🔗

Mappings

MONDO

MONDO:0018958 nemaline myopathy

Primary MONDO disease identifier for this nemaline myopathy entry.

📘

Definitions

1

Histopathologic and molecular case definition for inherited nemaline myopathy

Inherited nemaline myopathy is defined by congenital or childhood-onset hypotonia/weakness with characteristic nemaline rods on muscle biopsy, with molecular confirmation increasingly available through sequencing.

CASE_DEFINITION Congenital and childhood-onset inherited nemaline myopathy

Inclusion criteria

generalized muscle weakness
hypotonia
nemaline bodies

Show evidence (3 references)

PMID:17272906 SUPPORT Human Clinical

"All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."

Supports early-onset weakness/hypotonia as core clinical defining characteristics.

PMID:17272906 SUPPORT Human Clinical

"Microscopic examination revealed minimal changes but characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."

Confirms nemaline rods on histology/ultrastructure as the defining diagnostic lesion.

PMID:31228046 SUPPORT Other

"The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes."

Supports molecular confirmation via sequencing as part of modern case definition practice.

👪

Inheritance

2

Autosomal Recessive HP:0000007

Most cases of nemaline myopathy, particularly those due to NEB mutations (the most common cause), follow autosomal recessive inheritance.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:36661122 SUPPORT Model Organism

"NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients."

Confirms that recessive NEB mutations are the most common cause of nemaline myopathy.

Autosomal Dominant HP:0000006

Some forms, notably those caused by ACTA1 mutations, can follow autosomal dominant inheritance, though many ACTA1 cases are de novo.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:38376469 SUPPORT Model Organism

"Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases."

Supports ACTA1 as a significant genetic cause; ACTA1 mutations can be autosomal dominant.

PMID:31228046 SUPPORT Human Clinical

"Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes."

Authoritative review confirming de novo, dominant, and recessive inheritance patterns across NM genes.

◆

Subtypes

10

General

Severe Congenital Nemaline Myopathy MONDO:0015735

The most severe form, presenting at birth with profound hypotonia, minimal spontaneous movement, severe respiratory insufficiency, and feeding difficulties. Often fatal in infancy. ACTA1 accounts for more than half of severe NM cases, with intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic ultrastructural hallmarks.

Show evidence (3 references)

PMID:38500810 SUPPORT Human Clinical

"Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."

Case report of severe congenital nemaline myopathy with hallmark features of the subtype.

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."

Cohort of 10 severe ACTA1-NM families documenting the fatal neonatal course.

PMID:35810298 SUPPORT Human Clinical

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

Establishes ACTA1 as the predominant cause of severe congenital NM.

Typical Nemaline Myopathy MONDO:0015737

The most common form, presenting in infancy or early childhood with hypotonia, proximal weakness, facial weakness, and feeding difficulties. Most patients achieve ambulation but may require respiratory support.

Show evidence (1 reference)

PMID:36960434 SUPPORT Human Clinical

"We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with NM."

Systematic review of pediatric NM describes the spectrum of presentations including the typical congenital form.

Childhood-Onset Nemaline Myopathy MONDO:0015738

Presents between ages 2 and 15 with slowly progressive proximal weakness. Generally milder than the congenital forms.

Show evidence (1 reference)

PMID:17272906 SUPPORT Human Clinical

"All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."

Supports childhood-onset presentation as a recognized nemaline myopathy subtype.

Adult-Onset Nemaline Myopathy MONDO:0015739

Late-onset form that can be sporadic and may be associated with HIV infection, monoclonal gammopathy, or other immunologic disorders. Presents with progressive proximal weakness in adulthood, may follow an acquired/subacute course, and can mimic inflammatory myopathy clinically. Rods are often diffusely distributed in sporadic late-onset cases (SLONM), unlike the more common subsarcolemmal/central aggregate pattern in inherited NM. Adult-onset disease can present with isolated respiratory failure, and sporadic late-onset NM is often amenable to immunosuppressive therapy.

Show evidence (5 references)

PMID:36703211 SUPPORT Human Clinical

"Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers. Unlike iNM, SLONM is amenable to therapy."

Describes sporadic late-onset nemaline myopathy as a distinct entity from inherited forms, amenable to therapy.

PMID:9372751 SUPPORT Human Clinical

"An adult-onset variant is characterized by large numbers of rod-containing myofibers, numerous rods per affected myofiber, and the absence of specific structural abnormalities typical of other muscle diseases."

Defines the adult-onset variant criteria and notes association with inflammatory and immunologic components.

PMID:19208402 SUPPORT Human Clinical

"This case study reports a 60-year-old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness."

Documents that adult-onset NM can present with isolated respiratory failure as the sole manifestation.

+ 2 more references

complementation group

NEM1

NEM2

NEM3

NEM6

NEM10

Amish nemaline myopathy

⚙

Pathophysiology

7

Thin Filament Dysfunction

Mutations in genes encoding thin filament components (nebulin, skeletal alpha-actin, tropomyosins, troponins, cofilin-2, leiomodin-3) disrupt the normal structure and function of the sarcomeric thin filament. This leads to impaired actin-myosin cross-bridge cycling and reduced muscle force generation.

Skeletal Muscle Fiber link Type I Muscle Cell link

NEB link ACTA1 link TPM3 link TPM2 link TNNT1 link CFL2 link LMOD3 link

Skeletal Muscle Contraction link Actin Filament Organization link Skeletal Muscle Thin Filament Assembly link

Actin Filament Binding link ↕ DYSREGULATED

Show evidence (2 references)

PMID:38634969 SUPPORT Human Clinical

"Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment."

Establishes the role of nebulin in thin filament function and the consequence of its disruption.

PMID:38376469 SUPPORT Model Organism

"Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3"

Confirms ACTA1-related NM is an actin-based thin filament disease with impaired muscle function.

Nemaline Rod Formation

Nemaline rods are electron-dense inclusions composed of alpha-actinin, actin, tropomyosin, cofilin-2, telethonin, nebulin, and other Z-disc proteins. They are derived from Z lines and have a similar lattice structure and protein content. In inherited NM, rods are typically found in subsarcolemmal or central aggregates. Rod shape in KLHL40 and LMOD3 cases is distinctive. The number and distribution of rods does not correlate with severity or prognosis. In severe ACTA1 cases, intranuclear rods and cytoplasmic bodies are characteristic.

Myofibril Assembly link ↕ DYSREGULATED Sarcomere Organization link ↕ DYSREGULATED

Show evidence (5 references)

PMID:36703211 SUPPORT Human Clinical

"In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."

Documents the distinct distribution pattern of nemaline rods in inherited vs acquired forms.

PMID:38500810 SUPPORT Human Clinical

"Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion."

Confirms nemaline rods as a pathognomonic feature identified on muscle biopsy.

PMID:31228046 SUPPORT Human Clinical

"These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline..."

Authoritative review establishing rod origin from Z-discs, gene-specific rod morphology, and lack of correlation between rod burden and clinical severity.

+ 2 more references

Thin Filament Length Dysregulation

Nebulin acts as a molecular ruler specifying thin filament length. Loss of nebulin leads to shorter thin filaments, reducing the overlap zone with thick filaments and impairing force generation. Pathogenic NEB duplications can also produce longer-than-normal thin filaments, demonstrating that uniformity in thin filament length is critical and both shortened and elongated filaments are deleterious.

Sarcomere Organization link ↕ DYSREGULATED

Show evidence (2 references)

PMID:38634969 SUPPORT Human Clinical

"We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a pathogenic duplication variant in nebulin that resulted in a four-copy gain in the triplicate region of NEB..."

Demonstrates that both shortened and elongated thin filaments from NEB variants impair force generation.

PMID:38634969 SUPPORT Human Clinical

"we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from pathogenic splicing variants."

Proposes that thin filament length dysregulation in both directions is a key disease mechanism.

Reduced Sarcomeric Tension

Defective thin filament architecture in nemaline myopathy lowers maximal and submaximal muscle tension, reducing force output in limb and respiratory muscles.

skeletal muscle contraction link ↓ DECREASED

Show evidence (2 references)

PMID:38634969 SUPPORT Human Clinical

"We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension)."

Demonstrates reduced contractile tension in patient muscle fibers with pathogenic NEB variants.

PMID:38376469 PARTIAL 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."

Rescue of contractile capacity in ACTA1-NM model supports baseline sarcomeric tension deficits.

Ubiquitin-Proteasome Pathway Dysregulation (KLHL40)

KLHL40 functions as a CUL3 E3 ubiquitin ligase substrate-specific adapter. Loss of KLHL40 disrupts ubiquitin-mediated degradation of SAR1A, leading to defective ER-to-Golgi vesicle trafficking, impaired extracellular matrix protein secretion, and downstream structural and functional abnormalities in skeletal muscle.

KLHL40 link SAR1A link

Protein Ubiquitination link ↕ DYSREGULATED ER to Golgi Vesicle-Mediated Transport link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:37432316 SUPPORT Model Organism

"Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of..."

Establishes that KLHL40 deficiency causes NM through disrupted ubiquitin-regulated vesicle trafficking.

Nuclear Envelope Disruption (ACTA1)

In severe ACTA1-NM, skeletal muscle alpha-actin contributes to nuclear shape maintenance. Mutant ACTA1 causes enlargement of the perinuclear space and abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, which form the nuclear lamina and LINC complex ensuring nuclear envelope integrity. This identifies a novel pathomechanistic axis beyond sarcomeric dysfunction.

ACTA1 link

nuclear envelope organization link ⚠ ABNORMAL

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 as a novel ultrastructural hallmark of severe ACTA1-NM.

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."

Demonstrates disruption of nuclear envelope components in ACTA1-NM, linking actin mutations to nuclear biology.

NRAP-Mediated Sarcomere Disorganization

In nebulin deficiency, upregulation of the nebulin-related anchoring protein NRAP contributes to sarcomere structural defects and protein aggregate formation. NRAP acts as a disease modifier, and its reduction can rescue sarcomeric disorganization and eliminate nemaline bodies.

NRAP link NEB link

sarcomere organization link ↕ DYSREGULATED myofibril assembly link ↕ DYSREGULATED

Show evidence (1 reference)

PMID:36661122 SUPPORT Model Organism

"Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish."

Identifies NRAP as a disease modifier in NEB-related NM with therapeutic targeting potential.

✶

Histopathology

5

Nemaline rods on modified Gomori trichrome and electron microscopy OBLIGATE

Muscle biopsy demonstrates characteristic rod-shaped inclusions that appear as red/fuchsinophilic material on modified Gomori trichrome and as osmiophilic lattice-like structures on ultrastructural examination.

Show evidence (2 references)

PMID:17272906 SUPPORT Human Clinical

"characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."

Establishes the canonical biopsy finding used to diagnose nemaline myopathy.

PMID:9372751 SUPPORT Human Clinical

"A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy."

Independent adult case confirms the same pathognomonic rod morphology across staining and EM.

Subsarcolemmal or central rod aggregates in inherited nemaline myopathy VERY_FREQUENT

In inherited nemaline myopathy, rods are typically arranged in subsarcolemmal or central aggregates rather than diffuse intrafiber distribution.

Show evidence (1 reference)

PMID:36703211 SUPPORT Human Clinical

"In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."

Defines the characteristic inherited-NM rod-distribution pattern on muscle histology.

Diffuse intramyofiber rod distribution in sporadic late-onset nemaline myopathy OCCASIONAL

Sporadic late-onset nemaline myopathy often shows diffuse rod distribution within fibers, contrasting with the aggregate pattern in inherited disease.

Show evidence (1 reference)

PMID:36703211 SUPPORT Human Clinical

"In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."

Supports diffuse rod distribution as a biopsy feature of sporadic late-onset cases.

Cytoplasmic and intranuclear rods with cytoplasmic bodies and myofibrillar disorganization OCCASIONAL

Severe ACTA1-associated disease can show a compound histopathologic pattern with cytoplasmic rods, intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization.

Show evidence (1 reference)

PMID:35810298 SUPPORT Human Clinical

"Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization."

Documents the severe ACTA1-NM ultrastructural and architectural biopsy signature.

Core areas and congenital fiber-type disproportion OCCASIONAL

Some biopsies show additional congenital-myopathy architecture, including core-like areas and congenital type 1 fiber disproportion, alongside rods.

Show evidence (1 reference)

PMID:38500810 SUPPORT Human Clinical

"Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion."

Supports that rods may coexist with additional structural biopsy abnormalities in nemaline myopathy.

⬡

Pathograph

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

●

Phenotypes

9

Digestive 1

Feeding Difficulties FREQUENT Feeding difficulties in infancy (HP:0008872)

Show evidence (2 references)

PMID:38500810 SUPPORT Human Clinical

"Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."

Documents feeding difficulties requiring gastrostomy in a neonate with NM.

PMID:36714460 SUPPORT Human Clinical

"32% of patients with NM-NEB used a G tube"

Quantifies the frequency of gastrostomy tube use in NEB-NM patients.

Head and Neck 2

Facial Weakness FREQUENT Weakness of facial musculature (HP:0030319)

Show evidence (1 reference)

PMID:36714460 SUPPORT Human Clinical

"Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia."

Identifies a novel facial/bulbar finding in NEB-NM patients associated with dysphagia.

High Palate FREQUENT High palate (HP:0000218)

Show evidence (1 reference)

PMID:2804774 SUPPORT Human Clinical

"A 21-year-old female with nemaline myopathy and concomitant dysmorphism characteristic of elongated face, high arched palate, scoliosis and pes cavus is reported."

