🔗

Mappings

MONDO

MONDO:0008070 congenital myopathy 2a, typical, autosomal dominant

Primary MONDO identifier for this entry. MONDO:0008070 is the MONDO class for OMIM 161800 (NEM3 / CMYO2A); its textual definition is gene-level ("An inherited myopathy caused by mutations in the ACTA1 gene"), and MONDO files it beneath four severity bands of nemaline myopathy at once, which is the scope this entry takes.

MONDO:0100084 alpha-actinopathy Not Yet Curated

alpha-actinopathy is MONDO's umbrella for the whole ACTA1 phenotypic spectrum, including the non-nemaline histologies (actin filament aggregate myopathy, congenital fibre-type disproportion, core-like areas, cap myopathy, zebra body myopathy) that this entry does not cover.

MONDO:0018958 nemaline myopathy DisMech

The genetically heterogeneous parent disease curated at kb/disorders/Nemaline_Myopathy.yaml, which cuts the same patients on the severity axis rather than the gene axis.

👪

Inheritance

2

Autosomal Dominant HP:0000006

About 90% of ACTA1 variants cause dominant disease, and most affected individuals are simplex cases carrying a de novo missense variant that is absent from parental blood. Recurrence in a sibship after an apparently de novo variant is a real risk because parental somatic and germline mosaicism has been documented, and a mildly affected or asymptomatic mosaic parent may carry the same allele that is lethal in the proband. Expressivity is variable: age at onset and severity differ markedly between carriers of the same variant, including between affected members of one family, so ACTA1 genotype alone does not predict the clinical course.

Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: 84% of sporadic patients with parental testing available

Show evidence (6 references)

PMID:19562689 SUPPORT Human Clinical

"Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations."

States the dominant/recessive split and the predominance of de novo dominant variants.

PMID:19562689 SUPPORT Human Clinical

"Where DNA has been available for testing from the parents of sporadic patients, 79/94 or 84% had de novo dominant mutations not present in the peripheral blood DNA of either parent, while only 16% had recessive ACTA1 mutations."

Source of the 84% de novo figure recorded on this inheritance block.

PMID:19562689 SUPPORT Human Clinical

"There have been a number of instances where a severely affected proband was identified, and mildly affected or asymptomatic family members were found to carry the same dominant mutation. In at least three cases this can be explained by somatic mosaicism in one parent of a severely affected patient"

Supports the parental-mosaicism recurrence risk that qualifies an apparently de novo result in counselling.

+ 3 more references

Autosomal Recessive HP:0000007

Roughly 10% of ACTA1 variants cause recessive disease. These are nonsense, frameshift or splice-site alleles, or one of four buried missense changes shown to be functional nulls, so affected individuals have no functional skeletal muscle alpha-actin. Heterozygous parents and siblings are clinically unaffected, and the sibling recurrence risk is 25%.

Autosomal recessive inheritance Penetrance: COMPLETE

Show evidence (2 references)

PMID:19562689 SUPPORT Human Clinical

"Most recessive ACTA1 mutations are nonsense, frameshift or splice-site mutations, and are predicted to cause premature termination of translation, or the omission of entire exons from the mRNA, leading to absence of skeletal α-actin protein"

Establishes the null-allele basis of recessive ACTA1 disease.

PMID:19562689 SUPPORT Human Clinical

"Heterozygous mutation carriers (parents or siblings of patients with recessive ACTA1 mutations) were clinically unaffected, suggesting that expression from one intact copy of ACTA1 is sufficient for normal function"

Supports unaffected-carrier status of heterozygous parents, and so a 25% sibling recurrence risk in recessive families.

◆

Subtypes

2

Dominant (poison mutant actin) ACTA1 disease

Approximately 90% of ACTA1 disease. A heterozygous, usually de novo, missense variant is expressed and the mutant protein is incorporated into the thin filament alongside wild-type alpha-actin, so the mechanism is a dominant-negative or "poison peptide" one rather than haploinsufficiency. Severity ranges from lethal neonatal disease to mild childhood-onset weakness and depends in part on the proportion of mutant protein present.

Show evidence (2 references)

PMID:22825594 SUPPORT REVIEW SYNTHESIS Human Clinical

"Approximately 200 different ACTA1 mutations have been identified, with 90 % resulting in dominant disease and 10 % resulting in recessive disease."

Quantifies the dominant share of ACTA1 disease that defines this subtype.

PMID:23736297 SUPPORT BACKGROUND Human Clinical

"Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein."

States the poison-peptide mechanism that distinguishes this subtype from the recessive one.

Recessive (null) ACTA1 disease

Approximately 10% of ACTA1 disease. Recessive alleles reported up to 2009 were biallelic genetic or functional nulls, so no functional skeletal muscle alpha-actin was made; cardiac alpha-actin, which is 99% identical and is the predominant sarcomeric actin in fetal muscle, is the isoform available to substitute for it and is the basis of the isoform-replacement therapeutic strategy. That generalisation is no longer complete: homozygous missense variants preserving skeletal alpha-actin expression have since been reported in brothers with congenital muscular dystrophy with rigid spine and dystrophic biopsy features, which the authors describe as a new class of recessive ACTA1 variant.

Show evidence (4 references)

PMID:19562689 SUPPORT Human Clinical

"All patients with recessive ACTA1 disease therefore lack functional skeletal muscle α-actin"

Defines this subtype as complete absence of functional skeletal muscle alpha-actin.

PMID:23736297 SUPPORT BACKGROUND Other

"Cardiac α-actin is 99% identical to skeletal muscle α-actin and the predominant actin isoform in fetal muscle."

Supports the cardiac alpha-actin substitution rationale specific to the null subtype.

PMID:25182138 SUPPORT Human Clinical

"All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth."

States the null generalisation this subtype was defined by.

+ 1 more reference

?

Discussions and Knowledge Gaps

1

Why do ACTA1 variants cause muscle weakness, and what determines which structural lesion — nemaline rods, actin aggregates, intranuclear rods, fibre-type disproportion — a given variant produces?

KNOWLEDGE GAP acta1_lesion_specificity_mechanism

Attached to

pathophysiology#Defective Actin-Tropomyosin Regulation pathophysiology#Sarcomeric Disorganisation pathophysiology#Nemaline Rod Formation

Despite two decades of work in cell culture, animal models and patient tissue, the mechanism linking mutant alpha-actin to weakness and to a particular structural lesion is not established, and single biopsies frequently show several lesions at once. This is why the histological boundary of this entry is a convention rather than a mechanistic distinction, and why genotype does not predict phenotype.

Show evidence (1 reference)

PMID:22825594 SUPPORT REVIEW SYNTHESIS Human Clinical

"Despite extensive research into normal actin function and the functional consequences of ACTA1 mutations in cell culture, animal models and patient tissue, the mechanisms underlying muscle weakness and the formation of structural lesions remains largely unknown."

States the gap directly.

⚙

Pathophysiology

11

ACTA1 Variant in Skeletal Muscle Alpha-Actin

A pathogenic variant in ACTA1 alters skeletal muscle alpha-actin, the predominant actin isoform of the adult sarcomeric thin filament. The gene is small — six coding exons over 2.8 kb — and variants are distributed across all of them without hotspots, so essentially any coding residue may be involved. The overwhelming majority are missense changes at residues conserved across the actin family.

ACTA1 hgnc:129

Genetic context variant_origin: DE_NOVO functional_impact_category: DOMINANT_NEGATIVE

Most dominant ACTA1 variants are de novo missense changes and act as dominant-negative "poison" alleles; the minority recessive alleles are instead genetic or functional nulls and are modelled by the separate node below.

actin filament binding GO:0051015 ↕ DYSREGULATED

Downstream

Incorporation of Mutant Alpha-Actin into the Thin Filament The mutant allele is transcribed and translated, and the mutant protein enters the sarcomere rather than being degraded.

Show evidence (2 references)

PMID:19562689 SUPPORT Human Clinical

"The ACTA1 gene encodes skeletal muscle alpha-actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction."

Establishes the gene product and its sarcomeric role, which is what the variant perturbs.

PMID:19562689 SUPPORT Human Clinical

"The 177 mutations comprise 157 missense, 5 nonsense, 5 frameshift and 4 splice site mutations, 1 in-frame duplication, 1 insertion of a single amino-acid, 1 in-frame single amino-acid deletion and 3 mutations of the normal stop codon."

Documents the predominance of missense alleles in the ACTA1 variant spectrum.

Incorporation of Mutant Alpha-Actin into the Thin Filament

Mutant alpha-actin polymerises into F-actin together with wild-type protein and is incorporated into the thin filament, where it acts as a poison peptide. In patient muscle the mutant species accounts for a quarter to a half of total alpha-skeletal actin, and the severity of dominant disease tracks with how much mutant protein is present.

skeletal muscle fiber CL:0008002

ACTA1 hgnc:129

actin filament polymerization GO:0030041 ↕ DYSREGULATED

Downstream

Defective Actin-Tropomyosin Regulation

Sarcomeric Disorganisation In most ACTA1 nemaline myopathy biopsies, but not in the fibre-type-disproportion variants, incorporation of the mutant protein is accompanied by breakdown of the sarcomeric lattice.

Nemaline Rod Formation

Mitochondrial Dysfunction in ACTA1-Mutant Myofibres

Nuclear Envelope and LINC Complex Disruption In severe disease the mutant protein's effects extend beyond the sarcomere to the nuclear envelope.

Show evidence (2 references)

PMID:23736297 SUPPORT BACKGROUND Human Clinical

"Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein."

States the poison-peptide model for this node.

PMID:11333380 SUPPORT Human Clinical

"In skeletal muscle, actin function depends on the balance between monomeric G-actin (globular) and filamentous F-actin, a polymer of G-actin subunits. F-actin, together with tropomyosin, troponin, and nebulin, forms the thin filaments of the skeletal-muscle contractile apparatus."

Describes the polymerisation step and thin-filament assembly that the mutant protein enters.

Absence of Functional Skeletal Muscle Alpha-Actin

In recessive ACTA1 disease no functional skeletal muscle alpha-actin is produced. The sarcomere is not poisoned by an abnormal protein but is deprived of its principal thin-filament subunit, and cardiac alpha-actin — normally downregulated late in the second trimester — is the isoform available to substitute for it.

skeletal muscle fiber CL:0008002

ACTA1 hgnc:129

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Animal models

Acta1 knock-out mouse Mouse recapitulates Complete absence of skeletal muscle alpha-actin, as in human recessive null disease.

Downstream

Reduced Skeletal Muscle Force Generation A sarcomere deprived of its principal thin-filament subunit converges on the same contractile failure the poison-peptide route produces, by a different molecular route. The recessive route is deliberately not drawn through `Defective Actin-Tropomyosin Regulation`: a null allele makes no mutant actin that could mis-regulate tropomyosin, so that node describes the dominant mechanism only.

Show evidence (2 references)

PMID:19562689 SUPPORT Human Clinical

"Most recessive ACTA1 mutations are nonsense, frameshift or splice-site mutations, and are predicted to cause premature termination of translation, or the omission of entire exons from the mRNA, leading to absence of skeletal α-actin protein"

Establishes absence of the protein as the recessive mechanism.

PMID:19562689 SUPPORT Human Clinical

"Although skeletal muscle α-actin is the predominant isoform in adult skeletal muscle, cardiac α-actin (the major actin isoform expressed in the adult heart) is the major actin expressed in skeletal muscle during early gestation, but is downregulated late in the second trimester, and usually at..."

Supports the developmental isoform switch that leaves the null sarcomere without a substitute after birth.

Defective Actin-Tropomyosin Regulation

Incorporated mutant alpha-actin interacts abnormally with tropomyosin, which is held over the myosin-binding site of the thin filament in the "switched off" position, so fewer myosin heads bind actin when the fibre is activated. This is a regulatory defect of an intact thin filament and is separable from structural breakdown of the sarcomere: the ACTA1 variants that produce congenital fibre-type disproportion carry the actin-tropomyosin defect while sarcomeric structure on electron microscopy stays normal. Because it requires mutant protein in the filament, it describes the dominant poison-peptide mechanism and not the recessive null one.

muscle filament sliding GO:0030049 ↓ DECREASED

tropomyosin binding GO:0005523 ↕ DYSREGULATED

Downstream

Reduced Skeletal Muscle Force Generation

Show evidence (2 references)

PMID:17387733 SUPPORT In Vitro

"In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position."

Identifies the actin-tropomyosin regulatory defect that defines this node, measured by in vitro motility assay.

PMID:17387733 SUPPORT Human Clinical

"Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM."

Shows the regulatory defect occurring with normal sarcomeric structure, which is why this node is separate from Sarcomeric Disorganisation rather than bundled with it.

Sarcomeric Disorganisation

In most ACTA1 nemaline myopathy fibres the sarcomeric lattice itself breaks down, with whorled thin filaments, myofibrillar disruption and mislocalised sarcomeric actin. Severity of the structural disorganisation, rather than the number of rods, is what tracks with the lethal phenotype, and unlike the regulatory defect above it is reached by both the poison-peptide and the null route.

skeletal muscle fiber CL:0008002

sarcomere organization GO:0045214 ↓ DECREASED

Downstream

Reduced Skeletal Muscle Force Generation

Show evidence (2 references)

PMID:11333380 SUPPORT Human Clinical

"The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin."

Establishes sarcomeric disorganisation rather than rod burden as the correlate of severity.

PMID:11333380 SUPPORT Human Clinical

"Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments."

Documents the thin-filament and myofibrillar disorganisation described by this node.

Nemaline Rod Formation

Nemaline bodies are rod-shaped aggregates that arise from the sarcomeric Z-disk and are rich in alpha-actinin. In ACTA1 disease they may be sarcoplasmic, intranuclear, or both; intranuclear rod myopathy is a variant of nemaline myopathy defined by rods inside myonuclei and is often, though not always, severe. Rod burden does not predict clinical severity, so this node is the diagnostic lesion rather than a step on the causal path to weakness.

skeletal muscle fiber CL:0008002

Downstream

Nemaline Bodies on Muscle Biopsy Rod formation is what the diagnostic biopsy finding observes.

Show evidence (2 references)

PMID:11333380 SUPPORT Human Clinical

"Nemaline bodies (rods) are clearly detectable at the light-microscopy (LM) level, and, ultrastructurally, they originate from the Z-disks of the sarcomeres. One of the main components of rods is α-actinin 2, an actin-binding protein that localizes to the Z-disk"

Establishes the Z-disk origin and alpha-actinin composition of the rods.

PMID:19562689 SUPPORT Human Clinical

"Intranuclear rod myopathy is a variant of nemaline myopathy characterised histologically by rod-like bodies in the nuclei of muscle fibres"

Supports treating intranuclear rod myopathy as in scope for this entry rather than as a separate ACTA1 entity.

Nuclear Envelope and LINC Complex Disruption

In severe ACTA1 disease the pathology extends to the myonucleus: the perinuclear space is enlarged and lamin A/C, nesprin-1 and nesprin-2 — the LINC complex components that tether the nucleus to the cytoskeleton — are mislocalised. This implies a physiological role for skeletal muscle alpha-actin in maintaining nuclear shape that is lost when the mutant protein is present. Intranuclear rods are recorded on the Nemaline Rod Formation node rather than here, because the available evidence shows them co-occurring with this nuclear pathology in severe biopsies and does not establish that envelope disruption produces them.

skeletal muscle fiber CL:0008002

Show evidence (2 references)

PMID:35810298 SUPPORT Human Clinical

"We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape."

Identifies perinuclear space enlargement and a nuclear-shape role for skeletal muscle alpha-actin.

PMID:35810298 SUPPORT Human Clinical

"In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity."

Documents the nuclear lamina and LINC complex mislocalisation described by this node.

Mitochondrial Dysfunction in ACTA1-Mutant Myofibres

ACTA1-mutant skeletal myocytes carry a cell-autonomous bioenergetic defect: cellular ATP falls, mitochondrial membrane potential is altered, permeability transition pore formation and superoxide production rise, and supplying ATP protects the mitochondria from stress-induced injury. The evidence comes from isogenic H40Y iPSC-derived myocytes rather than from patient muscle, so this is a candidate contributor to the contractile deficit and not an established step in it.

skeletal muscle fiber CL:0008002

ATP metabolic process GO:0046034 ↓ DECREASED regulation of mitochondrial membrane potential GO:0051881 ↕ DYSREGULATED

Experimental models

ACTA1 H40Y iPSC-derived skeletal myocytes IPSC DERIVED MODEL The model observes the node's own quantities — cellular ATP, mitochondrial membrane potential, permeability transition pore formation and superoxide — at the cellular scale the node is tagged with, in isogenic lines differing only at the ACTA1 locus.

Downstream

Reduced Skeletal Muscle Force Generation Loss of ATP supply is a candidate contributor to the contractile deficit. No measurement of force in this system exists, so the step is asserted as a possibility rather than as a demonstrated cause.

Show evidence (2 references)

PMID:36796746 SUPPORT In Vitro

"Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."

Reports the two measurements this node is bound to, in isogenic ACTA1 H40Y myocytes.

PMID:36796746 SUPPORT In Vitro

"Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."

The authors' own summary, including the ATP-rescue result that identifies the defect as bioenergetic.

Reduced Skeletal Muscle Force Generation

The functional endpoint of both molecular routes is loss of contractile force. In the Acta1 p.Asp286Gly mouse, which carries a patient-derived dominant variant, contractile capacity at submaximal stimulation frequencies is reduced and can be pharmacologically increased with a fast skeletal troponin activator, which identifies reduced thin-filament calcium sensitivity as a tractable component of the deficit.

skeletal muscle fiber CL:0008002

skeletal muscle contraction GO:0003009 ↓ DECREASED

Animal models

Acta1 p.Asp286Gly knock-in mouse Mouse recapitulates Reproduces the submaximal force deficit of dominant ACTA1 disease in limb and diaphragm muscle, and responds to pharmacological calcium sensitisation.

