — UniProt P35609
Locus	Chromosome 1q42–1q43
ICD-10	G71.0 (muscular dystrophy) — no MPD6-specific code
ICD-11	8C70 (primary/hereditary myopathy) — no MPD6-specific code
MeSH	Distal myopathy maps under "Distal Myopathies" / "Muscular Dystrophies"

Synonyms / alternative names: Distal myopathy 6 (MPD6); adult-onset autosomal dominant distal myopathy; actininopathy; ACTN2-related distal myopathy; ACTN2 myopathy (dominant, non-congenital).

Information source. The knowledge base for MPD6 is derived from aggregated, disease-level resources — case series and family cohorts reported in the primary literature (Savarese 2019; Iruzubieta 2025), plus OMIM/gene-level curation — rather than from individual patient EHR data. The largest cohort to date comprises 37 patients from 11 families [PMID: 39812845].

2. Etiology

Primary cause — genetic. MPD6 is a monogenic disorder caused by heterozygous missense (and in some kindreds protein-extending frameshift) variants in ACTN2. In the founding study, a unique ACTN2 missense variant cosegregated with disease in all three Spanish families, while the Swedish family carried a different ACTN2 missense variant: "In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant." [PMID: 30900782].

Genetic risk factors. The causal variant in ACTN2 is both necessary and (with incomplete, age-dependent penetrance) largely sufficient. There are no established susceptibility loci or GWAS-identified common-variant risk factors for this Mendelian disease. Certain recurrent variants behave as founder alleles in specific populations (see §9).

Environmental / lifestyle risk factors. None are established. As a dominantly inherited sarcomeric disease, onset and progression are driven by genotype and age, not by toxins, infections, or lifestyle. No occupational or exposure risk factors have been reported.

Protective factors. No genetic or environmental protective factors have been identified. Reduced penetrance in some carriers implies the existence of modifiers, but none have been mapped.

Gene–environment interactions. No specific gene–environment interactions have been documented for MPD6. Mechanical loading (eccentric contraction) is biologically plausible as an aggravating factor given the Z-disk's role as the structure most vulnerable to eccentric damage [PMID: 21536590], but this remains inferred, not demonstrated, for MPD6.

3. Phenotypes

MPD6 phenotypes are clinical signs and physical manifestations of skeletal muscle weakness, with supporting laboratory/imaging abnormalities. The phenotype is genotype-dependent and ranges from asymptomatic to limb-girdle weakness with facial involvement [PMID: 39812845].

Phenotype	Type	Onset	Severity / progression	Frequency	Suggested HPO
Distal lower-limb weakness (ankle dorsiflexion / foot drop)	Clinical sign	Adult	Progressive; initial site	Characteristic, near-universal at onset	HP:0009053 (distal lower limb muscle weakness); HP:0009027 (ankle weakness)
Asymmetric muscle weakness	Clinical sign	Adult	Progressive	Common	asymmetry of HP:0003701 (proximal muscle weakness)
Proximal spread / limb-girdle weakness	Clinical sign	Later in course	Progressive	Genotype-dependent	HP:0003701 (proximal muscle weakness)
Facial weakness	Clinical sign	Variable	Variable	Some genotypes	HP:0030319 (facial palsy/weakness)
Gait disturbance / difficulty walking	Physical manifestation	Adult	Progressive	Common	HP:0001288 (gait disturbance)
Z-line disorganization / cores on biopsy	Lab (histology)	—	—	Present but non-specific	core myopathy features / HP:0003557 (increased fiber-diameter variability)
Cardiac involvement	Clinical sign	—	—	Not common	HP:0001638 (cardiomyopathy) — usually absent
Respiratory involvement	Clinical sign	—	—	Not common	HP:0002093 (respiratory insufficiency) — usually absent

The founding cohort described "adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles" [PMID: 30900782]. The larger 37-patient cohort confirmed that "the clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common." [PMID: 39812845].

Quality-of-life impact. Progressive foot drop and distal weakness impair gait, balance, and mobility, typically necessitating ankle-foot orthoses; proximal spread compromises stair climbing, rising from a chair, and daily activities. No disease-specific EQ-5D/SF-36/PROMIS data are published for MPD6; QoL impact is inferred to be moderate and progressive but non–life-limiting, given the usual sparing of cardiac and respiratory function.

4. Genetic / Molecular Information

Causal gene. ACTN2 (alpha-actinin-2), HGNC:164, NCBI Gene 88, chromosome 1q42–1q43, encoding UniProt P35609. ACTN2 is highly expressed in cardiac and skeletal muscle, is located in the sarcomere Z-disk, and links anti-parallel actin filaments while binding N-terminal titin — thereby contributing to sarcomere stability [PMID: 36116040].