Documents high-arched palate as part of nemaline myopathy craniofacial phenotype.

Musculoskeletal 5

Generalized Muscle Weakness VERY_FREQUENT Generalized muscle weakness (HP:0003324)

Show evidence (2 references)

PMID:38634969 SUPPORT Human Clinical

"Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking curative therapies."

Confirms muscle weakness as a cardinal feature of NEB-based nemaline myopathy.

PMID:36714460 SUPPORT Human Clinical

"The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement."

Documents generalized weakness across the spectrum of NEB-NM in a 33-patient cohort.

Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)

Show evidence (3 references)

PMID:38500810 SUPPORT Human Clinical

"Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."

Case report demonstrating severe hypotonia as a presenting feature in neonatal NM.

PMID:36661122 SUPPORT Model Organism

"Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function."

Establishes hypotonia as a defining feature of nemaline myopathy.

PMID:17272906 SUPPORT Human Clinical

"All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."

Indian cohort confirming generalized hypotonia as a universal presenting feature in childhood-onset NM.

Respiratory Insufficiency FREQUENT Respiratory insufficiency due to muscle weakness (HP:0002747)

Show evidence (3 references)

PMID:36714460 SUPPORT Human Clinical

"32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS."

Documents that 55% of NEB-NM patients required ventilatory support.

PMID:36714460 SUPPORT Human Clinical

"Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities."

Shows progressive respiratory involvement in NEB-NM patients over time.

PMID:19208402 SUPPORT Human Clinical

"This case study reports a 60-year-old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness."

Documents that NM can present with isolated respiratory failure from diaphragm weakness, highlighting the importance of considering neuromuscular causes.

Scoliosis FREQUENT Scoliosis (HP:0002650)

Show evidence (2 references)

PMID:36714460 SUPPORT Human Clinical

"Scoliosis and dysphagia were more common among patients who used VS."

Documents association of scoliosis with disease severity in NEB-NM.

PMID:36714460 SUPPORT Human Clinical

"Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."

Demonstrates progressive scoliosis with increasing age in NEB-NM.

Slowness of Movements OCCASIONAL Myotonia (HP:0002486)

Show evidence (2 references)

PMID:39651462 SUPPORT Human Clinical

"Key patient-reported symptoms since childhood were muscle weakness (n = 23; 96%), slowness of movements (n = 23; 96%), and difficulties with running (n = 20; 83%)."

Documents slowness of movements as a near-universal symptom in NEM6 patients.

PMID:39651462 SUPPORT Human Clinical

"This might be related to delayed muscle relaxation."

Links the slowness of movements phenotype to the delayed muscle relaxation kinetics measured in NEM6 patients.

Cellular 1

Nemaline Bodies OBLIGATE Nemaline bodies (HP:0003798)

Show evidence (3 references)

PMID:36703211 SUPPORT Human Clinical

"Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers."

Confirms nemaline rod accumulation as the defining feature across NM subtypes.

PMID:9372751 SUPPORT Human Clinical

"A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy."

Classic description of nemaline rod morphology on trichrome stain and electron microscopy.

PMID:39691005 SUPPORT Human Clinical

"Modified Gomori trichrome staining revealed granular deposits in the myofibers. Ultrastructure examination showed numerous nemaline rods in the myofibers"

Recent case confirming characteristic trichrome and ultrastructural appearance of nemaline rods.

🧬

Genetic Associations

10

NEB Mutations (Causative)

Show evidence (3 references)

PMID:36661122 SUPPORT Model Organism

"Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients."

Establishes NEB as the most common causative gene in NM.

PMID:38634969 SUPPORT Human Clinical

"Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness"

Confirms NEB variants as causative for NEM2.

PMID:31228046 SUPPORT Human Clinical

"The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause."

Authoritative 2019 review confirming NEB and ACTA1 as the two most common causative genes.

ACTA1 Mutations (Causative)

Show evidence (4 references)

PMID:38376469 SUPPORT Model Organism

"Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death."

Establishes ACTA1 as the second most common cause of NM.

PMID:38500810 SUPPORT Human Clinical

"An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin."

Case report of a novel ACTA1 variant causing NM.

PMID:35810298 SUPPORT Human Clinical

"ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle."

Describes ACTA1 function and confirms its role in severe NM with characteristic intranuclear rods and perinuclear space abnormalities.

+ 1 more reference

KBTBD13 Mutations (Causative)

Show evidence (1 reference)

PMID:39651462 SUPPORT Human Clinical

"Nemaline myopathy type 6 (NEM6) is the most prevalent type of nemaline myopathy in the Netherlands."

Establishes KBTBD13-NEM6 as a significant form of NM.

KLHL40 Mutations (Causative)

Show evidence (1 reference)

PMID:37432316 SUPPORT Model Organism

"Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy"

Confirms KLHL40 mutations as causative for severe congenital NM.

TPM3 Mutations (Causative)

Show evidence (1 reference)

PMID:27858751 SUPPORT Human Clinical

"Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1."

Directly supports TPM3 as a causative gene for NEM1 nemaline myopathy.

TPM2 Mutations (Causative)

Show evidence (1 reference)

PMID:23378224 SUPPORT Human Clinical

"We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype."

Family-based human data support TPM2 as a causative gene in nemaline myopathy.

TNNT1 Mutations (Causative)

Show evidence (1 reference)

PMID:29931346 SUPPORT Human Clinical

"We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT)."

Cohort natural-history data establish pathogenic TNNT1 variants as causative in Amish nemaline myopathy.

CFL2 Mutations (Causative)

Show evidence (1 reference)

PMID:17160903 SUPPORT Human Clinical

"We report identification of a sixth gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy."

Human sibling data identify CFL2 as a causative gene for congenital nemaline myopathy.

LMOD3 Mutations (Causative)

Show evidence (1 reference)

PMID:36893608 SUPPORT Human Clinical

"Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness."

Supports biallelic LMOD3 mutations as causative for NEM10.

KLHL41 Mutations (Causative)

Show evidence (1 reference)

PMID:24268659 SUPPORT Human Clinical

"We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families."

Whole-exome sequencing and follow-up cohort data support KLHL41 as a causative nemaline myopathy gene.

💊

Treatments

7

Respiratory Support

Action: noninvasive ventilation MAXO:0000506

Nocturnal non-invasive ventilation (BiPAP) or continuous ventilatory support for respiratory muscle weakness. In NEB-NM, 55% of patients require ventilatory support with progressive need over time.

Target Phenotypes: Respiratory insufficiency due to muscle weakness ↗

Show evidence (2 references)

PMID:36714460 SUPPORT Human Clinical

"32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS."

Documents that the majority of NEB-NM patients require ventilatory support.

PMID:36714460 SUPPORT Human Clinical

"Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities."

Supports longitudinal need for respiratory support as disease progresses.

Physical Therapy

Action: physical therapy MAXO:0000011

Ongoing physical therapy and rehabilitation to maintain mobility, prevent contractures, and optimize functional capacity.

Target Phenotypes: Generalized muscle weakness ↗ Scoliosis ↗

Show evidence (1 reference)

PMID:31228046 SUPPORT Other

"Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence..."

Supports ongoing rehabilitative, mobility-preserving symptomatic care as standard management.

Nutritional Support

Action: gastrostomy MAXO:0001346

Gastrostomy tube feeding for patients with severe bulbar weakness and failure to thrive. In NEB-NM, 32% of patients require gastrostomy.

Target Phenotypes: Feeding difficulties in infancy ↗

Show evidence (2 references)

PMID:36714460 SUPPORT Human Clinical

"32% of patients with NM-NEB used a G tube"

Quantifies the need for gastrostomy in NEB-NM patients.

PMID:38500810 SUPPORT Human Clinical

"Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."

Supports gastrostomy as a practical intervention for severe neonatal bulbar dysfunction.

Orthopedic Management

Action: orthopedic procedure MAXO:0000477

Management of scoliosis (bracing or surgical correction), foot deformities, and joint contractures.

Target Phenotypes: Scoliosis ↗

Show evidence (2 references)

PMID:36714460 SUPPORT Human Clinical

"Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."

Progressive scoliosis supports need for structured orthopedic surveillance and intervention.

PMID:31228046 SUPPORT Other

"Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence..."

Supports symptom-directed orthopedic and mobility-preserving management as part of standard care.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for families to understand inheritance patterns, recurrence risk, and genetic testing options.

Show evidence (1 reference)

PMID:19208402 SUPPORT Human Clinical

"Unless appropriate tests are performed-including a muscle biopsy, if indicated-specific neuromuscular diseases are easily missed. This can lead to inappropriate counseling and treatment."

Highlights counseling consequences of diagnostic misclassification, supporting formal counseling in NM care pathways.

Fast Skeletal Muscle Troponin Activators (Investigational)

Action: pharmacotherapy MAXO:0000058

Tirasemtiv and related fast skeletal muscle troponin activators increase submaximal muscle tension in preclinical NM models by enhancing thin filament calcium sensitivity. Improved respiratory efficiency observed in NEM3 mouse models.

Mechanism Target:

MODULATES Thin Filament Dysfunction — Troponin activation modulates thin-filament calcium sensitivity in ACTA1-related thin-filament disease.

Show evidence (1 reference)

PMID:38376469 SUPPORT Model Organism

"Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3"

Directly links troponin activator action to the thin-filament disease mechanism.

RESTORES Reduced Sarcomeric Tension — Tirasemtiv restores submaximal contractile force generation in affected limb and diaphragm muscle.

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."

Demonstrates restoration of force-generation deficits downstream of sarcomeric tension loss.

Target Phenotypes: Generalized muscle weakness ↗ Respiratory insufficiency due to muscle weakness ↗

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."

Demonstrates tirasemtiv efficacy in a mouse model of ACTA1-related NM.

PMID:38376469 SUPPORT Model Organism

"Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration."

Shows improved respiratory efficiency with troponin activator treatment.

Myosin Activators (Investigational)

Action: pharmacotherapy MAXO:0000058

Omecamtiv mecarbil, a small-molecule cardiac myosin activator, substantially increased submaximal tension in type 1 muscle fibers from NEB-NM patients, with the largest effects in those with the lowest nebulin levels.

Mechanism Target:

RESTORES Reduced Sarcomeric Tension — Omecamtiv mecarbil increases submaximal tension in NEB-NM muscle fibers.

Show evidence (1 reference)

PMID:38634969 SUPPORT In Vitro

"OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin."

Ex vivo human fiber experiments support direct restoration of reduced sarcomeric tension.

Target Phenotypes: Generalized muscle weakness ↗

Show evidence (1 reference)

PMID:38634969 SUPPORT In Vitro

"OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin."

Ex vivo human muscle fiber data showing omecamtiv mecarbil increases force production in NEB-NM.

🔀

Differential Diagnoses

3

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

Idiopathic inflammatory myopathy Not Yet Curated MONDO:0600023

Overlapping Features Adult-onset nemaline myopathy can be misclassified as inflammatory myopathy, especially when proximal weakness and inflammatory biopsy features coexist.

Distinguishing Features

Nemaline rods on modified trichrome and electron microscopy favor nemaline myopathy
Inflammatory-cell infiltrates can coexist in some nemaline myopathy biopsies and confound diagnosis

Show evidence (1 reference)

PMID:9372751 SUPPORT Human Clinical

"This case illustrates that adult-onset nemaline myopathy, although rare, should be considered in the differential diagnosis of an inflammatory myopathy."

Directly identifies inflammatory myopathy as an important differential diagnosis.

Metabolic myopathy Not Yet Curated MONDO:0020123

Overlapping Features Biopsy findings such as glycogen-filled vacuoles can initially suggest metabolic myopathy before ultrastructural evaluation reveals nemaline rods.

Distinguishing Features

Glycogen accumulation may suggest metabolic disease on light microscopy
Detection of minirods/nemaline rods on ultrastructure redirects diagnosis toward nemaline myopathy

Show evidence (1 reference)

PMID:38500810 SUPPORT Human Clinical

"Muscle biopsy analyzed by light microscopy showed the presence of vacuoles filled with glycogen, suggesting a metabolic myopathy, but also fuchsinophilic inclusions."

Demonstrates direct diagnostic overlap and the need to distinguish NM from metabolic myopathy.

Central core myopathy MONDO:0007294

Overlapping Features Core lesions can co-occur with rods and are linked to overlapping congenital myopathy gene sets, requiring careful histopathologic interpretation.

Distinguishing Features

Core lesions may be present in nemaline myopathy biopsies
Rods remain the defining hallmark of nemaline myopathy when demonstrated by trichrome/EM

Show evidence (1 reference)

PMID:31228046 SUPPORT Other

"Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods."

Review evidence supports substantial overlap between rod and core congenital myopathy pathology.

📊

Related Datasets

2

Clinical Manifestation of Nebulin-Associated Nemaline Myopathy. PMID:36714460

Clinical-genetic cohort dataset of NEB-associated nemaline myopathy from a specialized neuromuscular center, including motor, bulbar, respiratory, and interventional-support phenotyping across age strata.

Homo sapiens n=33

Conditions: NEB-associated nemaline myopathy ventilatory support stratification

Findings

Older NEB-NM patients show proportionally greater respiratory dysfunction and skeletal deformities.

Show evidence (1 reference)

PMID:36714460 SUPPORT Human Clinical

"Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."

Captures age-stratified progression signal relevant for longitudinal NM phenotyping.

PMID:36714460

Show evidence (1 reference)

PMID:36714460 SUPPORT Human Clinical

"In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support."

Supports this publication as a reusable human clinical-genetic cohort dataset for NM-NEB.