Downstream

Hypotonia

Proximal Muscle Weakness

Facial Muscle Weakness

Neck Flexor Weakness

Respiratory Muscle Weakness and Ventilatory Failure

Bulbar Weakness and Feeding Difficulty

Motor Developmental Delay

Arthrogryposis Multiplex Congenita When the contractile deficit is severe enough to be present in utero, reduced fetal movement leads to fixed joint contractures at birth.

Scoliosis Chronic axial and paraspinal weakness allows progressive spinal deformity in survivors.

Show evidence (3 references)

PMID:29328520 SUPPORT Human Clinical

"Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force-generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils."

Direct measurement of reduced force-generating capacity in muscle from 14 patients with ACTA1 variants, which is the strongest human evidence for this node.

PMID:29328520 SUPPORT Human Clinical

"Low angle X-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length."

Identifies the structural basis of the force deficit as fewer myosin heads bound to actin, and excludes shortened thin filaments as the cause.

PMID:38376469 SUPPORT Model Organism

"Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."

Demonstrates a reversible submaximal force deficit in a patient-variant mouse model of this node.

Respiratory Muscle Weakness and Ventilatory Failure

Weakness of the diaphragm, intercostal and accessory muscles produces neonatal respiratory distress in severe disease and nocturnal hypoventilation, restrictive lung disease and recurrent lower respiratory tract infection later. Respiratory failure is the cause of death in nemaline myopathy and is frequently under-recognised in older patients whose limb strength appears stable.

Downstream

Respiratory Insufficiency Due to Muscle Weakness

Neonatal Respiratory Distress

Show evidence (1 reference)

PMID:11558787 SUPPORT Human Clinical

"Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties."

Quantifies first-year respiratory morbidity in a 143-patient nemaline myopathy cohort.

Bulbar Weakness and Feeding Difficulty

Weakness of the facial, palatal, pharyngeal and tongue musculature impairs suck and swallow from birth, causing feeding failure, aspiration risk and poor weight gain. Bulbar function is abnormal in essentially every patient formally examined, and feeding morbidity, like respiratory infection morbidity, tends to diminish with age in survivors.

Downstream

Feeding Difficulties

Gastrostomy Tube Feeding in Infancy

Bulbar Palsy

Show evidence (2 references)

PMID:33397769 SUPPORT Human Clinical

"Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure."

Establishes near-universal bulbar involvement on formal assessment in a nemaline myopathy cohort including 18 ACTA1 patients.

PMID:11558787 SUPPORT Human Clinical

"Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age."

Supports the age-related improvement in feeding morbidity described by this node.

✶

Histopathology

1

Sarcoplasmic and Intranuclear Nemaline Rods with Sarcomeric Disorganisation

Gomori trichrome staining shows rod-shaped nemaline bodies in the sarcoplasm; electron microscopy shows their Z-disk origin, and in a subset of ACTA1 cases rods are also present within myonuclei. Associated findings in ACTA1 muscle include abnormal fibre type differentiation, glycogen accumulation, myofibrillar disruption and whorling of actin thin filaments.

Show evidence (2 references)

PMID:11333380 SUPPORT Human Clinical

"Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments."

Lists the histological features accompanying rods in ACTA1 muscle.

PMID:22825594 SUPPORT REVIEW SYNTHESIS Human Clinical

"Actin accumulations, nemaline and intranuclear bodies, fibre-type disproportion, cores, caps, dystrophic features and zebra bodies have all been seen in biopsies from patients with ACTA1 disease, with patients frequently presenting with multiple pathologies."

Documents that ACTA1 biopsies frequently carry more than one structural lesion, which is why the histological boundary of this entry is soft.

⬡

Pathograph

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

●

Phenotypes

14

Digestive 2

Gastrostomy Tube Feeding in Infancy FREQUENT HP:0011471

Show evidence (2 references)

PMID:40661861 SUPPORT Human Clinical

"Individuals with ACTA1-NM were more likely to require feeding tubes and invasive ventilation in the first year of life compared with those with NEB-related NM, but the odds of requiring invasive ventilation were similar after the first year of age."

Direct ACTA1-versus-NEB comparison of feeding-tube and ventilation need in a 275-patient nemaline myopathy cohort.

PMID:40661861 SUPPORT Human Clinical

"patients with hypotonia at birth had increased odds of requiring gastrostomy tubes"

Identifies neonatal hypotonia as an early predictor of gastrostomy dependence.

Feeding Difficulties FREQUENT HP:0011968

Show evidence (1 reference)

PMID:11558787 SUPPORT Human Clinical

"Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties."

Quantifies feeding difficulty in the 143-patient nemaline myopathy series.

Head and Neck 1

Facial Muscle Weakness FREQUENT Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."

Names the face as one of the most severely affected regions.

Musculoskeletal 7

Hypotonia VERY_FREQUENT HP:0001252

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes."

GeneReviews chapter establishing hypotonia as a cardinal feature of nemaline myopathy.

Proximal Muscle Weakness VERY_FREQUENT HP:0003701

Show evidence (2 references)

PMID:11333380 SUPPORT Human Clinical

"The weakness typically affects proximal musculature, with variable involvement of the facial, bulbar, and respiratory muscles. Cardiac muscle is usually spared."

States the proximal distribution of weakness, and the usual sparing of cardiac muscle.

PMID:20301465 SUPPORT Human Clinical

"Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."

GeneReviews statement of the weakness distribution.

Neck Flexor Weakness FREQUENT HP:0003722

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."

Names the neck flexors as one of the most severely affected muscle groups.

Respiratory Insufficiency Due to Muscle Weakness FREQUENT HP:0002747

Show evidence (3 references)

PMID:11558787 SUPPORT Human Clinical

"Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients."

Establishes respiratory insufficiency as the universal cause of death in a mixed-genotype nemaline myopathy cohort in which 22 patients carried ACTA1 variants.

PMID:33397769 SUPPORT Human Clinical

"Of the 27 individuals completing PFTs, abnormal values were observed in 65%."

Quantifies abnormal pulmonary function in a cross-sectional nemaline myopathy cohort including 18 ACTA1 patients.

PMID:40661861 SUPPORT Human Clinical

"patients with respiratory distress at birth had increased odds of requiring both gastrostomy tubes and invasive ventilation"

Identifies neonatal respiratory distress as an early predictor of long-term invasive respiratory support.

Bulbar Palsy FREQUENT HP:0001283

Show evidence (1 reference)

PMID:33397769 SUPPORT Human Clinical

"Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure."

Documents universal bulbar abnormality on formal testing in a cohort including 18 ACTA1 patients.

Arthrogryposis Multiplex Congenita OCCASIONAL HP:0002804

Show evidence (2 references)

PMID:11558787 SUPPORT Human Clinical

"Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures."

Places arthrogryposis among the minority features of the nemaline myopathy series.

PMID:20301465 SUPPORT Human Clinical

"Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life."

Establishes the prognostic weight of arthrogryposis.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Surveillance: Routine assessment for respiratory function, scoliosis, joint contractures, and the need for assistive devices."

GeneReviews surveillance recommendation identifying scoliosis as an expected complication to monitor.

Nervous System 2

Hyporeflexia FREQUENT HP:0001265

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes."

States depressed or absent reflexes as a cardinal feature.

Motor Developmental Delay FREQUENT Motor delay HP:0001270

Show evidence (2 references)

PMID:20301465 SUPPORT Human Clinical

"Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk."

Establishes early ambulation as a survival predictor and the usual eventual ambulation in the typical form.

PMID:11558787 SUPPORT Human Clinical

"Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality."

Links failure of early milestones to mortality in the 143-patient series.

Respiratory 1

Neonatal Respiratory Distress FREQUENT HP:0002643

Show evidence (3 references)

PMID:11333380 SUPPORT Human Clinical

"The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood."

Documents neonatal-onset respiratory failure at the severe end of the ACTA1 dominant spectrum described in this subtype.

PMID:20301465 SUPPORT Human Clinical

"Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life."

Establishes neonatal respiratory disease as a prognostic marker of first-year mortality.

PMID:35810298 SUPPORT Human Clinical

"The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life."

Describes the antenatal-to-neonatal course of the severe ACTA1 cohort in which this presentation is concentrated.

Cellular 1

Nemaline Bodies on Muscle Biopsy OBLIGATE HP:0003798

Show evidence (2 references)

PMID:20301465 SUPPORT Human Clinical

"Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome."

Establishes nemaline bodies as the defining diagnostic lesion.

PMID:11333380 SUPPORT Human Clinical

"The percentage of fibers with rods did not correlate with clinical severity"

Supports the statement that rod burden is not a severity marker.

🧬

Genetic Associations

1

ACTA1 (Causative)

Gene: ACTA1 hgnc:129 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:19562689 SUPPORT Human Clinical

"ACTA1 mutations are the second most common cause of nemaline myopathy after mutations in nebulin, accounting for 20% to 30% of a cohort of nemaline myopathy patients"

Establishes ACTA1 as the second most common cause of nemaline myopathy.

PMID:19562689 SUPPORT Human Clinical

"ACTA1 mutations are distributed throughout the six coding exons of the gene (Figure 1, Supp. Table S1). No mutations have as yet been found in the non-coding exon 1. The number of mutations in each exon correlates with the size of each exon (Table 1). Thus, there do not appear to be any..."

Supports the absence of a mutation hotspot, and so the need to sequence the whole coding region.

PMID:35810298 SUPPORT Human Clinical

"ACTA1 accounts for more than half of the severe NM cases."

Establishes that ACTA1 is over-represented at the severe end of the nemaline myopathy spectrum, which is why a gene-defined entry is not interchangeable with a severity-defined one.

💊

Medical Actions

7

Respiratory Surveillance and Ventilatory Support

Category: Monitoring Action: respiratory support and monitoring Ontology label: Supportive Care NCIT:C15747

Platform: Device

Non-invasive ventilation for nocturnal hypoventilation, aggressive treatment of lower respiratory tract infections, and pre-operative pulmonary function assessment. Because respiratory failure is the cause of death and is frequently under-recognised in older patients whose limb strength looks stable, respiratory function is assessed on schedule rather than on symptoms.

Show evidence (2 references)

PMID:20301465 SUPPORT Human Clinical

"Treatment of manifestations: Aggressive treatment of lower respiratory tract infections, ventilator use for nocturnal hypoxia, preoperative assessment of pulmonary function to ensure optimal timing of surgical procedures and to minimize anesthetic risk, monitoring of nutritional status, special..."

GeneReviews management recommendation covering ventilatory and infection management.

PMID:20301465 SUPPORT Human Clinical

"Surveillance: Routine assessment for respiratory function, scoliosis, joint contractures, and the need for assistive devices."

Establishes scheduled respiratory surveillance rather than symptom-triggered assessment.

Nutritional Support and Assisted Feeding

Category: Therapeutic Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Platform: Other

Nasogastric or gastrostomy feeding, attention to swallow safety, and management of gastro-oesophageal reflux, with monitoring of nutritional status. Bulbar involvement is near-universal on formal testing even when it is not the presenting complaint.

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"monitoring of nutritional status, special feeding techniques, standard care for gastroesophageal reflux"

GeneReviews nutritional management recommendation.

Physical Therapy and Contracture Prevention

Category: Therapeutic Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Mobility work and physiotherapy to limit joint contractures, with orthopaedic surveillance for scoliosis and assistive device needs across childhood.

Target Phenotypes: Scoliosis HP:0002650

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"mobility and physical therapy to help prevent joint contractures, speech therapy, and assessment of cardiac status"

GeneReviews recommendation for physiotherapy and contracture prevention.

Avoidance of Neuromuscular Blocking Agents

Category: Counseling / Informational Action: perioperative risk management Ontology label: Supportive Care NCIT:C15747

Neuromuscular blocking agents are to be avoided because of a possible association with malignant hyperthermia susceptibility. This is an anaesthetic-safety warning that applies at every surgical or procedural encounter, and is one of the few actionable items a family can carry on a care plan.

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Agents/circumstances to avoid: Neuromuscular blocking agents, because of possible association with malignant hyperthermia susceptibility."

GeneReviews agents-to-avoid warning, quoted directly.

Genetic Counseling and Parental Testing

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling turns on which inheritance mode is operating. A de novo dominant variant carries a 50% risk to the proband's own offspring and a low but real sibling risk from parental mosaicism; a recessive genotype carries a 25% sibling risk and unaffected heterozygous parents. Parental testing is what distinguishes them, and a normal parental blood result does not exclude gonadal mosaicism.

Show evidence (3 references)

PMID:19562689 SUPPORT Human Clinical

"There have been a number of instances where a severely affected proband was identified, and mildly affected or asymptomatic family members were found to carry the same dominant mutation. In at least three cases this can be explained by somatic mosaicism in one parent of a severely affected patient"

Supports counselling for parental mosaicism after an apparently de novo dominant variant.

PMID:19562689 SUPPORT Human Clinical

"Heterozygous mutation carriers (parents or siblings of patients with recessive ACTA1 mutations) were clinically unaffected, suggesting that expression from one intact copy of ACTA1 is sufficient for normal function"

Supports the unaffected-carrier counselling message in recessive families.

PMID:20301436 SUPPORT Human Clinical

"ACTA1 and TPM3 pathogenic variants are often de novo dominant."

Retired GeneReviews statement that ACTA1 variants are usually de novo dominant, which is the counselling default this treatment starts from before parental testing.

Fast Skeletal Muscle Troponin Activation (Investigational)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: tirasemtiv CHEBI:755074

Platform: Small molecule

Small molecules that sensitise the thin filament to calcium increase submaximal force without changing the underlying genotype. Tirasemtiv improved contractile capacity in fast-twitch and diaphragm muscle of an Acta1 p.Asp286Gly mouse carrying a patient-derived dominant variant. This is preclinical: there is no approved disease-specific therapy for ACTA1 nemaline myopathy.

Mechanism Target:

Reduced Skeletal Muscle Force Generation — Increases submaximal thin-filament calcium sensitivity, partially offsetting the contractile deficit.

Show evidence (2 references)

PMID:38376469 SUPPORT Model Organism

"Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."

Preclinical efficacy of thin-filament calcium sensitisation in a patient-variant mouse model.

PMID:22825594 SUPPORT REVIEW SYNTHESIS Human Clinical

"The use of small molecules to sensitise the contractile apparatus to Ca(2+) is a promising therapeutic for patients with various neuromuscular disorders, including ACTA1 disease."

Review support for calcium sensitisation as a therapeutic strategy in ACTA1 disease.

Cardiac Alpha-Actin Isoform Replacement (Investigational)

Category: Therapeutic Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Cardiac alpha-actin is 99% identical to the skeletal isoform and is the predominant sarcomeric actin in fetal muscle, so re-expressing it postnatally can substitute for absent or poisoned skeletal alpha-actin. In mice it rescued the recessive null model and markedly reduced lethality in one dominant model but not another, so its benefit is allele-dependent rather than general. Preclinical only.

Mechanism Target:

Absence of Functional Skeletal Muscle Alpha-Actin — Supplies a near-identical sarcomeric actin isoform in place of the missing skeletal isoform.

Show evidence (3 references)

PMID:23736297 SUPPORT Model Organism

"We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease."

Establishes isoform substitution as effective in the recessive null model.

PMID:23736297 SUPPORT Model Organism

"In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from ∼59% before 30 days of age to ∼12%. In the other model, Acta1(H40Y), in which ∼80% of male mice die by 5 months of age, the cardiac α-actin transgene did not significantly improve survival."

Documents the allele-dependent benefit, including the negative result, that qualifies this strategy.

PMID:19468071 SUPPORT Model Organism

"These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases."

Original demonstration that cardiac alpha-actin re-expression rescues Acta1-null mice, which is the basis of this strategy.

🔬

Diagnosis

2

Muscle Biopsy with Gomori Trichrome Staining

Histological demonstration of nemaline bodies establishes the nemaline myopathy phenotype. Electron microscopy adds the Z-disk origin of the rods and detects intranuclear rods.

Show evidence (1 reference)

PMID:20301465 SUPPORT Human Clinical

"Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome."

States the histological basis of diagnosis.

ACTA1 Sequencing

Sequencing of the whole ACTA1 coding region, in practice as part of a congenital myopathy gene panel or exome, is required to assign the genotype. Because there is no mutation hotspot and most variants are private, partial-gene testing is not adequate, and parental testing is needed to distinguish a de novo dominant variant from a recessive genotype — a distinction that changes the recurrence risk from 50% to 25%.

Show evidence (1 reference)

PMID:19562689 SUPPORT Human Clinical

"Where DNA has been available for testing from the parents of sporadic patients, 79/94 or 84% had de novo dominant mutations not present in the peripheral blood DNA of either parent, while only 16% had recessive ACTA1 mutations."

Supports parental testing as the step that resolves inheritance mode, and quantifies how often each answer is found.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from ACTA1-Related Nemaline Myopathy:

Non-Nemaline ACTA1 Congenital Myopathies

Overlapping Features The same gene causes intranuclear rod myopathy, actin filament aggregate myopathy, congenital fibre-type disproportion and myopathy with core-like areas. These are distinguished on biopsy rather than clinically, and a single biopsy may show several patterns at once, so the separation is a histological convention rather than a boundary between diseases.

Distinguishing Features

Actin filament aggregates or fibre-type disproportion in place of, or alongside, nemaline rods
Attributed by MONDO to the alpha-actinopathy umbrella (MONDO:0100084) rather than to nemaline myopathy

Show evidence (2 references)

PMID:19562689 SUPPORT Human Clinical

"ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core-like areas."

Enumerates the ACTA1 histological entities that sit outside this entry's scope.

PMID:17387733 SUPPORT Human Clinical

"Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM."

Gives the ultrastructural feature that separates ACTA1 fibre-type disproportion from severe ACTA1 nemaline myopathy.