Pathogenic variants.

Variant (protein)	cDNA	Type	Inheritance / phenotype	Population / note
p.Ile134Asn	—	Missense	Dominant distal/LGMD	Belgian founder (shared haplotype) [PMID: 39812845]
p.Cys487Arg	—	Missense	Dominant distal/LGMD	Basque-Spanish founder (shared haplotype) [PMID: 39812845]
p.Phe835Serfs*66	c.2504delT	Frameshift, C-terminal extension	Dominant, distal myopathy w/ multi-minicores	Aggregation-forming [PMID: 34170073]
p.Arg506Gly	c.1516A>G	Missense (biallelic)	Recessive (distinct entity)	Palestinian founder [PMID: 38311799]
c.1840-2A>T	—	Splice-site	Expands spectrum	[PMID: 36116040]

Variant classification (ACMG/AMP). Founder and cosegregating variants are classified pathogenic/likely pathogenic based on segregation and functional data. However, the ACTN2 mutation-update review cautions that "limited segregation and functional data are available to support the pathogenicity of most previously reported missense variants and clear-cut genotype-phenotype correlations are currently only demonstrated for some ACTN2-related myopathies." [PMID: 36116040] — i.e., many ACTN2 missense changes remain VUS.

Variant types: predominantly missense (dominant distal/LGMD and recessive forms) and frameshift with C-terminal protein extension (dominant, aggregation-prone). Congenital "Multiple structured Core Disease" (MsCD) arises from de novo missense and deletion variants [PMID: 30701273].

Allele frequency. Pathogenic ACTN2 MPD6 variants are private/rare and essentially absent or ultra-rare in gnomAD, consistent with a highly penetrant dominant disease allele. (By contrast, the ACTN3 R577X null polymorphism is common in ~20% of the general population — a different gene [PMID: 21536590].)

Somatic vs germline: germline (inherited, autosomal dominant). De novo germline events cause the congenital MsCD phenotype.

Functional consequences. The dominant distal disease acts through a toxic gain-of-function / dominant-negative mechanism (aggregation), not haploinsufficiency. Frameshift, protein-extending variants form alpha-actinin-2 aggregates [PMID: 39095936]; a specific frameshift increased alpha-actinin-2 expression and produced abnormal Z-line organization [PMID: 34170073]. For an MsCD missense variant, mutant protein localized correctly to the Z-line with unaltered levels, arguing against haploinsufficiency for that variant [PMID: 30701273].

Modifier genes. None specifically mapped for MPD6. Biologically, the paralog ACTN3 modulates Z-disk composition and elastic properties (loss of alpha-actinin-3 up-regulates alpha-actinin-2 and changes Z-disk protein interactions) [PMID: 21536590], making ACTN3 genotype a plausible but unproven modifier.

Epigenetic information / chromosomal abnormalities. No disease-specific DNA-methylation, histone-modification, or large-scale chromosomal abnormalities have been reported for MPD6. It is a point-mutation/small-indel disorder.

5. Environmental Information

Environmental factors: None established. MPD6 is a monogenic disease with no known toxic, radiation, pollution, or occupational contributors.

Lifestyle factors: None established as causal. Physical activity involving eccentric loading could theoretically stress a compromised Z-disk (inferred from Z-disk vulnerability to eccentric damage [PMID: 21536590]), but no clinical evidence links lifestyle to MPD6 onset or progression.

Infectious agents: Not applicable — MPD6 has no infectious etiology.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

A heterozygous ACTN2 variant (missense, or frameshift causing a C-terminal protein extension) is inherited in the germline → leads to production of a structurally altered alpha-actinin-2 protein.
The altered protein results in reduced solubility and thermal destabilization of the alpha-actinin-2 molecule (demonstrated for actin-binding-domain substitutions) [PMID: 42481460] → promotes misfolding.
Misfolded/protein-extended alpha-actinin-2 leads to formation of alpha-actinin-2 aggregates within the muscle fiber (demonstrated for dominant protein-extending frameshift variants; not seen for recessive missense variants) [PMID: 39095936].
Branch A (dominant distal / frameshift): aggregation + increased alpha-actinin-2 expression → abnormal Z-line organization [PMID: 34170073].
Branch B (congenital MsCD missense/deletion): mutant protein incorporates at the Z-line and results in sarcomeric disorganization and cores with Z-line defects even without detectable aggregation [PMID: 30701273].
Z-line disorganization and core formation result in impaired sarcomere structural integrity and contractile force (impaired muscle force demonstrated in AAV-transduced mouse muscle; motor deficits in zebrafish) [PMID: 30701273].
Chronic sarcomeric dysfunction leads to progressive muscle fiber degeneration/loss (the defining feature shared with muscular dystrophies) [PMID: 33458580] — inferred for MPD6 from the dystrophic paradigm and biopsy findings rather than mechanistically dissected.
Fiber loss manifests first in distal lower-limb muscles (ankle dorsiflexors) — producing foot drop — then spreads proximally to limb-girdle muscles, with genotype-dependent severity [PMID: 30900782; PMID: 39812845].