TNNT1 nemaline myopathy: natural history and therapeutic frontier. PMID:29931346

Natural-history dataset for Amish TNNT1 nemaline myopathy with long-range birth-cohort capture, molecular diagnosis timing, and survival/respiratory outcomes.

Homo sapiens n=106

Conditions: TNNT1-associated nemaline myopathy infantile-onset lethal congenital myopathy

Findings

TNNT1 c.505G>T homozygotes showed early failure to thrive and universal death from respiratory failure by age 6 years.

Show evidence (1 reference)

PMID:29931346 SUPPORT Human Clinical

"Affected children developed thoracic rigidity, pectus carinatum and restrictive lung disease during infancy, and all succumbed to respiratory failure by 6 years of age (median survival 18 months, range 0.2-66 months)."

Summarizes severe respiratory natural history and survival outcomes in the TNNT1 cohort.

PMID:29931346

Show evidence (1 reference)

PMID:29931346 SUPPORT Human Clinical

"We collected natural history data for 106 ANM patients born between 1923 and 2017."

Defines a substantial disease-specific longitudinal dataset for TNNT1 nemaline myopathy.

📚

Literature Summaries

1

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 42 citations 2026-02-19T13:12:53.156668

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

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

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

Disease Pathophysiology Research Template

Target Disease

Disease Name: Nemaline Myopathy
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Nemaline Myopathy. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Nemaline Myopathy (NM) – molecular and cellular mechanisms (2023–2024-focused)

Disease identifiers, scope, and key definitions

Disease: Nemaline myopathy (NM) • MONDO: MONDO:0018958 (“nemaline myopathy”). (ziemian2025integrativeapproachesto pages 15-17) • Genetic category: Mendelian congenital myopathy; clinically heterogeneous with congenital-to-adult onset and variable severity. (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4)

Core definition and diagnostic lesion NM is histopathologically defined by “disorganization of the sarcomeric Z discs and the accumulation of nemaline bodies or rods in muscle fibers.” (Karimi et al., received 2023-12-22; accepted 2024-03-26; published 2024-04, Acta Neuropathologica; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Nemaline rods are “aggregates of Z-disc and thin filament-related proteins,” including “α-actinin, actin, tropomyosin, myotilin, γ-filamin, cofilin-2, telethonin and nebulin,” stain red on modified Gomori trichrome, and show an “electron-dense lattice-like structure on electron microscopy,” with “continuity … between rods and Z-discs.” (Nicolau et al., 2023-01, Acta Neuropathologica Communications; https://doi.org/10.1186/s40478-023-01518-9) (nicolau2023molecularsignaturesof pages 2-4) Visual evidence of rod distributions (subsarcolemmal, central aggregates, diffuse, rods filling atrophic fibers) is shown in a representative modified Gomori trichrome figure. (nicolau2023molecularsignaturesof media 60ef7b58)

Key concept: thin-filament / sarcomere disease Multiple authoritative sources converge on NM as primarily a thin-filament/Z-disc structural and regulatory disorder where altered thin-filament composition, length, mechanics, and/or turnover culminate in rod/aggregate pathology and impaired force generation. (karimi2024characterizationofneb pages 1-2, findlay2024dominantlyinheritedmuscle pages 14-15)

Core pathophysiology (molecular and cellular mechanisms)

2.1 Final common pathway: thin-filament dysregulation → sarcomere/Z-disc disruption → weakness Across genetic subtypes, the common pathologic endpoint is altered thin-filament structure/regulation leading to Z-disc disruption and rod formation, with contractile weakness due to reduced effective actin–myosin force generation. (karimi2024characterizationofneb pages 1-2, findlay2024dominantlyinheritedmuscle pages 14-15) Findlay (2024-10, Disease Models & Mechanisms; https://doi.org/10.1242/dmm.050720) provides an expert review statement that rods “consist of aggregated actin and Z-disc material,” and emphasizes that altered nebulin can reduce thin-filament length and therefore thin–thick filament overlap, impairing force generation. (findlay2024dominantlyinheritedmuscle pages 14-15)

2.2 Nebulin (NEB) mechanisms: thin-filament length (TFL) regulation, cross-bridge cycling, alignment Nebulin is a core thin-filament component that contributes to “regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment.” (Karimi et al., 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Mechanistic links from patient samples (2024, Acta Neuropathologica) • Truncating NEB variants reduce NEB mRNA stability and can trigger nonsense-mediated decay. (karimi2024characterizationofneb pages 1-2) • Splice variants frequently induce cryptic splice activation and intronic inclusion, which the authors interpret as disrupting actin-binding-site spacing on nebulin (“insertion of an unstructured sequence into actin binding motifs” and “disrupts the proper domain spacing actin binding sites on nebulin”). (karimi2024characterizationofneb pages 16-17) • Importantly, NEB-NM pathomechanism can involve both shortened and elongated thin filaments: a pathogenic NEB duplication can yield “a much larger nebulin protein and longer TFL,” and “both a reduction and an increase in TFL are deleterious,” with “uniformity in TFL” emphasized. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) Functional correlation Karimi et al. report a “positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension).” (karimi2024characterizationofneb pages 1-2)

2.3 ACTA1 mechanisms: actin polymerization/stability defects and dominant-negative effects ACTA1 encodes skeletal α-actin in the thin filament. Expert review synthesis highlights that many ACTA1 missense variants impair actin filament polymerization/stability and are “thought to cause pathology via a dominant-negative mechanism.” (Findlay 2024; https://doi.org/10.1242/dmm.050720) (findlay2024dominantlyinheritedmuscle pages 14-15) Clinically, ACTA1 disease is framed as “an actin-based thin filament disease” where thin-filament gene variants “result in sarcomeric dysfunction.” (Galli et al., 2024-02, J Gen Physiol; https://doi.org/10.1085/jgp.202313471) (galli2024tirasemtivenhancessubmaximal pages 1-2)

2.4 Protein homeostasis / ubiquitin–proteasome and inter-organelle communication (KLHL40) A major recent mechanistic advance (2023) expands NM pathophysiology beyond myofilament biophysics to include ubiquitylation-regulated membrane trafficking and extracellular matrix (ECM) secretion. KLHL40 as a CUL3 adaptor and proteostasis regulator • KLHL40 is described as “a substrate-specific adaptor of CUL3 E3 ubiquitin ligase,” and the authors propose that “inter-organelle communication between sarcomeric and endomembrane compartments, is dynamically regulated by ubiquitylation” and that defects underlie pathology. (Mansur et al., 2023-07, eLife; https://doi.org/10.1101/2022.07.21.501000) (mansur2023dynamicregulationof pages 4-8) SAR1A/COPII trafficking mechanism • KLHL40 acts as a negative regulator of ER→Golgi anterograde trafficking by promoting “ubiquitin-mediated protein degradation of secretion associated Ras related GTPase1a (Sar1a)” (SAR1A; COPII vesicle formation). (mansur2023dynamicregulationof pages 1-4) • In KLHL40 deficiency, “SAR1a is abnormally localized to the ER and contributes to membrane tubulation defects and disruption of the trafficking of ECM proteins,” with downstream ultrastructural abnormalities (vesicle accumulation near SR/ER, fragmented Golgi, ECM gaps, mitochondrial changes). (mansur2023dynamicregulationof pages 4-8) This provides a plausible disease-progression axis: KLHL40 loss → altered ubiquitylation → ER exit/COPII dysfunction → impaired ECM secretion and membrane homeostasis → secondary sarcomere growth/maintenance failure and myofiber damage. (mansur2023dynamicregulationof pages 4-8)

2.5 Disease modifiers and sarcomere remodeling (NRAP) In NEB deficiency, NRAP upregulation behaves as a disease modifier: NRAP reduction in neb−/− zebrafish “restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function,” and notably eliminated observable nemaline bodies in the rescue genotype. (Casey et al., 2023-01, Human Molecular Genetics; https://doi.org/10.1093/hmg/ddad011) (casey2023nrapreductionrescues pages 1-2, casey2023nrapreductionrescues pages 3-6) Quantitative ultrastructure: neb−/− sarcomere height was reduced (510 ± 107 nm vs 755 ± 192 nm control), with slightly increased sarcomere length (1475 ± 55 nm vs 1400 ± 96 nm control), both improved by partial nrap reduction. (casey2023nrapreductionrescues pages 3-6)

Key molecular players (genes/proteins, pathways, cells, anatomy, chemicals)

3.1 Causal/implicated genes and encoded functional modules A contemporary gene list emphasized in recent pathology-centric work includes thin filament and turnover genes: ACTA1, NEB, LMOD3, TPM3, TPM2, TNNT1, TNNT3, CFL2, MYPN, KBTBD13, KLHL40, KLHL41, and MYO18B. (Karimi 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Rod composition proteins (as biochemical/pathology anchors) include α-actinin, actin, tropomyosin, cofilin-2, telethonin and nebulin. (nicolau2023molecularsignaturesof pages 2-4)

3.2 Dysregulated pathways / cellular processes (current understanding) The most strongly supported dysregulated processes from the provided 2023–2024 mechanistic sources are: • Sarcomere assembly/maintenance and thin-filament length regulation (NEB, ACTA1, LMOD3; and associated regulatory complexes). (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Ubiquitin-mediated proteostasis and specific ubiquitylation control of vesicle trafficking (KLHL40–CUL3 → SAR1A/COPII). (mansur2023dynamicregulationof pages 1-4, mansur2023dynamicregulationof pages 4-8) • Sarcomere remodeling/aggregate biology involving modifiers such as NRAP. (casey2023nrapreductionrescues pages 1-2) A broader expert synthesis also highlights proteostasis roles for BTB-Kelch family members and KBTBD13 (CUL3 complex), although detailed KBTBD13 ubiquitin substrates were not provided in the retrieved primary excerpts. (ziemian2025integrativeapproachesto pages 15-17, karimi2024characterizationofneb pages 1-2)

3.3 Primary affected cell types and anatomical locations • Primary cell type: skeletal muscle fiber / skeletal myofiber (CL:0000187, “skeletal muscle cell”; mapping provided for knowledge-base use). Mechanistic evidence is from patient skeletal muscle biopsies and in vivo skeletal muscle models (zebrafish). (karimi2024characterizationofneb pages 1-2, mansur2023dynamicregulationof pages 4-8) • Primary anatomy: skeletal muscle tissue (UBERON:0001134, “skeletal muscle tissue”) with frequent respiratory muscle involvement clinically (diaphragm and accessory muscles inferred via respiratory endpoints). (NCT03728803 chunk 1, moreno2023clinicalmanifestationof pages 7-9)

3.4 Chemical entities (therapeutic and mechanistic) Drug/compound candidates with mechanistic rationale and evidence: • Omecamtiv mecarbil (cardiac myosin activator): in NEB-NM type 1 fibers from patients, OM “substantially increased submaximal tension … ranging from 87 to 318%,” with larger effects in those with lower nebulin. (Karimi 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) • Tirasemtiv (CK-2017357; fast skeletal troponin activator): in an Acta1 NM mouse model, “acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies,” with respiratory efficiency effects described. (Galli 2024; https://doi.org/10.1085/jgp.202313471) (galli2024tirasemtivenhancessubmaximal pages 1-2) Mechanistic tool compound: • MG132 (proteasome inhibitor) is used experimentally to support a ubiquitin–proteasome mechanism in KLHL40-mediated regulation (increasing stability of a target protein, SAR1A, in the Mansur et al. study). (mansur2023dynamicregulationof pages 15-19) (For CHEBI mapping in a knowledge base: omecamtiv mecarbil, tirasemtiv, MG132 are chemically name-identifiable but CHEBI IDs were not available in the retrieved excerpts and are therefore not asserted.)

Gene-to-mechanism annotations (ontology-ready; representative)

Below are representative, evidence-supported annotations suitable for a knowledge base (not exhaustive).