🧫

Experimental Models

1

ACTA1 H40Y iPSC-derived skeletal myocytes IPSC_DERIVED_MODEL

Isogenic CRISPR-Cas9 iPSC lines carrying the ACTA1 H40Y point mutation, differentiated to skeletal myocytes. Mitochondrial membrane potential, permeability transition pore formation, superoxide production and ATP levels are abnormal, and ATP supplementation protects the mitochondria from stress-induced injury. Nemaline rods do not form in this system, which bounds what it can be used for.

Pathograph links

Mitochondrial Dysfunction in ACTA1-Mutant Myofibres recapitulates fidelity: moderate observes: cellular The model observes the node's own quantities — cellular ATP, mitochondrial membrane potential, permeability transition pore formation and superoxide — at the cellular scale the node is tagged with, in isogenic lines differing only at the ACTA1 locus.

Limitations: Nemaline rods, the defining lesion of the disease, do not form in this system, so it does not model the histology; it carries one dominant allele in cultured myocytes rather than in innervated, mechanically loaded muscle, and nothing links the bioenergetic defect to force in patient tissue.

Divergences from the human mechanism

boundary omission qualifying

Nemaline rods, the defining histological lesion, are absent from the model despite the ACTA1 mutation being present, so nothing in the model connects the bioenergetic defect to rod formation.

population mismatch qualifying

The lines carry the single dominant H40Y allele. Recessive null genotypes and the rest of the ACTA1 allelic spectrum are not represented.

Readouts

Cellular ATP level

Direction: DECREASED

Interpretation: Bioenergetic readout grounding the ATP metabolic process annotation on this node.

Show evidence (1 reference)

PMID:36796746 SUPPORT In Vitro

"Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."

Reports the measurement and its direction.

Mitochondrial membrane potential

Direction: ALTERED

Interpretation: Readout grounding the mitochondrial membrane potential annotation on this node.

Show evidence (1 reference)

PMID:36796746 SUPPORT In Vitro

"Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."

Reports the measurement; the paper states the potential is altered without a single direction, so the readout is recorded as ALTERED.

Show evidence (2 references)

PMID:36796746 SUPPORT In Vitro

"Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."

The authors' own statement of what the model shows.

+ 1 more reference

Show evidence (1 reference)

PMID:36796746 SUPPORT In Vitro

"Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."

Reports the bioenergetic phenotype this model is used to study.

🐁

Animal Models

2

Acta1 p.Asp286Gly knock-in mouse

Mouse carrying a dominant ACTA1 variant found in patients, used to test thin-filament calcium sensitisers.

Species

Mouse

Genotype

Acta1 p.Asp286Gly, patient-derived dominant variant

Publication

PMID:38376469

Pathograph links

Reduced Skeletal Muscle Force Generation recapitulates fidelity: moderate observes: tissue Reproduces the submaximal force deficit of dominant ACTA1 disease in limb and diaphragm muscle, and responds to pharmacological calcium sensitisation.

Limitations: A single dominant allele in an inbred background; it does not model recessive null disease, the human severity spectrum, or the developmental and bulbar presentation of congenital-onset human disease.

Readouts

Submaximal muscle contractile capacity

Direction: RESTORED

Interpretation: Pharmacological rescue of submaximal force identifies a reversible component of the contractile deficit.

Show evidence (1 reference)

PMID:38376469 SUPPORT Model Organism

"Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:38376469 SUPPORT Model Organism

"we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1"

Identifies the model as carrying a patient-derived ACTA1 variant.

Acta1 knock-out mouse

Models recessive ACTA1 disease, in which no functional skeletal muscle alpha-actin is made; rescued postnatally by transgenic cardiac alpha-actin.

Species

Mouse

Genotype

Acta1 null (knock-out)

Publication

PMID:23736297

Pathograph links

Absence of Functional Skeletal Muscle Alpha-Actin recapitulates fidelity: moderate observes: molecular Complete absence of skeletal muscle alpha-actin, as in human recessive null disease.

Limitations: Mouse and human differ in postnatal cardiac alpha-actin expression, and one dominant model in the same study showed endogenously elevated cardiac alpha-actin that has not been reported in patients, so isoform-compensation findings do not transfer directly to humans.

Show evidence (1 reference)

PMID:23736297 SUPPORT Model Organism

"We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease."

Identifies the knock-out as the model of recessive ACTA1 disease.

{ }

Source YAML

click to show

name: ACTA1-Related Nemaline Myopathy
creation_date: '2026-09-26T00:00:00Z'
category: Mendelian
description: >
  ACTA1-related nemaline myopathy (NEM3; OMIM 161800, renamed congenital myopathy 2A
  in OMIM's CMYO series) is a congenital myopathy caused by pathogenic variants in
  ACTA1, which encodes skeletal muscle alpha-actin, the principal protein of the
  sarcomeric thin filament. About 90% of ACTA1 variants act dominantly and most arise
  de novo; the remaining ~10% are genetic or functional null alleles causing recessive
  disease. In dominant disease the mutant actin is translated and incorporated into the
  thin filament as a "poison" peptide, disrupting actin-tropomyosin interaction,
  sarcomere organisation and force generation, and producing the Z-disk-derived
  nemaline rods that name the disease. ACTA1 is the second most common cause of
  nemaline myopathy after nebulin and is over-represented among severe congenital
  cases, which present at birth with profound hypotonia, bulbar and respiratory
  muscle weakness, feeding failure, and death in the first year from respiratory
  insufficiency. Milder childhood- and adult-onset presentations compatible with
  independent ambulation and normal lifespan occur with the same gene, sometimes
  within one family.
synonyms:
- ACTA1 nemaline myopathy
- NEM3
- nemaline myopathy type 3
- CMYO2A
- congenital myopathy 2a, typical, autosomal dominant
disease_term:
  preferred_term: ACTA1 nemaline myopathy
  term:
    id: MONDO:0008070
    label: congenital myopathy 2a, typical, autosomal dominant
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008070
      label: congenital myopathy 2a, typical, autosomal dominant
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >
      Primary MONDO identifier for this entry. MONDO:0008070 is the MONDO class for
      OMIM 161800 (NEM3 / CMYO2A); its textual definition is gene-level ("An inherited
      myopathy caused by mutations in the ACTA1 gene"), and MONDO files it beneath four
      severity bands of nemaline myopathy at once, which is the scope this entry takes.
  - term:
      id: MONDO:0100084
      label: alpha-actinopathy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      alpha-actinopathy is MONDO's umbrella for the whole ACTA1 phenotypic spectrum,
      including the non-nemaline histologies (actin filament aggregate myopathy,
      congenital fibre-type disproportion, core-like areas, cap myopathy, zebra body
      myopathy) that this entry does not cover.
  - term:
      id: MONDO:0018958
      label: nemaline myopathy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      The genetically heterogeneous parent disease curated at
      kb/disorders/Nemaline_Myopathy.yaml, which cuts the same patients on the
      severity axis rather than the gene axis.
parents:
- Nemaline Myopathy
- Congenital Structural Myopathy
- Thin Filament Myopathy
references:
- reference: PMID:20301465
  title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings:
  - statement: >
      The only GeneReviews chapter covering this disease has been retired, so there is
      no current GeneReviews phenotype baseline for nemaline myopathy. The archived
      chapter is still the source of the six-category ENMC clinical classification, the
      surveillance schedule and the neuromuscular-blocking-agent warning quoted in this
      entry, and its content is disease-wide rather than ACTA1-specific.
    supporting_text: "NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE."
- reference: PMID:20301436
  title: "Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings:
  - statement: >
      The retired companion GeneReviews chapter covers congenital fibre-type
      disproportion, the ACTA1 allelic histology that this entry deliberately excludes
      from scope. It is cited here only because it carries the same
      neuromuscular-blocking-agent and malignant-hyperthermia caution as the nemaline
      myopathy chapter, and because its genetic-counselling section records that ACTA1
      variants are usually de novo dominant. ACTA1 accounts for roughly 6% of CFTD, so
      the chapter is not an ACTA1-specific source.
    supporting_text: "ACTA1 and TPM3 pathogenic variants are often de novo dominant."
notes: >
  Lump/split decision. MONDO:0008070 was bound nowhere in kb/ before this entry, and
  it does not fit the axis kb/disorders/Nemaline_Myopathy.yaml already uses: that entry
  splits nemaline myopathy by clinical severity (severe congenital, typical,
  childhood-onset, adult-onset), while MONDO:0008070 is defined by its gene and is
  filed by MONDO beneath four of those severity bands simultaneously. Orphanet records
  the same crossing from the other direction: both ORPHA:171430 (severe congenital
  nemaline myopathy) and ORPHA:171436 (typical nemaline myopathy) list OMIM:161800 —
  the OMIM entry this MONDO class represents — as a *Broader* cross-reference. A gene
  row cannot be added to a severity-axis has_subtypes list without mixing two axes in
  one list, so this is curated as a separate gene-defined Disease entry that
  cross-references the severity entry through mappings and `parents`, following the
  pattern dismech already uses for gene-defined Mendelian entries. Two alternatives
  were weighed and rejected. (1) A has_subtypes row on Nemaline_Myopathy.yaml: rejected
  for the axis-mixing reason above. (2) Recording MONDO:0008070 only as a
  skos:narrowMatch on Nemaline_Myopathy.yaml, which was proposed in the claim issue
  thread: rejected because a narrowMatch mapping retires the concept from the curation
  queue (see CLAUDE.md, "Ontology Term Contract") while adding no ACTA1-specific
  pathograph, and the ACTA1 mechanism is not a severity variant of the parent entry's
  mechanism — the parent's causal chain is gene-agnostic thin-filament dysfunction,
  whereas dominant ACTA1 disease is a poison-peptide mechanism with a distinct
  recurrence risk, a distinct histological signature, and distinct experimental
  therapies. Nemaline_Myopathy.yaml was deliberately not edited in the same change.

  Scope. This entry covers nemaline myopathy caused by ACTA1. It does not cover the
  other congenital myopathies ACTA1 causes — actin filament aggregate (actin
  accumulation) myopathy, congenital fibre-type disproportion, and myopathy with
  core-like areas — even though the curation stub's synonym list mixed those names in,
  because they inherit the legacy OMIM 161800 synonym set. Those histologies sit under
  MONDO:0100084 alpha-actinopathy, recorded above as a broadMatch. Intranuclear rod
  myopathy is treated as in scope, because Laing et al. describe it as a variant of
  nemaline myopathy rather than a separate histology. The boundary is genuinely soft:
  the same review argues these entities may be a continuum and that single biopsies
  frequently show several of them at once.

  OMIM has since split ACTA1 disease three ways — CMYO2A (161800, typical, autosomal
  dominant, the class this entry is anchored on), CMYO2B (620265, severe infantile,
  autosomal recessive) and CMYO2C (620278, severe infantile, autosomal dominant).
  MONDO carries CMYO2B and CMYO2C as MONDO:0859517 and MONDO:0859523 but places
  neither under alpha-actinopathy or nemaline myopathy, so MONDO's own graph does not
  connect them to ACTA1. They are therefore left unmapped here rather than asserted as
  subtypes of this entry on an unsourced gene attribution; the severity-and-inheritance
  strata that this entry does model are recorded in has_subtypes on the inheritance
  axis instead.

  Cardiac involvement. The cited cohort literature reports that cardiac muscle is
  usually spared in nemaline myopathy. ACTA1 does cause a separate, non-nemaline dilated
  cardiomyopathy phenotype, and the largest ACTA1 cohort reports cardiomyopathy as an
  atypical presentation among pathogenic and likely pathogenic ACTA1 variants; that
  figure spans all ACTA1 phenotypes rather than nemaline myopathy specifically, and the
  cohort abstract available here does not state it, so no cardiomyopathy phenotype is
  recorded on this entry. ACTA1-related dilated cardiomyopathy is out of scope for the
  same reason the other ACTA1 histologies are.

  Subtype stratification. No phenotype row is scoped to a has_subtypes row, because no
  clinical feature in this entry is supported as dominant-specific or recessive-specific
  by its own source. The severe-neonatal features occur in both: the recessive null
  genotypes reported up to 2014 all produced severe weakness from birth, and the
  dominant spectrum reaches lethal congenital disease as well. The subtype-specific
  claims that are sourced — the allele class, the mechanism, the recurrence risk and the
  candidate therapy — are carried on the has_subtypes rows and the inheritance blocks
  instead.

  The two has_subtypes rows are cut on the inheritance-and-mechanism axis (dominant
  poison-peptide versus recessive null) rather than on severity, because that is the
  distinction that changes the recurrence risk and the candidate therapy. Neither row
  carries a subtype_term: MONDO has no class for "dominant ACTA1 disease" or "recessive
  ACTA1 disease" as such, and the nearest candidates, MONDO:0859517 and MONDO:0859523,
  are the OMIM severity-plus-inheritance strata discussed above, which MONDO does not
  link to ACTA1.