Inferred vs demonstrated: Steps 2–4 are experimentally demonstrated in cell and animal models; the coupling from aggregation to fiber loss (step 5) is inferred.

Mechanistic detail by category

Protein dysfunction (central). Alpha-actinin-2 is an antiparallel homodimer with three domains: an N-terminal actin-binding domain (ABD) comprising two calponin-homology (CH) domains; a central rod of four spectrin-like repeats mediating dimerization; and a C-terminal calmodulin-like domain with EF-hands. Disease variants destabilize the protein: "All variants display reduced solubility, with actin-binding domain (ABD) substitutions showing pronounced thermal instability by differential scanning fluorimetry." [PMID: 42481460], with SEC-MALS/SAXS revealing a strong propensity for aggregation. CH-domain mutations perturb F-actin binding and Z-disc localization/dynamics: "both mutants have reduced F-actin binding affinity … both mutations additionally affect Z-disc localization and dynamic behaviour." [PMID: 27287556]. The dominant misfolding/aggregation is the unifying molecular lesion: "dominant frameshift variants causing a protein extension do form alpha-actinin-2 aggregates. The results suggest that alpha-actinin-2 aggregation is the disease mechanism…" [PMID: 39095936].
Cellular processes. Protein aggregation and proteostatic stress; abnormal Z-line assembly; myofibrillar disarray; fiber-size variability and eventual fiber loss. GO terms: GO:0030018 (Z disc), GO:0006457 (protein folding), GO:0030239 (myofibril assembly), GO:0006936 (muscle contraction).
Molecular pathways / interactions. Alpha-actinin-2 is a Z-disk hub binding actin, titin, and multiple Z-disk partners (ZASP/LDB3, myotilin, telethonin). Disruption of these interactions destabilizes the sarcomere. Beyond structure, the spectrin-repeat domain binds and regulates ion channels (see below) — relevant to ACTN2 cardiac phenotypes but not the primary driver of the skeletal distal myopathy.
Ion-channel / electrophysiological role (cardiac-relevant branch). Alpha-actinin-2 interacts with the cardiac sodium channel Nav1.5: "We identified alpha-actinin-2 as an interacting partner of the cytoplasmic loop connecting domains III and IV of Na(v)1.5 … the spectrin-like repeat domain is essential for binding of alpha-actinin-2 to Na(v)1.5." [PMID: 19943616], and "the interaction with alpha-actinin-2 increases sodium channel density without changing their gating properties" [PMID: 19943616]. This explains why some ACTN2 variants present as idiopathic ventricular fibrillation [PMID: 35975100] — a phenotype distinct from MPD6, in which cardiac involvement is uncommon.
Metabolic changes / immune involvement: No primary metabolic or autoimmune mechanism; MPD6 is a structural sarcomeric proteinopathy, not an inflammatory or metabolic myopathy.
Tissue damage mechanism: Mechanical failure of the Z-disk under contractile load with progressive myofiber degeneration; the Z-disk is the sarcomeric structure most vulnerable to (eccentric) mechanical damage [PMID: 21536590].
Transcriptomics/proteomics: Variant-specific increases in alpha-actinin-2 protein levels have been observed for a frameshift allele [PMID: 34170073]; no comprehensive MPD6 muscle transcriptome/proteome dataset is yet available.

Upstream vs downstream: Upstream = the ACTN2 mutation and consequent protein misfolding/aggregation; downstream = Z-line disorganization → contractile deficit → fiber loss → clinical weakness. Cell type: skeletal muscle fiber (CL:0000188). Biological process GO: GO:0030239 (myofibril assembly), GO:0006936 (muscle contraction).

7. Anatomical Structures Affected

Organ / system level. Primary organ affected: skeletal muscle (musculoskeletal / muscular system). In the dominant distal form, cardiac and respiratory systems are usually spared [PMID: 39812845]. (Cardiac muscle is affected in the separate ACTN2-cardiomyopathy spectrum, not in MPD6.)

Distribution (muscle MRI signature). In the 37-patient cohort, "the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus" [PMID: 39812845]. A machine-learning model found the most differentiating features were involvement of tibialis anterior and gluteus medius with preservation of quadratus femoris [PMID: 39812845]. The recessive form shows selective hamstrings/adductors (thigh) and anterior tibial group/soleus (lower leg) [PMID: 38311799].

Level	Structure	Suggested UBERON / CL / GO
Organ/system	Skeletal muscle (musculoskeletal system)	UBERON:0001134 (skeletal muscle tissue)
Muscle group	Tibialis anterior	UBERON:0001385
Muscle group	Soleus	UBERON:0011906
Muscle group	Gluteus medius/minimus	UBERON:0001500 (gluteal muscle)
Muscle group	Hamstrings	UBERON:0011907 (biceps femoris)
Cell	Skeletal muscle fiber	CL:0000188 (skeletal muscle cell)
Subcellular	Sarcomere Z-disk	GO:0030018 (Z disc)
Subcellular	Myofibril / sarcomere	GO:0030016 (myofibril), GO:0030017 (sarcomere)

Lateralization: Characteristically asymmetric [PMID: 30900782; PMID: 38311799].

8. Temporal Development

Onset. Adult-onset (the "adult-onset" descriptor is part of the disease name). Onset pattern is insidious/chronic, beginning with asymmetric ankle-dorsiflexion weakness (foot drop) [PMID: 30900782]. (De novo ACTN2 variants can cause a congenital core myopathy — MsCD — a distinct, earlier-onset presentation [PMID: 30701273].)

Progression. Slowly progressive. Weakness begins distally in the lower limbs and later spreads proximally to limb-girdle muscles [PMID: 30900782]. Severity is genotype-dependent, spanning asymptomatic carriers to limb-girdle weakness with facial involvement [PMID: 39812845].

Course / duration. Chronic, lifelong, progressive. No relapsing-remitting or episodic pattern; no spontaneous remission. Because cardiac and respiratory systems are usually spared, the course is generally not life-limiting.

Critical periods / intervention windows. No pharmacologic window is defined (no disease-modifying therapy exists). The practical intervention window is symptomatic — orthotic and rehabilitative management once distal weakness begins.

9. Inheritance and Population

Epidemiology. MPD6 is ultra-rare. No formal prevalence/incidence figures are established; knowledge derives from a small number of families. The largest published series comprises 37 patients from 11 families (Spanish and Belgian) [PMID: 39812845]; the founding report described 4 families [PMID: 30900782].

Inheritance. Autosomal dominant (heterozygous ACTN2 variant), with incomplete, age-dependent penetrance and variable, genotype-dependent expressivity [PMID: 39812845]. A biologically and clinically distinct autosomal recessive ACTN2 myopathy exists (biallelic p.Arg506Gly) and must not be conflated with MPD6 [PMID: 38311799].

Penetrance / expressivity. Penetrance is incomplete and age-dependent (asymptomatic adult carriers occur); expressivity ranges from asymptomatic to limb-girdle weakness with facial involvement depending on the specific variant [PMID: 39812845].

Anticipation / mosaicism: No evidence of genetic anticipation (not a repeat-expansion disorder). Germline mosaicism has not been specifically reported.

Founder effects. - p.Ile134Asn — Belgian founder allele (unique shared haplotype indicating common ancestry) [PMID: 39812845]. - p.Cys487Arg — Basque-Spanish founder allele (unique shared haplotype) [PMID: 39812845]. - (Recessive) p.Arg506Gly — Palestinian founder, confirmed by haplotype analysis: "all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families" [PMID: 38311799].

"Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry." [PMID: 39812845].

Consanguinity / carrier frequency. Consanguinity is relevant to the recessive form (Palestinian founder) but not to dominant MPD6. Dominant pathogenic alleles are private/ultra-rare in gnomAD; no meaningful carrier frequency applies to a dominant disease.

Population demographics. Reported families are of Spanish (including Basque), Belgian, and Swedish origin (dominant form) [PMID: 30900782; PMID: 39812845], and Palestinian (recessive form) [PMID: 38311799]. No strong sex bias is reported (autosomal inheritance). Age distribution reflects adult onset.

10. Diagnostics

Genetic testing (definitive). Diagnosis rests on identification of a pathogenic ACTN2 variant. The recommended approach is next-generation sequencing — a distal-myopathy/neuromuscular gene panel (which should include ACTN2 alongside the ~20 dominant distal-myopathy genes such as DNM2, MATR3, VCP, MYOT, LDB3/ZASP, FLNC, TIA1, HNRNPA1, DES, MYH7, TTN) [PMID: 33458580], or whole-exome sequencing with segregation analysis. Single-gene ACTN2 testing is appropriate when the MRI/clinical picture is characteristic or a family variant is known. Because many ACTN2 missense variants remain VUS, segregation and functional evidence are often needed to confirm pathogenicity [PMID: 36116040].

Muscle MRI (key adjunct). A characteristic selective-involvement pattern supports the diagnosis and directs biopsy site: predominant involvement of tibialis anterior, soleus, gluteus medius/minimus, and hamstrings, with relative preservation of quadratus femoris [PMID: 39812845]. Muscle MRI is broadly established as crucial for myopathy diagnosis, biopsy-site selection, and activity assessment [PMID: 41066296].

Muscle biopsy / histopathology. Findings are non-specific (myopathic changes; variability in fiber diameter) but may show Z-line disorganization, cores/multi-minicores, and alpha-actinin-2 aggregates/abnormal Z-line organization [PMID: 34170073; PMID: 30701273]. Immunohistochemistry for alpha-actinin-2 can reveal aggregation.

Laboratory tests. Serum creatine kinase (CK) is typically normal or only mildly elevated (as in many distal myopathies). No specific circulating biomarker exists.

Electrophysiology. EMG shows a myopathic pattern; nerve conduction studies are normal (distinguishing from neuropathy).

Clinical criteria / differential diagnosis. No formal consensus criteria exist; diagnosis integrates adult-onset asymmetric distal (foot-drop) weakness, characteristic MRI, myopathic EMG, supportive biopsy, and a confirmed ACTN2 variant. Differential diagnosis includes other distal myopathies (e.g., Welander, Markesbery-Griggs/ZASP, Udd/titinopathy, GNE myopathy, dysferlinopathy, myofibrillar myopathies) [PMID: 33458580], inclusion body myositis (asymmetric distal/proximal weakness, normal CK possible) [PMID: 37038366], and acquired causes of distal/asymmetric weakness such as vasculitic or inflammatory myopathy [PMID: 37900606; PMID: 33863518].

Omics-based diagnostics: Not routinely used; RNA-seq/proteomics are research tools.

Screening. No population or newborn screening exists (ultra-rare, adult-onset, dominant). Cascade genetic testing of at-risk relatives is appropriate once a familial variant is identified.

11. Outcome / Prognosis

Survival / mortality. Generally not life-limiting in the dominant distal form, because "Cardiac and respiratory involvement were not common." [PMID: 39812845]. No disease-specific mortality data are published.

Morbidity / function. The main burden is progressive mobility impairment from foot drop and distal-to-proximal weakness, often requiring ankle-foot orthoses and, with proximal spread, assistance for stairs and transfers. Facial weakness occurs with some genotypes [PMID: 39812845]. No formal disability/QoL instrument data (EQ-5D, SF-36, PROMIS) are published for MPD6.

Disease course / complications. Slowly progressive weakness; complications are secondary to reduced mobility (falls, deconditioning). Cardiomyopathy and respiratory failure are uncommon in dominant MPD6 [PMID: 39812845] — a key prognostic distinction from ACTN2-cardiomyopathy.

Recovery potential. None — progressive and irreversible; management is supportive, not curative.

Prognostic factors. Genotype is the principal prognostic determinant (asymptomatic → limb-girdle severity is genotype-dependent) [PMID: 39812845]. Aggregation-forming (protein-extending) variants are mechanistically more clearly pathogenic [PMID: 39095936]. No validated prognostic biomarkers exist.

12. Treatment

There is no disease-modifying or curative therapy for MPD6. Management is supportive and rehabilitative.

Supportive / rehabilitative care (mainstay): Ankle-foot orthoses (AFOs) for foot drop; physiotherapy to maintain range of motion and strength; occupational therapy and assistive/mobility devices as proximal weakness develops; fall-prevention. (NCIT: Physical Therapy C15917; Orthotic Device C50094; Rehabilitation Therapy C15326.)
Pharmacotherapy: None disease-specific. No approved drug targets alpha-actinin-2 aggregation.
Advanced therapeutics (none approved; conceptual): For a dominant toxic gain-of-function/aggregation mechanism, allele-selective silencing (antisense oligonucleotides or siRNA targeting the mutant ACTN2 allele) is a rational future strategy — but no clinical trials or NCT identifiers exist for MPD6.
Surgical: None specific; orthopedic interventions (e.g., for contractures) only as needed.
Cardiac/respiratory monitoring: Given that cardiac/respiratory involvement is uncommon [PMID: 39812845] but ACTN2 is a recognized cardiomyopathy gene, baseline cardiac evaluation (ECG/echocardiography) is prudent, individualized to genotype and family history.
Pharmacogenomics / personalized medicine: Not applicable currently; care is genotype-informed mainly for counseling and prognosis.

Treatment outcomes / adverse events: Rehabilitative measures improve function and safety without disease-specific pharmacologic adverse events; no response-rate data from trials exist.

13. Prevention

Primary prevention: Not applicable to an inherited dominant disease beyond reproductive options. Preimplantation genetic testing (PGT) or prenatal diagnosis is possible when a familial pathogenic ACTN2 variant is known.
Secondary prevention: Cascade genetic testing of at-risk relatives enables early identification, counseling, and baseline cardiac assessment.
Tertiary prevention: Rehabilitation, orthotics, fall-prevention, and contracture prevention to limit disability once symptomatic.
Genetic counseling (central): Essential — 50% transmission risk per offspring for a heterozygous carrier; counseling must address incomplete/age-dependent penetrance and variable, genotype-dependent expressivity [PMID: 39812845]. For the distinct recessive ACTN2 myopathy, carrier counseling in founder populations (e.g., Palestinian for p.Arg506Gly) applies [PMID: 38311799].
Immunization / public health / environmental interventions: Not applicable (non-infectious, non-environmental Mendelian disease).

14. Other Species / Natural Disease

Taxonomy / orthologs. ACTN2 is evolutionarily conserved. Model orthologs: mouse Actn2 (Mus musculus, NCBI Taxon 10090; NCBI Gene 11472) and zebrafish actn2 (Danio rerio, NCBI Taxon 7955). Both have been used to model ACTN2 disease [PMID: 30701273].
Natural disease in animals. No well-characterized naturally occurring ACTN2 distal myopathy is documented in companion animals or wildlife (no established OMIA entry for a spontaneous animal actininopathy).
Comparative biology. The conserved Z-disk role of alpha-actinin-2 across vertebrates underlies successful cross-species modeling; wild-type alpha-actinin-2 expression does not cause anomalies, whereas mutant protein produces sarcomeric disorganization in both zebrafish and mouse — demonstrating conservation of the disease mechanism [PMID: 30701273].
Transmission / zoonosis: Not applicable.

15. Model Organisms

Model	Type	Genetic approach	Key phenotype recapitulated	Reference
Zebrafish (Danio rerio)	Vertebrate, in vivo	Exogenous expression of mutant alpha-actinin-2	Motor deficits; sarcomeric disorganization	[PMID: 30701273]
Mouse (Mus musculus)	Mammalian, in vivo	AAV-mediated expression of mutant ACTN2 in muscle	Impaired muscle force; cores and Z-line defects; sarcomeric disorganization	[PMID: 30701273]
C2C12 myoblasts/myotubes	Cellular, in vitro	Expression of ACTN2 variants	Alpha-actinin-2 aggregates (dominant frameshift); no aggregates (recessive missense)	[PMID: 39095936]
Cultured myotubes	In vitro	MsCD missense variant	Correct Z-line localization, unaltered levels (argues against haploinsufficiency)	[PMID: 30701273]

Phenotype recapitulation. Animal models faithfully reproduce the human structural pathology: "Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice." [PMID: 30701273], and "In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects." [PMID: 30701273]. The C2C12 model recapitulates the dominant aggregation mechanism and distinguishes it from recessive variants [PMID: 39095936].

Limitations. Existing models use exogenous/overexpression of mutant protein (zebrafish, AAV-mouse) rather than physiological knock-in at endogenous levels; they capture structural pathology and force deficits but not the slow adult-onset, distal-predominant progression seen in patients. No germline knock-in mouse recapitulating adult-onset distal MPD6 has been reported.

Mechanistic Model / Interpretation

  Heterozygous ACTN2 variant (missense OR C-terminal-extending frameshift)
              │  (germline, autosomal dominant)
              ▼
      Structurally altered alpha-actinin-2  →  reduced solubility,
              │                 thermal destabilization  [42481460]
              ▼
MISFOLDING  ── branch A (dominant frameshift/extension) ──► Z-disk AGGREGATES [39095936, 34170073]
    │                                              + increased ACTN2 expression
    └─ branch B (congenital MsCD missense/del) ──► correct Z-line targeting,
                                                   but CORES + Z-line defects [30701273]
              │
              ▼
      Z-line disorganization / impaired sarcomere integrity
              ▼
      ↓ contractile force  (mouse force deficit; zebrafish motor deficit) [30701273]
              ▼
      Progressive myofiber degeneration & loss  [33458580 — dystrophic paradigm; inferred]
              ▼
   ASYMMETRIC DISTAL LOWER-LIMB WEAKNESS (foot drop) → proximal/limb-girdle spread
              │  (genotype-dependent severity) [30900782, 39812845]
              ▼
      Usually SPARES heart & respiration [39812845]

  ── Parallel (cardiac-relevant, NOT primary in MPD6) ──
  Spectrin-repeat domain binds Nav1.5 → modulates Na+ channel surface density [19943616]
   → some ACTN2 variants → arrhythmia / idiopathic VF [35975100]

Synthesis. MPD6 is best understood as a dominant sarcomeric proteinopathy of the Z-disk. The unifying lesion is a destabilized alpha-actinin-2 that misfolds and — for dominant protein-extending alleles — aggregates, poisoning Z-disk assembly (a dominant-negative/toxic gain-of-function effect rather than simple loss of function). This distinguishes MPD6 both from the recessive ACTN2 myopathy (missense, non-aggregating, distinct phenotype and Palestinian founder) [PMID: 38311799] and from ACTN2 cardiomyopathy/arrhythmia, where the protein's separate ion-channel–scaffolding role via its spectrin-repeat domain becomes pathogenically relevant [PMID: 19943616; PMID: 35975100]. The single gene ACTN2 thus produces a spectrum — dominant distal MPD6, congenital MsCD, recessive myopathy, and cardiomyopathy — whose divergent phenotypes track with variant type, domain location, aggregation propensity, and zygosity.

Evidence Base

PMID	Study	Role in this report
30900782	Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations (Savarese et al.)	Defining paper — dominant ACTN2 missense variants, adult-onset asymmetric distal phenotype, disease concept
39812845	Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy (Iruzubieta et al.)	Largest cohort (37 pts/11 families) — genotype-dependent phenotype, MRI signature, founder alleles, cardiac/respiratory sparing
39095936	Protein-extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation	Establishes aggregation as the dominant mechanism (frameshift aggregates; recessive missense do not)
34170073	A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores	Independent family: increased ACTN2, abnormal Z-line, aggregate formation
30701273	ACTN2 mutations cause "Multiple structured Core Disease" (MsCD) (Lornage et al.)	Zebrafish + mouse models; cores/Z-line defects; argues against haploinsufficiency for MsCD variant
42481460	Comprehensive biophysical/structural profiling of alpha-actinin-2 variants (Noureddine et al.)	Variant destabilization, reduced solubility, aggregation propensity
27287556	HCM mutations in the CH domain of ACTN2 affect actin binding and Z-disc incorporation	CH-domain variants alter actin binding and Z-disc dynamics
19943616	Cell membrane expression of Nav1.5 is modulated by alpha-actinin-2 interaction (Ziane et al.)	Spectrin-repeat/Nav1.5 interaction → cardiac electrophysiology branch
35975100	Novel ACTN2 missense variant associated with idiopathic VF	ACTN2 arrhythmia phenotype (distinct from MPD6)
38311799	Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy	Distinct recessive entity; Palestinian founder
36116040	Mutation update for the ACTN2 gene	Domain/localization biology; caution on VUS and genotype–phenotype correlations
33458580	Panorama of the distal myopathies	Nosology; ACTN2 among ~20 dominant distal-myopathy genes; dystrophic paradigm
21536590	α-actinin-3 deficiency and contraction-induced damage	Z-disk vulnerability to eccentric damage; ACTN2/ACTN3 Z-disk biology (modifier plausibility)
41066296	Myopathies: Radiologist's essential tips	Role of muscle MRI in myopathy diagnosis/biopsy targeting

Evidence source types: human clinical/genetic (30900782, 39812845, 34170073, 38311799, 35975100, 36116040); in vivo model organism (30701273 — zebrafish/mouse); in vitro cell/biophysical (39095936, 42481460, 27287556, 19943616); review/nosology (33458580, 41066296, 21536590).

Limitations and Knowledge Gaps

Small evidence base. The entire dominant-disease literature rests on a handful of families (largest series 37 patients) [PMID: 39812845]; prevalence, incidence, sex ratio, and natural-history metrics are not formally established.
VUS burden. Many ACTN2 missense variants lack segregation/functional confirmation; genotype–phenotype correlations are demonstrated for only some variants [PMID: 36116040].
Mechanistic gap (aggregation → fiber loss). The step from Z-disk aggregation to progressive myofiber degeneration is inferred from the dystrophic paradigm, not dissected in MPD6 muscle.
Model limitations. Existing zebrafish/mouse models rely on overexpression rather than endogenous knock-in and do not reproduce the slow, adult-onset, distal progression [PMID: 30701273].
No omics datasets. No published MPD6-specific transcriptomic, proteomic, or single-cell datasets exist.
No QoL / outcome instruments. No EQ-5D/SF-36/PROMIS or validated functional-outcome data for MPD6.
No therapeutics. No disease-modifying treatment, biomarker, or clinical trial (no NCT) exists.

Proposed Follow-up Experiments / Actions

Generate an endogenous knock-in mouse for a recurrent dominant allele (e.g., p.Cys487Arg or a protein-extending frameshift) to model adult-onset distal progression and test disease-modifying strategies.
Allele-selective silencing proof-of-concept. Test mutant-allele–specific ASO/siRNA in patient iPSC-derived myotubes and knock-in models, given the dominant aggregation mechanism [PMID: 39095936].
Aggregation-focused biomarkers. Quantify alpha-actinin-2 aggregate load and proteostatic-stress markers in patient biopsies as candidate progression biomarkers.
Multi-omics of patient muscle. Bulk/single-nucleus RNA-seq and proteomics of affected vs preserved muscles (guided by the MRI signature [PMID: 39812845]) to map downstream degeneration pathways.
Prospective natural-history registry with standardized MRI (tibialis anterior/soleus/gluteus medius scoring) and functional outcomes to define progression rate and penetrance curves.
Systematic variant reclassification. Combine biophysical destabilization/aggregation assays [PMID: 42481460] with segregation data to resolve ACTN2 VUS.
Cardiac surveillance study. Prospectively assess subclinical cardiac/electrophysiologic involvement across MPD6 genotypes, given alpha-actinin-2's Nav1.5-scaffolding role [PMID: 19943616].

Ontology Term Quick-Reference

Disease: MONDO:0014138; OMIM:615197
Gene/protein: ACTN2 (HGNC:164, NCBI Gene 88); UniProt P35609
Phenotype (HPO): HP:0009053 (distal lower limb muscle weakness), HP:0003701 (proximal muscle weakness), HP:0001288 (gait disturbance), HP:0030319 (facial weakness), HP:0001638 (cardiomyopathy — usually absent)
Cell (CL): CL:0000188 (skeletal muscle cell / myofiber)
Anatomy (UBERON): UBERON:0001134 (skeletal muscle tissue), UBERON:0001385 (tibialis anterior), UBERON:0011906 (soleus), UBERON:0001500 (gluteal muscle)
Subcellular / process (GO): GO:0030018 (Z disc), GO:0030016 (myofibril), GO:0030239 (myofibril assembly), GO:0006457 (protein folding), GO:0006936 (muscle contraction)
Treatment (NCIT): C15917 (Physical Therapy), C50094 (Orthotic Device), C15326 (Rehabilitation Therapy)

Report compiled from 5 completed investigation iterations, 30 reviewed papers, and 8 confirmed findings. All quoted statements are verbatim from the cited PubMed abstracts.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	17
On topic	12
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	23
Resolved	21
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	17
Terms named correctly	11
Terms named as a different term	3
Terms whose name is worth a second look	3

Terms the report names something else

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

MONDO:0014138 (3 mentions) - the report calls it "Mondo"; MONDO calls it nemaline myopathy 8
UBERON:0011906 (2 mentions) - the report calls it "Soleus", "soleus"; UBERON calls it muscle head
UBERON:0011907 (1 mention) - the report calls it "biceps femoris"; UBERON calls it gastrocnemius medialis

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:0001638 (2 mentions) - the report calls it "cardiomyopathy — usually absent"; HP calls it Cardiomyopathy
CL:0000188 (3 mentions) - the report calls it "skeletal muscle cell / myofiber"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
UBERON:0001500 (2 mentions) - the report calls it "gluteal muscle"; UBERON calls it muscle of manus, and lists "hand muscle" among its other names

Terms named inconsistently

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

UBERON:0001385 - called "Tibialis anterior", "tibialis anterior"
UBERON:0011906 - called "Soleus", "soleus"

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: OMIM.

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3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Distal Myopathy 6, Adult-Onset, Autosomal Dominant

Executive summary

1. Disease information

Definition and identifiers

2. Etiology

Causal and genetic risk factors

Environmental, protective, and gene–environment factors

3. Phenotypes

4. Genetic and molecular information

Gene and variants

Allelic disorders and modifiers

5. Environmental information

6. Mechanism and pathophysiology

Proposed causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended workflow

Differential diagnosis

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms and research systems

Recent developments and expert assessment

Key source record and abstract wording

Artifacts

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)