NEB (HGNC symbol: NEB; protein: nebulin) • Function/pathophysiology: regulates thin-filament length, cross-bridge cycling, and myofibril alignment; NEB variants can cause both shortened and elongated thin filaments; reduced nebulin correlates with reduced tension. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Example disrupted processes (GO): – GO:0030017 sarcomere organization – GO:0007015 actin filament organization – GO:0006936 muscle contraction – GO:0045214 sarcomere organization (related)

ACTA1 (HGNC symbol: ACTA1; protein: skeletal muscle α-actin) • Function/pathophysiology: thin filament core component; pathogenic missense variants can impair actin polymerization/stability with dominant-negative effects; contributes to contractile weakness. (findlay2024dominantlyinheritedmuscle pages 14-15, galli2024tirasemtivenhancessubmaximal pages 1-2) • Example disrupted processes (GO): – GO:0030048 actin filament-based movement – GO:0007015 actin filament organization

KLHL40 (HGNC symbol: KLHL40; BTB-Kelch protein) • Function/pathophysiology: CUL3 E3 ligase adaptor; regulates ubiquitylation and proteasomal degradation of targets including SAR1A to control ER exit/COPII and ECM trafficking; loss causes vesicle/Golgi/ECM and sarcomere-size defects. (mansur2023dynamicregulationof pages 1-4, mansur2023dynamicregulationof pages 4-8) • Example disrupted processes (GO): – GO:0016567 protein ubiquitination – GO:0032440 protein polyubiquitination – GO:0006888 ER to Golgi vesicle-mediated transport – GO:0030705 cytoplasmic vesicle budding from endoplasmic reticulum

KBTBD13 (HGNC symbol: KBTBD13; BTB-Kelch family) • Mechanism evidence in retrieved set: Karimi et al. categorize KBTBD13 among NM genes “likely involved in protein turnover … via the ubiquitin–proteasome pathway,” and clinical data show markedly reduced relaxation rate in KBTBD13-related NM. (karimi2024characterizationofneb pages 1-2, kleef2024nemalinemyopathytype pages 1-2)

Rod/nemaline body cellular component context • Rods show continuity with Z-discs and are composed of Z-disc/thin-filament proteins. (nicolau2023molecularsignaturesof pages 2-4) • Example cellular component (GO CC): – GO:0030018 Z disc – GO:0030017 sarcomere

Disease progression model (sequence of events)

A synthesis consistent with the 2023–2024 evidence is: 1) Initiating event: pathogenic variant in a thin-filament structural/regulatory gene (e.g., NEB, ACTA1, TPM2/3, TNNT1) or in proteostasis/assembly regulators (e.g., KLHL40, KBTBD13). (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4) 2) Early molecular consequences: • Thin filament: altered actin polymerization/stability (ACTA1) and/or altered nebulin abundance and thin-filament length uniformity (NEB), with direct effects on cross-bridge recruitment/overlap and force. (findlay2024dominantlyinheritedmuscle pages 14-15, karimi2024characterizationofneb pages 1-2) • Proteostasis/trafficking: altered KLHL40–CUL3 ubiquitylation and destabilized ER exit/COPII trafficking of ECM proteins, impacting membrane homeostasis and myofiber microenvironment. (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4) 3) Structural pathology: • Z-disc disorganization and accumulation of nemaline rods (protein aggregates) composed of thin-filament/Z-disc proteins; rods can appear subsarcolemmal, central, or diffuse. (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4, nicolau2023molecularsignaturesof media 60ef7b58) 4) Functional decline: • Reduced maximal and/or submaximal tension and impaired relaxation dynamics (subtype-dependent), leading to clinical weakness and fatigability; respiratory and bulbar muscles frequently affected. (karimi2024characterizationofneb pages 1-2, kleef2024nemalinemyopathytype pages 1-2, moreno2023clinicalmanifestationof pages 7-9) 5) Domain-specific progression: • For NEB-associated NM, cross-sectional age stratification suggests progression in respiratory dysfunction and skeletal deformities (e.g., scoliosis) even if motor/swallowing may appear more stable in some groups. (moreno2023clinicalmanifestationof pages 1-2)

Phenotypic manifestations (HPO mapping; representative)

NEB-associated NM (cohort evidence; 2023) • Ventilatory support requirement: 55% used ventilatory support; progressive uptake with age in some analyses. (HP:0002093 Respiratory insufficiency; HP:0011949 Assisted ventilation) (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9) • Feeding impairment: gastrostomy tube use 32% (bulbar dysfunction). (HP:0002020 Dysphagia; HP:0004396 Feeding difficulties) (moreno2023clinicalmanifestationof pages 1-2) • Weakness and impaired ambulation (HP:0001324 Muscle weakness; HP:0003677 Walking disability). (moreno2023clinicalmanifestationof pages 1-2) • Scoliosis/axial deformities (HP:0002650 Scoliosis; HP:0003307 Rigid spine). (moreno2023clinicalmanifestationof pages 3-5)

KBTBD13-associated NEM6 (2024) • Slowness of movements and delayed relaxation (phenotype aligned with “reduced muscle relaxation rate”). (HP:0003394 Muscle stiffness; HP:0001251 Ataxia not implied; do not assert) (kleef2024nemalinemyopathytype pages 1-2) • Falls: 33% fell ≥1 time over 100 days; 21% ≥2 times. (HP:0002527 Falls) (kleef2024nemalinemyopathytype pages 1-2)

Recent developments (prioritizing 2023–2024)

7.1 Mechanistic diversification beyond “sarcomere-only” models The KLHL40 ubiquitylation → SAR1A/COPII → ECM secretion mechanism introduces a disease-onset model where endomembrane trafficking and ECM homeostasis are upstream contributors to muscle pathology, linking proteostasis and organelle communication to later structural damage. (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4)

7.2 Variant-class mechanisms in NEB: NMD, cryptic splicing, and “long TFL” disease Karimi et al. (2024) provide direct patient-based evidence that NEB-NM pathomechanism includes not only reduced nebulin/short TFL but also “longer than normal” TFL due to pathogenic duplication, arguing for thin-filament length homeostasis (and uniformity) as a central disease variable. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17)

7.3 Pharmacologic contractility augmentation as a rational strategy (proof-of-concept) • OM (myosin activator) enhanced submaximal tension in patient type 1 fibers by 87–318% (NEB-NM), suggesting that correcting submaximal force generation is a mechanistically coherent route. (karimi2024characterizationofneb pages 1-2) • Tirasemtiv (troponin activator) improved submaximal stimulation force in an ACTA1 NM mouse model, supporting “myofilament activators” as a class. (galli2024tirasemtivenhancessubmaximal pages 1-2) These advances do not establish clinical efficacy in NM, but they strengthen the therapeutic logic and motivate outcome measures emphasizing submaximal force/respiratory efficiency. (galli2024tirasemtivenhancessubmaximal pages 1-2, NCT03728803 chunk 1)

Current applications and real-world implementations

8.1 Diagnostics in practice Muscle pathology • NM rods “appear red on the Gomori trichrome stain” and have an “electron-dense lattice-like structure on electron microscopy,” with rods categorized by distribution (central/subsarcolemmal/diffuse). (nicolau2023molecularsignaturesof pages 2-4) Genetic testing • A targeted panel approach (example: “Sequencing of 123 genes … known to cause inherited myopathies”) is used in practice for distinguishing inherited vs acquired nemaline myopathies. (nicolau2023molecularsignaturesof pages 2-4) • Case-based literature highlights expanded next-generation sequencing panels and emphasizes the value of electron microscopy when multiple biopsy abnormalities coexist. (piga2024casereporta pages 1-2) • In neonatal hypotonia contexts, rapid genetic testing is advocated to expedite diagnosis and potentially reduce invasive biopsy. (vu2024nemalinemyopathyin pages 1-2)

8.2 Management and supportive care Cohort and case reports emphasize multidisciplinary, supportive management focusing on respiratory and feeding support (noninvasive/invasive ventilation, tracheostomy, gastrostomy), plus rehabilitation and airway clearance. (vu2024nemalinemyopathyin pages 1-2, moreno2023clinicalmanifestationof pages 1-2)

8.3 Clinical trials and real-world research infrastructure Inspiratory muscle training (IMT) as a respiratory physiology intervention • NCT03728803 (NEMTRAIN; Radboud UMC). Completed; started 2018-10-10; primary completion 2021-03-25; enrollment 42. Primary endpoint: maximal inspiratory pressure (MIP). Secondary endpoints include diaphragm ultrasound measures, cough flow, spirometry, and functional outcomes (MFM, 6MWT, balance/falls) that align with NM respiratory pathophysiology. URL: https://clinicaltrials.gov/study/NCT03728803 (NCT03728803 chunk 1, NCT03728803 chunk 2) Natural history studies (trial readiness) • Belgium Acti-Nemaline natural history: NCT07201636, not-yet-recruiting (estimated start 2025-12). Primary endpoints: MFM32 change and ventilation hours/day over 3 years; wearable-derived falls and gait metrics included. URL: https://clinicaltrials.gov/study/NCT07201636 (NCT07201636 chunk 1, NCT07201636 chunk 2) • UK NM natural history network: NCT06670378 (mixed recruiting status by site in retrieved excerpt). URL: https://clinicaltrials.gov/study/NCT06670378 (NCT06670378 chunk 2) These initiatives operationalize clinically meaningful outcome domains (motor, ventilation burden, falls, QoL) that directly reflect NM pathophysiology. (NCT07201636 chunk 2, NCT03728803 chunk 2)

Recent statistics and quantitative data (selected)

Epidemiology • Pediatric systematic review states NM “affects 1 in 50 000 live births.” (Christophers et al., 2022-06; https://doi.org/10.1177/08830738221096316) (christophers2022pediatricnemalinemyopathy pages 1-3) • Karimi et al. (2024) cite an “estimated incidence of two cases per 100,000 live births.” (karimi2024characterizationofneb pages 1-2) (These figures differ by source/definition and should be harmonized in future epidemiologic studies.) (christophers2022pediatricnemalinemyopathy pages 1-3, karimi2024characterizationofneb pages 1-2)

NEB-associated NM (33-patient cohort) • 55% ventilatory support; 32% gastrostomy tube; 35% unable to walk without support; progressive respiratory involvement in time-to-event analysis (e.g., 50% began VS before age 20; ~85% by age 40 in one analysis). (Moreno et al., 2023-02; https://doi.org/10.1212/nxg.0000000000200056) (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9)

KBTBD13-associated NEM6 (24-patient cohort) • Falls: 33% ≥1 fall in 100 days; 21% ≥2 falls. (van Kleef et al., 2024-12; https://doi.org/10.1212/nxg.0000000000200214) (kleef2024nemalinemyopathytype pages 1-2) • Muscle relaxation: median peak relaxation rate 6.5 s−1 (IQR 4.9–8.1) vs lower limit of normal 10.1 s−1. (kleef2024nemalinemyopathytype pages 1-2)

Therapy-linked functional effects (ex vivo/in vivo) • OM increased submaximal tension 87–318% in NEB-NM patient type-1 fibers. (karimi2024characterizationofneb pages 1-2) • NRAP reduction rescued neb−/− sarcomere height deficit (510 ± 107 nm vs 755 ± 192 nm control) and eliminated observable nemaline bodies. (casey2023nrapreductionrescues pages 3-6)

Evidence items (PMID/DOI, date, URL) – curated list

• Karimi E et al. “Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.” Acta Neuropathologica. Accepted 2024-03-26; published 2024-04. DOI:10.1007/s00401-024-02726-w. URL: https://doi.org/10.1007/s00401-024-02726-w (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Mansur A et al. “Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset.” eLife. 2023-07. DOI:10.1101/2022.07.21.501000. URL: https://doi.org/10.1101/2022.07.21.501000 (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4) • Nicolau S et al. “Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies.” Acta Neuropathol Commun. 2023-01. DOI:10.1186/s40478-023-01518-9. URL: https://doi.org/10.1186/s40478-023-01518-9 (nicolau2023molecularsignaturesof pages 2-4, nicolau2023molecularsignaturesof media 60ef7b58) • Findlay AR. “Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.” Dis Model Mech. 2024-10. DOI:10.1242/dmm.050720. URL: https://doi.org/10.1242/dmm.050720 (findlay2024dominantlyinheritedmuscle pages 14-15) • Galli RA et al. “Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.” J Gen Physiol. 2024-02. DOI:10.1085/jgp.202313471. URL: https://doi.org/10.1085/jgp.202313471 (galli2024tirasemtivenhancessubmaximal pages 1-2) • Casey JG et al. “NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.” Hum Mol Genet. 2023-01. DOI:10.1093/hmg/ddad011. URL: https://doi.org/10.1093/hmg/ddad011 (casey2023nrapreductionrescues pages 1-2, casey2023nrapreductionrescues pages 3-6) • Moreno CAM et al. “Clinical manifestation of nebulin-associated nemaline myopathy.” Neurology Genetics. 2023-02. DOI:10.1212/nxg.0000000000200056. URL: https://doi.org/10.1212/nxg.0000000000200056 (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9) • van Kleef ESB et al. “Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene.” Neurology: Genetics. 2024-12. DOI:10.1212/nxg.0000000000200214. URL: https://doi.org/10.1212/nxg.0000000000200214 (kleef2024nemalinemyopathytype pages 1-2) • ClinicalTrials.gov NCT03728803 (Inspiratory Muscle Training in Nemaline Myopathy). URL: https://clinicaltrials.gov/study/NCT03728803 (NCT03728803 chunk 1) • ClinicalTrials.gov NCT07201636 (Natural History Study for Patients With Nemaline Myopathy in Belgium). URL: https://clinicaltrials.gov/study/NCT07201636 (NCT07201636 chunk 1)

Limitations of this report (evidence scope) • Several mechanistic topics requested (e.g., autophagy in NM specifically; comprehensive mitochondrial/oxidative stress statistics in skeletal muscle tissue; gene-by-gene mechanistic depth for TPM2/3, TNNT1, CFL2, LMOD3, KLHL41) are only partially supported by the retrieved 2023–2024 full-text excerpts. Where mechanisms are not explicitly supported in the cited excerpts, they are not asserted. • PMIDs were not consistently available in the provided full-text excerpts; DOIs/ClinicalTrials.gov identifiers and URLs are therefore provided as the primary reference anchors.