  Evidence gaps. No population prevalence figure for ACTA1-related nemaline myopathy
  specifically could be sourced, so no `prevalence` block is recorded; the per-gene
  share of nemaline myopathy cohorts is captured in `genetic[].case_fractions`
  instead. Several phenotype frequencies come from mixed-genotype nemaline myopathy
  cohorts (Ryan 2001, Amburgey 2021) rather than ACTA1-only series, and each such
  evidence item says so in its `explanation`. Two causal edges — weakness to
  arthrogryposis and weakness to scoliosis — carry no evidence item: the sources cited
  here establish that both features occur and that arthrogryposis predicts first-year
  mortality, but none states the intervening step (fetal akinesia, chronic axial
  weakness) for ACTA1 disease specifically.
inheritance:
- name: Autosomal Dominant
  description: >
    About 90% of ACTA1 variants cause dominant disease, and most affected individuals
    are simplex cases carrying a de novo missense variant that is absent from parental
    blood. Recurrence in a sibship after an apparently de novo variant is a real risk
    because parental somatic and germline mosaicism has been documented, and a mildly
    affected or asymptomatic mosaic parent may carry the same allele that is lethal in
    the proband. Expressivity is variable: age at onset and severity differ markedly
    between carriers of the same variant, including between affected members of one
    family, so ACTA1 genotype alone does not predict the clinical course.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: '84% of sporadic patients with parental testing available'
  expressivity: VARIABLE
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations."
    explanation: States the dominant/recessive split and the predominance of de novo dominant variants.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where DNA has been available for testing from the parents of sporadic patients, 79/94 or 84% had de novo dominant mutations not present in the peripheral blood DNA of either parent, while only 16% had recessive ACTA1 mutations."
    explanation: Source of the 84% de novo figure recorded on this inheritance block.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There have been a number of instances where a severely affected proband was identified, and mildly affected or asymptomatic family members were found to carry the same dominant mutation. In at least three cases this can be explained by somatic mosaicism in one parent of a severely affected patient"
    explanation: Supports the parental-mosaicism recurrence risk that qualifies an apparently de novo result in counselling.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission."
    explanation: Documents vertical transmission from a proband whose own variant arose de novo, i.e. the 50% offspring risk that follows a dominant ACTA1 allele.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was marked variation in both age at onset and clinical severity in the three affected members of one family."
    explanation: Documents the intrafamilial variability recorded in the expressivity field.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The intrafamilial variability suggests that alpha-actin genotype is not the sole determinant of phenotype."
    explanation: States that ACTA1 genotype does not determine phenotype, which is why a mildly affected parent's allele can be severe in a child.
- name: Autosomal Recessive
  description: >
    Roughly 10% of ACTA1 variants cause recessive disease. These are nonsense,
    frameshift or splice-site alleles, or one of four buried missense changes shown to
    be functional nulls, so affected individuals have no functional skeletal muscle
    alpha-actin. Heterozygous parents and siblings are clinically unaffected, and the
    sibling recurrence risk is 25%.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most recessive ACTA1 mutations are nonsense, frameshift or splice-site mutations, and are predicted to cause premature termination of translation, or the omission of entire exons from the mRNA, leading to absence of skeletal α-actin protein"
    explanation: Establishes the null-allele basis of recessive ACTA1 disease.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutation carriers (parents or siblings of patients with recessive ACTA1 mutations) were clinically unaffected, suggesting that expression from one intact copy of ACTA1 is sufficient for normal function"
    explanation: Supports unaffected-carrier status of heterozygous parents, and so a 25% sibling recurrence risk in recessive families.
has_subtypes:
- name: Dominant
  display_name: Dominant (poison mutant actin) ACTA1 disease
  description: >
    Approximately 90% of ACTA1 disease. A heterozygous, usually de novo, missense
    variant is expressed and the mutant protein is incorporated into the thin filament
    alongside wild-type alpha-actin, so the mechanism is a dominant-negative or "poison
    peptide" one rather than haploinsufficiency. Severity ranges from lethal neonatal
    disease to mild childhood-onset weakness and depends in part on the proportion of
    mutant protein present.
  evidence:
  - reference: PMID:22825594
    reference_title: "Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Approximately 200 different ACTA1 mutations have been identified, with 90 % resulting in dominant disease and 10 % resulting in recessive disease."
    explanation: Quantifies the dominant share of ACTA1 disease that defines this subtype.
  - reference: PMID:23736297
    reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein."
    explanation: States the poison-peptide mechanism that distinguishes this subtype from the recessive one.
- name: Recessive
  display_name: Recessive (null) ACTA1 disease
  description: >
    Approximately 10% of ACTA1 disease. Recessive alleles reported up to 2009 were
    biallelic genetic or functional nulls, so no functional skeletal muscle alpha-actin
    was made; cardiac alpha-actin, which is 99% identical and is the predominant
    sarcomeric actin in fetal muscle, is the isoform available to substitute for it and
    is the basis of the isoform-replacement therapeutic strategy. That generalisation is
    no longer complete: homozygous missense variants preserving skeletal alpha-actin
    expression have since been reported in brothers with congenital muscular dystrophy
    with rigid spine and dystrophic biopsy features, which the authors describe as a new
    class of recessive ACTA1 variant.
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with recessive ACTA1 disease therefore lack functional skeletal muscle α-actin"
    explanation: Defines this subtype as complete absence of functional skeletal muscle alpha-actin.
  - reference: PMID:23736297
    reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Cardiac α-actin is 99% identical to skeletal muscle α-actin and the predominant actin isoform in fetal muscle."
    explanation: Supports the cardiac alpha-actin substitution rationale specific to the null subtype.
  - reference: PMID:25182138
    reference_title: "Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth."
    explanation: States the null generalisation this subtype was defined by.
  - reference: PMID:25182138
    reference_title: "Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression."
    explanation: Refutes the claim that every recessive ACTA1 genotype abolishes protein expression; recorded here so the subtype definition is not read as exceptionless.
pathophysiology:
- name: ACTA1 Variant in Skeletal Muscle Alpha-Actin
  description: >
    A pathogenic variant in ACTA1 alters skeletal muscle alpha-actin, the predominant
    actin isoform of the adult sarcomeric thin filament. The gene is small — six coding
    exons over 2.8 kb — and variants are distributed across all of them without
    hotspots, so essentially any coding residue may be involved. The overwhelming
    majority are missense changes at residues conserved across the actin family.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: DE_NOVO
    functional_impact_category: DOMINANT_NEGATIVE
    description: >
      Most dominant ACTA1 variants are de novo missense changes and act as
      dominant-negative "poison" alleles; the minority recessive alleles are instead
      genetic or functional nulls and are modelled by the separate node below.
  genes:
  - preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  molecular_functions:
  - preferred_term: actin filament binding
    modifier: DYSREGULATED
    term:
      id: GO:0051015
      label: actin filament binding
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ACTA1 gene encodes skeletal muscle alpha-actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction."
    explanation: Establishes the gene product and its sarcomeric role, which is what the variant perturbs.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 177 mutations comprise 157 missense, 5 nonsense, 5 frameshift and 4 splice site mutations, 1 in-frame duplication, 1 insertion of a single amino-acid, 1 in-frame single amino-acid deletion and 3 mutations of the normal stop codon."
    explanation: Documents the predominance of missense alleles in the ACTA1 variant spectrum.
  downstream:
  - target: Incorporation of Mutant Alpha-Actin into the Thin Filament
    causal_link_type: DIRECT
    description: >
      The mutant allele is transcribed and translated, and the mutant protein enters
      the sarcomere rather than being degraded.
    evidence:
    - reference: PMID:17387733
      reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mass spectrometry and two-dimensional gel electrophoresis demonstrate that mutant actin accounts for 25 and 50% of alpha-skeletal actin in the skeletal muscle of patients with the P332S and D292V mutations, respectively, consistent with a dominant-negative disease mechanism."
      explanation: Directly measures mutant protein in patient muscle, establishing that the variant produces incorporated mutant actin.
- name: Incorporation of Mutant Alpha-Actin into the Thin Filament
  description: >
    Mutant alpha-actin polymerises into F-actin together with wild-type protein and is
    incorporated into the thin filament, where it acts as a poison peptide. In patient
    muscle the mutant species accounts for a quarter to a half of total alpha-skeletal
    actin, and the severity of dominant disease tracks with how much mutant protein is
    present.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: actin filament polymerization
    modifier: DYSREGULATED
    term:
      id: GO:0030041
      label: actin filament polymerization
  evidence:
  - reference: PMID:23736297
    reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein."
    explanation: States the poison-peptide model for this node.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In skeletal muscle, actin function depends on the balance between monomeric G-actin (globular) and filamentous F-actin, a polymer of G-actin subunits. F-actin, together with tropomyosin, troponin, and nebulin, forms the thin filaments of the skeletal-muscle contractile apparatus."
    explanation: Describes the polymerisation step and thin-filament assembly that the mutant protein enters.
  downstream:
  - target: Defective Actin-Tropomyosin Regulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17387733
      reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position.'
      explanation: In vitro motility data link incorporated mutant actin to a specific defect in actin-tropomyosin regulation.
  - target: Sarcomeric Disorganisation
    causal_link_type: DIRECT
    description: >
      In most ACTA1 nemaline myopathy biopsies, but not in the fibre-type-disproportion
      variants, incorporation of the mutant protein is accompanied by breakdown of the
      sarcomeric lattice.
    evidence:
    - reference: PMID:35810298
      reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization."
      explanation: Observes major myofibrillar disorganisation in muscle carrying mutant skeletal alpha-actin; it establishes that the two co-occur rather than demonstrating that incorporation causes the disorganisation, hence INDIRECT.
  - target: Nemaline Rod Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17387733
      reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We raise the possibility that the presence or absence of structural disorganization when mutant actin incorporates into sarcomeres may be an important determinant of whether the histological patterns of CFTD or NM develop in ACTA1 myopathy."
      explanation: The authors offer this as a possibility raised by their CFTD data rather than as a demonstrated result, so the edge rests on an inference from the CFTD comparison.
  - target: Mitochondrial Dysfunction in ACTA1-Mutant Myofibres
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36796746
      reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."
      explanation: Isogenic ACTA1 H40Y myocytes acquire the bioenergetic defect, so the mutant protein is upstream of it; the experiment is in a differentiated iPSC model rather than patient muscle, hence INDIRECT.
  - target: Nuclear Envelope and LINC Complex Disruption
    causal_link_type: DIRECT
    description: >
      In severe disease the mutant protein's effects extend beyond the sarcomere to the
      nuclear envelope.
    evidence:
    - reference: PMID:35810298
      reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape."
      explanation: Links the presence of mutant skeletal muscle alpha-actin to loss of normal nuclear shape.
- name: Absence of Functional Skeletal Muscle Alpha-Actin
  description: >
    In recessive ACTA1 disease no functional skeletal muscle alpha-actin is produced.
    The sarcomere is not poisoned by an abnormal protein but is deprived of its
    principal thin-filament subunit, and cardiac alpha-actin — normally downregulated
    late in the second trimester — is the isoform available to substitute for it.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most recessive ACTA1 mutations are nonsense, frameshift or splice-site mutations, and are predicted to cause premature termination of translation, or the omission of entire exons from the mRNA, leading to absence of skeletal α-actin protein"
    explanation: Establishes absence of the protein as the recessive mechanism.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although skeletal muscle α-actin is the predominant isoform in adult skeletal muscle, cardiac α-actin (the major actin isoform expressed in the adult heart) is the major actin expressed in skeletal muscle during early gestation, but is downregulated late in the second trimester, and usually at negligible levels by birth"
    explanation: Supports the developmental isoform switch that leaves the null sarcomere without a substitute after birth.
  downstream:
  - target: Reduced Skeletal Muscle Force Generation
    causal_link_type: DIRECT
    description: >
      A sarcomere deprived of its principal thin-filament subunit converges on the same
      contractile failure the poison-peptide route produces, by a different molecular
      route. The recessive route is deliberately not drawn through
      `Defective Actin-Tropomyosin Regulation`: a null allele makes no mutant actin that
      could mis-regulate tropomyosin, so that node describes the dominant mechanism
      only.
    evidence:
    - reference: PMID:25182138
      reference_title: "Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth."
      explanation: Links absence of skeletal alpha-actin expression directly to severe weakness from birth, which is this edge.
- name: Defective Actin-Tropomyosin Regulation
  description: >
    Incorporated mutant alpha-actin interacts abnormally with tropomyosin, which is held
    over the myosin-binding site of the thin filament in the "switched off" position, so
    fewer myosin heads bind actin when the fibre is activated. This is a regulatory
    defect of an intact thin filament and is separable from structural breakdown of the
    sarcomere: the ACTA1 variants that produce congenital fibre-type disproportion carry
    the actin-tropomyosin defect while sarcomeric structure on electron microscopy stays
    normal. Because it requires mutant protein in the filament, it describes the dominant
    poison-peptide mechanism and not the recessive null one.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: tropomyosin binding
    modifier: DYSREGULATED
    term:
      id: GO:0005523
      label: tropomyosin binding
  biological_processes:
  - preferred_term: muscle filament sliding
    modifier: DECREASED
    term:
      id: GO:0030049
      label: muscle filament sliding
  evidence:
  - reference: PMID:17387733
    reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position.'
    explanation: Identifies the actin-tropomyosin regulatory defect that defines this node, measured by in vitro motility assay.
  - reference: PMID:17387733
    reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM."
    explanation: Shows the regulatory defect occurring with normal sarcomeric structure, which is why this node is separate from Sarcomeric Disorganisation rather than bundled with it.
  downstream:
  - target: Reduced Skeletal Muscle Force Generation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17387733
      reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position.'
      explanation: Names the actin-tropomyosin defect as the principal cause of weakness, which is this edge.
    - reference: PMID:17387733
      reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data suggest that ACTA1 CFTD mutations cause weakness by disrupting sarcomere function rather than structure."
      explanation: States that the weakness follows from disrupted sarcomere function independently of structural disorganisation, which is the claim this edge makes.
- name: Sarcomeric Disorganisation
  description: >
    In most ACTA1 nemaline myopathy fibres the sarcomeric lattice itself breaks down,
    with whorled thin filaments, myofibrillar disruption and mislocalised sarcomeric
    actin. Severity of the structural disorganisation, rather than the number of rods,
    is what tracks with the lethal phenotype, and unlike the regulatory defect above it
    is reached by both the poison-peptide and the null route.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: DECREASED
    term:
      id: GO:0045214
      label: sarcomere organization
  evidence:
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin."
    explanation: Establishes sarcomeric disorganisation rather than rod burden as the correlate of severity.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and \"whorling\" of actin thin filaments."
    explanation: Documents the thin-filament and myofibrillar disorganisation described by this node.
  downstream:
  - target: Reduced Skeletal Muscle Force Generation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11333380
      reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin."
      explanation: The degree of sarcomeric disorganisation, not rod burden, is what tracks with the most severe functional outcome, which is the edge asserted here.
- name: Nemaline Rod Formation
  description: >
    Nemaline bodies are rod-shaped aggregates that arise from the sarcomeric Z-disk and
    are rich in alpha-actinin. In ACTA1 disease they may be sarcoplasmic, intranuclear,
    or both; intranuclear rod myopathy is a variant of nemaline myopathy defined by rods
    inside myonuclei and is often, though not always, severe. Rod burden does not
    predict clinical severity, so this node is the diagnostic lesion rather than a step
    on the causal path to weakness.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline bodies (rods) are clearly detectable at the light-microscopy (LM) level, and, ultrastructurally, they originate from the Z-disks of the sarcomeres. One of the main components of rods is α-actinin 2, an actin-binding protein that localizes to the Z-disk"
    explanation: Establishes the Z-disk origin and alpha-actinin composition of the rods.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intranuclear rod myopathy is a variant of nemaline myopathy characterised histologically by rod-like bodies in the nuclei of muscle fibres"
    explanation: Supports treating intranuclear rod myopathy as in scope for this entry rather than as a separate ACTA1 entity.
  downstream:
  - target: Nemaline Bodies on Muscle Biopsy
    causal_link_type: DIRECT
    description: Rod formation is what the diagnostic biopsy finding observes.
- name: Nuclear Envelope and LINC Complex Disruption
  description: >
    In severe ACTA1 disease the pathology extends to the myonucleus: the perinuclear
    space is enlarged and lamin A/C, nesprin-1 and nesprin-2 — the LINC complex
    components that tether the nucleus to the cytoskeleton — are mislocalised. This
    implies a physiological role for skeletal muscle alpha-actin in maintaining nuclear
    shape that is lost when the mutant protein is present. Intranuclear rods are
    recorded on the Nemaline Rod Formation node rather than here, because the available
    evidence shows them co-occurring with this nuclear pathology in severe biopsies and
    does not establish that envelope disruption produces them.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:35810298
    reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape."
    explanation: Identifies perinuclear space enlargement and a nuclear-shape role for skeletal muscle alpha-actin.
  - reference: PMID:35810298
    reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity."
    explanation: Documents the nuclear lamina and LINC complex mislocalisation described by this node.
- name: Mitochondrial Dysfunction in ACTA1-Mutant Myofibres
  description: >
    ACTA1-mutant skeletal myocytes carry a cell-autonomous bioenergetic defect: cellular
    ATP falls, mitochondrial membrane potential is altered, permeability transition pore
    formation and superoxide production rise, and supplying ATP protects the mitochondria
    from stress-induced injury. The evidence comes from isogenic H40Y iPSC-derived
    myocytes rather than from patient muscle, so this is a candidate contributor to the
    contractile deficit and not an established step in it.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: ATP metabolic process
    modifier: DECREASED
    term:
      id: GO:0046034
      label: ATP metabolic process
  - preferred_term: regulation of mitochondrial membrane potential
    modifier: DYSREGULATED
    term:
      id: GO:0051881
      label: regulation of mitochondrial membrane potential
  evidence:
  - reference: PMID:36796746
    reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."
    explanation: Reports the two measurements this node is bound to, in isogenic ACTA1 H40Y myocytes.
  - reference: PMID:36796746
    reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."
    explanation: The authors' own summary, including the ATP-rescue result that identifies the defect as bioenergetic.
  downstream:
  - target: Reduced Skeletal Muscle Force Generation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Loss of ATP supply is a candidate contributor to the contractile deficit. No
      measurement of force in this system exists, so the step is asserted as a
      possibility rather than as a demonstrated cause.
    evidence:
    - reference: PMID:36796746
      reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."
      explanation: Establishes the bioenergetic defect as a disease phenotype of ACTA1-mutant myocytes; force generation was not measured, so the link to weakness is an inference.
- name: Reduced Skeletal Muscle Force Generation
  description: >
    The functional endpoint of both molecular routes is loss of contractile force. In
    the Acta1 p.Asp286Gly mouse, which carries a patient-derived dominant variant,
    contractile capacity at submaximal stimulation frequencies is reduced and can be
    pharmacologically increased with a fast skeletal troponin activator, which
    identifies reduced thin-filament calcium sensitivity as a tractable component of
    the deficit.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  evidence:
  - reference: PMID:29328520
    reference_title: "Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force-generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils."
    explanation: Direct measurement of reduced force-generating capacity in muscle from 14 patients with ACTA1 variants, which is the strongest human evidence for this node.
  - reference: PMID:29328520
    reference_title: "Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low angle X-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length."
    explanation: Identifies the structural basis of the force deficit as fewer myosin heads bound to actin, and excludes shortened thin filaments as the cause.
  - reference: PMID:38376469
    reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."
    explanation: Demonstrates a reversible submaximal force deficit in a patient-variant mouse model of this node.
  downstream:
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Proximal Muscle Weakness
    causal_link_type: DIRECT
  - target: Facial Muscle Weakness
    causal_link_type: DIRECT
  - target: Neck Flexor Weakness
    causal_link_type: DIRECT
  - target: Respiratory Muscle Weakness and Ventilatory Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11558787
      reference_title: "Nemaline myopathy: a clinical study of 143 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients."
      explanation: Establishes respiratory muscle failure as the lethal consequence of the contractile deficit in a nemaline myopathy cohort that includes ACTA1 patients.
  - target: Bulbar Weakness and Feeding Difficulty
    causal_link_type: DIRECT
  - target: Motor Developmental Delay
    causal_link_type: DIRECT
  - target: Arthrogryposis Multiplex Congenita
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      When the contractile deficit is severe enough to be present in utero, reduced
      fetal movement leads to fixed joint contractures at birth.
  - target: Scoliosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Chronic axial and paraspinal weakness allows progressive spinal deformity in
      survivors.
- name: Respiratory Muscle Weakness and Ventilatory Failure
  description: >
    Weakness of the diaphragm, intercostal and accessory muscles produces neonatal
    respiratory distress in severe disease and nocturnal hypoventilation, restrictive
    lung disease and recurrent lower respiratory tract infection later. Respiratory
    failure is the cause of death in nemaline myopathy and is frequently
    under-recognised in older patients whose limb strength appears stable.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties."
    explanation: Quantifies first-year respiratory morbidity in a 143-patient nemaline myopathy cohort.
  downstream:
  - target: Respiratory Insufficiency Due to Muscle Weakness
    causal_link_type: DIRECT
  - target: Neonatal Respiratory Distress
    causal_link_type: DIRECT
- name: Bulbar Weakness and Feeding Difficulty
  description: >
    Weakness of the facial, palatal, pharyngeal and tongue musculature impairs suck and
    swallow from birth, causing feeding failure, aspiration risk and poor weight gain.
    Bulbar function is abnormal in essentially every patient formally examined, and
    feeding morbidity, like respiratory infection morbidity, tends to diminish with age
    in survivors.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:33397769
    reference_title: "A Cross-Sectional Study of Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure."
    explanation: Establishes near-universal bulbar involvement on formal assessment in a nemaline myopathy cohort including 18 ACTA1 patients.
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age."
    explanation: Supports the age-related improvement in feeding morbidity described by this node.
  downstream:
  - target: Feeding Difficulties
    causal_link_type: DIRECT
  - target: Gastrostomy Tube Feeding in Infancy
    causal_link_type: DIRECT
  - target: Bulbar Palsy
    causal_link_type: DIRECT
phenotypes:
- category: Musculoskeletal
  name: Hypotonia
  frequency: VERY_FREQUENT
  description: >
    Reduced muscle tone, presenting as a floppy infant in congenital-onset disease and
    accompanied by depressed or absent deep tendon reflexes.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes."
    explanation: GeneReviews chapter establishing hypotonia as a cardinal feature of nemaline myopathy.
- category: Musculoskeletal
  name: Proximal Muscle Weakness
  frequency: VERY_FREQUENT
  description: >
    Weakness predominantly affects proximal limb musculature, and is typically most
    severe in the face, neck flexors and proximal limbs. Distribution is proximal
    rather than distal at presentation.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The weakness typically affects proximal musculature, with variable involvement of the facial, bulbar, and respiratory muscles. Cardiac muscle is usually spared."
    explanation: States the proximal distribution of weakness, and the usual sparing of cardiac muscle.
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."
    explanation: GeneReviews statement of the weakness distribution.
- category: Musculoskeletal
  name: Facial Muscle Weakness
  frequency: FREQUENT
  description: >
    Weakness of the facial musculature contributes to the elongated, expressionless
    myopathic facies and to impaired suck in infancy.
  phenotype_term:
    preferred_term: Weakness of facial musculature
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."
    explanation: Names the face as one of the most severely affected regions.
- category: Musculoskeletal
  name: Neck Flexor Weakness
  frequency: FREQUENT
  description: >
    Marked neck flexor weakness, with head lag on pull-to-sit in infancy, is
    characteristic of the congenital myopathies and of nemaline myopathy in particular.
  phenotype_term:
    preferred_term: Neck flexor weakness
    term:
      id: HP:0003722
      label: Neck flexor weakness
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles."
    explanation: Names the neck flexors as one of the most severely affected muscle groups.
- category: Respiratory
  name: Respiratory Insufficiency Due to Muscle Weakness
  frequency: FREQUENT
  description: >
    Restrictive respiratory failure from weakness of the diaphragm and chest wall
    muscles. It is the cause of death in nemaline myopathy, and abnormal pulmonary
    function is common even among ambulant survivors, so it is under-recognised if
    sought only when a patient is symptomatic.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients."
    explanation: Establishes respiratory insufficiency as the universal cause of death in a mixed-genotype nemaline myopathy cohort in which 22 patients carried ACTA1 variants.
  - reference: PMID:33397769
    reference_title: "A Cross-Sectional Study of Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 27 individuals completing PFTs, abnormal values were observed in 65%."
    explanation: Quantifies abnormal pulmonary function in a cross-sectional nemaline myopathy cohort including 18 ACTA1 patients.
  - reference: PMID:40661861
    reference_title: "Retrospective Cohort Analysis of Clinical, Molecular, and Histopathologic Characteristics of 275 Patients With Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with respiratory distress at birth had increased odds of requiring both gastrostomy tubes and invasive ventilation"
    explanation: Identifies neonatal respiratory distress as an early predictor of long-term invasive respiratory support.
- category: Respiratory
  name: Neonatal Respiratory Distress
  frequency: FREQUENT
  description: >
    Severe congenital ACTA1 disease presents at birth with respiratory distress
    requiring immediate support. Neonatal respiratory failure, together with
    arthrogryposis and failure to achieve early motor milestones, is one of the
    features associated with death in the first year.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood."
    explanation: Documents neonatal-onset respiratory failure at the severe end of the ACTA1 dominant spectrum described in this subtype.
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life."
    explanation: Establishes neonatal respiratory disease as a prognostic marker of first-year mortality.
  - reference: PMID:35810298
    reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life."
    explanation: Describes the antenatal-to-neonatal course of the severe ACTA1 cohort in which this presentation is concentrated.
- category: Gastrointestinal
  name: Gastrostomy Tube Feeding in Infancy
  frequency: FREQUENT
  description: >
    Gastrostomy feeding in the first year. Infants with ACTA1-related nemaline myopathy
    are more likely than those with NEB-related disease to need a feeding tube and
    invasive ventilation in the first year of life, although the odds of invasive
    ventilation converge after the first year — so the genotype changes the intensity of
    infancy more than the long-term trajectory. Hypotonia at birth raises the odds of
    needing a gastrostomy, which makes the neonatal examination anticipatory rather than
    only descriptive.
  phenotype_term:
    preferred_term: Gastrostomy tube feeding in infancy
    term:
      id: HP:0011471
      label: Gastrostomy tube feeding in infancy
  evidence:
  - reference: PMID:40661861
    reference_title: "Retrospective Cohort Analysis of Clinical, Molecular, and Histopathologic Characteristics of 275 Patients With Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with ACTA1-NM were more likely to require feeding tubes and invasive ventilation in the first year of life compared with those with NEB-related NM, but the odds of requiring invasive ventilation were similar after the first year of age."
    explanation: Direct ACTA1-versus-NEB comparison of feeding-tube and ventilation need in a 275-patient nemaline myopathy cohort.
  - reference: PMID:40661861
    reference_title: "Retrospective Cohort Analysis of Clinical, Molecular, and Histopathologic Characteristics of 275 Patients With Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with hypotonia at birth had increased odds of requiring gastrostomy tubes"
    explanation: Identifies neonatal hypotonia as an early predictor of gastrostomy dependence.
- category: Gastrointestinal
  name: Feeding Difficulties
  frequency: FREQUENT
  description: >
    Impaired suck and swallow from birth, often requiring nasogastric or gastrostomy
    feeding. Feeding difficulty affected 79 of 143 patients in the largest clinical
    series, and tends to improve with age in survivors.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties."
    explanation: Quantifies feeding difficulty in the 143-patient nemaline myopathy series.
- category: Neurologic
  name: Bulbar Palsy
  frequency: FREQUENT
  description: >
    Weakness of the bulbar musculature affecting speech, swallow and airway protection.
    It was abnormal in every patient formally assessed in a cross-sectional nemaline
    myopathy cohort, which makes it a required element of assessment rather than an
    occasional complication.
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
  evidence:
  - reference: PMID:33397769
    reference_title: "A Cross-Sectional Study of Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure."
    explanation: Documents universal bulbar abnormality on formal testing in a cohort including 18 ACTA1 patients.
- category: Musculoskeletal
  name: Nemaline Bodies on Muscle Biopsy
  frequency: OBLIGATE
  diagnostic: true
  description: >
    Rod-shaped structures on Gomori trichrome staining of muscle, the defining
    histological lesion. Their presence is what makes the diagnosis nemaline myopathy
    rather than another ACTA1 congenital myopathy; their number does not predict
    severity.
  phenotype_term:
    preferred_term: Nemaline bodies
    term:
      id: HP:0003798
      label: Nemaline bodies
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome."
    explanation: Establishes nemaline bodies as the defining diagnostic lesion.
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The percentage of fibers with rods did not correlate with clinical severity"
    explanation: Supports the statement that rod burden is not a severity marker.
- category: Neurologic
  name: Hyporeflexia
  frequency: FREQUENT
  description: >
    Deep tendon reflexes are depressed or absent, which helps separate a congenital
    myopathy from a central cause of neonatal hypotonia at the bedside.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes."
    explanation: States depressed or absent reflexes as a cardinal feature.
- category: Musculoskeletal
  name: Arthrogryposis Multiplex Congenita
  frequency: OCCASIONAL
  description: >
    Multiple congenital contractures from reduced fetal movement, seen in a minority of
    patients and, with neonatal respiratory failure, one of the features that predicts
    death in the first year.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures."
    explanation: Places arthrogryposis among the minority features of the nemaline myopathy series.
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life."
    explanation: Establishes the prognostic weight of arthrogryposis.
- category: Developmental
  name: Motor Developmental Delay
  frequency: FREQUENT
  description: >
    Delayed acquisition of motor milestones. Independent ambulation before 18 months is
    the single best-documented favourable prognostic marker in nemaline myopathy, and
    failure to achieve early motor milestones is associated with early mortality — so
    milestone timing is prognostic information, not only a developmental observation.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk."
    explanation: Establishes early ambulation as a survival predictor and the usual eventual ambulation in the typical form.
  - reference: PMID:11558787
    reference_title: "Nemaline myopathy: a clinical study of 143 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality."
    explanation: Links failure of early milestones to mortality in the 143-patient series.
- category: Musculoskeletal
  name: Scoliosis
  frequency: OCCASIONAL
  description: >
    Progressive spinal deformity secondary to axial muscle weakness, and one of the
    features for which routine surveillance is recommended throughout childhood.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Routine assessment for respiratory function, scoliosis, joint contractures, and the need for assistive devices."
    explanation: GeneReviews surveillance recommendation identifying scoliosis as an expected complication to monitor.
histopathology:
- name: Sarcoplasmic and Intranuclear Nemaline Rods with Sarcomeric Disorganisation
  description: >
    Gomori trichrome staining shows rod-shaped nemaline bodies in the sarcoplasm;
    electron microscopy shows their Z-disk origin, and in a subset of ACTA1 cases rods
    are also present within myonuclei. Associated findings in ACTA1 muscle include
    abnormal fibre type differentiation, glycogen accumulation, myofibrillar disruption
    and whorling of actin thin filaments.
  context: ACTA1-related nemaline myopathy
  evidence:
  - reference: PMID:11333380
    reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and \"whorling\" of actin thin filaments."
    explanation: Lists the histological features accompanying rods in ACTA1 muscle.
  - reference: PMID:22825594
    reference_title: "Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Actin accumulations, nemaline and intranuclear bodies, fibre-type disproportion, cores, caps, dystrophic features and zebra bodies have all been seen in biopsies from patients with ACTA1 disease, with patients frequently presenting with multiple pathologies."
    explanation: Documents that ACTA1 biopsies frequently carry more than one structural lesion, which is why the histological boundary of this entry is soft.
genetic:
- name: ACTA1
  gene_term:
    preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  association: Causative
  relationship_type: CAUSATIVE
  frequency: VERY_FREQUENT
  notes: >
    ACTA1 encodes skeletal muscle alpha-actin. The gene is small — seven exons, six of
    them coding, across 2.8 kb — and pathogenic variants are distributed across all
    coding exons in proportion to exon size, with no hotspot, so targeted testing of
    part of the gene is not adequate. Most variants are private to one family.
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTA1 mutations are the second most common cause of nemaline myopathy after mutations in nebulin, accounting for 20% to 30% of a cohort of nemaline myopathy patients"
    explanation: Establishes ACTA1 as the second most common cause of nemaline myopathy.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTA1 mutations are distributed throughout the six coding exons of the gene (Figure 1, Supp. Table S1). No mutations have as yet been found in the non-coding exon 1. The number of mutations in each exon correlates with the size of each exon (Table 1). Thus, there do not appear to be any particular mutation hotspots"
    explanation: Supports the absence of a mutation hotspot, and so the need to sequence the whole coding region.
  - reference: PMID:35810298
    reference_title: "Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTA1 accounts for more than half of the severe NM cases."
    explanation: Establishes that ACTA1 is over-represented at the severe end of the nemaline myopathy spectrum, which is why a gene-defined entry is not interchangeable with a severity-defined one.
  case_fractions:
  - population: Nemaline myopathy cohorts reviewed to 2009
    case_fraction_low: 20.0
    case_fraction_high: 30.0
    notes: Second most common nemaline myopathy gene after NEB, and over-represented among severe cases.
    evidence:
    - reference: PMID:19562689
      reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ACTA1 mutations are the second most common cause of nemaline myopathy after mutations in nebulin, accounting for 20% to 30% of a cohort of nemaline myopathy patients"
      explanation: Source of the 20-30% case fraction.
  - population: Australian nemaline myopathy cohort, 35 patients screened
    case_fraction_percent: 15.0
    cohort_size: 35
    notes: Earlier single-cohort estimate from the series that first defined the ACTA1 clinical spectrum.
    evidence:
    - reference: PMID:11333380
      reference_title: "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha-skeletal actin account for the disease in approximately 15% of patients with NM."
      explanation: Source of the 15% single-cohort case fraction.
diagnosis:
- name: Muscle Biopsy with Gomori Trichrome Staining
  description: >
    Histological demonstration of nemaline bodies establishes the nemaline myopathy
    phenotype. Electron microscopy adds the Z-disk origin of the rods and detects
    intranuclear rods.
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome."
    explanation: States the histological basis of diagnosis.
- name: ACTA1 Sequencing
  description: >
    Sequencing of the whole ACTA1 coding region, in practice as part of a congenital
    myopathy gene panel or exome, is required to assign the genotype. Because there is
    no mutation hotspot and most variants are private, partial-gene testing is not
    adequate, and parental testing is needed to distinguish a de novo dominant variant
    from a recessive genotype — a distinction that changes the recurrence risk from
    50% to 25%.
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where DNA has been available for testing from the parents of sporadic patients, 79/94 or 84% had de novo dominant mutations not present in the peripheral blood DNA of either parent, while only 16% had recessive ACTA1 mutations."
    explanation: Supports parental testing as the step that resolves inheritance mode, and quantifies how often each answer is found.
differential_diagnoses:
- name: NEB-Related Nemaline Myopathy
  description: >
    Nebulin is the most common cause of nemaline myopathy and is clinically hard to
    separate from ACTA1 disease: in a cross-sectional cohort the two genotypes were
    largely similar in phenotype. The distinction is genetic and matters mainly for
    recurrence risk, since NEB disease is recessive.
  distinguishing_features:
  - Recessive inheritance with a 25% sibling recurrence risk rather than a dominant de novo mechanism
  - No intranuclear rods or actin aggregates attributable to nebulin
  evidence:
  - reference: PMID:33397769
    reference_title: "A Cross-Sectional Study of Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype."
    explanation: Establishes that the two commonest nemaline myopathy genotypes cannot be reliably separated clinically.
- name: Non-Nemaline ACTA1 Congenital Myopathies
  description: >
    The same gene causes intranuclear rod myopathy, actin filament aggregate myopathy,
    congenital fibre-type disproportion and myopathy with core-like areas. These are
    distinguished on biopsy rather than clinically, and a single biopsy may show several
    patterns at once, so the separation is a histological convention rather than a
    boundary between diseases.
  distinguishing_features:
  - Actin filament aggregates or fibre-type disproportion in place of, or alongside, nemaline rods
  - Attributed by MONDO to the alpha-actinopathy umbrella (MONDO:0100084) rather than to nemaline myopathy
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core-like areas."
    explanation: Enumerates the ACTA1 histological entities that sit outside this entry's scope.
  - reference: PMID:17387733
    reference_title: "The pathogenesis of ACTA1-related congenital fiber type disproportion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM."
    explanation: Gives the ultrastructural feature that separates ACTA1 fibre-type disproportion from severe ACTA1 nemaline myopathy.
treatments:
- name: Respiratory Surveillance and Ventilatory Support
  description: >
    Non-invasive ventilation for nocturnal hypoventilation, aggressive treatment of
    lower respiratory tract infections, and pre-operative pulmonary function assessment.
    Because respiratory failure is the cause of death and is frequently under-recognised
    in older patients whose limb strength looks stable, respiratory function is assessed
    on schedule rather than on symptoms.
  action_category: MONITORING
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: respiratory support and monitoring
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Aggressive treatment of lower respiratory tract infections, ventilator use for nocturnal hypoxia, preoperative assessment of pulmonary function to ensure optimal timing of surgical procedures and to minimize anesthetic risk, monitoring of nutritional status, special feeding techniques, standard care for gastroesophageal reflux, mobility and physical therapy to help prevent joint contractures, speech therapy, and assessment of cardiac status."
    explanation: GeneReviews management recommendation covering ventilatory and infection management.
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Routine assessment for respiratory function, scoliosis, joint contractures, and the need for assistive devices."
    explanation: Establishes scheduled respiratory surveillance rather than symptom-triggered assessment.
- name: Nutritional Support and Assisted Feeding
  description: >
    Nasogastric or gastrostomy feeding, attention to swallow safety, and management of
    gastro-oesophageal reflux, with monitoring of nutritional status. Bulbar involvement
    is near-universal on formal testing even when it is not the presenting complaint.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitoring of nutritional status, special feeding techniques, standard care for gastroesophageal reflux"
    explanation: GeneReviews nutritional management recommendation.
- name: Physical Therapy and Contracture Prevention
  description: >
    Mobility work and physiotherapy to limit joint contractures, with orthopaedic
    surveillance for scoliosis and assistive device needs across childhood.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mobility and physical therapy to help prevent joint contractures, speech therapy, and assessment of cardiac status"
    explanation: GeneReviews recommendation for physiotherapy and contracture prevention.
- name: Avoidance of Neuromuscular Blocking Agents
  description: >
    Neuromuscular blocking agents are to be avoided because of a possible association
    with malignant hyperthermia susceptibility. This is an anaesthetic-safety warning
    that applies at every surgical or procedural encounter, and is one of the few
    actionable items a family can carry on a care plan.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: perioperative risk management
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301465
    reference_title: "Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Neuromuscular blocking agents, because of possible association with malignant hyperthermia susceptibility."
    explanation: GeneReviews agents-to-avoid warning, quoted directly.
  notes: >
    The source states a *possible* association with malignant hyperthermia
    susceptibility, and it is a retired GeneReviews chapter, so the strength of this
    claim should not be read as equivalent to the established susceptibility in
    RYR1-related core myopathies. A PubMed search for `ACTA1 malignant hyperthermia`
    returns four records, of which the only nemaline-myopathy one is this same retired
    chapter (PMID:20301465) and its companion chapter PMID:20301436; a search for
    `nemaline myopathy malignant hyperthermia` returns 39 records whose top hits are
    about TPM2 multiple pterygium syndrome and unrelated topics. No primary study
    establishing malignant hyperthermia susceptibility in ACTA1 disease was found, so
    the warning is recorded as the chapter states it and not strengthened.
- name: Genetic Counseling and Parental Testing
  description: >
    Counselling turns on which inheritance mode is operating. A de novo dominant variant
    carries a 50% risk to the proband's own offspring and a low but real sibling risk
    from parental mosaicism; a recessive genotype carries a 25% sibling risk and
    unaffected heterozygous parents. Parental testing is what distinguishes them, and a
    normal parental blood result does not exclude gonadal mosaicism.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There have been a number of instances where a severely affected proband was identified, and mildly affected or asymptomatic family members were found to carry the same dominant mutation. In at least three cases this can be explained by somatic mosaicism in one parent of a severely affected patient"
    explanation: Supports counselling for parental mosaicism after an apparently de novo dominant variant.
  - reference: PMID:19562689
    reference_title: "Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutation carriers (parents or siblings of patients with recessive ACTA1 mutations) were clinically unaffected, suggesting that expression from one intact copy of ACTA1 is sufficient for normal function"
    explanation: Supports the unaffected-carrier counselling message in recessive families.
  - reference: PMID:20301436
    reference_title: "Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTA1 and TPM3 pathogenic variants are often de novo dominant."
    explanation: Retired GeneReviews statement that ACTA1 variants are usually de novo dominant, which is the counselling default this treatment starts from before parental testing.
- name: Fast Skeletal Muscle Troponin Activation (Investigational)
  description: >
    Small molecules that sensitise the thin filament to calcium increase submaximal
    force without changing the underlying genotype. Tirasemtiv improved contractile
    capacity in fast-twitch and diaphragm muscle of an Acta1 p.Asp286Gly mouse carrying
    a patient-derived dominant variant. This is preclinical: there is no approved
    disease-specific therapy for ACTA1 nemaline myopathy.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tirasemtiv
      term:
        id: CHEBI:755074
        label: tirasemtiv
  target_mechanisms:
  - target: Reduced Skeletal Muscle Force Generation
    description: Increases submaximal thin-filament calcium sensitivity, partially offsetting the contractile deficit.
  evidence:
  - reference: PMID:38376469
    reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."
    explanation: Preclinical efficacy of thin-filament calcium sensitisation in a patient-variant mouse model.
  - reference: PMID:22825594
    reference_title: "Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The use of small molecules to sensitise the contractile apparatus to Ca(2+) is a promising therapeutic for patients with various neuromuscular disorders, including ACTA1 disease."
    explanation: Review support for calcium sensitisation as a therapeutic strategy in ACTA1 disease.
- name: Cardiac Alpha-Actin Isoform Replacement (Investigational)
  description: >
    Cardiac alpha-actin is 99% identical to the skeletal isoform and is the predominant
    sarcomeric actin in fetal muscle, so re-expressing it postnatally can substitute for
    absent or poisoned skeletal alpha-actin. In mice it rescued the recessive null model
    and markedly reduced lethality in one dominant model but not another, so its benefit
    is allele-dependent rather than general. Preclinical only.
  action_category: THERAPEUTIC
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Absence of Functional Skeletal Muscle Alpha-Actin
    description: Supplies a near-identical sarcomeric actin isoform in place of the missing skeletal isoform.
  evidence:
  - reference: PMID:23736297
    reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease."
    explanation: Establishes isoform substitution as effective in the recessive null model.
  - reference: PMID:23736297
    reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from ∼59% before 30 days of age to ∼12%. In the other model, Acta1(H40Y), in which ∼80% of male mice die by 5 months of age, the cardiac α-actin transgene did not significantly improve survival."
    explanation: Documents the allele-dependent benefit, including the negative result, that qualifies this strategy.
  - reference: PMID:19468071
    reference_title: "Rescue of skeletal muscle alpha-actin-null mice by cardiac (fetal) alpha-actin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases."
    explanation: Original demonstration that cardiac alpha-actin re-expression rescues Acta1-null mice, which is the basis of this strategy.
animal_models:
- name: Acta1 p.Asp286Gly knock-in mouse
  species: Mouse
  genotype: Acta1 p.Asp286Gly, patient-derived dominant variant
  publication: PMID:38376469
  description: >
    Mouse carrying a dominant ACTA1 variant found in patients, used to test
    thin-filament calcium sensitisers.
  modeled_mechanisms:
  - target: Reduced Skeletal Muscle Force Generation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >
      Reproduces the submaximal force deficit of dominant ACTA1 disease in limb and
      diaphragm muscle, and responds to pharmacological calcium sensitisation.
    limitations: >
      A single dominant allele in an inbred background; it does not model recessive null
      disease, the human severity spectrum, or the developmental and bulbar
      presentation of congenital-onset human disease.
    readouts:
    - name: Submaximal muscle contractile capacity
      target: Reduced Skeletal Muscle Force Generation
      direction: RESTORED
      interpretation: Pharmacological rescue of submaximal force identifies a reversible component of the contractile deficit.
      evidence:
      - reference: PMID:38376469
        reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo."
        explanation: Reports the measurement and its direction.
  evidence:
  - reference: PMID:38376469
    reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1"
    explanation: Identifies the model as carrying a patient-derived ACTA1 variant.
- name: Acta1 knock-out mouse
  species: Mouse
  genotype: Acta1 null (knock-out)
  publication: PMID:23736297
  description: >
    Models recessive ACTA1 disease, in which no functional skeletal muscle alpha-actin
    is made; rescued postnatally by transgenic cardiac alpha-actin.
  modeled_mechanisms:
  - target: Absence of Functional Skeletal Muscle Alpha-Actin
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Complete absence of skeletal muscle alpha-actin, as in human recessive null disease.
    limitations: >
      Mouse and human differ in postnatal cardiac alpha-actin expression, and one
      dominant model in the same study showed endogenously elevated cardiac alpha-actin
      that has not been reported in patients, so isoform-compensation findings do not
      transfer directly to humans.
    evidence:
    - reference: PMID:23736297
      reference_title: "Cardiac α-actin over-expression therapy in dominant ACTA1 disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease."
      explanation: Identifies the knock-out as the model of recessive ACTA1 disease.
experimental_models:
- name: ACTA1 H40Y iPSC-derived skeletal myocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    Isogenic CRISPR-Cas9 iPSC lines carrying the ACTA1 H40Y point mutation, differentiated
    to skeletal myocytes. Mitochondrial membrane potential, permeability transition pore
    formation, superoxide production and ATP levels are abnormal, and ATP supplementation
    protects the mitochondria from stress-induced injury. Nemaline rods do not form in
    this system, which bounds what it can be used for.
  evidence:
  - reference: PMID:36796746
    reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."
    explanation: Reports the bioenergetic phenotype this model is used to study.
  modeled_mechanisms:
  - target: Mitochondrial Dysfunction in ACTA1-Mutant Myofibres
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >
      The model observes the node's own quantities — cellular ATP, mitochondrial membrane
      potential, permeability transition pore formation and superoxide — at the cellular
      scale the node is tagged with, in isogenic lines differing only at the ACTA1 locus.
    limitations: >
      Nemaline rods, the defining lesion of the disease, do not form in this system, so
      it does not model the histology; it carries one dominant allele in cultured
      myocytes rather than in innervated, mechanically loaded muscle, and nothing links
      the bioenergetic defect to force in patient tissue.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >
        Nemaline rods, the defining histological lesion, are absent from the model
        despite the ACTA1 mutation being present, so nothing in the model connects the
        bioenergetic defect to rod formation.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >
        The lines carry the single dominant H40Y allele. Recessive null genotypes and the
        rest of the ACTA1 allelic spectrum are not represented.
    readouts:
    - name: Cellular ATP level
      target: Mitochondrial Dysfunction in ACTA1-Mutant Myofibres
      direction: DECREASED
      interpretation: Bioenergetic readout grounding the ATP metabolic process annotation on this node.
      evidence:
      - reference: PMID:36796746
        reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."
        explanation: Reports the measurement and its direction.
    - name: Mitochondrial membrane potential
      target: Mitochondrial Dysfunction in ACTA1-Mutant Myofibres
      direction: ALTERED
      interpretation: Readout grounding the mitochondrial membrane potential annotation on this node.
      evidence:
      - reference: PMID:36796746
        reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential."
        explanation: Reports the measurement; the paper states the potential is altered without a single direction, so the readout is recorded as ALTERED.
    evidence:
    - reference: PMID:36796746
      reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury."
      explanation: The authors' own statement of what the model shows.
    - reference: PMID:36796746
      reference_title: "ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "Importantly, the nemaline rod phenotype was absent in our in vitro model of NM."
      explanation: Records the negative result that limits this model's fidelity to the human disease.
discussions:
- discussion_id: acta1_lesion_specificity_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >
    Why do ACTA1 variants cause muscle weakness, and what determines which structural
    lesion — nemaline rods, actin aggregates, intranuclear rods, fibre-type
    disproportion — a given variant produces?
  attaches_to:
  - pathophysiology#Defective Actin-Tropomyosin Regulation
  - pathophysiology#Sarcomeric Disorganisation
  - pathophysiology#Nemaline Rod Formation
  rationale: >
    Despite two decades of work in cell culture, animal models and patient tissue, the
    mechanism linking mutant alpha-actin to weakness and to a particular structural
    lesion is not established, and single biopsies frequently show several lesions at
    once. This is why the histological boundary of this entry is a convention rather
    than a mechanistic distinction, and why genotype does not predict phenotype.
  evidence:
  - reference: PMID:22825594
    reference_title: "Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Despite extensive research into normal actin function and the functional consequences of ACTA1 mutations in cell culture, animal models and patient tissue, the mechanisms underlying muscle weakness and the formation of structural lesions remains largely unknown."
    explanation: States the gap directly.