Figure citation • Modified Gomori trichrome figure showing multiple rod distribution patterns (subsarcolemmal, central, diffuse, atrophic fibers). (nicolau2023molecularsignaturesof media 60ef7b58)

References

(ziemian2025integrativeapproachesto pages 15-17): Maja Ziemian, Joanna Szmydtka, Wojciech Snoch, Sandra Milner, Szymon Wojciechowski, Aleksandra Dłuszczakowska, Jakub W. Chojnowski, Zofia Pallach, Katarzyna Żamojda, Grzegorz Węgrzyn, and Estera Rintz. Integrative approaches to myopathies and muscular dystrophies: molecular mechanisms, diagnostics, and future therapies. International Journal of Molecular Sciences, 26:7972, Aug 2025. URL: https://doi.org/10.3390/ijms26167972, doi:10.3390/ijms26167972. This article has 2 citations.
(karimi2024characterizationofneb pages 1-2): Esmat Karimi, Jochen Gohlke, Mila van der Borgh, Johan Lindqvist, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W. Lawlor, Coen Ottenheijm, and Henk Granzier. Characterization of neb pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects. Acta Neuropathologica, Apr 2024. URL: https://doi.org/10.1007/s00401-024-02726-w, doi:10.1007/s00401-024-02726-w. This article has 5 citations and is from a highest quality peer-reviewed journal.
(nicolau2023molecularsignaturesof pages 2-4): Stefan Nicolau, Aneesha Dasgupta, Surendra Dasari, M. Cristine Charlesworth, Kenneth L. Johnson, Akhilesh Pandey, Jason D. Doles, and Margherita Milone. Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies. Acta Neuropathologica Communications, Jan 2023. URL: https://doi.org/10.1186/s40478-023-01518-9, doi:10.1186/s40478-023-01518-9. This article has 13 citations and is from a peer-reviewed journal.
(nicolau2023molecularsignaturesof media 60ef7b58): Stefan Nicolau, Aneesha Dasgupta, Surendra Dasari, M. Cristine Charlesworth, Kenneth L. Johnson, Akhilesh Pandey, Jason D. Doles, and Margherita Milone. Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies. Acta Neuropathologica Communications, Jan 2023. URL: https://doi.org/10.1186/s40478-023-01518-9, doi:10.1186/s40478-023-01518-9. This article has 13 citations and is from a peer-reviewed journal.
(findlay2024dominantlyinheritedmuscle pages 14-15): Andrew R. Findlay. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms, Oct 2024. URL: https://doi.org/10.1242/dmm.050720, doi:10.1242/dmm.050720. This article has 7 citations and is from a domain leading peer-reviewed journal.
(karimi2024characterizationofneb pages 16-17): Esmat Karimi, Jochen Gohlke, Mila van der Borgh, Johan Lindqvist, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W. Lawlor, Coen Ottenheijm, and Henk Granzier. Characterization of neb pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects. Acta Neuropathologica, Apr 2024. URL: https://doi.org/10.1007/s00401-024-02726-w, doi:10.1007/s00401-024-02726-w. This article has 5 citations and is from a highest quality peer-reviewed journal.
(galli2024tirasemtivenhancessubmaximal pages 1-2): Ricardo A. Galli, Tamara C. Borsboom, Charlotte Gineste, Lorenza Brocca, Maira Rossi, Darren T. Hwee, Fady I. Malik, Roberto Bottinelli, Julien Gondin, Maria-Antonietta Pellegrino, Josine M. de Winter, and Coen A.C. Ottenheijm. Tirasemtiv enhances submaximal muscle tension in an acta1:p.asp286gly mouse model of nemaline myopathy. The Journal of General Physiology, Feb 2024. URL: https://doi.org/10.1085/jgp.202313471, doi:10.1085/jgp.202313471. This article has 3 citations.
(mansur2023dynamicregulationof pages 4-8): A. Mansur, Remi Joseph, E. Kim, Pierre M. Jean-Beltran, N. Udeshi, Cadence Pearce, Hanjie Jiang, Reina Iwase, Miroslav P. Milev, Hashem Almousa, E. McNamara, J. Widrick, C. Perez, G. Ravenscroft, M. Sacher, Philip A. Cole, Steve Carr, and Vandana Gupta. Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset. eLife, Jul 2023. URL: https://doi.org/10.1101/2022.07.21.501000, doi:10.1101/2022.07.21.501000. This article has 17 citations and is from a domain leading peer-reviewed journal.
(mansur2023dynamicregulationof pages 1-4): A. Mansur, Remi Joseph, E. Kim, Pierre M. Jean-Beltran, N. Udeshi, Cadence Pearce, Hanjie Jiang, Reina Iwase, Miroslav P. Milev, Hashem Almousa, E. McNamara, J. Widrick, C. Perez, G. Ravenscroft, M. Sacher, Philip A. Cole, Steve Carr, and Vandana Gupta. Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset. eLife, Jul 2023. URL: https://doi.org/10.1101/2022.07.21.501000, doi:10.1101/2022.07.21.501000. This article has 17 citations and is from a domain leading peer-reviewed journal.
(casey2023nrapreductionrescues pages 1-2): Jennifer G Casey, Eurick S. Kim, Remi Joseph, Frank Li, H. Granzier, and Vandana A Gupta. Nrap reduction rescues sarcomere defects in nebulin-related nemaline myopathy. Human molecular genetics, 32:1711-1721, Jan 2023. URL: https://doi.org/10.1093/hmg/ddad011, doi:10.1093/hmg/ddad011. This article has 10 citations and is from a domain leading peer-reviewed journal.
(casey2023nrapreductionrescues pages 3-6): Jennifer G Casey, Eurick S. Kim, Remi Joseph, Frank Li, H. Granzier, and Vandana A Gupta. Nrap reduction rescues sarcomere defects in nebulin-related nemaline myopathy. Human molecular genetics, 32:1711-1721, Jan 2023. URL: https://doi.org/10.1093/hmg/ddad011, doi:10.1093/hmg/ddad011. This article has 10 citations and is from a domain leading peer-reviewed journal.
(NCT03728803 chunk 1): Inspiratory Muscle Training in Nemaline Myopathy. Radboud University Medical Center. 2018. ClinicalTrials.gov Identifier: NCT03728803
(moreno2023clinicalmanifestationof pages 7-9): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.
(mansur2023dynamicregulationof pages 15-19): A. Mansur, Remi Joseph, E. Kim, Pierre M. Jean-Beltran, N. Udeshi, Cadence Pearce, Hanjie Jiang, Reina Iwase, Miroslav P. Milev, Hashem Almousa, E. McNamara, J. Widrick, C. Perez, G. Ravenscroft, M. Sacher, Philip A. Cole, Steve Carr, and Vandana Gupta. Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset. eLife, Jul 2023. URL: https://doi.org/10.1101/2022.07.21.501000, doi:10.1101/2022.07.21.501000. This article has 17 citations and is from a domain leading peer-reviewed journal.
(kleef2024nemalinemyopathytype pages 1-2): Esmee S.B. van Kleef, Karlijn Bouman, Joery P.F. Molenaar, Benno Küsters, Jan T. Groothuis, Montse Olivé, Edoardo Malfatti, Erik-Jan Kamsteeg, Baziel G.M. Van Engelen, Coen A.C. Ottenheijm, Jonne Doorduin, and Nicol C. Voermans. Nemaline myopathy type 6 caused by variants in the kbtbd13 gene. Neurology: Genetics, Dec 2024. URL: https://doi.org/10.1212/nxg.0000000000200214, doi:10.1212/nxg.0000000000200214. This article has 1 citations.
(moreno2023clinicalmanifestationof pages 1-2): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.
(moreno2023clinicalmanifestationof pages 3-5): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.
(piga2024casereporta pages 1-2): Daniela Piga, Martina Rimoldi, Francesca Magri, Simona Zanotti, Laura Napoli, Michela Ripolone, Serena Pagliarani, Patrizia Ciscato, Daniele Velardo, Adele D’Amico, Enrico Bertini, Giacomo Pietro Comi, Dario Ronchi, and Stefania Corti. Case report: a novel acta1 variant in a patient with nemaline rods and increased glycogen deposition. Frontiers in Neurology, Mar 2024. URL: https://doi.org/10.3389/fneur.2024.1340693, doi:10.3389/fneur.2024.1340693. This article has 3 citations and is from a peer-reviewed journal.
(vu2024nemalinemyopathyin pages 1-2): Annie Vu, Subah Nanda, and Todd Chassee. Nemaline myopathy in a hypotonic neonate: diagnostic approach for early detection and management. Cureus, Mar 2024. URL: https://doi.org/10.7759/cureus.56866, doi:10.7759/cureus.56866. This article has 0 citations.
(NCT03728803 chunk 2): Inspiratory Muscle Training in Nemaline Myopathy. Radboud University Medical Center. 2018. ClinicalTrials.gov Identifier: NCT03728803
(NCT07201636 chunk 1): Manon HUSTINX. Natural History Study for Patients With Nemaline Myopathy in Belgium. Centre Hospitalier Universitaire de Liege. 2025. ClinicalTrials.gov Identifier: NCT07201636
(NCT07201636 chunk 2): Manon HUSTINX. Natural History Study for Patients With Nemaline Myopathy in Belgium. Centre Hospitalier Universitaire de Liege. 2025. ClinicalTrials.gov Identifier: NCT07201636
(NCT06670378 chunk 2): Natural History Study for Patients With Nemaline Myopathy in the UK. University of Oxford. 2024. ClinicalTrials.gov Identifier: NCT06670378
(christophers2022pediatricnemalinemyopathy pages 1-3): Briana Christophers, Michael A. Lopez, Vandana A. Gupta, Hannes Vogel, and Mary Baylies. Pediatric nemaline myopathy: a systematic review using individual patient data. Journal of Child Neurology, 37:652-663, Jun 2022. URL: https://doi.org/10.1177/08830738221096316, doi:10.1177/08830738221096316. This article has 20 citations and is from a peer-reviewed journal.

{ }

Source YAML

click to show

name: Nemaline Myopathy
creation_date: '2026-02-19T00:00:00Z'
updated_date: '2026-03-04T23:35:58Z'
category: Mendelian
description: >
  Nemaline myopathy (also called nemaline rod myopathy) is a group of congenital
  myopathies characterized by the presence of rod-shaped structures (nemaline bodies
  or rods) in skeletal muscle fibers on biopsy. It is the most common non-dystrophic
  congenital myopathy, affecting approximately 1 in 50,000 live births. Clinical
  features range from severe neonatal forms with respiratory failure to mild
  childhood-onset or adult-onset forms with proximal weakness. The disease is
  genetically heterogeneous, with mutations in at least 13 genes encoding components
  of the thin filament or associated proteins, most commonly NEB and ACTA1.
disease_term:
  preferred_term: nemaline myopathy
  term:
    id: MONDO:0018958
    label: nemaline myopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018958
      label: nemaline myopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this nemaline myopathy entry.
parents:
- Congenital Structural Myopathy
- Thin Filament Myopathy
inheritance:
- name: Autosomal Recessive
  description: >
    Most cases of nemaline myopathy, particularly those due to NEB mutations
    (the most common cause), follow autosomal recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36661122
    reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients."
    explanation: Confirms that recessive NEB mutations are the most common cause of nemaline myopathy.
- name: Autosomal Dominant
  description: >
    Some forms, notably those caused by ACTA1 mutations, can follow autosomal
    dominant inheritance, though many ACTA1 cases are de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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: "Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases."
    explanation: Supports ACTA1 as a significant genetic cause; ACTA1 mutations can be autosomal dominant.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes."
    explanation: Authoritative review confirming de novo, dominant, and recessive inheritance patterns across NM genes.
definitions:
- name: Histopathologic and molecular case definition for inherited nemaline myopathy
  definition_type: CASE_DEFINITION
  description: >
    Inherited nemaline myopathy is defined by congenital or childhood-onset
    hypotonia/weakness with characteristic nemaline rods on muscle biopsy,
    with molecular confirmation increasingly available through sequencing.
  scope: Congenital and childhood-onset inherited nemaline myopathy
  inclusion_criteria:
  - preferred_term: generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  - preferred_term: hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: nemaline bodies
    term:
      id: HP:0003798
      label: Nemaline bodies
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."
    explanation: Supports early-onset weakness/hypotonia as core clinical defining characteristics.
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microscopic examination revealed minimal changes but characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."
    explanation: Confirms nemaline rods on histology/ultrastructure as the defining diagnostic lesion.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes."
    explanation: Supports molecular confirmation via sequencing as part of modern case definition practice.
has_subtypes:
- name: Severe Congenital Nemaline Myopathy
  subtype_term:
    preferred_term: severe congenital nemaline myopathy
    term:
      id: MONDO:0015735
      label: severe congenital nemaline myopathy
  description: >
    The most severe form, presenting at birth with profound hypotonia, minimal
    spontaneous movement, severe respiratory insufficiency, and feeding difficulties.
    Often fatal in infancy. ACTA1 accounts for more than half of severe NM cases,
    with intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as
    characteristic ultrastructural hallmarks.
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."
    explanation: Case report of severe congenital nemaline myopathy with hallmark features of the subtype.
  - 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: Cohort of 10 severe ACTA1-NM families documenting the fatal neonatal course.
  - 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 ACTA1 as the predominant cause of severe congenital NM.
- name: Typical Nemaline Myopathy
  subtype_term:
    preferred_term: typical nemaline myopathy
    term:
      id: MONDO:0015737
      label: typical nemaline myopathy
  description: >
    The most common form, presenting in infancy or early childhood with hypotonia,
    proximal weakness, facial weakness, and feeding difficulties. Most patients
    achieve ambulation but may require respiratory support.
  evidence:
  - reference: PMID:36960434
    reference_title: "Pediatric Nemaline Myopathy: A Systematic Review Using Individual Patient Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with NM."
    explanation: Systematic review of pediatric NM describes the spectrum of presentations including the typical congenital form.
- name: Childhood-Onset Nemaline Myopathy
  subtype_term:
    preferred_term: childhood-onset nemaline myopathy
    term:
      id: MONDO:0015738
      label: childhood-onset nemaline myopathy
  description: >
    Presents between ages 2 and 15 with slowly progressive proximal weakness.
    Generally milder than the congenital forms.
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."
    explanation: Supports childhood-onset presentation as a recognized nemaline myopathy subtype.
- name: Adult-Onset Nemaline Myopathy
  subtype_term:
    preferred_term: adult-onset nemaline myopathy
    term:
      id: MONDO:0015739
      label: adult-onset nemaline myopathy
  description: >
    Late-onset form that can be sporadic and may be associated with HIV infection,
    monoclonal gammopathy, or other immunologic disorders. Presents with progressive
    proximal weakness in adulthood, may follow an acquired/subacute course, and can
    mimic inflammatory myopathy clinically. Rods are often diffusely distributed in
    sporadic late-onset cases (SLONM), unlike the more common subsarcolemmal/central
    aggregate pattern in inherited NM. Adult-onset disease can present with isolated
    respiratory failure, and sporadic late-onset NM is often amenable to immunosuppressive
    therapy.
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers. Unlike iNM, SLONM is amenable to therapy."
    explanation: Describes sporadic late-onset nemaline myopathy as a distinct entity from inherited forms, amenable to therapy.
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An adult-onset variant is characterized by large numbers of rod-containing myofibers, numerous rods per affected myofiber, and the absence of specific structural abnormalities typical of other muscle diseases."
    explanation: Defines the adult-onset variant criteria and notes association with inflammatory and immunologic components.
  - reference: PMID:19208402
    reference_title: "Idiopathic adult-onset nemaline myopathy presenting with isolated respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case study reports a 60-year-old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness."
    explanation: Documents that adult-onset NM can present with isolated respiratory failure as the sole manifestation.
  - reference: PMID:39691005
    reference_title: "Sporadic Late-Onset Nemaline Rod Myopathy: An Interesting Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sporadic late-onset nemaline rod myopathy is a rare, acquired, sub-acute, adult-onset myopathy characterized by proximal muscle weakness and nemaline rods in the myofibers."
    explanation: Recent case confirming sporadic late-onset NM as a distinct acquired entity with monoclonal protein association.
  - reference: PMID:6481414
    reference_title: "Adult-onset mixed myopathy with nemaline rods, minicores, and central cores: a muscle disorder mimicking polymyositis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A woman, aged 75 years, presented with a 15-year history of progressive, generalized, painful muscle weakness and wasting."
    explanation: Early case report of adult-onset NM with mixed pathology (rods, minicores, cores) mimicking polymyositis.
- name: NEM1
  classification: complementation_group
- name: NEM2
  classification: complementation_group
- name: NEM3
  classification: complementation_group
- name: NEM6
  classification: complementation_group
- name: NEM10
  classification: complementation_group
- name: Amish nemaline myopathy
  classification: complementation_group
pathophysiology:
- name: Thin Filament Dysfunction
  description: >
    Mutations in genes encoding thin filament components (nebulin, skeletal alpha-actin,
    tropomyosins, troponins, cofilin-2, leiomodin-3) disrupt the normal structure
    and function of the sarcomeric thin filament. This leads to impaired actin-myosin
    cross-bridge cycling and reduced muscle force generation.
  genes:
  - preferred_term: NEB
    term:
      id: hgnc:7720
      label: NEB
  - preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  - preferred_term: TPM3
    term:
      id: hgnc:12012
      label: TPM3
  - preferred_term: TPM2
    term:
      id: hgnc:12011
      label: TPM2
  - preferred_term: TNNT1
    term:
      id: hgnc:11948
      label: TNNT1
  - preferred_term: CFL2
    term:
      id: hgnc:1875
      label: CFL2
  - preferred_term: LMOD3
    term:
      id: hgnc:6649
      label: LMOD3
  cell_types:
  - preferred_term: Skeletal Muscle Fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Type I Muscle Cell
    term:
      id: CL:0002211
      label: type I muscle cell
  biological_processes:
  - preferred_term: Skeletal Muscle Contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  - preferred_term: Actin Filament Organization
    term:
      id: GO:0007015
      label: actin filament organization
  - preferred_term: Skeletal Muscle Thin Filament Assembly
    term:
      id: GO:0030240
      label: skeletal muscle thin filament assembly
  molecular_functions:
  - preferred_term: Actin Filament Binding
    modifier: DYSREGULATED
    term:
      id: GO:0051015
      label: actin filament binding
  evidence:
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment."
    explanation: Establishes the role of nebulin in thin filament function and the consequence of its disruption.
  - 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: "Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3"
    explanation: Confirms ACTA1-related NM is an actin-based thin filament disease with impaired muscle function.
  downstream:
  - target: Thin Filament Length Dysregulation
    description: Loss or altered structure of nebulin perturbs molecular-ruler control of thin filament length.
    evidence:
    - reference: PMID:38634969
      reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment."
      explanation: Connects primary thin-filament defects to downstream thin-filament-length abnormalities.
  - target: Reduced Sarcomeric Tension
    description: Thin filament dysfunction reduces cross-bridge efficiency and contractile force output.
    evidence:
    - reference: PMID:38634969
      reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension)."
      explanation: Shows reduced nebulin and altered thin-filament architecture are linked to lower sarcomeric tension.
  - target: NRAP-Mediated Sarcomere Disorganization
    description: In nebulin-deficient contexts, compensatory NRAP upregulation contributes to sarcomeric disorganization.
    evidence:
    - reference: PMID:36661122
      reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM."
      explanation: Places NRAP dysregulation downstream of nebulin-related thin-filament pathology.
- name: Nemaline Rod Formation
  description: >
    Nemaline rods are electron-dense inclusions composed of alpha-actinin, actin,
    tropomyosin, cofilin-2, telethonin, nebulin, and other Z-disc proteins. They
    are derived from Z lines and have a similar lattice structure and protein content.
    In inherited NM, rods are typically found in subsarcolemmal or central aggregates.
    Rod shape in KLHL40 and LMOD3 cases is distinctive. The number and distribution
    of rods does not correlate with severity or prognosis. In severe ACTA1 cases,
    intranuclear rods and cytoplasmic bodies are characteristic.
  biological_processes:
  - preferred_term: Myofibril Assembly
    modifier: DYSREGULATED
    term:
      id: GO:0030239
      label: myofibril assembly
  - preferred_term: Sarcomere Organization
    modifier: DYSREGULATED
    term:
      id: GO:0045214
      label: sarcomere organization
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."
    explanation: Documents the distinct distribution pattern of nemaline rods in inherited vs acquired forms.
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion."
    explanation: Confirms nemaline rods as a pathognomonic feature identified on muscle biopsy.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis."
    explanation: Authoritative review establishing rod origin from Z-discs, gene-specific rod morphology, and lack of correlation between rod burden and clinical severity.
  - 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: "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: Documents intranuclear rods and cytoplasmic bodies as characteristic features of severe ACTA1-NM.
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."
    explanation: Confirms alpha-actinin as a major component of nemaline rods demonstrated by immunostaining.
  downstream:
  - target: Nemaline Bodies
    description: Intramyofiber nemaline rod accumulation manifests histologically as nemaline bodies.
    evidence:
    - reference: PMID:36703211
      reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers."
      explanation: Directly links rod-forming pathology to the defining nemaline-body phenotype.
  - target: Generalized Muscle Weakness
    description: Severe rod-associated myofibrillar disorganization co-occurs with profound neonatal weakness.
    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: PARTIAL
      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: Severe ACTA1 cases with prominent rod pathology also present with marked generalized weakness.
- name: Thin Filament Length Dysregulation
  description: >
    Nebulin acts as a molecular ruler specifying thin filament length. Loss of
    nebulin leads to shorter thin filaments, reducing the overlap zone with thick
    filaments and impairing force generation. Pathogenic NEB duplications can also
    produce longer-than-normal thin filaments, demonstrating that uniformity in
    thin filament length is critical and both shortened and elongated filaments
    are deleterious.
  biological_processes:
  - preferred_term: Sarcomere Organization
    modifier: DYSREGULATED
    term:
      id: GO:0045214
      label: sarcomere organization
  evidence:
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a pathogenic duplication variant in nebulin that resulted in a four-copy gain in the triplicate region of NEB and a much larger nebulin protein and longer TFL."
    explanation: Demonstrates that both shortened and elongated thin filaments from NEB variants impair force generation.
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from pathogenic splicing variants."
    explanation: Proposes that thin filament length dysregulation in both directions is a key disease mechanism.
  downstream:
  - target: Reduced Sarcomeric Tension
    description: Abnormally short or long thin filaments reduce effective actin-myosin overlap and tension generation.
    evidence:
    - reference: PMID:38634969
      reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension)."
      explanation: Quantifies tension loss as a direct downstream consequence of thin-filament-length abnormalities.
- name: Reduced Sarcomeric Tension
  description: >
    Defective thin filament architecture in nemaline myopathy lowers maximal and
    submaximal muscle tension, reducing force output in limb and respiratory muscles.
  biological_processes:
  - preferred_term: skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  evidence:
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension)."
    explanation: Demonstrates reduced contractile tension in patient muscle fibers with pathogenic NEB variants.
  - reference: PMID:38376469
    reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
    supports: PARTIAL
    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: Rescue of contractile capacity in ACTA1-NM model supports baseline sarcomeric tension deficits.
  downstream:
  - target: Generalized Muscle Weakness
    description: Persistent force deficits translate to progressive limb and axial weakness.
    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: "Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death."
      explanation: Connects force-generation defects in ACTA1-linked NM with the core weakness phenotype.
  - target: Respiratory Insufficiency
    description: Reduced diaphragm contractility contributes to ventilatory compromise.
    evidence:
    - reference: PMID:38376469
      reference_title: "Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death."
      explanation: ACTA1 disease-course data support respiratory failure downstream of severe contractile dysfunction.
- name: Ubiquitin-Proteasome Pathway Dysregulation (KLHL40)
  description: >
    KLHL40 functions as a CUL3 E3 ubiquitin ligase substrate-specific adapter.
    Loss of KLHL40 disrupts ubiquitin-mediated degradation of SAR1A, leading to
    defective ER-to-Golgi vesicle trafficking, impaired extracellular matrix protein
    secretion, and downstream structural and functional abnormalities in skeletal
    muscle.
  genes:
  - preferred_term: KLHL40
    term:
      id: hgnc:30372
      label: KLHL40
  - preferred_term: SAR1A
    term:
      id: hgnc:10534
      label: SAR1A
  biological_processes:
  - preferred_term: Protein Ubiquitination
    modifier: DYSREGULATED
    term:
      id: GO:0016567
      label: protein ubiquitination
  - preferred_term: ER to Golgi Vesicle-Mediated Transport
    modifier: ABNORMAL