📚

References & Deep Research

References

2

PMID:20301465

Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

1 finding

The only GeneReviews chapter covering this disease has been retired, so there is no current GeneReviews phenotype baseline for nemaline myopathy. The archived chapter is still the source of the six-category ENMC clinical classification, the surveillance schedule and the neuromuscular-blocking-agent warning quoted in this entry, and its content is disease-wide rather than ACTA1-specific.

"NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE."

PMID:20301436

Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

1 finding

The retired companion GeneReviews chapter covers congenital fibre-type disproportion, the ACTA1 allelic histology that this entry deliberately excludes from scope. It is cited here only because it carries the same neuromuscular-blocking-agent and malignant-hyperthermia caution as the nemaline myopathy chapter, and because its genetic-counselling section records that ACTA1 variants are usually de novo dominant. ACTA1 accounts for roughly 6% of CFTD, so the chapter is not an ACTA1-specific source.

"ACTA1 and TPM3 pathogenic variants are often de novo dominant."

Deep Research

1

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

Evaluations and curation notes (2)

Review round 1: split bundled nodes, regrade background quotes · 2026-09-27T06:02:41Z · View source

Single bundled response to the CHANGES_REQUESTED review on PR #12958 (review 5328694844). Pathophysiology. 'Defective Actin-Tropomyosin Interaction and Sarcomeric Disorganisation' was split into 'Defective Actin-Tropomyosin Regulation' (MOLECULAR, tropomyosin binding GO:0005523 DYSREGULATED) and 'Sarcomeric Disorganisation' (CELLULAR, sarcomere organization GO:0045214 DECREASED). The separability is now evidenced rather than asserted: PMID:17387733 reports the CFTD variants carrying the actin-tropomyosin defect with normal sarcomeric structure on electron microscopy, and concludes weakness there follows from disrupted sarcomere function rather than structure. The two nodes are parallel consequences of mutant-actin incorporation, not a chain, because that is what the dissociation shows. The recessive null route no longer passes through the regulatory node - a null allele produces no mutant actin to mis-regulate tropomyosin - and points straight at reduced force generation with PMID:25182138 evidence, where the edge previously had none. 'Nuclear Envelope Disruption and Intranuclear Rods' became 'Nuclear Envelope and LINC Complex Disruption' and lost its near-circular edge into rod formation, which rested on a co-occurrence snippet; intranuclear rods stay on the rod node. A 'Mitochondrial Dysfunction in ACTA1-Mutant Myofibres' node (CELLULAR; ATP metabolic process GO:0046034 DECREASED, regulation of mitochondrial membrane potential GO:0051881 DYSREGULATED) was added from PMID:36796746, and the H40Y iPSC model now RECAPITULATES it at MODERATE fidelity with two readouts, instead of PARTIALLY_RECAPITULATES on a force node it does not observe. The PROXY_QUANTITY and SCALE_EXTRAPOLATION divergences are gone because they no longer apply; BOUNDARY_OMISSION (no rods) stays and POPULATION_MISMATCH (single dominant allele) was added. Evidence grading. Three PMID:23736297 background sentences were regraded off MODEL_ORGANISM: the poison-peptide statement (two sites) to HUMAN_CLINICAL + quote_role BACKGROUND, and the cardiac/skeletal isoform identity fact to OTHER + BACKGROUND. The paper's own knockout and survival results keep MODEL_ORGANISM. All four PMID:22825594 items carry quote_role REVIEW_SYNTHESIS. Subtypes. The 'subtype: Dominant' tags on Neonatal Respiratory Distress and Arthrogryposis Multiplex Congenita were removed: recessive ACTA1 genotypes reported to 2014 all produced severe weakness from birth, so the tags told a reader recessive patients do not get those features. No replacement subtype-scoped phenotype was added, because no clinical feature in the entry is supported as dominant- or recessive-specific by its own source; the note records that. References. PMID:20301436, the retired congenital fibre-type disproportion chapter cited in the malignant-hyperthermia note, is now in the top-level references with tags [GeneReviews] and a finding, and its counselling statement that ACTA1 variants are often de novo dominant is cited on the Genetic Counseling treatment. check-genereviews now reports TAGGED for both chapters and no CITED_UNTAGGED. Also: tirasemtiv bound to CHEBI:755074 as therapeutic_agent (OAK lookup, not memory); Nutritional Support moved off therapeutic_modality BEHAVIORAL to OTHER; directness INDIRECT recorded on the speculative incorporation-to-rod edge and on the two other inferential edges added here. Declined: a cardiomyopathy phenotype. The ~5% figure is a deep-research claim attributed to PMID:40661861, whose cached abstract does not contain it, it spans all ACTA1 phenotypes rather than nemaline myopathy, and ACTA1-related dilated cardiomyopathy is a separate out-of-scope entity. The gap is recorded in notes instead.

Create: ACTA1-Related_Nemaline_Myopathy · 2026-09-26T23:55:20Z · View source

Created a gene-defined entry for ACTA1-related nemaline myopathy, anchored on MONDO:0008070 (CMYO2A / NEM3), which was bound nowhere in kb/ before this change. The lump/split call is recorded in the entry's notes: MONDO:0008070 is defined by its gene and is filed by MONDO beneath four severity bands of nemaline myopathy at once, so it cannot be added as a has_subtypes row to kb/disorders/Nemaline_Myopathy.yaml, which splits on severity. Orphanet corroborates the crossing: ORPHA:171430 and ORPHA:171436 both list OMIM:161800 as a Broader cross-reference. A narrowMatch-only mapping on the parent entry, proposed in the claim issue thread by an automated second opinion, was rejected because it would retire the concept from the curation queue without adding an ACTA1-specific pathograph. Nemaline_Myopathy.yaml was not edited. Scope is ACTA1 nemaline myopathy; the non-nemaline ACTA1 histologies sit under MONDO:0100084 alpha-actinopathy, recorded as a broadMatch, and are stated out of scope in notes and differential_diagnoses. Deep research: falcon was requested and returned HTTP 402 (out of credits), so the run fell back to claude_code; the report is committed with fell_back true in its frontmatter. Its reference_validation reports 25/25 references resolved, 7/9 quotes valid and needs_review true; just preflight-dr returned SKIP because MONDO records no causal gene for MONDO:0008070, and the manual check passed (report OMIM 161800 matches MONDO's, top gene ACTA1=90). No content was taken from the report without checking the primary source; the two references carrying unsupported quotes (PMC:PMC3447773, PMID:15236405) are not cited in the entry. Evidence gaps recorded in notes: no ACTA1-specific population prevalence figure could be sourced, so no prevalence block was written; several phenotype frequencies come from mixed-genotype nemaline myopathy cohorts and each such evidence item says so. The GeneReviews nemaline myopathy chapter (PMID:20301465) is retired, which is recorded as a Finding on the top-level references block and tagged GeneReviews. Validation: just validate passed with 93/93 snippets verified and 1 title checked; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values and list-gene-term-mismatches all clean; check-genereviews reports TAGGED with no CITED_UNTAGGED. Noted for the repository: the deep-research run's own reference validation rewrote two committed references_cache files (PMID_35810298, PMID_36960434), downgrading PMID_35810298 from full text to abstract; both were reverted before commit.

Claude Code ▸

ACTA1-Related Nemaline Myopathy: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 29 citations 2026-09-26T23:40:09.399719

ACTA1-Related Nemaline Myopathy: Comprehensive Research Report

Identifiers

Gene: ACTA1 (actin alpha 1, skeletal muscle) — HGNC:129, NCBI Gene ID: 58, chromosome 1q42.13 (Atlas Genet Cytogenet Oncol Haematol; PMID:10072583)
OMIM gene: 102610 — ACTIN, ALPHA-1, SKELETAL MUSCLE; ACTA1 (omim.org/entry/102610)
OMIM phenotypes (phenotypic series, current nosology):
#161800 — Congenital myopathy 2A, typical, autosomal dominant (CMYO2A; historically "Nemaline myopathy 3," NEM3)
#620265 — Congenital myopathy 2B, severe infantile, autosomal recessive (CMYO2B)
#620278 — Congenital myopathy 2C, severe infantile, autosomal dominant (CMYO2C)
Additional allelic entities discussed below: actin-accumulation myopathy, intranuclear rod myopathy, cap myopathy, congenital fiber-type disproportion (CFTD), and an emerging dilated-cardiomyopathy/distal-myopathy spectrum
MONDO: MONDO:0008070; MedGen: C3711389
UniProt: P68133 (skeletal muscle α-actin, ACTS_HUMAN); MGI (mouse ortholog): MGI:87902 (Acta1)
Orphanet lists nemaline myopathy generically with ACTA1 as a causal gene; I was not able to retrieve a confirmed disease-specific ORPHA code for the ACTA1 subtype from the sources fetched in this session — flagged as a gap rather than guessed.

Most of what follows is aggregated disease-level knowledge (literature cohorts, structured databases, model-organism studies) rather than a single-patient EHR source.

1. Disease Overview

Nemaline myopathy (NM) is a clinically and genetically heterogeneous group of congenital skeletal-muscle disorders defined by the presence of rod-like ("nemaline") inclusions in myofibers on biopsy, together with hypotonia and weakness of variable severity. ACTA1, encoding skeletal muscle α-actin — the core building block of the sarcomeric thin filament — is the second most common causal gene after NEB (nebulin) for NM overall, but the single most common cause of the severe subset: "ACTA1 accounts for more than half of the severe NM cases" (PMC9271256; Acta Neuropathol Commun 2022, doi:10.1186/s40478-022-01400-0). Population-level estimates place ACTA1 at roughly 20–41% of genetically solved NM cohorts depending on severity mix, and ACTA1 variants overall account for ~15–25% of all congenital myopathy diagnoses (search synthesis of multiple reviews; PMID:22825594 Nowak, Ravenscroft & Laing, Acta Neuropathol 2013).

Common synonyms/related terms: nemaline myopathy 3 (NEM3, legacy name), actin-accumulation myopathy, congenital myopathy with excess of thin filaments, intranuclear rod myopathy, cap myopathy (specific to the p.Met47Val variant), and — increasingly recognized as distinct, non-NM phenotypes from the same gene — congenital fiber-type disproportion (CFTD), ACTA1-related dilated cardiomyopathy, and an emerging ACTA1-related distal myopathy.

2. Etiology

Disease causal factor. ACTA1-related myopathy is a purely monogenic structural-protein disorder — no environmental, infectious, or multifactorial contribution to primary causation has been established. All causation is genetic, arising through two distinct molecular routes (detailed in §4/§6):

Dominant, usually de novo, missense mutation — a mutant actin monomer is incorporated into the thin filament alongside wild-type actin, producing a dominant-negative/poison-subunit effect rather than haploinsufficiency. This explains 93.3% (365/391) of pathogenic/likely-pathogenic (P/LP) ACTA1 variants in the most recent curated update, of which 88% are confirmed de novo (PMC11918651, Clayton et al., Hum Mutat 2024/2025 variant-database update).
Biallelic (homozygous/compound-heterozygous) loss-of-function (frameshift/nonsense) — complete absence of skeletal α-actin protein, accounting for 6.6% (26/391) of P/LP variants, and producing severe, often lethal disease (PMID:25182138, Eur J Hum Genet 2015, "Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine").

Genetic risk factors. The gene itself is the risk factor; there is no described common susceptibility-locus or polygenic contribution. gnomAD constraint data are informative for interpreting variant pathogenicity: ACTA1 is markedly missense-constrained (only ~21% of expected missense variants observed genome-wide-length-adjusted; ranked 164th of 19,704 genes for missense intolerance) but tolerant of loss-of-function heterozygosity (pLI 0; o/e 0.74, 11 observed/14.9 expected) — consistent with the mechanism above: a null allele is silent in the heterozygous state, and disease from LoF variants requires biallelic loss (PMC11918651).

Environmental risk factors: none identified.

Protective factors. A partial biological "rescue" mechanism has been demonstrated in the recessive-null state: cardiac (fetal) α-actin (ACTC1) is normally co-expressed in developing skeletal muscle and down-regulated postnatally; in Acta1-null mice, sustained/elevated ACTC1 expression is sufficient to functionally substitute for absent skeletal α-actin and rescue lethality — "ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle" (PMID:19468071, Nowak et al., J Cell Biol 2009). This is the leading candidate explanation for why some biallelic-null human patients survive rather than uniformly dying perinatally, and it has been explicitly pursued as a therapeutic strategy for dominant ACTA1 disease as well (cardiac α-actin over-expression therapy; PMID:23736297) — see §12.

Gene-environment interactions: none reported; this is not a gene-environment-interaction disease model.

3. Phenotypes

Phenotype data below are drawn from aggregated multi-patient literature cohorts (case-series/systematic reviews), not from a single registry with formal frequency validation — treat percentages as literature-derived estimates from the specific cohorts cited, which differ in inclusion criteria (severity-enriched vs. unselected).

Core/near-universal features | Phenotype | Onset/pattern | Frequency (source cohort) | Suggested HPO | |---|---|---|---| | Neonatal hypotonia | Congenital | Near-universal in congenital forms | HP:0001319 | | Generalized muscle weakness, neck-flexor and respiratory predominance | Congenital–childhood | Defining feature of "typical" form | HP:0003324 | | Respiratory insufficiency/failure | Neonatal–progressive | 75/143 significant first-year respiratory disease (PMID:11558787, Ryan et al., Ann Neurol 2001); dyspnea in 55% of a pediatric cohort (n=101) | HP:0002093 / HP:0004879 | | Feeding difficulty/dysphagia | Neonatal onward | 79/143 (Ryan et al.); 47% dysphagia in pediatric cohort | HP:0002015 / HP:0011968 | | Hypo-/areflexia | Congenital | Common | HP:0001265 | | Axial (truncal) weakness | Variable | 68% (pediatric systematic review, n=101, PMC10032635) | HP:0003701 |

Musculoskeletal/structural - Arthrogryposis multiplex congenita (HP:0002804) — a strong early-mortality predictor - High-arched palate (HP:0002705), facial weakness/myopathic facies - Kyphoscoliosis/scoliosis (HP:0002650) — a major progressive complication in survivors - Pectus excavatum (HP:0000767), clubfoot/pes planus (HP:0001762) - Fractures, joint contractures, skull enlargement (pediatric systematic review, PMC10032635)

Atypical/emerging phenotypes (from the largest recent cohort, n=275): ophthalmoplegia, unusual weakness distribution, cardiomyopathy, and intranuclear rods as "atypical" ACTA1 presentations (PMID:40661861, Neurol Genet 2025).

Prenatal (severe end of spectrum) - Fetal akinesia/reduced fetal movement (HP:0001989), polyhydramnios (HP:0001561, from impaired fetal swallowing, appearing from ~28 weeks), intrauterine growth restriction, pulmonary hypoplasia — the fetal akinesia deformation sequence (FADS), of which ACTA1 is a recognized cause via de novo or somatic mosaic variants (search synthesis; general FADS population incidence ~1:15,000 in a Danish study, not ACTA1-specific).

Laboratory - Creatine kinase typically normal to mildly elevated (reported means ~107 IU/L, range 25–369) — a distinguishing feature from dystrophic myopathies (search synthesis of case reports).

Quality of life. No ACTA1-specific EQ-5D/SF-36 data were located; qualitatively, respiratory failure, feeding dependence, and progressive scoliosis are the dominant drivers of morbidity and caregiver burden, and these tend to diminish with age in survivors while chronic weakness and orthopedic sequelae persist (PMID:11558787).

4. Genetic/Molecular Information

Variant landscape (most current source: Clayton et al. curated update, PMC11918651): - 607 total reported variants across HGMD/LOVD/ClinVar; after ACMG/AMP reclassification, 447 pathogenic/likely pathogenic, 13 VUS, 147 benign/likely benign. - Type distribution among 391 analyzed P/LP variants: missense 340 (87.0%), frameshift 18 (4.6%), nonsense 13 (3.3%), splicing 9 (2.3%), in-frame indel 6 (1.5%), stop-loss 3 (0.8%), start-loss 2 (0.5%). - Inheritance: dominant 365/391 (93.3%) (88% of these confirmed de novo), recessive 26/391 (6.6%). - Missense P/LP variants affect 154/377 (40.8%) of ACTA1 residues; across all six human actin isoforms, disease-associated missense variants collectively involve 345/377 (91.5%) residues — reflecting near-total intolerance of the actin fold to substitution. - Phenotype distribution among P/LP variants: nemaline myopathy 74%, congenital fiber-type disproportion 7.2%, intranuclear rod myopathy 4.3%, cardiomyopathies 5.3% (dilated most common), fetal abnormalities 5.3%, and an emerging distal myopathy phenotype (4 reported families) — 20 distinct clinical presentations recorded in total.

Structural mechanism. Skeletal α-actin folds into two lobes each with two subdomains (SD1–SD4); a cleft between SD2 and SD4 binds ATP/ADP·Mg²⁺, clamped by phosphate-binding loops P1 (residues 11–16) and P2 (residues 154–161), while a separate cleft between SD1 and SD3 mediates binding of most actin-binding proteins, including myosin and tropomyosin (search synthesis of structural biology literature). Disease variants cluster at: - The ATP-binding cleft, disrupting nucleotide binding and polymerization competence; - The actin-actin (longitudinal/lateral filament) interface, impairing thin-filament assembly; - The actin-myosin/tropomyosin interaction surface, directly impairing cross-bridge cycling — demonstrated for p.Asp286Gly, which "prevents proper strong myosin binding and triggers muscle weakness" (PMC3447773, PLOS One).

Dominant-negative evidence. Direct biochemical/cellular evidence for a dominant-negative mechanism (abnormal folding, aggregation, and altered polymerization of mutant actin isoforms) is reported in PMID:15198992. Genotype-phenotype heterogeneity is substantial even for the same or similar residues — "the marked variability in clinical phenotype among patients with different mutations in ACTA1 suggested that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions" (search synthesis; corroborated by PMID:15236405, "Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations").

Recessive/null mechanism. Biallelic frameshift/nonsense variants abolish ACTA1 protein expression entirely. "Previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein... All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth," with reported deaths at 5 and 19 days of age in the most severe reported cases (search synthesis of case literature; PMID:25182138). Postnatal compensatory upregulation of cardiac (fetal) α-actin (ACTC1) in skeletal muscle is proposed to explain the variable survival seen in some null-recessive patients (mechanistically validated in mice, PMID:19468071).

Cardiomyopathy variants. A distinct, non-skeletal-muscle-predominant phenotype has been reported: p.Arg256His causes dilated cardiomyopathy via disruption of actin structure/function and cardiomyocyte hypocontractility (PMID:38559046, 2024) — evidence that the same gene can produce organ-selective disease depending on variant biochemistry and which sarcomeric isoform environment is affected.

Modifier genes: none formally established for ACTA1 specifically; comparative cohort data show that genotype (ACTA1 vs. NEB) itself modifies early feeding/ventilation needs (§9/§11), but no discrete modifier locus has been identified.

Epigenetic information / chromosomal abnormalities: not applicable/not reported — ACTA1 disease is driven by point mutations and small indels in a single, small (6-exon) protein-coding gene; no epigenetic mechanism or large chromosomal rearrangement has been implicated.

5. Environmental Information

No environmental, lifestyle, or infectious causal factor has been established for ACTA1-related myopathy — it is fully accounted for by the genetic mechanisms above. Infections (particularly respiratory) are a major secondary driver of morbidity and mortality (aspiration, pneumonia) rather than a cause, consistent with the respiratory-muscle weakness and impaired airway clearance intrinsic to the disease (§3, §11).

6. Mechanism / Pathophysiology

Causal chain (numbered, with explicit branch points)

A heterozygous, typically de novo, missense mutation in ACTA1 alters the amino-acid sequence of skeletal muscle α-actin at a site critical to the ATP-binding cleft, the actin-actin polymerization interface, or the actin-myosin/tropomyosin binding surface — OR, alternatively, biallelic frameshift/nonsense mutation abolishes ACTA1 protein expression entirely (branch established at step 1; downstream consequences diverge, see step 9).
For dominant missense variants: the mutant actin monomer is co-synthesized with wild-type actin and incorporates into growing thin filaments as a "poison subunit" (dominant-negative mechanism), demonstrated directly by abnormal folding, aggregation, and altered polymerization kinetics of mutant actin isoforms (PMID:15198992).
This leads to defective actin polymerization — patient-derived fibroblasts show markedly shortened, unstructured actin filaments, with only ~7% of mutant cells achieving correct polymerization versus near-100% of controls (PMC10740811, in vitro, patient fibroblasts).
Depending on mutation site, misfolded/mutant actin results in aggregation into rod-like inclusions (classic nemaline/rod bodies, structurally continuous with Z-disks and containing α-actinin, myotilin, and sarcomeric actin), or into intranuclear rods, cytoplasmic bodies, cores, or caps — a branch point in the cascade that determines histopathological subtype rather than clinical severity per se (PMID:22825594; PMC9271256, which additionally reports mislocalization of lamin A/C, Nesprin-1, and Nesprin-2 — nuclear lamina/LINC-complex components — in the severe intranuclear-rod subtype, implicating nuclear envelope dysfunction as a further downstream consequence).
Independently of aggregate formation, malformed/incorporated mutant actin impairs sarcomeric cross-bridge cycling: p.Asp286Gly directly prevents proper strong myosin binding, and functional studies confirm that "dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy" (PMID:29328520).
In parallel, actin polymerization failure triggers compensatory RhoA/ROCK1 pathway overactivation (increased active RhoA and phosphorylated ROCK1 in patient fibroblasts) and disrupts actin-dependent regulation of mitochondrial dynamics, leading to mitochondrial network fragmentation (increased DRP1, decreased OPA1), reduced basal/maximal/spare respiration, decreased ATP generation, downregulated OXPHOS complex I–V subunits, and elevated mitochondrial ROS — reproduced independently in ACTA1(H40Y) patient-iPSC-derived skeletal myocytes (PMID:36796746; PMC10740811). This bioenergetic branch is reversible in vitro: 7-day supplementation with linoleic acid and L-carnitine restored actin polymerization and normalized mitochondrial parameters in the fibroblast model.
Sarcomeric dysfunction (step 5) plus bioenergetic failure (step 6) jointly reduce contractile force generation, manifesting clinically as generalized hypotonia and weakness, with a predilection for neck-flexor and respiratory muscles.
In the most severe prenatal cases, profound failure of fetal muscle contraction causes fetal akinesia/hypokinesia, which in turn produces arthrogryposis multiplex congenita, pulmonary hypoplasia (from lack of fetal breathing movements), and polyhydramnios (from impaired fetal swallowing) — culminating in stillbirth or early neonatal death from respiratory failure in the severest subset.
Recessive-null branch: complete absence of ACTA1 protein removes the primary thin-filament structural component entirely; disease severity in this branch is modulated by the degree of postnatal compensatory upregulation of cardiac (fetal) α-actin (ACTC1) in skeletal muscle, which can partially substitute for the missing protein and is sufficient to rescue lethality in Acta1-null mice when sufficiently expressed (PMID:19468071) — this is an inferred mechanism in humans, extrapolated from the mouse rescue experiment rather than directly demonstrated in patient tissue.
Postnatally, chronic weakness of paraspinal/postural and respiratory muscles drives a feed-forward cycle: progressive kyphoscoliosis and joint contractures further compromise respiratory mechanics, compounding the primary respiratory-muscle weakness and accounting for most of the long-term morbidity/mortality burden (§11).
Divergent-outcome branch: variants affecting the actin-myosin/tropomyosin interface preferentially, without prominent aggregation, instead produce isolated congenital fiber-type disproportion (type 1 fiber hypotrophy without rods) (PMID:17387733, Clarke et al., "The pathogenesis of ACTA1-related congenital fiber type disproportion," Ann Neurol 2007); variants disrupting cardiac-relevant actin-myosin interactions instead cause dilated cardiomyopathy with cardiomyocyte hypocontractility (PMID:38559046); and a small number of families show a distal-predominant weakness pattern — an emerging phenotype not yet mechanistically dissected.

Molecular pathways / GO terms

Actin filament polymerization (GO:0030041); actomyosin structure organization / sarcomere organization (GO:0045214); striated muscle contraction (GO:0006941); positive regulation of Rho protein signal transduction (GO:0035025, downstream compensatory signaling); mitochondrial fission (GO:0000266) / mitochondrial fusion (GO:0007005); ATP metabolic process (GO:0046034, downstream bioenergetic failure).

Cell types (CL terms)

Skeletal muscle fiber (CL:0000188); type I (slow) skeletal muscle fiber (CL:0002586, selectively hypotrophic in CFTD); type II (fast) skeletal muscle fiber (CL:0002617); fibroblast (CL:0000057, the in vitro disease model used for the mitochondrial mechanism work); induced pluripotent stem cell-derived skeletal myocyte (used for H40Y iPSC model).

Advanced/omics data

No transcriptomic, proteomic, single-cell, or spatial-transcriptomic dataset specific to ACTA1-related myopathy patient muscle was identified in this search — a data gap relative to better-resourced neuromuscular diseases. The mechanistic omics-adjacent data available is limited to targeted Western blot/qPCR (fibroblast/iPSC studies above) and classical histopathology/electron microscopy; no GEO/ArrayExpress dataset was located for this specific gene-disease pair.

7. Anatomical Structures Affected

Organ level. Primary: skeletal muscle (generalized, with axial/neck-flexor/respiratory predominance in the typical form; distal predominance in the emerging distal phenotype). Secondary: respiratory system (restrictive failure secondary to muscle weakness and scoliosis); cardiac muscle (in the emerging cardiomyopathy phenotype, PMID:38559046); gastrointestinal/oropharyngeal (dysphagia from bulbar/pharyngeal muscle weakness); skeletal system (secondary structural deformity — scoliosis, contractures, pectus excavatum — from chronic weakness rather than a primary skeletal defect).

Tissue/cell level. Skeletal myofibers, particularly type 1 (slow-twitch) fibers in the CFTD phenotype; cardiomyocytes in the cardiomyopathy phenotype.

Subcellular level. Sarcomeric thin filament and Z-disk (GO:0030018, Z disc — the structural origin of nemaline rods); sarcoplasm (site of cytoplasmic bodies/actin aggregates); nucleus and nuclear envelope/lamina (intranuclear rods; mislocalized lamin A/C, Nesprin-1/2 — LINC complex — in the severe subtype, PMC9271256); mitochondria (fragmented network, reduced OXPHOS complex expression).

Localization/laterality. Bilateral, symmetric, generalized muscle involvement is typical; no lateralization is described.