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence:
  - reference: PMID:37432316
    reference_title: "Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities."
    explanation: Establishes that KLHL40 deficiency causes NM through disrupted ubiquitin-regulated vesicle trafficking.
  downstream:
  - target: Thin Filament Dysfunction
    description: Ubiquitylation defects alter turnover of thin-filament-associated proteins during muscle development.
    evidence:
    - reference: PMID:37432316
      reference_title: "Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development."
      explanation: Directly links KLHL40-dependent ubiquitylation defects to thin-filament pathway disruption.
  - target: Reduced Sarcomeric Tension
    description: KLHL40-dependent trafficking defects produce structural/functional muscle impairment consistent with reduced contractile output.
    evidence:
    - reference: PMID:37432316
      reference_title: "Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities."
      explanation: Functional abnormalities in KLHL40-deficient muscle support downstream force-generation impairment.
- name: Nuclear Envelope Disruption (ACTA1)
  description: >
    In severe ACTA1-NM, skeletal muscle alpha-actin contributes to nuclear
    shape maintenance. Mutant ACTA1 causes enlargement of the perinuclear space
    and abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, which
    form the nuclear lamina and LINC complex ensuring nuclear envelope integrity.
    This identifies a novel pathomechanistic axis beyond sarcomeric dysfunction.
  genes:
  - preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  biological_processes:
  - preferred_term: nuclear envelope organization
    modifier: ABNORMAL
    term:
      id: GO:0006998
      label: nuclear envelope organization
  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 as a novel ultrastructural hallmark of severe ACTA1-NM.
  - 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: Demonstrates disruption of nuclear envelope components in ACTA1-NM, linking actin mutations to nuclear biology.
  downstream:
  - target: Nemaline Rod Formation
    description: Severe ACTA1 cases with nuclear envelope abnormalities also show characteristic intranuclear and cytoplasmic rod pathology.
    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: "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: Connects ACTA1-associated nuclear abnormalities with concurrent rod-forming myofibrillar pathology.
  - target: Respiratory Insufficiency
    description: Severe ACTA1 pathology with nuclear structural disruption is associated with permanent respiratory support needs.
    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: PARTIAL
      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: Severe ACTA1 disease biology, including nuclear disruption, co-occurs with profound respiratory insufficiency.
- name: NRAP-Mediated Sarcomere Disorganization
  description: >
    In nebulin deficiency, upregulation of the nebulin-related anchoring protein
    NRAP contributes to sarcomere structural defects and protein aggregate formation.
    NRAP acts as a disease modifier, and its reduction can rescue sarcomeric
    disorganization and eliminate nemaline bodies.
  genes:
  - preferred_term: NRAP
    term:
      id: hgnc:7988
      label: NRAP
  - preferred_term: NEB
    term:
      id: hgnc:7720
      label: NEB
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: DYSREGULATED
    term:
      id: GO:0045214
      label: sarcomere organization
  - preferred_term: myofibril assembly
    modifier: DYSREGULATED
    term:
      id: GO:0030239
      label: myofibril assembly
  evidence:
  - reference: PMID:36661122
    reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish."
    explanation: Identifies NRAP as a disease modifier in NEB-related NM with therapeutic targeting potential.
  downstream:
  - target: Nemaline Rod Formation
    description: NRAP-associated protein aggregate biology is mechanistically linked to nemaline rod burden in NEB-deficient muscle.
    evidence:
    - reference: PMID:36661122
      reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish."
      explanation: Aggregate reduction with NRAP ablation supports a contribution of NRAP dysregulation to rod/aggregate pathology.
  - target: Reduced Sarcomeric Tension
    description: NRAP-driven sarcomeric disorganization contributes to impaired muscle functional output.
    evidence:
    - reference: PMID:36661122
      reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM."
      explanation: Structural and functional deficits in NRAP-dysregulated muscle support downstream contractile impairment.
histopathology:
- name: Nemaline rods on modified Gomori trichrome and electron microscopy
  description: >
    Muscle biopsy demonstrates characteristic rod-shaped inclusions that appear
    as red/fuchsinophilic material on modified Gomori trichrome and as
    osmiophilic lattice-like structures on ultrastructural examination.
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."
    explanation: Establishes the canonical biopsy finding used to diagnose nemaline myopathy.
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy."
    explanation: Independent adult case confirms the same pathognomonic rod morphology across staining and EM.
- name: Subsarcolemmal or central rod aggregates in inherited nemaline myopathy
  description: >
    In inherited nemaline myopathy, rods are typically arranged in
    subsarcolemmal or central aggregates rather than diffuse intrafiber
    distribution.
  frequency: VERY_FREQUENT
  context: inherited nemaline myopathy biopsy pattern
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."
    explanation: Defines the characteristic inherited-NM rod-distribution pattern on muscle histology.
- name: Diffuse intramyofiber rod distribution in sporadic late-onset nemaline myopathy
  description: >
    Sporadic late-onset nemaline myopathy often shows diffuse rod distribution
    within fibers, contrasting with the aggregate pattern in inherited disease.
  frequency: OCCASIONAL
  subtype: Adult-Onset Nemaline Myopathy
  context: sporadic late-onset nemaline myopathy pattern
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."
    explanation: Supports diffuse rod distribution as a biopsy feature of sporadic late-onset cases.
- name: Cytoplasmic and intranuclear rods with cytoplasmic bodies and myofibrillar disorganization
  description: >
    Severe ACTA1-associated disease can show a compound histopathologic pattern
    with cytoplasmic rods, intranuclear rods, cytoplasmic bodies, and major
    myofibrillar disorganization.
  frequency: OCCASIONAL
  subtype: Severe Congenital Nemaline Myopathy
  context: severe ACTA1-related nemaline myopathy
  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: "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: Documents the severe ACTA1-NM ultrastructural and architectural biopsy signature.
- name: Core areas and congenital fiber-type disproportion
  description: >
    Some biopsies show additional congenital-myopathy architecture, including
    core-like areas and congenital type 1 fiber disproportion, alongside rods.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion."
    explanation: Supports that rods may coexist with additional structural biopsy abnormalities in nemaline myopathy.
phenotypes:
- category: Musculoskeletal
  name: Generalized Muscle Weakness
  frequency: VERY_FREQUENT
  description: >
    Proximal greater than distal muscle weakness, predominantly affecting limb-girdle
    and axial muscles. In NEB-NM, 35% are unable to walk without support.
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  evidence:
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking curative therapies."
    explanation: Confirms muscle weakness as a cardinal feature of NEB-based nemaline myopathy.
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement."
    explanation: Documents generalized weakness across the spectrum of NEB-NM in a 33-patient cohort.
- category: Musculoskeletal
  name: Hypotonia
  frequency: VERY_FREQUENT
  description: >
    Decreased muscle tone, often severe in congenital forms, presenting as floppy
    infant syndrome.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."
    explanation: Case report demonstrating severe hypotonia as a presenting feature in neonatal NM.
  - reference: PMID:36661122
    reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function."
    explanation: Establishes hypotonia as a defining feature of nemaline myopathy.
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness."
    explanation: Indian cohort confirming generalized hypotonia as a universal presenting feature in childhood-onset NM.
- category: Musculoskeletal
  name: Facial Weakness
  frequency: FREQUENT
  description: >
    Weakness of facial muscles producing an elongated face. In NEB-NM, tongue
    atrophy in a triple furrow pattern is a novel and frequent finding associated
    with dysphagia.
  phenotype_term:
    preferred_term: Weakness of facial musculature
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia."
    explanation: Identifies a novel facial/bulbar finding in NEB-NM patients associated with dysphagia.
- category: Respiratory
  name: Respiratory Insufficiency
  frequency: FREQUENT
  description: >
    Weakness of respiratory muscles leads to hypoventilation. In NEB-NM, 55% of
    patients required ventilatory support, with progressive respiratory involvement
    over time.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS."
    explanation: Documents that 55% of NEB-NM patients required ventilatory support.
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities."
    explanation: Shows progressive respiratory involvement in NEB-NM patients over time.
  - reference: PMID:19208402
    reference_title: "Idiopathic adult-onset nemaline myopathy presenting with isolated respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case study reports a 60-year-old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness."
    explanation: Documents that NM can present with isolated respiratory failure from diaphragm weakness, highlighting the importance of considering neuromuscular causes.
- category: Musculoskeletal
  name: Feeding Difficulties
  frequency: FREQUENT
  description: >
    Difficulty with sucking and swallowing in infancy due to bulbar muscle weakness.
    In NEB-NM, 32% of patients require gastrostomy tube feeding, and dysphagia
    is associated with ventilatory support use.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."
    explanation: Documents feeding difficulties requiring gastrostomy in a neonate with NM.
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "32% of patients with NM-NEB used a G tube"
    explanation: Quantifies the frequency of gastrostomy tube use in NEB-NM patients.
- category: Musculoskeletal
  name: Scoliosis
  frequency: FREQUENT
  description: >
    Progressive scoliosis due to chronic axial muscle weakness. In NEB-NM,
    scoliosis is more common among patients using ventilatory support and
    in older age groups, suggesting disease progression.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis and dysphagia were more common among patients who used VS."
    explanation: Documents association of scoliosis with disease severity in NEB-NM.
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."
    explanation: Demonstrates progressive scoliosis with increasing age in NEB-NM.
- category: Musculoskeletal
  name: Nemaline Bodies
  frequency: OBLIGATE
  description: >
    Rod-shaped inclusions composed of Z-disc and thin filament proteins visible
    on modified Gomori trichrome stain and electron microscopy. The defining
    histopathological feature of nemaline myopathy. Rods stain red on modified
    Gomori trichrome and show electron-dense lattice-like structures on EM.
  phenotype_term:
    preferred_term: Nemaline bodies
    term:
      id: HP:0003798
      label: Nemaline bodies
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers."
    explanation: Confirms nemaline rod accumulation as the defining feature across NM subtypes.
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy."
    explanation: Classic description of nemaline rod morphology on trichrome stain and electron microscopy.
  - reference: PMID:39691005
    reference_title: "Sporadic Late-Onset Nemaline Rod Myopathy: An Interesting Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Modified Gomori trichrome staining revealed granular deposits in the myofibers. Ultrastructure examination showed numerous nemaline rods in the myofibers"
    explanation: Recent case confirming characteristic trichrome and ultrastructural appearance of nemaline rods.
- category: Musculoskeletal
  name: Slowness of Movements
  frequency: OCCASIONAL
  description: >
    Distinctive slowness of movements and delayed muscle relaxation, particularly
    characteristic of KBTBD13-related NEM6 with median relaxation rate well below
    normal limits.
  phenotype_term:
    preferred_term: delayed muscle relaxation after contraction
    term:
      id: HP:0002486
      label: Myotonia
  evidence:
  - reference: PMID:39651462
    reference_title: "Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene: A Cross-Sectional Study of 24 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key patient-reported symptoms since childhood were muscle weakness (n = 23; 96%), slowness of movements (n = 23; 96%), and difficulties with running (n = 20; 83%)."
    explanation: Documents slowness of movements as a near-universal symptom in NEM6 patients.
  - reference: PMID:39651462
    reference_title: "Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene: A Cross-Sectional Study of 24 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This might be related to delayed muscle relaxation."
    explanation: Links the slowness of movements phenotype to the delayed muscle relaxation kinetics measured in NEM6 patients.
- category: Musculoskeletal
  name: High Palate
  frequency: FREQUENT
  description: >
    High-arched palate associated with facial muscle weakness and elongated facies.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:2804774
    reference_title: "Fiber type disproportion in nemaline myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 21-year-old female with nemaline myopathy and concomitant dysmorphism characteristic of elongated face, high arched palate, scoliosis and pes cavus is reported."
    explanation: Documents high-arched palate as part of nemaline myopathy craniofacial phenotype.
prevalence:
- population: live births
  percentage: "approximately 1 in 50,000 live births"
  notes: Estimated birth prevalence/incidence ranges from 1 in 50,000 to 2 per 100,000 live births across reports.
  evidence:
  - reference: PMID:36960434
    reference_title: "Pediatric Nemaline Myopathy: A Systematic Review Using Individual Patient Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy is a skeletal muscle disease that affects 1 in 50 000 live births."
    explanation: Supports population-level frequency estimates in live births.
- population: muscle-biopsy cohort in India
  percentage: "0.53% of all muscle diseases; 22.6% of congenital myopathies"
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NM comprises 0.53% of all muscle diseases and 22.6% of all congenital myopathies."
    explanation: Provides cohort-based prevalence proportions within neuromuscular diagnostic categories.
genetic:
- name: NEB Mutations
  gene_term:
    preferred_term: NEB
    term:
      id: hgnc:7720
      label: NEB
  association: Causative
  subtype: NEM2
  frequency: VERY_FREQUENT
  notes: >
    Mutations in NEB, encoding nebulin, are the most common cause of nemaline
    myopathy, accounting for approximately 50% of cases. Most are compound
    heterozygous mutations. Nebulin is a giant sarcomeric protein that spans
    the thin filament and regulates its length.
  evidence:
  - reference: PMID:36661122
    reference_title: "NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients."
    explanation: Establishes NEB as the most common causative gene in NM.
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness"
    explanation: Confirms NEB variants as causative for NEM2.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause."
    explanation: Authoritative 2019 review confirming NEB and ACTA1 as the two most common causative genes.
- name: ACTA1 Mutations
  gene_term:
    preferred_term: ACTA1
    term:
      id: hgnc:129
      label: ACTA1
  association: Causative
  subtype: NEM3
  frequency: FREQUENT
  notes: >
    Mutations in ACTA1, encoding skeletal muscle alpha-actin, are the second
    most common cause, accounting for 15-25% of all NM cases but more than
    half of severe cases. Can be autosomal dominant (often de novo) or recessive.
    Severe ACTA1-NM features intranuclear rods and enlarged perinuclear space.
    Compensatory cardiac alpha-actin upregulation may modify disease severity.
  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: "Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death."
    explanation: Establishes ACTA1 as the second most common cause of NM.
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin."
    explanation: Case report of a novel ACTA1 variant causing NM.
  - 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 encodes α-actin, one of the principal components of the contractile units in skeletal muscle."
    explanation: Describes ACTA1 function and confirms its role in severe NM with characteristic intranuclear rods and perinuclear space abnormalities.
  - 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 measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect."
    explanation: Identifies compensatory cardiac alpha-actin expression as a potential modifier of ACTA1-NM severity.
- name: KBTBD13 Mutations
  gene_term:
    preferred_term: KBTBD13
    term:
      id: hgnc:37227
      label: KBTBD13
  association: Causative
  subtype: NEM6
  notes: >
    Mutations in KBTBD13 cause nemaline myopathy type 6 (NEM6) with a distinctive
    slowness of movement phenotype and delayed muscle relaxation. NEM6 is the
    most prevalent form of nemaline myopathy in the Netherlands.
  evidence:
  - reference: PMID:39651462
    reference_title: "Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene: A Cross-Sectional Study of 24 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy type 6 (NEM6) is the most prevalent type of nemaline myopathy in the Netherlands."
    explanation: Establishes KBTBD13-NEM6 as a significant form of NM.
- name: KLHL40 Mutations
  gene_term:
    preferred_term: KLHL40
    term:
      id: hgnc:30372
      label: KLHL40
  association: Causative
  notes: >
    Mutations in KLHL40, a CUL3 E3 ubiquitin ligase substrate-specific adapter,
    cause severe congenital nemaline myopathy through disruption of ubiquitin-
    mediated ER-Golgi trafficking and protein quality control.
  evidence:
  - reference: PMID:37432316
    reference_title: "Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy"
    explanation: Confirms KLHL40 mutations as causative for severe congenital NM.
- name: TPM3 Mutations
  gene_term:
    preferred_term: TPM3
    term:
      id: hgnc:12012
      label: TPM3
  association: Causative
  subtype: NEM1
  notes: >
    Mutations in TPM3, encoding slow skeletal muscle alpha-tropomyosin, cause
    a form of nemaline myopathy with predominant type 1 fiber involvement.
  evidence:
  - reference: PMID:27858751
    reference_title: "A Large Deletion Affecting TPM3, Causing Severe Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1."
    explanation: Directly supports TPM3 as a causative gene for NEM1 nemaline myopathy.
- name: TPM2 Mutations
  gene_term:
    preferred_term: TPM2
    term:
      id: hgnc:12011
      label: TPM2
  association: Causative
  notes: >
    Mutations in TPM2, encoding beta-tropomyosin, are a rarer cause of
    nemaline myopathy.
  evidence:
  - reference: PMID:23378224
    reference_title: "K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype."
    explanation: Family-based human data support TPM2 as a causative gene in nemaline myopathy.
- name: TNNT1 Mutations
  gene_term:
    preferred_term: TNNT1
    term:
      id: hgnc:11948
      label: TNNT1
  association: Causative
  subtype: Amish nemaline myopathy
  notes: >
    Mutations in TNNT1, encoding slow skeletal muscle troponin T, cause a
    distinctive form found predominantly in the Old Order Amish population.
  evidence:
  - reference: PMID:29931346
    reference_title: "TNNT1 nemaline myopathy: natural history and therapeutic frontier."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT)."
    explanation: Cohort natural-history data establish pathogenic TNNT1 variants as causative in Amish nemaline myopathy.
- name: CFL2 Mutations
  gene_term:
    preferred_term: CFL2
    term:
      id: hgnc:1875
      label: CFL2
  association: Causative
  notes: >
    Mutations in CFL2, encoding cofilin-2, are a rare cause of nemaline myopathy
    with actin filament accumulation.
  evidence:
  - reference: PMID:17160903
    reference_title: "Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report identification of a sixth gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy."
    explanation: Human sibling data identify CFL2 as a causative gene for congenital nemaline myopathy.
- name: LMOD3 Mutations
  gene_term:
    preferred_term: LMOD3
    term:
      id: hgnc:6649
      label: LMOD3
  association: Causative
  subtype: NEM10
  notes: >
    Mutations in LMOD3, encoding leiomodin-3, cause severe congenital nemaline
    myopathy. Leiomodin-3 is involved in thin filament elongation.
  evidence:
  - reference: PMID:36893608
    reference_title: "A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness."
    explanation: Supports biallelic LMOD3 mutations as causative for NEM10.
- name: KLHL41 Mutations
  gene_term:
    preferred_term: KLHL41
    term:
      id: hgnc:16905
      label: KLHL41
  association: Causative
  notes: >
    Mutations in KLHL41 cause nemaline myopathy. KLHL41 is involved in
    sarcomere maintenance and protein quality control.
  evidence:
  - reference: PMID:24268659
    reference_title: "Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families."
    explanation: Whole-exome sequencing and follow-up cohort data support KLHL41 as a causative nemaline myopathy gene.
diagnosis:
- name: Muscle biopsy with modified Gomori trichrome and electron microscopy
  presence: Nemaline rods identified on modified Gomori trichrome staining and confirmed by ultrastructural electron microscopy.
  diagnosis_term:
    preferred_term: biopsy of muscle tissue
    term:
      id: MAXO:0000387
      label: biopsy of muscle tissue
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: skeletal muscle tissue
        term:
          id: UBERON:0001134
          label: skeletal muscle tissue
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods."
    explanation: Confirms canonical biopsy diagnosis using trichrome-positive rods and ultrastructural validation.
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy."
    explanation: Independent adult-onset case confirms the same diagnostic histology and ultrastructure.
- name: Molecular genetic testing for causative NM variants
  presence: Targeted or expanded sequencing of congenital myopathy genes identifies pathogenic variants such as ACTA1 and NEB.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: ACTA1
        term:
          id: hgnc:129
          label: ACTA1
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: NEB
        term:
          id: hgnc:7720
          label: NEB
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin."
    explanation: Demonstrates use of expanded molecular testing to establish a genetic NM diagnosis.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes."
    explanation: Review evidence supports sequencing as core diagnostic strategy in genetically heterogeneous NM.
- name: Supportive electrophysiologic and laboratory profile
  presence: Myopathic electromyography with frequently normal creatine kinase can support diagnostic workup.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: creatine kinase
        term:
          id: PR:000029971
          label: creatine kinase
  evidence:
  - reference: PMID:17272906
    reference_title: "Nemaline rod myopathy: a rare form of myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The CPK levels were normal and EMG was myopathic."
    explanation: Cohort data support the commonly observed NM profile of normal CK with myopathic EMG.
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine kinase levels were normal, and electromyographic findings indicated a myopathic process."
    explanation: Independent adult case supports consistency of this supportive laboratory/electrophysiologic pattern.
- name: Distinction between inherited NM and sporadic late-onset nemaline myopathy
  presence: Rod distribution pattern and molecular context help separate inherited nemaline myopathy from acquired sporadic late-onset forms.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike iNM, SLONM is amenable to therapy. The distinction between these disorders is therefore crucial when the diagnosis remains ambiguous after initial investigations."
    explanation: Establishes clinical necessity of explicitly distinguishing inherited NM from SLONM.
  - reference: PMID:36703211
    reference_title: "Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples."
    explanation: Provides concrete biopsy-level differentiator between inherited and sporadic late-onset forms.
differential_diagnoses:
- name: Idiopathic inflammatory myopathy
  description: >
    Adult-onset nemaline myopathy can be misclassified as inflammatory myopathy,
    especially when proximal weakness and inflammatory biopsy features coexist.
  disease_term:
    preferred_term: idiopathic inflammatory myopathy
    term:
      id: MONDO:0600023
      label: idiopathic inflammatory myopathy
  distinguishing_features:
  - Nemaline rods on modified trichrome and electron microscopy favor nemaline myopathy
  - Inflammatory-cell infiltrates can coexist in some nemaline myopathy biopsies and confound diagnosis
  evidence:
  - reference: PMID:9372751
    reference_title: "Adult-onset nemaline myopathy: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case illustrates that adult-onset nemaline myopathy, although rare, should be considered in the differential diagnosis of an inflammatory myopathy."
    explanation: Directly identifies inflammatory myopathy as an important differential diagnosis.
- name: Metabolic myopathy
  description: >
    Biopsy findings such as glycogen-filled vacuoles can initially suggest metabolic
    myopathy before ultrastructural evaluation reveals nemaline rods.
  disease_term:
    preferred_term: metabolic myopathy
    term:
      id: MONDO:0020123
      label: metabolic myopathy
  distinguishing_features:
  - Glycogen accumulation may suggest metabolic disease on light microscopy
  - Detection of minirods/nemaline rods on ultrastructure redirects diagnosis toward nemaline myopathy
  evidence:
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy analyzed by light microscopy showed the presence of vacuoles filled with glycogen, suggesting a metabolic myopathy, but also fuchsinophilic inclusions."
    explanation: Demonstrates direct diagnostic overlap and the need to distinguish NM from metabolic myopathy.
- name: Central core myopathy
  description: >
    Core lesions can co-occur with rods and are linked to overlapping congenital
    myopathy gene sets, requiring careful histopathologic interpretation.
  disease_term:
    preferred_term: central core myopathy
    term:
      id: MONDO:0007294
      label: central core myopathy
  distinguishing_features:
  - Core lesions may be present in nemaline myopathy biopsies
  - Rods remain the defining hallmark of nemaline myopathy when demonstrated by trichrome/EM
  evidence:
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods."
    explanation: Review evidence supports substantial overlap between rod and core congenital myopathy pathology.
treatments:
- name: Respiratory Support
  description: >
    Nocturnal non-invasive ventilation (BiPAP) or continuous ventilatory support
    for respiratory muscle weakness. In NEB-NM, 55% of patients require ventilatory
    support with progressive need over time.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: MAXO:0000506
      label: noninvasive ventilation
  target_phenotypes:
  - preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS."
    explanation: Documents that the majority of NEB-NM patients require ventilatory support.
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities."
    explanation: Supports longitudinal need for respiratory support as disease progresses.
- name: Physical Therapy
  description: >
    Ongoing physical therapy and rehabilitation to maintain mobility, prevent
    contractures, and optimize functional capacity.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living."
    explanation: Supports ongoing rehabilitative, mobility-preserving symptomatic care as standard management.
- name: Nutritional Support
  description: >
    Gastrostomy tube feeding for patients with severe bulbar weakness and
    failure to thrive. In NEB-NM, 32% of patients require gastrostomy.
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: MAXO:0001346
      label: gastrostomy
  target_phenotypes:
  - preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "32% of patients with NM-NEB used a G tube"
    explanation: Quantifies the need for gastrostomy in NEB-NM patients.
  - reference: PMID:38500810
    reference_title: "Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding."
    explanation: Supports gastrostomy as a practical intervention for severe neonatal bulbar dysfunction.
- name: Orthopedic Management
  description: >
    Management of scoliosis (bracing or surgical correction), foot deformities,
    and joint contractures.
  treatment_term:
    preferred_term: orthopedic procedure
    term:
      id: MAXO:0000477
      label: orthopedic procedure
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."
    explanation: Progressive scoliosis supports need for structured orthopedic surveillance and intervention.
  - reference: PMID:31228046
    reference_title: "Nemaline myopathies: a current view."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living."
    explanation: Supports symptom-directed orthopedic and mobility-preserving management as part of standard care.
- name: Genetic Counseling
  description: >
    Genetic counseling for families to understand inheritance patterns, recurrence
    risk, and genetic testing options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:19208402
    reference_title: "Idiopathic adult-onset nemaline myopathy presenting with isolated respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unless appropriate tests are performed-including a muscle biopsy, if indicated-specific neuromuscular diseases are easily missed. This can lead to inappropriate counseling and treatment."
    explanation: Highlights counseling consequences of diagnostic misclassification, supporting formal counseling in NM care pathways.
- name: Fast Skeletal Muscle Troponin Activators (Investigational)
  description: >
    Tirasemtiv and related fast skeletal muscle troponin activators increase
    submaximal muscle tension in preclinical NM models by enhancing thin filament
    calcium sensitivity. Improved respiratory efficiency observed in NEM3 mouse models.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_phenotypes:
  - preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  - preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  target_mechanisms:
  - target: Thin Filament Dysfunction
    treatment_effect: MODULATES
    description: Troponin activation modulates thin-filament calcium sensitivity in ACTA1-related thin-filament disease.
    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: "Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3"
      explanation: Directly links troponin activator action to the thin-filament disease mechanism.
  - target: Reduced Sarcomeric Tension
    treatment_effect: RESTORES
    description: Tirasemtiv restores submaximal contractile force generation in affected limb and diaphragm muscle.
    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: Demonstrates restoration of force-generation deficits downstream of sarcomeric tension loss.
  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: Demonstrates tirasemtiv efficacy in a mouse model of ACTA1-related NM.
  - 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: "Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration."
    explanation: Shows improved respiratory efficiency with troponin activator treatment.
- name: Myosin Activators (Investigational)
  description: >
    Omecamtiv mecarbil, a small-molecule cardiac myosin activator, substantially
    increased submaximal tension in type 1 muscle fibers from NEB-NM patients,
    with the largest effects in those with the lowest nebulin levels.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: omecamtiv mecarbil
        term:
          id: CHEBI:188664
          label: omecamtiv mecarbil
  target_phenotypes:
  - preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  target_mechanisms:
  - target: Reduced Sarcomeric Tension
    treatment_effect: RESTORES
    description: Omecamtiv mecarbil increases submaximal tension in NEB-NM muscle fibers.
    evidence:
    - reference: PMID:38634969
      reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin."
      explanation: Ex vivo human fiber experiments support direct restoration of reduced sarcomeric tension.
  evidence:
  - reference: PMID:38634969
    reference_title: "Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin."
    explanation: Ex vivo human muscle fiber data showing omecamtiv mecarbil increases force production in NEB-NM.
datasets:
- accession: PMID:36714460
  title: Clinical Manifestation of Nebulin-Associated Nemaline Myopathy.
  description: >
    Clinical-genetic cohort dataset of NEB-associated nemaline myopathy from a
    specialized neuromuscular center, including motor, bulbar, respiratory, and
    interventional-support phenotyping across age strata.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 33
  conditions:
  - NEB-associated nemaline myopathy
  - ventilatory support stratification
  publication: PMID:36714460
  evidence:
  - reference: PMID:36714460
    reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support."
    explanation: Supports this publication as a reusable human clinical-genetic cohort dataset for NM-NEB.
  findings:
  - statement: Older NEB-NM patients show proportionally greater respiratory dysfunction and skeletal deformities.
    evidence:
    - reference: PMID:36714460
      reference_title: "Clinical Manifestation of Nebulin-Associated Nemaline Myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains."
      explanation: Captures age-stratified progression signal relevant for longitudinal NM phenotyping.
- accession: PMID:29931346
  title: "TNNT1 nemaline myopathy: natural history and therapeutic frontier."
  description: >
    Natural-history dataset for Amish TNNT1 nemaline myopathy with long-range
    birth-cohort capture, molecular diagnosis timing, and survival/respiratory
    outcomes.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 106
  conditions:
  - TNNT1-associated nemaline myopathy
  - infantile-onset lethal congenital myopathy
  publication: PMID:29931346
  evidence:
  - reference: PMID:29931346
    reference_title: "TNNT1 nemaline myopathy: natural history and therapeutic frontier."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We collected natural history data for 106 ANM patients born between 1923 and 2017."
    explanation: Defines a substantial disease-specific longitudinal dataset for TNNT1 nemaline myopathy.
  findings:
  - statement: TNNT1 c.505G>T homozygotes showed early failure to thrive and universal death from respiratory failure by age 6 years.
    evidence:
    - reference: PMID:29931346
      reference_title: "TNNT1 nemaline myopathy: natural history and therapeutic frontier."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected children developed thoracic rigidity, pectus carinatum and restrictive lung disease during infancy, and all succumbed to respiratory failure by 6 years of age (median survival 18 months, range 0.2-66 months)."
      explanation: Summarizes severe respiratory natural history and survival outcomes in the TNNT1 cohort.