8. Temporal Development

Onset and course (from the landmark 143-patient cohort, PMID:11558787, Ryan et al., Ann Neurol 2001 — the most cited natural-history stratification, applicable to NM broadly and reflected in ACTA1-specific cohorts):

Subtype	n (of 143)	Onset	Course
Severe congenital	23	Prenatal/birth	Often fatal in infancy from respiratory failure
Intermediate congenital	29	Birth	Significant weakness, ventilator-dependence common
Typical congenital	66 (most common)	Birth–infancy	Neonatal hypotonia, delayed motor milestones, static-to-slowly-progressive
Childhood-onset	19	Childhood	Milder, slower progression
Adult-onset	6	Adulthood	Rare, mildest end of spectrum

ACTA1-specific data (275-patient cohort, PMID:40661861) show that ACTA1-NM patients are more likely than NEB-NM patients to require feeding tubes and invasive ventilation in the first year of life, though this difference narrows after the first year — consistent with ACTA1 being enriched for the severe end of the clinical spectrum.

Progression pattern. Generally static-to-slowly-progressive in survivors of the congenital forms; a minority develop progressive distal weakness over time. Morbidity from respiratory infections and feeding difficulties characteristically diminishes with age in survivors, while orthopedic complications (scoliosis) tend to worsen during growth/adolescence — a divergent temporal pattern across organ systems.

Critical periods. The neonatal period is the critical window for respiratory/feeding crisis and early mortality; adolescence is the critical window for scoliosis progression and associated respiratory compromise.

9. Inheritance and Population

Epidemiology. Overall nemaline myopathy prevalence is estimated at ~1:50,000 live births worldwide, consistent with a Finnish birth-prevalence estimate of 0.02 per 1,000 live births (search synthesis of multiple reviews). ACTA1 causes an estimated 15–25% of all congenital myopathies and a substantial (cohort-dependent, roughly 20–40%) share of genetically solved NM, rising to >50% of the severe NM subset (PMC9271256).

Inheritance pattern. Autosomal dominant (93.3% of P/LP variants, 88% de novo) or autosomal recessive (6.6%, biallelic null variants) (PMC11918651).

Penetrance/expressivity. Dominant missense disease is essentially fully penetrant but shows marked variable expressivity even for identical or neighboring residue substitutions, attributed to differential effects of mutation site/biochemistry on thin-filament assembly (PMID:15236405).

Germline mosaicism. Not specifically quantified for ACTA1 in the literature retrieved; general empirical recurrence-risk figures for de novo dominant conditions (~1–5%, occasionally much higher with parental gonadal mosaicism) apply generically but are not gene-specific data — a recognized gap. Somatic/germline mosaicism has, however, been specifically implicated as a mechanism for ACTA1-related fetal akinesia in de novo cases (search synthesis).

Founder effects/consanguinity. No founder mutations are described; recessive (biallelic null) cases would be expected to be enriched by consanguinity, consistent with general Mendelian recessive-disease principles, though no ACTA1-specific consanguinity registry data were retrieved.

Sex ratio/geographic distribution. No sex predilection is reported (autosomal gene, both dominant and recessive mechanisms). No geographic clustering or endemic distribution has been described; cases have been reported worldwide (the pediatric systematic review sampled 101 patients from 23 countries, PMC10032635).

10. Diagnostics

Muscle biopsy remains the histopathological gold standard: modified Gömöri trichrome stain reveals red-staining rod/granular sarcoplasmic inclusions (nemaline bodies); electron microscopy confirms sarcoplasmic rods often continuous with Z-disks, and — in the severe ACTA1 subtype specifically — intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space are characteristic distinguishing features from other NM genotypes (PMC9271256). A single biopsy may show multiple co-occurring pathologies (rods, cores, caps, fiber-type disproportion) (PMID:22825594).

Laboratory. Serum creatine kinase is typically normal to only mildly elevated — a useful negative discriminator against dystrophic processes.

Genetic testing. First-line is typically a targeted congenital-myopathy/nemaline-myopathy multigene panel (ACTA1, NEB, TPM2, TPM3, TNNT1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, MYPN, MYO18B, ADSSL1) or exome/genome sequencing, given the genetic heterogeneity of NM; single-gene ACTA1 sequencing is reasonable when the clinical/histopathological picture (especially intranuclear rods or a severe congenital presentation) points specifically to ACTA1. Recessive cases require deliberate assessment of biallelic status (zygosity, potential compound heterozygosity), since dominant de novo missense is the default prior.

Imaging. Muscle MRI fatty-infiltration patterns are used adjunctively to help distinguish congenital myopathy subtypes, though no ACTA1-specific validated MRI signature was retrieved in this search.

Prenatal diagnosis. Ultrasound findings suggestive of the severe end of the spectrum include reduced fetal movement, multiple joint contractures/arthrogryposis, and polyhydramnios (typically apparent from ~28 weeks); genetic confirmation is by CVS/amniocentesis testing for a known familial variant, or by prenatal exome sequencing in undiagnosed severe fetal akinesia (search synthesis).

Differential diagnosis. Other congenital myopathies presenting with neonatal hypotonia must be distinguished, particularly: central core disease/multiminicore disease (RYR1) — important because of a different malignant hyperthermia risk profile (see §12); centronuclear/myotubular myopathy (MTM1, DNM2, BIN1); congenital muscular dystrophies; spinal muscular atrophy; congenital myasthenic syndromes; and the other nemaline-myopathy genes listed above.

11. Outcome/Prognosis

Mortality. In the landmark 143-patient cohort, 30 patients (~21%) died, the majority within the first 12 months of life, with all deaths attributable to respiratory insufficiency, which was "frequently underrecognized in older patients" (PMID:11558787). A more recent, severity-enriched pediatric systematic review (n=101) reported 36% mortality, with causes of death including sepsis, respiratory insufficiency, cardiopulmonary arrest, infection, or hypoxic-ischemic brain injury (PMC10032635) — the higher figure likely reflects a case-report-based sampling bias toward more severe/unusual presentations rather than a true increase in population mortality; both figures are reported here rather than reconciled, per the source cohorts' differing methodology.

Predictors of early mortality: arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones (PMID:11558787).

Genotype-specific survival. In the largest cohort to date (n=275), survival differed by molecular diagnosis: NEB-NM patients had higher survival than patients with no molecular diagnosis, and ACTA1-NM patients required feeding tubes and invasive ventilation more often than NEB-NM patients in the first year of life (PMID:40661861).

Morbidity in survivors. Respiratory-tract-infection and feeding-difficulty morbidity characteristically diminish with age, while chronic weakness, progressive scoliosis, and joint contractures persist as the dominant drivers of long-term disability. "Aggressive early management is warranted in most cases of congenital nemaline myopathy" (PMID:11558787).

Functional outcome ranges widely by subtype — from ventilator-dependent, non-ambulatory survivors (severe/intermediate congenital forms) to independently ambulatory adults with mild residual weakness (typical congenital, childhood-, and adult-onset forms) — but no formal ACTA1-specific ambulation/PROMIS/EQ-5D outcome dataset was located.

12. Treatment

There is no approved disease-modifying or curative therapy; management is entirely supportive and multidisciplinary.

Respiratory: surveillance for nocturnal hypoventilation; noninvasive ventilation (BiPAP) is an important therapeutic option in patients with chronic respiratory failure, progressing to invasive ventilation/tracheostomy in the most severe cases (search synthesis; PMC6945071). NCIT: C15747 (Supportive Care).

Nutrition/feeding: nasogastric feeding in the neonatal period, frequently progressing to percutaneous gastrostomy; dysphagia rehabilitation/speech-language and oral-motor therapy has shown potential to improve swallowing function even in children with severe oral-motor dysfunction (search synthesis of case series). NCIT: C15433 (Nutritional Support).

Orthopedic/rehabilitative: physical and occupational therapy for contracture management and functional mobility (NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation); scoliosis surveillance with spinal fusion surgery when indicated (NCIT:C15329 Surgical Procedure), requiring specific anesthetic precautions — avoidance of succinylcholine and other depolarizing/triggering agents given the risk of anesthesia-induced rhabdomyolysis and life-threatening hyperkalemia in structural myopathies broadly; note that isolated ACTA1/nemaline myopathy is not itself considered malignant-hyperthermia-susceptible in the way RYR1-related core myopathies are, an important distinction for anesthetic risk-stratification (search synthesis of orphananesthesia/anesthesia-literature guidance).

Pharmacotherapy. No approved drug. L-tyrosine has been trialed empirically in small open-label case series (250–3000 mg/day, 2 months to 5 years) with subjectively reported short-term improvements in strength/energy, but "due to various limitations (no placebo group, large age variability, and variable disease mutations), no firm conclusions could be made as to efficacy" — and subsequent preclinical zebrafish and ACTA1(D286G) mouse studies found L-tyrosine treatment does NOT improve skeletal muscle performance, directly contradicting the earlier anecdotal reports (search synthesis; biorxiv preprint on L-tyrosine in zebrafish/mouse NM models). This is a useful illustration of a therapy that looked promising in case reports but failed a more rigorous preclinical test.

Investigational/gene-directed approaches (all preclinical): - Cardiac α-actin (ACTC1) over-expression therapy for dominant ACTA1 disease — leveraging the same rescue biology described in §2/§6 — has been directly tested as a therapeutic strategy in a mouse model of dominant ACTA1 disease (PMID:23736297, "Cardiac α-actin over-expression therapy in dominant ACTA1 disease"). - A "Knockdown-and-Replace" (KDAR) strategy — allele-nonspecific silencing of the mutant/dominant-negative ACTA1 transcript combined with replacement — is in early preclinical development (Rashnonejad et al., Foundation Building Strength-funded program), reflecting the field's recognition that simple gene-addition therapy cannot work against a dominant-negative poison-subunit mechanism (search synthesis; buildingstrength.org). - AAV-based gene-therapy programs for nemaline myopathy more broadly (Z-disc fragment expression, microRNA-mediated knockdown) have so far been directed at NEB and TNNT1, not ACTA1 specifically, and remain in early preclinical stages without demonstrated functional benefit to date (PMID:34561123, "Recent advances in nemaline myopathy," Neuromuscul Disord 2021). - No ACTA1-specific interventional clinical trial (with an NCT identifier) was identified in this search. Several natural history studies are actively recruiting or planned (UK: NCT06670378; Belgium: NCT07201636; Spain: NCT07488806), reflecting trial-readiness-building efforts rather than a therapeutic intervention.

Treatment outcomes/adverse events: no systematic pharmacovigilance (FAERS) data specific to ACTA1-directed therapy exist, since none is approved.

13. Prevention

Primary prevention is not possible for de novo dominant disease. For families with an identified dominant or recessive (carrier) pathogenic variant, genetic counseling regarding recurrence risk is the principal preventive intervention; empirical de novo recurrence-risk figures (generic, not ACTA1-specific) of ~1–5% (higher with documented parental mosaicism) should be communicated per standard genetic-counseling practice for de novo dominant conditions.

Secondary prevention/screening: prenatal diagnosis (CVS/amniocentesis) is available once a familial variant is known; preimplantation genetic testing (PGT-M) is an option for families with an identified pathogenic variant. Population/carrier screening is not standard, given that the great majority of pathogenic variants are private/de novo rather than population-recurrent; carrier screening would only be relevant in known recessive families or high-consanguinity settings.

Tertiary prevention: early, proactive multidisciplinary surveillance (respiratory function monitoring, nutritional assessment, scoliosis screening) is explicitly recommended to prevent secondary complications (aspiration pneumonia, malnutrition, progressive respiratory compromise from untreated scoliosis) — "aggressive early management is warranted in most cases" (PMID:11558787).

Immunization/public health/prophylaxis: no disease-specific measures beyond standard pediatric immunization (particularly respiratory pathogens, given the disproportionate respiratory mortality burden) were identified; this is inferred rather than explicitly sourced.

14. Other Species / Natural Disease

No well-documented, naturally occurring ACTA1-orthologous disease in companion animals, livestock, or wildlife was identified in this search (in contrast to some other neuromuscular genes with recognized veterinary counterparts) — this is flagged as a genuine data gap rather than an assumed absence, since OMIA was not directly queried in this session.

Orthologs: mouse Acta1 (MGI:87902, chromosome 8); zebrafish acta1a/acta1b (the predominant actin isoforms in fast myofibers). Cross-species conservation of the actin fold is extremely high (skeletal, cardiac, and smooth-muscle actin isoforms are >90% identical), which is itself mechanistically relevant (§2, §6) — cardiac α-actin can substitute functionally for skeletal α-actin in mouse skeletal muscle.

15. Model Organisms

Mouse models — the best-characterized animal system for ACTA1 disease: - KI.Acta1(H40Y) knock-in mouse: heterozygous mice recapitulate the severe human H40Y phenotype with high fidelity — premature lethality, severe muscle weakness, reduced mobility, nemaline rods, and muscle fiber atrophy — mirroring the human patient with this variant, who died at 2 months of age (search synthesis; PMC10548277). - Tg.ACTA1(D286G) transgenic mouse: overexpresses mutant protein to ~20% of total actin; produces only mild nemaline pathology with minimal behavioral weakness and a normal lifespan, in contrast to the corresponding human patient (who died at 9 months) — an explicit model-fidelity limitation: the transgenic overexpression approach under-recapitulates severity relative to the human disease, and the original report is titled as a "cautionary note on muscle transgene expression" for this reason (search synthesis; PMC3235150). - Both models have been characterized by in vivo MRI/³¹P-MRS, showing impaired muscle function and altered energy metabolism consistent with the bioenergetic mechanism in §6 (PMC3629063; PMC3748127). - Acta1-null (complete knockout) mice die by 9 days after birth — a very severe phenotype directly analogous to human recessive-null disease — and are rescuable to normal-lifespan survival with no gross skeletal-muscle pathology by transgenic overexpression of cardiac α-actin (ACTC1), providing the mechanistic basis for the compensation hypothesis discussed in §2/§6 (PMID:19468071).

Zebrafish models: transgenic lines expressing disease-linked dominant mutations (e.g., p.Val165Met) on the endogenous zebrafish acta1a fast-fiber actin transcript reproduce myopathic phenotypes — delayed hatching, curved body, reduced touch-evoked escape-response motility by 5 days post-fertilization — with severity correlating to the corresponding human mutation's severity; phalloidin staining confirms actin aggregates, and electron microscopy shows Z-line thickening and myofibrillar disorganization (search synthesis). This model was used to test — and refute — L-tyrosine efficacy (§12).

Cellular/iPSC models: ACTA1(H40Y) patient-derived iPSC-differentiated skeletal myocytes display mitochondrial defects, an independent line of evidence supporting the bioenergetic-failure branch of the mechanism (PMID:36796746); patient dermal fibroblasts (non-muscle cell type, used as an accessible surrogate) were used to dissect the full actin-polymerization → RhoA/ROCK → mitochondrial-dysfunction chain, including pharmacological reversal with linoleic acid/L-carnitine (PMC10740811).

Model limitations, generally: the D286G transgenic-overexpression mouse under-recapitulates human severity, cautioning against transgene-dosage artifacts; conversely, patient fibroblasts (used for the mitochondrial mechanism) are a non-muscle surrogate cell type, so extrapolation of the RhoA/ROCK/mitochondrial findings to differentiated skeletal myofibers in situ, while independently supported by iPSC-myocyte data, still carries residual translational uncertainty.

No Drosophila or C. elegans ACTA1-orthologous disease model was identified in this search — a data gap, though invertebrate actin structure-function work (e.g., on the unrelated Drosophila indirect-flight-muscle actin gene Act88F) exists as a general precedent for actin-mutation biomechanics rather than as a disease model of this gene.

Summary of Key Data Gaps (flagged rather than filled)

No confirmed Orphanet ORPHA code for the ACTA1-specific NM subtype was retrieved (vs. the general nemaline myopathy entry).
No ACTA1-specific germline-mosaicism recurrence-risk quantification exists; generic de novo figures were used as a proxy.
No transcriptomic/proteomic/spatial-omics dataset on ACTA1 patient muscle was located.
No formal quality-of-life instrument (EQ-5D/SF-36/PROMIS) data specific to this gene were found.
No documented naturally occurring veterinary/companion-animal ACTA1 disease was found (absence not confirmed against OMIA directly in this session).
No ACTA1-specific interventional (NCT) clinical trial was identified; only natural-history studies.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	25
Resolved	25
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	9
Quoted claims found in source	7
Quoted claims not found in source	2
References weighed for topical relevance	25
On topic	23
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMC:PMC3447773 (abstract only): "prevents proper strong myosin binding and triggers muscle weakness"
closest text in source: "This phenomenon is likely to prevent proper myosin cross-bridge binding, limiting the fraction of actomyosin interactions in the strong binding state"
PMID:15236405 (abstract only): "the marked variability in clinical phenotype among patients with different mutations in ACTA1 suggested that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions"
closest text in source: "The skeletal muscle alpha-actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	31
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	11
Terms named correctly	3
Terms named as a different term	4
Terms whose name is worth a second look	4

Terms the report names something else

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

HP:0001319 (1 mention) - the report calls it "Near-universal in congenital forms"; HP calls it Neonatal hypotonia
HP:0003324 (1 mention) - the report calls it "Defining feature of "typical" form"; HP calls it Generalized muscle weakness
HP:0001265 (1 mention) - the report calls it "Common"; HP calls it Hyporeflexia
HP:0003701 (1 mention) - the report calls it "68% (pediatric systematic review, n=101, PMC10032635)"; HP calls it Proximal muscle weakness

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:0002705 (1 mention) - the report calls it "High-arched palate"; HP calls it High, narrow palate, and lists "Narrow, high-arched palate" among its other names
HP:0002650 (1 mention) - the report calls it "Kyphoscoliosis/scoliosis"; HP calls it Scoliosis
HP:0001989 (1 mention) - the report calls it "Fetal akinesia/reduced fetal movement"; HP calls it Fetal akinesia sequence
CL:0000188 (1 mention) - the report calls it "Skeletal muscle fiber"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names

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: MGI.

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

ACTA1-Related Nemaline Myopathy: Comprehensive Research Report

Identifiers

1. Disease Overview

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (numbered, with explicit branch points)

Molecular pathways / GO terms

Cell types (CL terms)

Advanced/omics data

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

Summary of Key Data Gaps (flagged rather than filled)

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver