👪

Inheritance

2

Autosomal dominant HP:0000006

FSHD usually follows autosomal dominant inheritance, although penetrance and severity are variable.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:17924332 SUPPORT Human Clinical

"Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is mainly characterized by progressive wasting and weakness of the facial, shoulder, and upper-arm muscles."

Human genetic study directly states the canonical autosomal dominant inheritance pattern of FSHD.

Digenic inheritance (FSHD2) HP:0010984

FSHD2 arises digenically: disease requires both an SMCHD1 (or other chromatin-modifier) mutation and, in trans, an FSHD-permissive 4qA D4Z4 haplotype carrying the DUX4 polyadenylation signal. Neither locus alone is sufficient to cause disease.

Digenic inheritance

Show evidence (1 reference)

PMID:23143600 SUPPORT Human Clinical

"FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression."

This study defines FSHD2 as digenic, requiring both an SMCHD1 mutation and an FSHD-permissive D4Z4 haplotype.

◆

Subtypes

2

FSHD1 MONDO:0008030

Classic form caused by contraction of the D4Z4 repeat array on a permissive chromosome 4qA background. This accounts for the large majority of genetically confirmed FSHD.

Show evidence (1 reference)

PMID:17924332 SUPPORT Human Clinical

"Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD; contractions on the other chromosomes are nonpathogenic."

Establishes the 4q35 D4Z4 contraction on a permissive 4qA haplotype as the genetic basis of FSHD1.

FSHD2 MONDO:0008031

Contraction-independent form with D4Z4 hypomethylation on a permissive 4qA background, usually associated with pathogenic variants in chromatin repressors such as SMCHD1.

Show evidence (1 reference)

PMID:19728363 SUPPORT Human Clinical

"In 15 FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q."

Defines the contraction-independent epigenetic FSHD2 phenotype with shared D4Z4 hypomethylation.

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Pathophysiology

3

D4Z4 Epigenetic Derepression

FSHD develops when D4Z4 contraction or contraction-independent hypomethylation occurs on a permissive 4qA subtelomere, relaxing chromatin and enabling pathogenic DUX4 expression.

Downstream

DUX4 Misexpression in Skeletal Muscle Loss of repression at the FSHD locus permits aberrant DUX4 expression in differentiated skeletal muscle.

Sensorineural hearing impairment Severe early-onset FSHD with large 4q35 deletions can include sensorineural hearing loss through extra-muscular intermediates not represented in the skeletal-muscle pathograph.

Retinal vasculopathy Retinal vasculopathy travels with the same large-deletion, early-onset end of the D4Z4 contraction spectrum as hearing loss, so it is placed here alongside it rather than downstream of myofiber loss.

Show evidence (2 references)

PMID:19728363 SUPPORT Human Clinical

"To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD."

Establishes that pathogenic D4Z4 contraction requires a permissive 4qA background rather than repeat size alone.

PMID:29478599 SUPPORT Human Clinical

"Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline."

Summarizes the central epigenetic lesion linking D4Z4 contraction to pathogenic DUX4 derepression.

DUX4 Misexpression in Skeletal Muscle

Intermittent DUX4 expression in skeletal muscle activates an embryonic transcriptional program and promotes muscle fiber toxicity and death.

Skeletal Muscle Fiber CL:0000188

DUX4 hgnc:50800 ↑ INCREASED

apoptotic process GO:0006915

Downstream

Progressive Myofiber Loss and Fatty Replacement Recurrent DUX4-mediated injury drives chronic muscle degeneration with incomplete repair and replacement by fat and fibrous tissue.

Show evidence (1 reference)

PMID:32576599 SUPPORT In Vitro

"Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death."

Patient-derived myotube work directly connects DUX4 activation to the downstream transcriptional program and muscle-cell toxicity.

Progressive Myofiber Loss and Fatty Replacement

The clinical pattern of FSHD reflects chronic degeneration of selected facial, scapular, humeral, truncal, and lower-extremity muscles, usually with marked asymmetry and variable progression.

Downstream

Facial weakness Early involvement of the muscles of facial expression contributes to incomplete eye closure, poor smile excursion, and facial asymmetry.

Scapular winging Periscapular weakness destabilizes the scapulothoracic joint and limits active shoulder elevation.

Muscle weakness Progressive weakness extends to upper arm, trunk, pelvic-girdle, and distal lower-extremity muscles.

Myalgia Chronic biomechanical strain and ongoing muscle pathology contribute to frequent shoulder and low-back pain.

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"FSHD symptoms usually start around the second decade and are most commonly characterized by asymmetric weakness affecting the face, shoulder, and arms, followed by the distal lower extremities and pelvic girdle."

Registry-based clinical data capture the stereotyped anatomic spread and asymmetry of muscle involvement in FSHD.

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Pathograph

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

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Phenotypes

6

Ear 1

Sensorineural hearing impairment OCCASIONAL HP:0000407

Show evidence (1 reference)

PMID:19049553 SUPPORT Human Clinical

"Sensorineural hearing loss was found in four patients, who presented infantile-onset dystrophic phenotype."

Supports hearing loss as a recognized extra-muscular phenotype in severe early-onset FSHD with large 4q35 deletions.

Head and Neck 1

Facial weakness VERY_FREQUENT Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:17924332 SUPPORT Human Clinical

"Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is mainly characterized by progressive wasting and weakness of the facial, shoulder, and upper-arm muscles."

This classic genetic study summarizes the canonical early distribution of weakness in FSHD.

Musculoskeletal 1

Muscle weakness VERY_FREQUENT HP:0001324

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"FSHD symptoms usually start around the second decade and are most commonly characterized by asymmetric weakness affecting the face, shoulder, and arms, followed by the distal lower extremities and pelvic girdle."

Supports both the distribution and the asymmetric progression of weakness in FSHD.

Constitutional 1

Myalgia FREQUENT HP:0003326

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back."

Large registry-based study shows that pain is common and localizes to the shoulder and lumbar regions most affected by weakness and posture.

Other 2

Scapular winging VERY_FREQUENT HP:0003691

Show evidence (1 reference)

PMID:18056023 SUPPORT Human Clinical

"Participants: Thirteen patients with bilateral winged scapula affected by facioscapulohumeral muscular dystrophy."

Surgical series directly documents scapular winging as a common and functionally important manifestation of FSHD.

Retinal vasculopathy OCCASIONAL Abnormal retinal vascular morphology HP:0008046

Show evidence (2 references)

PMID:30923442 SUPPORT Human Clinical

"early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement"

Places retinal vasculopathy among the extramuscular features and ties it to large D4Z4 deletions.

PMID:30923442 SUPPORT Human Clinical

"patients with FSHD had retinal vasculopathy with features resembling Coats"

Characterizes the vasculopathy as Coats-like, which is the specific ophthalmologic pattern described.

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Genetic Associations

2

D4Z4 repeat contraction on permissive 4qA haplotype (Causative repeat contraction)

Gene: DUX4 hgnc:50800

Show evidence (1 reference)

PMID:17924332 SUPPORT Human Clinical

"Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD; contractions on the other chromosomes are nonpathogenic."

Establishes the pathogenic requirement for contraction on a permissive 4qA background in FSHD1.

SMCHD1 (Causative chromatin modifier variant on a permissive D4Z4 background)

Gene: SMCHD1 hgnc:29090

Show evidence (1 reference)

PMID:29478599 SUPPORT Human Clinical

"The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation."

Review-level summary directly links SMCHD1-mediated chromatin failure to FSHD2 pathogenesis.

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Medical Actions

3

Aerobic Exercise Training

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

Regular endurance training can improve fitness, walking speed, and self-assessed health without evidence of exercise-induced muscle damage.

Show evidence (1 reference)

PMID:26156512 SUPPORT Human Clinical

"This randomized, controlled study showed that regular endurance training improves fitness, walking speed, and self-assessed health in patients with FSHD without causing muscle damage."

Randomized controlled evidence supports structured aerobic training as a safe supportive intervention in FSHD.

Scapulopexy

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Scapular fixation surgery can improve shoulder range of motion and reduce disabling winging in appropriately selected patients.

Show evidence (1 reference)

PMID:18056023 SUPPORT Human Clinical

"All patients experienced improvement in active range of motion of the shoulder and all of them had clinical improvement with complete resolution of the winged scapula."

Long-term retrospective series supports scapulopexy as an effective intervention for symptomatic scapular winging in selected FSHD patients.

Pain Management and Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Pain-directed pharmacologic and nonpharmacologic management, assistive devices, and multidisciplinary rehabilitation remain central to current care because pain is common and materially affects quality of life.

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"Management of pain should be considered when treating FSHD1 patients."

Registry-based outcome data support pain-directed supportive care as a necessary component of FSHD management.

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Biochemical Markers

1

Creatine Kinase (Mildly elevated)

Context: Serum creatine kinase is often normal to mildly elevated rather than markedly increased.

📈

Progression

2

Typical onset

Age: Adolescence to early adulthood

Facial weakness and scapular instability usually appear first; the age at onset and severity vary widely across individuals and families.

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"FSHD symptoms usually start around the second decade and are most commonly characterized by asymmetric weakness affecting the face, shoulder, and arms, followed by the distal lower extremities and pelvic girdle. Not all patients have the complete phenotype of FSHD, and clinical severity varies..."

Supports onset around the second decade and the wide phenotypic variability across affected individuals and families.

Descending asymmetric progression

Age: Adulthood

Weakness usually spreads from face and shoulder girdle to upper arms, trunk, distal lower extremities, and pelvic girdle with marked side-to-side asymmetry.

Show evidence (1 reference)

PMID:29053898 SUPPORT Human Clinical

"FSHD symptoms usually start around the second decade and are most commonly characterized by asymmetric weakness affecting the face, shoulder, and arms, followed by the distal lower extremities and pelvic girdle."

Describes the characteristic asymmetric distribution and descending spread of weakness from face and shoulder/arm involvement to distal lower extremities and pelvic girdle.

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Prevalence

1

Symptomatic population in the Netherlands

Point Prevalence 12.0 per 100,000 1–9 per 10,000

Population-based capture-recapture analysis estimated approximately 2,000 symptomatic affected individuals in the Netherlands.

Show evidence (1 reference)

PMID:25122204 SUPPORT Human Clinical

"The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals."

Population-based prevalence estimate for symptomatic FSHD from a national registry analysis.

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Related Datasets

5

Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy geo:GSE261617

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in muscle-specific DUX4-expressing (DUX4-Tg) mice. Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice.

mouse BULK RNA SEQ n=23

PMID:40591405

Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

DUX4.6 siRNA in vitro activity in FSHD patient-derived myotubes geo:GSE291267

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease caused by the aberrant ectopic expression of DUX4 in skeletal muscle. There are no approved therapies for FSHD to date, and strategies aimed at reducing DUX4 expression in skeletal muscle of FSHD patients are promising therapeutic approaches. Here we demonstrate DUX4.6 siRNA activity in reducing DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro.

human BULK RNA SEQ n=32

PMID:41994867

Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy geo:GSE201185

human MULTI OMICS n=11

Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

A circulating biomarker for severity of facioscapulohumeral muscular dystrophy ega:EGAS00001007350

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie FSHD pathogenesis and mechanisms including PAX7 target gene repression have been proposed.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Facioscapulohumeral Muscular Dystrophy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

3D tissue engineered human skeletal muscle modelling Facioscapulohumeral Muscular Dystrophy ega:EGAS50000000502

acioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a 3D tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Facioscapulohumeral Muscular Dystrophy"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

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Clinical Trials

4

NCT05747924 NOT_APPLICABLE ACTIVE_NOT_RECRUITING

Phase 1/2 FORTITUDE study of delpacibart braxlosiran (AOC 1020), an antibody-oligonucleotide conjugate designed to reduce DUX4 mRNA in FSHD1 and FSHD2.

Show evidence (1 reference)

clinicaltrials:NCT05747924 SUPPORT Human Clinical

"A Randomized, Double-blind, Placebo-controlled, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of AOC 1020 Administered Intravenously to Participants with Facioscapulohumeral Muscular Dystrophy (FSHD)"

Supports active clinical development of a DUX4-targeting oligonucleotide therapy in FSHD.

NCT06131983 NOT_APPLICABLE RECRUITING

Phase 1/2a dose-escalation study of ARO-DUX4, an RNA interference therapeutic targeting DUX4 in FSHD1.

Show evidence (1 reference)

clinicaltrials:NCT06131983 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ARO-DUX4 in participants with facioscapulohumeral muscular dystrophy Type 1 (FSHD1)."

Supports ongoing clinical testing of a second DUX4-silencing therapeutic strategy.

NCT05397470 PHASE_III TERMINATED

Phase III REACH trial of losmapimod, a p38alpha/beta inhibitor intended to suppress the DUX4 transcriptional program in FSHD.

Show evidence (1 reference)

clinicaltrials:NCT05397470 SUPPORT Human Clinical

"This is a study to evaluate the safety and efficacy of losmapimod in treating participants with Facioscapulohumeral Muscular Dystrophy (FSHD)."

Shows that p38-mediated DUX4 suppression advanced to late-stage clinical testing, even though the program did not succeed.

NCT07435129 PHASE_II NOT_RECRUITING

Phase II FORGE study of apitegromab, a myostatin-pathway therapy intended to improve muscle function rather than directly suppress DUX4.

Show evidence (1 reference)

clinicaltrials:NCT07435129 SUPPORT Human Clinical

"A randomized Phase 2 study to evaluate the efficacy and safety of apitegromab as a monotherapy in participant with FSHD"

Supports ongoing parallel development of muscle-function-directed therapy in FSHD.

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Animal Models

1

Xenopus frg1 gain- and loss-of-function vascular model Candidate-gene dosage model of the vascular component of FSHD

The only model to address why FSHD has an ophthalmologic component at all. frg1 is expressed in frog vasculature; knocking it down reduces angiogenesis and DAB2 expression, and overexpressing it produces excess vessel branching, vessel dilation and edema. Read carefully, this is a candidate-gene result from before the field settled on DUX4: it shows that a gene at the FSHD locus can produce a vascular phenotype when its dose is wrong, not that FRG1 dosage is what causes vasculopathy in patients.

Species

Xenopus laevis

Genotype

FRG1 morpholino knockdown and frg1 mRNA overexpression in embryos and tadpoles

Genes

FRG1 hgnc:3954

Publication

PMID:19383939

Retained as a candidate-gene model with its caveats intact rather than dropped: FRG1 has largely been displaced by DUX4 as the FSHD effector, but no DUX4-based account of the retinal vasculopathy has replaced this one, so the vascular feature currently has no better mechanistic model.

{ }

Source YAML

click to show

name: Facioscapulohumeral Muscular Dystrophy
creation_date: "2026-04-21T04:46:26Z"
description: >-
  Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited
  muscular dystrophy characterized by progressive, often asymmetric weakness
  that typically begins in the facial and scapular muscles and later involves
  the upper arms, trunk, and lower extremities. The core disease mechanism is
  loss of epigenetic repression at the D4Z4 locus on chromosome 4q35, which
  permits pathogenic expression of the embryonic transcription factor DUX4 in
  skeletal muscle. Most cases are FSHD1 due to D4Z4 repeat contraction on a
  permissive 4qA haplotype, whereas FSHD2 reflects contraction-independent
  hypomethylation, usually from pathogenic variants in chromatin regulators such
  as SMCHD1. There is no approved disease-modifying therapy; current management
  is supportive, while the therapeutic pipeline remains centered on DUX4
  suppression and muscle function preservation.
category: Genetic
parents:
- Muscular Dystrophy
- Neuromuscular Disease
disease_term:
  preferred_term: facioscapulohumeral muscular dystrophy
  term:
    id: MONDO:0001347
    label: facioscapulohumeral muscular dystrophy
inheritance:
- name: Autosomal dominant
  description: >-
    FSHD usually follows autosomal dominant inheritance, although penetrance
    and severity are variable.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:17924332
    reference_title: "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is
      mainly characterized by progressive wasting and weakness of the facial,
      shoulder, and upper-arm muscles.
    explanation: >-
      Human genetic study directly states the canonical autosomal dominant
      inheritance pattern of FSHD.
- name: Digenic inheritance (FSHD2)
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    FSHD2 arises digenically: disease requires both an SMCHD1 (or other
    chromatin-modifier) mutation and, in trans, an FSHD-permissive 4qA D4Z4
    haplotype carrying the DUX4 polyadenylation signal. Neither locus alone is
    sufficient to cause disease.
  evidence:
  - reference: PMID:23143600
    reference_title: "Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a
      normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4
      expression.
    explanation: >-
      This study defines FSHD2 as digenic, requiring both an SMCHD1 mutation and
      an FSHD-permissive D4Z4 haplotype.
has_subtypes:
- name: FSHD1
  subtype_term:
    preferred_term: facioscapulohumeral muscular dystrophy 1
    term:
      id: MONDO:0008030
      label: facioscapulohumeral muscular dystrophy 1
  description: >-
    Classic form caused by contraction of the D4Z4 repeat array on a
    permissive chromosome 4qA background. This accounts for the large
    majority of genetically confirmed FSHD.
  evidence:
  - reference: PMID:17924332
    reference_title: "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD;
      contractions on the other chromosomes are nonpathogenic.
    explanation: Establishes the 4q35 D4Z4 contraction on a permissive 4qA haplotype as the genetic basis of FSHD1.
- name: FSHD2
  subtype_term:
    preferred_term: facioscapulohumeral muscular dystrophy 2
    term:
      id: MONDO:0008031
      label: facioscapulohumeral muscular dystrophy 2
  description: >-
    Contraction-independent form with D4Z4 hypomethylation on a permissive
    4qA background, usually associated with pathogenic variants in chromatin
    repressors such as SMCHD1.
  evidence:
  - reference: PMID:19728363
    reference_title: "Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 15 FSHD families without D4Z4 contractions but with at least one
      4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on
      chromosomes 4q and 10q.
    explanation: Defines the contraction-independent epigenetic FSHD2 phenotype with shared D4Z4 hypomethylation.
prevalence:
- population: Symptomatic population in the Netherlands
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 12.0
  percentage: 12 per 100,000
  notes: >-
    Population-based capture-recapture analysis estimated approximately 2,000
    symptomatic affected individuals in the Netherlands.
  evidence:
  - reference: PMID:25122204
    reference_title: "Population-based incidence and prevalence of facioscapulohumeral dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence rate was 12/100,000, equivalent to 2,000 affected
      individuals.
    explanation: >-
      Population-based prevalence estimate for symptomatic FSHD from a
      national registry analysis.
progression:
- phase: Typical onset
  age_range: Adolescence to early adulthood
  notes: >-
    Facial weakness and scapular instability usually appear first; the age at
    onset and severity vary widely across individuals and families.
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FSHD symptoms usually start around the second decade and are most
      commonly characterized by asymmetric weakness affecting the face,
      shoulder, and arms, followed by the distal lower extremities and pelvic
      girdle. Not all patients have the complete phenotype of FSHD, and
      clinical severity varies widely among patients, including great
      variability of weakness within families.
    explanation: Supports onset around the second decade and the wide phenotypic variability across affected individuals and families.
- phase: Descending asymmetric progression
  age_range: Adulthood
  notes: >-
    Weakness usually spreads from face and shoulder girdle to upper arms,
    trunk, distal lower extremities, and pelvic girdle with marked
    side-to-side asymmetry.
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FSHD symptoms usually start around the second decade and are most
      commonly characterized by asymmetric weakness affecting the face,
      shoulder, and arms, followed by the distal lower extremities and pelvic
      girdle.
    explanation: Describes the characteristic asymmetric distribution and descending spread of weakness from face and shoulder/arm involvement to distal lower extremities and pelvic girdle.
pathophysiology:
- name: D4Z4 Epigenetic Derepression
  description: >-
    FSHD develops when D4Z4 contraction or contraction-independent
    hypomethylation occurs on a permissive 4qA subtelomere, relaxing
    chromatin and enabling pathogenic DUX4 expression.
  evidence:
  - reference: PMID:19728363
    reference_title: "Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To develop FSHD, D4Z4 contraction needs to occur on a specific
      genetic background. Only contractions associated with the 4qA161
      haplotype cause FSHD.
    explanation: >-
      Establishes that pathogenic D4Z4 contraction requires a permissive
      4qA background rather than repeat size alone.
  - reference: PMID:29478599
    reference_title: "Facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies demonstrate that contraction in the number of D4Z4
      repeats results in chromatin relaxation and transcriptional
      de-repression of DUX4, a gene normally expressed only in the
      germline.
    explanation: >-
      Summarizes the central epigenetic lesion linking D4Z4 contraction to
      pathogenic DUX4 derepression.
  downstream:
  - target: DUX4 Misexpression in Skeletal Muscle
    description: >-
      Loss of repression at the FSHD locus permits aberrant DUX4 expression
      in differentiated skeletal muscle.
    evidence:
    - reference: PMID:29478599
      reference_title: "Facioscapulohumeral muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recent studies demonstrate that contraction in the number of D4Z4
        repeats results in chromatin relaxation and transcriptional
        de-repression of DUX4, a gene normally expressed only in the germline.
      explanation: >-
        Directly links D4Z4 repeat contraction and chromatin relaxation to
        derepressed DUX4 expression.
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe early-onset FSHD with large 4q35 deletions can include
      sensorineural hearing loss through extra-muscular intermediates not
      represented in the skeletal-muscle pathograph.
  - target: Retinal vasculopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Retinal vasculopathy travels with the same large-deletion, early-onset end
      of the D4Z4 contraction spectrum as hearing loss, so it is placed here
      alongside it rather than downstream of myofiber loss.
    evidence:
    - reference: PMID:30923442
      reference_title: "A Pediatric Review of Facioscapulohumeral Muscular Dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement"
      explanation: Supports the edge from the size of the D4Z4 contraction to the extramuscular ophthalmologic feature.
- name: DUX4 Misexpression in Skeletal Muscle
  description: >-
    Intermittent DUX4 expression in skeletal muscle activates an embryonic
    transcriptional program and promotes muscle fiber toxicity and death.
  genes:
  - preferred_term: DUX4
    term:
      id: hgnc:50800
      label: DUX4
    modifier: INCREASED
  cell_types:
  - preferred_term: Skeletal Muscle Fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:32576599
    reference_title: "p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of
      repression at the D4Z4 locus leading to aberrant double homeobox 4
      (DUX4) expression in skeletal muscle. Activation of this early
      embryonic transcription factor results in the expression of its target
      genes causing muscle fiber death.
    explanation: >-
      Patient-derived myotube work directly connects DUX4 activation to the
      downstream transcriptional program and muscle-cell toxicity.
  downstream:
  - target: Progressive Myofiber Loss and Fatty Replacement
    description: >-
      Recurrent DUX4-mediated injury drives chronic muscle degeneration with
      incomplete repair and replacement by fat and fibrous tissue.
    evidence:
    - reference: PMID:32576599
      reference_title: "p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Activation of this early embryonic transcription factor results in the
        expression of its target genes causing muscle fiber death.
      explanation: >-
        Patient-derived myotube evidence links DUX4 activation to downstream
        muscle fiber death, supporting the DUX4-to-myofiber-loss edge.
- name: Progressive Myofiber Loss and Fatty Replacement
  description: >-
    The clinical pattern of FSHD reflects chronic degeneration of selected
    facial, scapular, humeral, truncal, and lower-extremity muscles, usually
    with marked asymmetry and variable progression.
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FSHD symptoms usually start around the second decade and are most
      commonly characterized by asymmetric weakness affecting the face,
      shoulder, and arms, followed by the distal lower extremities and
      pelvic girdle.
    explanation: >-
      Registry-based clinical data capture the stereotyped anatomic spread
      and asymmetry of muscle involvement in FSHD.
  downstream:
  - target: Facial weakness
    description: >-
      Early involvement of the muscles of facial expression contributes to
      incomplete eye closure, poor smile excursion, and facial asymmetry.
    evidence:
    - reference: PMID:17924332
      reference_title: "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is
        mainly characterized by progressive wasting and weakness of the facial,
        shoulder, and upper-arm muscles.
      explanation: >-
        Supports facial weakness as a direct clinical consequence of the
        progressive muscle involvement in FSHD.
  - target: Scapular winging
    description: >-
      Periscapular weakness destabilizes the scapulothoracic joint and
      limits active shoulder elevation.
    evidence:
    - reference: PMID:18056023
      reference_title: "Fixation of winged scapula in facioscapulohumeral muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Participants: Thirteen patients with bilateral winged scapula affected
        by facioscapulohumeral muscular dystrophy.
      explanation: >-
        Clinical surgical series documents scapular winging as an FSHD
        manifestation linked to shoulder-girdle muscle involvement.
  - target: Muscle weakness
    description: >-
      Progressive weakness extends to upper arm, trunk, pelvic-girdle, and
      distal lower-extremity muscles.
    evidence:
    - reference: PMID:29053898
      reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        FSHD symptoms usually start around the second decade and are most
        commonly characterized by asymmetric weakness affecting the face,
        shoulder, and arms, followed by the distal lower extremities and pelvic
        girdle.
      explanation: >-
        Supports the anatomic spread of progressive FSHD muscle weakness.
  - target: Myalgia
    description: >-
      Chronic biomechanical strain and ongoing muscle pathology contribute to
      frequent shoulder and low-back pain.
    evidence:
    - reference: PMID:29053898
      reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pain was reported most frequently in the shoulders and lower back.
        These localizations are consistent with the findings of previous
        studies.10 We hypothesize that the degree of pain in these two locations
        may be exacerbated by the fact that the muscles in this region are
        amongst the weakest muscle groups in FSHD1.
      explanation: >-
        Clinical registry data support the pain distribution and provide a
        mechanistic hypothesis connecting pain to the weakest muscle groups.
phenotypes:
- name: Facial weakness
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Weakness of the facial musculature is often an early and characteristic
    manifestation of FSHD.
  phenotype_term:
    preferred_term: facial weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:17924332
    reference_title: "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is
      mainly characterized by progressive wasting and weakness of the
      facial, shoulder, and upper-arm muscles.
    explanation: >-
      This classic genetic study summarizes the canonical early distribution
      of weakness in FSHD.
- name: Scapular winging
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Weakness of scapular stabilizers produces winging and limits active
    shoulder abduction and flexion.
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:18056023
    reference_title: "Fixation of winged scapula in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants: Thirteen patients with bilateral winged scapula
      affected by facioscapulohumeral muscular dystrophy.
    explanation: >-
      Surgical series directly documents scapular winging as a common and
      functionally important manifestation of FSHD.
- name: Muscle weakness
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Weakness is typically asymmetric and descends from facial and shoulder
    muscles to the upper arms, trunk, distal lower extremities, and pelvic
    girdle.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FSHD symptoms usually start around the second decade and are most
      commonly characterized by asymmetric weakness affecting the face,
      shoulder, and arms, followed by the distal lower extremities and
      pelvic girdle.
    explanation: >-
      Supports both the distribution and the asymmetric progression of
      weakness in FSHD.
- name: Myalgia
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Chronic pain commonly affects the shoulders and lower back and is an
    important contributor to disability and reduced quality of life.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 398 patients, 88.6% reported pain at the time of study. The most
      frequent locations were shoulders and lower back.
    explanation: >-
      Large registry-based study shows that pain is common and localizes to
      the shoulder and lumbar regions most affected by weakness and posture.
- name: Sensorineural hearing impairment
  category: Otolaryngologic
  frequency: OCCASIONAL
  description: >-
    Hearing impairment is an extra-muscular feature seen mainly in severe
    early-onset disease with very short 4q35 fragments.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:19049553
    reference_title: "Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensorineural hearing loss was found in four patients, who presented
      infantile-onset dystrophic phenotype.
    explanation: >-
      Supports hearing loss as a recognized extra-muscular phenotype in
      severe early-onset FSHD with large 4q35 deletions.
- name: Retinal vasculopathy
  category: Ophthalmologic
  frequency: OCCASIONAL
  description: >-
    A telangiectatic, sometimes exudative retinal vasculopathy resembling Coats
    disease is the ophthalmologic extramuscular feature of FSHD. Like hearing
    loss, it clusters in early-onset disease with large D4Z4 deletions, and it
    is the human counterpart of the vascular arm of the disease that the frog
    FRG1 model addresses.
  phenotype_term:
    preferred_term: Retinal vasculopathy
    term:
      id: HP:0008046
      label: Abnormal retinal vascular morphology
  evidence:
  - reference: PMID:30923442
    reference_title: "A Pediatric Review of Facioscapulohumeral Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement"
    explanation: Places retinal vasculopathy among the extramuscular features and ties it to large D4Z4 deletions.
  - reference: PMID:30923442
    reference_title: "A Pediatric Review of Facioscapulohumeral Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with FSHD had retinal vasculopathy with features resembling Coats"
    explanation: Characterizes the vasculopathy as Coats-like, which is the specific ophthalmologic pattern described.
biochemical:
- name: Creatine Kinase
  presence: Mildly elevated
  context: >-
    Serum creatine kinase is often normal to mildly elevated rather than
    markedly increased.
genetic:
- name: D4Z4 repeat contraction on permissive 4qA haplotype
  subtype: FSHD1
  association: Causative repeat contraction
  gene_term:
    preferred_term: DUX4
    term:
      id: hgnc:50800
      label: DUX4
  notes: >-
    Most genetically confirmed cases reflect contraction of the D4Z4 repeat
    array on a permissive 4qA chromosome. Repeat contraction alone is not
    sufficient if it occurs on nonpermissive haplotypes.
  evidence:
  - reference: PMID:17924332
    reference_title: "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD;
      contractions on the other chromosomes are nonpathogenic.
    explanation: >-
      Establishes the pathogenic requirement for contraction on a permissive
      4qA background in FSHD1.
- name: SMCHD1
  subtype: FSHD2
  association: Causative chromatin modifier variant on a permissive D4Z4 background
  gene_term:
    preferred_term: SMCHD1
    term:
      id: hgnc:29090
      label: SMCHD1
  notes: >-
    In FSHD2, pathogenic variants in SMCHD1 impair chromatin repression and
    lead to contraction-independent D4Z4 hypomethylation with inappropriate
    DUX4 expression.
  evidence:
  - reference: PMID:29478599
    reference_title: "Facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The chromatin changes in this form of FSHD (FSHD2) are the result, in
      most cases, of mutations in SMCHD1, a gene on chromosome 18 involved
      in chromatin regulation.
    explanation: >-
      Review-level summary directly links SMCHD1-mediated chromatin failure
      to FSHD2 pathogenesis.
treatments:
- name: Aerobic Exercise Training
  description: >-
    Regular endurance training can improve fitness, walking speed, and
    self-assessed health without evidence of exercise-induced muscle damage.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:26156512
    reference_title: "Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy: RCT study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This randomized, controlled study showed that regular endurance
      training improves fitness, walking speed, and self-assessed health in
      patients with FSHD without causing muscle damage.
    explanation: >-
      Randomized controlled evidence supports structured aerobic training as
      a safe supportive intervention in FSHD.
- name: Scapulopexy
  description: >-
    Scapular fixation surgery can improve shoulder range of motion and reduce
    disabling winging in appropriately selected patients.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18056023
    reference_title: "Fixation of winged scapula in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients experienced improvement in active range of motion of the
      shoulder and all of them had clinical improvement with complete
      resolution of the winged scapula.
    explanation: >-
      Long-term retrospective series supports scapulopexy as an effective
      intervention for symptomatic scapular winging in selected FSHD
      patients.
- name: Pain Management and Supportive Care
  description: >-
    Pain-directed pharmacologic and nonpharmacologic management, assistive
    devices, and multidisciplinary rehabilitation remain central to current
    care because pain is common and materially affects quality of life.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29053898
    reference_title: "Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management of pain should be considered when treating FSHD1 patients.
    explanation: >-
      Registry-based outcome data support pain-directed supportive care as a
      necessary component of FSHD management.
animal_models:
- name: Xenopus frg1 gain- and loss-of-function vascular model
  species: Xenopus laevis
  genotype: FRG1 morpholino knockdown and frg1 mRNA overexpression in embryos and tadpoles
  category: Candidate-gene dosage model of the vascular component of FSHD
  publication: PMID:19383939
  description: >-
    The only model to address why FSHD has an ophthalmologic component at all.
    frg1 is expressed in frog vasculature; knocking it down reduces angiogenesis
    and DAB2 expression, and overexpressing it produces excess vessel branching,
    vessel dilation and edema. Read carefully, this is a candidate-gene result
    from before the field settled on DUX4: it shows that a gene at the FSHD locus
    can produce a vascular phenotype when its dose is wrong, not that FRG1 dosage
    is what causes vasculopathy in patients.
  genes:
  - preferred_term: FRG1
    term:
      id: hgnc:3954
      label: FRG1
  modeled_mechanisms:
  - target: Retinal vasculopathy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Produces a disturbed vascular phenotype from misexpression of a gene at the
      FSHD locus, offering a mechanism for a disease feature that the
      DUX4-in-skeletal-muscle account does not reach.
    limitations: >-
      Three gaps separate this from the human phenotype. The readouts are
      whole-embryo and tadpole vasculature, not retina, so the tissue in which
      patients present is not examined. The manipulation is systemic
      overexpression of frg1, whereas FRG1 is a candidate whose upregulation in
      patient muscle has been contested and which the field has largely
      displaced in favour of DUX4 — so the model may be modelling a gene that
      is not the effector. And the direction is inverted between arms:
      knockdown reduces angiogenesis while overexpression increases branching,
      so the model does not by itself say which dose change, if either,
      corresponds to the patient state.
    readouts:
    - name: Blood vessel branching and vessel diameter after frg1 overexpression
      target: Retinal vasculopathy
      direction: INCREASED
      interpretation: >-
        The pro-angiogenic arm — excess branching, dilated vessels and edema —
        is the phenotype offered as a vascular counterpart of the human feature.
      evidence:
      - reference: PMID:19383939
        reference_title: "FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "tadpoles subjected to frg1 overexpression displayed the pro-angiogenic phenotypes of increased blood vessel branching and dilation of blood vessels, and developed edemas, suggesting that their circulation was disrupted"
        explanation: Reports the measured vascular phenotype under frg1 overexpression.
    - name: Angiogenesis and DAB2 expression after FRG1 knockdown
      target: Retinal vasculopathy
      direction: DECREASED
      interpretation: >-
        The loss-of-function arm establishes that frg1 is required for normal
        vessel development, which is what makes the overexpression phenotype a
        dosage effect rather than a nonspecific toxicity.
      evidence:
      - reference: PMID:19383939
        reference_title: "FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "expression of FRG1 was found to be essential for the development of the vasculature, as a knockdown of FRG1 resulted in decreased angiogenesis and reduced expression of the angiogenic regulator DAB2"
        explanation: Reports the knockdown arm and the molecular readout used for it.
    evidence:
    - reference: PMID:19383939
      reference_title: "FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, the systemic upregulation of the FRG1 protein shows the potential for acquiring a disrupted vascular phenotype, providing the first link between a FSHD candidate gene and the vascular component of FSHD pathology."
      explanation: >-
        The authors' own claim is a demonstrated potential and a first link, not
        an established disease mechanism, which is the level this link asserts.
    - reference: PMID:19383939
      reference_title: "FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that endogenous frg1 is expressed in both the developing and adult vasculature in Xenopus."
      explanation: Establishes that the gene is expressed in the tissue whose phenotype the model scores.
  notes: >-
    Retained as a candidate-gene model with its caveats intact rather than
    dropped: FRG1 has largely been displaced by DUX4 as the FSHD effector, but
    no DUX4-based account of the retinal vasculopathy has replaced this one, so
    the vascular feature currently has no better mechanistic model.
clinical_trials:
- name: NCT05747924
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Phase 1/2 FORTITUDE study of delpacibart braxlosiran (AOC 1020), an
    antibody-oligonucleotide conjugate designed to reduce DUX4 mRNA in FSHD1
    and FSHD2.
  evidence:
  - reference: clinicaltrials:NCT05747924
    reference_title: "A Randomized, Double-blind, Placebo-controlled, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of AOC 1020 Administered Intravenously to Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Randomized, Double-blind, Placebo-controlled, Phase 1/2 Study to
      Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics,
      and Exploratory Efficacy of AOC 1020 Administered Intravenously to
      Participants with Facioscapulohumeral Muscular Dystrophy (FSHD)
    explanation: >-
      Supports active clinical development of a DUX4-targeting
      oligonucleotide therapy in FSHD.
  notes: >-
    ClinicalTrials.gov listed this study as Active, not recruiting on
    2025-04-01; phase 1/2 was mapped to NOT_APPLICABLE because the schema does
    not include combined phases.
- name: NCT06131983
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Phase 1/2a dose-escalation study of ARO-DUX4, an RNA interference
    therapeutic targeting DUX4 in FSHD1.
  evidence:
  - reference: clinicaltrials:NCT06131983
    reference_title: "A Phase1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-DUX4 in Adult Patients and Adolescent Patients With Facioscapulohumeral Muscular Dystrophy Type 1"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the safety, tolerability,
      pharmacokinetics (PK) and pharmacodynamics (PD) of ARO-DUX4 in
      participants with facioscapulohumeral muscular dystrophy Type 1
      (FSHD1).
    explanation: >-
      Supports ongoing clinical testing of a second DUX4-silencing
      therapeutic strategy.
  notes: >-
    ClinicalTrials.gov listed this study as Recruiting on 2026-02-06; phase
    1/2a was mapped to NOT_APPLICABLE because the schema does not include
    combined phases.
- name: NCT05397470
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Phase III REACH trial of losmapimod, a p38alpha/beta inhibitor intended to
    suppress the DUX4 transcriptional program in FSHD.
  evidence:
  - reference: clinicaltrials:NCT05397470
    reference_title: "A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a study to evaluate the safety and efficacy of losmapimod in
      treating participants with Facioscapulohumeral Muscular Dystrophy
      (FSHD).
    explanation: >-
      Shows that p38-mediated DUX4 suppression advanced to late-stage
      clinical testing, even though the program did not succeed.
  notes: >-
    ClinicalTrials.gov listed the study as Terminated on 2025-11-10 after
    results posting.
- name: NCT07435129
  phase: PHASE_II
  status: NOT_RECRUITING
  description: >-
    Phase II FORGE study of apitegromab, a myostatin-pathway therapy intended
    to improve muscle function rather than directly suppress DUX4.
  evidence:
  - reference: clinicaltrials:NCT07435129
    reference_title: "A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter, 52-Week Study Evaluating the Efficacy and Safety of Apitegromab in Participants With Facioscapulohumeral Muscular Dystrophy (FORGE)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A randomized Phase 2 study to evaluate the efficacy and safety of
      apitegromab as a monotherapy in participant with FSHD
    explanation: >-
      Supports ongoing parallel development of muscle-function-directed
      therapy in FSHD.
  notes: >-
    ClinicalTrials.gov listed this study as not yet recruiting on 2026-02-27;
    mapped to schema enum NOT_RECRUITING.
datasets:
- accession: geo:GSE261617
  title: Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy
  description: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in muscle-specific DUX4-expressing (DUX4-Tg) mice. Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 23
  publication: PMID:40591405
  notes: Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE291267
  title: DUX4.6 siRNA in vitro activity in FSHD patient-derived myotubes
  description: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease caused by the aberrant ectopic expression of DUX4 in skeletal muscle. There are no approved therapies for FSHD to date, and strategies aimed at reducing DUX4 expression in skeletal muscle of FSHD patients are promising therapeutic approaches. Here we demonstrate DUX4.6 siRNA activity in reducing DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 32
  publication: PMID:41994867
  notes: Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE201185
  title: Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_count: 11
  notes: Identified by GEO DataSets index search for Facioscapulohumeral Muscular Dystrophy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001007350
  title: A circulating biomarker for severity of facioscapulohumeral muscular dystrophy
  description: Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie FSHD pathogenesis and mechanisms including PAX7 target gene repression have been proposed.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Facioscapulohumeral Muscular Dystrophy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000502
  title: 3D tissue engineered human skeletal muscle modelling Facioscapulohumeral Muscular Dystrophy
  description: acioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a 3D tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Facioscapulohumeral Muscular Dystrophy"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Facioscapulohumeral Muscular Dystrophy. Core disease mechanisms, molecular...

Asta Scientific Corpus Retrieval 20 citations 2026-04-22T21:54:51.169538

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Facioscapulohumeral Muscular Dystrophy. Core disease mechanisms, molecular...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

Authors: S. Lassche, C. Ottenheijm, N. Voermans, H. Westeneng, B. Janssen et al.
Year: 2013
Venue: BMC Neurology
URL: https://www.semanticscholar.org/paper/868ee81fe48b5199729eda6ddea2866f5512e503
DOI: 10.1186/1471-2377-13-144
PMID: 24119284
PMCID: 3852245
Citations: 15
Influential citations: 1
Summary: The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.
Evidence snippets:
Snippet 1 (score: 0.605) > BackgroundAlthough muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD.Methods/DesignEvaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments.DiscussionThis study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.

[2] Diagnosis, Pathogenesis and Treatment of Muscular Dystrophy

Authors: M. Bozzi
Year: 2025
Venue: Biomedicines
URL: https://www.semanticscholar.org/paper/e9c585567287a136c52df952d8f374aa96ae1090
DOI: 10.3390/biomedicines13081820
PMID: 40868075
PMCID: 12383284
Summary: Muscular dystrophies are a group of inherited genetic disorders that involve an ever-growing number of genes [...].
Evidence snippets:
Snippet 1 (score: 0.587) > Muscular dystrophies are a group of inherited genetic disorders that involve an evergrowing number of genes. Nowadays, more than 50 genes have been linked to different muscular dystrophies [1]. This genetic variability accounts for the wide heterogeneity of phenotypes observed in patients. From a clinical and pathological standpoint, muscular dystrophies are characterized by varying ages of onset and a broad spectrum of symptoms, including severe forms that impact other organs and tissues, particularly the central nervous system. Nevertheless, muscular dystrophies exhibit common histopathological and molecular characteristics that reflect disease progression. The primary shared feature is the accumulation of fibrotic tissue, which results from muscle fiber degeneration and cell death, ongoing inflammation, and increased oxidative stress. These factors contribute to the infiltration of inflammatory cells and the oxidation of lipids and proteins [2]. In the most severe forms of muscular dystrophy, cardiomyopathy and respiratory dysfunction occur during disease progression, severely affecting the patients' quality of life and strongly reducing their lifespan. Duchenne muscular dystrophy, Myotonic dystrophy type 1, and Facioscapulohumeral muscular dystrophy are some of the most common forms of muscular dystrophies. In particular, due to mutations in the dystrophin gene, Duchenne muscular dystrophy has an incidence of about 1 in 5000 live males every year [3]. > Early diagnosis is essential for effectively managing disease progression, and it should include genetic testing. However, establishing an accurate diagnosis can be challenging, as individuals with mutations in the same gene may present with diverse clinical manifestations. Therefore, a comprehensive approach integrating clinical evaluation, molecular testing, and tissue analysis is critical for achieving a precise diagnosis and informing a reliable prognosis [4,5]. > At present, there is no definitive cure for muscular dystrophy. Glucocorticoid therapy remains the cornerstone of muscular dystrophy treatment, helping to delay disease progression and improve muscle strength. However, its use is associated with significant side effects, including adrenal suppression, growth delay, weakened bone health, and the onset of metabolic syndrome [6]. This highlights the need to develop innovative therapeutic strategies.

[3] Current Therapeutic Approaches in FSHD

Authors: Leo H. Wang, R. Tawil
Year: 2020
Venue: Journal of Neuromuscular Diseases
URL: https://www.semanticscholar.org/paper/65038a0ff08223c00ba4710a13bd42c87be28ac6
DOI: 10.3233/JND-200554
PMID: 33579868
PMCID: 8203219
Citations: 30
Influential citations: 1
Summary: The underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD are reviewed.
Evidence snippets:
Snippet 1 (score: 0.580) > Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. Over the last decade, a consensus was reached regarding the underlying cause of FSHD allowing—for the first time—a targeted approach to treatment. FSHD is the result of a toxic gain-of-function from de-repression of the DUX4 gene, a gene not normally expressed in skeletal muscle. With a clear therapeutic target, there is increasing interest in drug development for FSHD, an interest buoyed by the recent therapeutic successes in other neuromuscular diseases. Herein, we review the underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD.

[4] The Notch signaling pathway in skeletal muscle health and disease

Authors: D. Vargas-Franco, R. Kalra, Isabelle Draper, C. A. Pacak, A. Asakura et al.
Year: 2022
Venue: Muscle & Nerve
URL: https://www.semanticscholar.org/paper/2bc32ef6a1acc95f1c31b7e3ef5a268aadda4024
DOI: 10.1002/mus.27684
PMID: 35968817
PMCID: 9804383
Citations: 37
Summary: The clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases are reviewed.
Evidence snippets:
Snippet 1 (score: 0.563) > Since the landmark discovery in 1986 of DMD (dystrophin), 1 the causative gene for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), dozens of additional genes have been associated with various phenotypic subtypes of muscular dystrophy. > Common disease mechanisms across multiple subtypes have, however, been more difficult to identify, with only a few major clusters such as the dystroglycanopathies identified to date. Given the common phenotypic features within muscular dystrophy categories, such as limb-girdle muscular dystrophy (LGMD), there is a high likelihood that convergent disease mechanisms exist across more muscular dystrophy subtypes than is currently recognized. > There are therapeutic implications of identifying deeper biological ties between muscular dystrophy subtypes. In recent years, the US Food and Drug Administration (FDA) has approved several molecular and genetic therapies for neuromuscular disorders that target specific genes and even specific mutation types within those genes. These approaches are being applied to ever rarer forms of muscular dystrophies. However, proceeding through the preclinical and clinical research studies needed to attain FDA approval for a new therapy is lengthy and costly, and on the current trajectory it will be decades before molecular and genetic therapies are available for all known subtypes of muscular dystrophy. > The identification and characterization of disease mechanisms that are shared by multiple muscular dystrophy subtypes could pave the way for new pathway-based treatments that have therapeutic effects for multiple disease subtypes. 2 This has the potential to accelerate the timeline for broader therapeutic coverage of patients with muscular dystrophy, with a greater impact on the entire muscular dystrophy population. > One disease mechanism that bears further analysis is the Notch signaling pathway, which is known to maintain muscle stem cell (MuSC, also known as satellite cell) quiescence. Recently, three different muscle disease genes that are known to interact with the Notch signaling pathway have been identified: MEGF10, POGLUT1, and most recently JAG2.

[5] Meeting report: the 2021 FSHD International Research Congress

Authors: S. Jagannathan, Jessica C. de Greef, Lawrence J. Hayward, K. Yokomori, D. Gabellini et al.
Year: 2022
Venue: Skeletal Muscle
URL: https://www.semanticscholar.org/paper/7444edfc105226463dbdb4a3252fa3cc611a2048
DOI: 10.1186/s13395-022-00287-8
Summary: The 2021 FSHD International Research Congress, held virtually on June 24–25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHd.
Evidence snippets:
Snippet 1 (score: 0.561) > Facioscapulohumeral muscular dystrophy (FSHD) is the second most common genetic myopathy, characterized by slowly progressing and highly heterogeneous muscle wasting with a typical onset in the late teens/early adulthood [1]. Although the etiology of the disease for both FSHD type 1 and type 2 has been attributed to gain-of-toxic function stemming from aberrant DUX4 expression, the exact pathogenic mechanisms involved in muscle wasting have yet to be elucidated [2–4]. The 2021 FSHD International Research Congress, held virtually on June 24–25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHD [NCT04003974].

[6] Facioscapulohumeral Muscular Dystrophy.

Authors: Renatta N Knox
Year: 2018
Venue: Continuum
URL: https://www.semanticscholar.org/paper/aeb5eff3a6fc5398a8b8f1485693ed1a6cc4746a
DOI: 10.1007/978-1-4614-6430-3_84-2
PMID: 41037169
Citations: 225
Influential citations: 19
Summary: An overview of the distinctive genetic mechanisms underlying FSHD, its clinical manifestations, including pediatric-specific features, treatment, and the evolving landscape of clinical trials targeting disease-modifying therapies is provided.
Evidence snippets:
Snippet 1 (score: 0.555) > OBJECTIVE > Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting individuals across the lifespan with variable severity. This article provides an overview of the distinctive genetic mechanisms underlying FSHD, its clinical manifestations, including pediatric-specific features, treatment, and the evolving landscape of clinical trials targeting disease-modifying therapies. > LATEST DEVELOPMENTS > FSHD arises from derepression of the transcription factor DUX4, which is toxic to skeletal muscle. This misexpression leads to a characteristic and progressive pattern of muscle weakness involving the facial, shoulder girdle, upper extremity, trunk, and leg muscles. Extramuscular manifestations, such as pain and fatigue, are frequently reported. Children with a severe, early-onset phenotype experience higher rates of extramuscular features, including hearing loss, cognitive impairment, and spinal deformities. Advances in the understanding of DUX4 as the causative gene, combined with innovations in gene therapy, gene editing, small-molecule development, and drug delivery, have catalyzed the initiation of several clinical trials focusing on disease-targeted treatments in the near future. > ESSENTIAL POINTS > FSHD is caused by toxic expression of DUX4 and presents with progressive, often asymmetric muscle weakness and extramuscular manifestations in a subset of patients. Advances in genetic understanding and therapeutic development have led to clinical trials targeting DUX4. Although care remains supportive, the field is entering an era of promising disease-modifying strategies.

[7] The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression

Authors: Macarena Díaz-Ubilla, Mauricio A Retamal
Year: 2025
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/2fc946973feb1d3970f29459e88eb639d3cd5bf9
DOI: 10.3390/ijms26010373
PMID: 39796228
PMCID: 11719937
Summary: This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function and explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.
Evidence snippets:
Snippet 1 (score: 0.539) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most prevalent types of muscular dystrophy, affecting between 1 in 8000 to 1 in 22,000 people worldwide [1][2][3]. This condition is caused by a genetic mutation and is characterized by a slow, progressive, and asymmetric weakening of specific muscle groups, including the muscles of the face, shoulder girdle, arms, abdominal wall, hips, and thighs [2,4]. The clinical presentation of FSHD is highly variable, even among individuals with the same genetic background, such as monozygotic twins, where differences in disease severity and muscle involvement have been documented [5,6]. This variability extends to the pattern of disease progression, which is often unpredictable and varies widely from person to person [3,7,8]. The unpredictable nature of FSHD likely reflects underlying uncertainties at the molecular level, particularly the factors governing the expression of the disease-causing gene, DUX4. Although DUX4 is a critical factor in the pathogenesis of FSHD, its expression is rare, detected in only 1 out of 1000 FSHD myoblasts and in approximately 1 out of 200 myotube nuclei during in vitro studies [9]. Despite extensive research, the DUX4 protein has not been successfully detected in muscle biopsies from FSHD patients [9,10]. However, even with such low levels of DUX4 expression, muscle atrophy continues to progress, affecting both initially impacted and surrounding healthy muscle fibers and eventually spreading to additional muscle groups. This suggests that FSHD involves a broader mechanism of pathogenic factor transmission between muscle cells, which accelerates muscle damage. One possible mechanism behind this transmission involves connexin (Cx) hemichannels, which facilitate the exchange of signaling molecules between the cell cytoplasm and the extracellular environment [11][12][13].

[8] Cellular and molecular mechanisms underlying muscular dystrophy

Authors: F. Rahimov, L. Kunkel
Year: 2013
Venue: The Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/f40d5c11c05bfed36ed352efec2330b6b6ade1ba
DOI: 10.1083/jcb.201212142
PMID: 23671309
PMCID: 3653356
Citations: 233
Influential citations: 12
Summary: The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle and distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes are revealed.
Evidence snippets:
Snippet 1 (score: 0.538) > The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

[9] Therapeutic advances in muscular dystrophy

Authors: D. Leung, K. Wagner
Year: 2013
Venue: Annals of Neurology
URL: https://www.semanticscholar.org/paper/22bac6d00e252299778eb2908eb9c77674e1b562
DOI: 10.1002/ana.23989
PMID: 23939629
PMCID: 3886293
Citations: 79
Influential citations: 1
Summary: Treatment developments in 3 of the most common forms of muscular dystrophy are discussed, with the large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggesting there will be an improved quality of life for individuals with muscular dystroke.
Evidence snippets:
Snippet 1 (score: 0.533) > The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. Ann Neurol 2013;74:404–411

[10] A Hypothesis for Mechanisms of Weakness Distribution in Muscular Dystrophies

Authors: Alexander Khlebtovsky, F. Benninger, I. Steiner
Year: 2018
Venue: Journal of neurological disorders
URL: https://www.semanticscholar.org/paper/bef89c402a7ddbbd127f4c1fd0472b4c04e87b7e
DOI: 10.4172/2329-6895.1000389
Citations: 2
Influential citations: 1
Summary: A classification of muscle weakness in muscular dystrophies could enable predicting the function of newly identified myopathy-related genes according to their clinical presentation, and show that muscle weakness often follows a common pattern.
Evidence snippets:
Snippet 1 (score: 0.530) > Abnormal proteins that present with more or less simultaneous involvement of proximal and distal muscles are briefly reviewed according to: protein location and function, name of disease caused with possible mechanisms of myopathy, and levels of proof for the pathophysiological mechanism/s. Proteins in this group have a wide range of functions, including: cell signalling, muscle differentiation and apoptosis. However, the pathophysiology causing myopathy is unknown. > additional factors are involved other than proper protein dysfunction and muscle cell signaling. Furthermore, the degenerative muscle diseases caused by more complicated mechanisms than isolated protein dysfunction, such as myotonic dystrophy and facioscapulohumeral muscular dystrophy, represent exceptions to our hypothesis.

[11] Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

Authors: A. Rawls, Bridget K. Diviak, Cameron I. Smith, Grant W. Severson, Sofia A. Acosta et al.
Year: 2023
Venue: Biomolecules
URL: https://www.semanticscholar.org/paper/2d7f023c19774543c7e0bfca5c0dfb0b1aab2b39
DOI: 10.3390/biom13101536
PMID: 37892218
PMCID: 10605463
Citations: 9
Summary: The pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies are examined to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair.
Evidence snippets:
Snippet 1 (score: 0.525) > Muscular dystrophies (MDs) are genetic degenerative neuromuscular diseases characterized by progressive muscle weakness that results in significant morbidity.To date, mutations in 57 genes have been identified that cause nine specific classes of muscular dystrophy [1].Dystrophies are classified based on the specific gene involved and clinical features such as muscles affected, rate of disease progression, histopathology, and age of diagnosis.Inflammation is a common factor in the pathogenesis and progression of many types of MD.Chronic inflammation exacerbates muscle damage, induces fibrotic deposition and fatty replacement of myofibers, and impedes the regenerative process of skeletal muscle. > There are no curative treatments for any dystrophies currently, but new AAV and base editing approaches to provide the missing proteins or fix the genetic lesion provide hope.Though there is tremendous curative potential, these genetic approaches will not treat all dystrophies or even all versions of a single dystrophy.For example, there are more than 7000 known mutations in dystrophin that result in Duchenne muscular dystrophy (DMD) [2].Therefore, understanding the mechanisms underlying inflammation and other pathogenic processes will aid in identifying therapeutic approaches that can ameliorate the progression of these diseases.Preclinical and clinical treatments that specifically target inflammation and fibrosis are the subject of this review.

[12] Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies

Authors: Guangbin Xia, N. Terada, T. Ashizawa
Year: 2018
Venue: Current Stem Cell Reports
URL: https://www.semanticscholar.org/paper/94a0f0ec0fcc7956f4f564ed7b9052cad3b908ce
DOI: 10.1007/s40778-018-0145-5
PMID: 30524939
PMCID: 6244555
Citations: 13
Summary: Current applications of iPSC as disease models of MDs for studies of pathogenic mechanisms and therapeutic development and high-throughput screening using disease-specific human iPSCs has become a powerful technology in drug discovery.
Evidence snippets:
Snippet 1 (score: 0.515) > In genotype-phenotype correlations in MDs, we should note two types of heterogeneities: (1) the same pattern of muscular dystrophies can be caused by mutations in different genes and (2) the different mutations in the same gene may cause different patterns of muscular dystrophy. In terms of pathogenic mechanism, myotonic dystrophy type 1 (DM1) and type 2 (DM2) and oculopharyngeal muscular dystrophy (OPMD) belong to a distinct group of muscular dystrophy caused by RNA gain-of-function from trinucleotide repeat expansion [2][3][4][7][8][9][10], while facioscapulohumeral muscular dystrophy (FSHD) is caused by the contraction of microsatellite D4Z4 repeats [11], and the remaining MDs are caused by point mutations, deletions, duplications, and inversions [6]. Patents with MDs are often succumbed to a long arduous clinical course of progressive muscle weakness and wasting often resulting in significant disability and various complications. There is currently no cure for MDs, and available treatments are supportive care or of limited efficacy. Appropriate disease models are important for elucidation of disease mechanism and identification of treatment target.

[13] The FSHD jigsaw: are we placing the tiles in the right position?

Authors: Valentina Salsi, G. Vattemi, R. Tupler
Year: 2023
Venue: Current Opinion in Neurology
URL: https://www.semanticscholar.org/paper/7a8931a1a0f0ce046716d159fe70a749fc6ef3c8
DOI: 10.1097/WCO.0000000000001176
PMID: 37338810
PMCID: 10487374
Citations: 12
Summary: The main objectives of the scientific community on Facioscapulohumeral muscular dystrophy were summarized and the moving trajectories of research from the past to the present were summarized.
Evidence snippets:
Snippet 1 (score: 0.515) > Purpose of review Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present. Recent findings To date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations. Accordingly, FSHD drug development has been escalating in the last years in an attempt to silence DUX4 or to block its downstream effectors. Breakthroughs in the field include the awareness that new biomarkers and outcome measures are required for tracking disease progression and patient stratification. The need to develop personalized therapeutic strategies is also crucial according to the phenotypic variability observed in FSHD subjects. Summary We analysed 121 literature reports published between 2021 and 2023 to assess the most recent advances in FSHD clinical and molecular research.

[14] Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

Authors: W. Chiu, Ya-Hsin Hsun, Kao-Jung Chang, A. Yarmishyn, Yu-Jer Hsiao et al.
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/421f0212b8e3f567e050b3191da99fe550b243a8
DOI: 10.3390/ijms21249589
PMID: 33339321
PMCID: 7767109
Citations: 14
Summary: The current development of gene therapy is reviewed and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy, Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophies Type 2C (LGMD2C).
Evidence snippets:
Snippet 1 (score: 0.515) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common muscular dystrophies with a prevalence ranging between 2.03 and 6.8 per 100,000 persons [95]. The disease onset typically occurs in the twenties but is also detected at other ages. The muscle weakness deteriorates as the onset persists in a classic pattern: first, the facial and shoulder girdle muscles are affected, then the lower extremities, both distal and proximal. Variations in the age of onset, disease pattern, disease progression, and severity of muscle weakness among FSHD individuals results in disease severity ranging from mildly affected/asymptomatic to wheelchair-bound (20% of FSDH patients) [96,97]. Extramuscular manifestations include hearing loss [98,99] and loss of vision resulting from retinal vascular abnormalities [100,101], exudative retinopathy, and Coat's syndrome [102]. > Autosomal dominant FSHD is caused by the derepression of DUX4, a transcriptional regulator, whose target genes are toxic to skeletal muscle [103][104][105]. Unlike DMD, which is caused by mutations in the coding region of a single gene, FSHD requires mixed aberrations of genetic and epigenetic nature to result in DUX4 derepression and cause clinical symptoms. DUX4 is located on D4Z4 macrosatellite repeat array on chromosome 4q35 with each D4Z4 repeat (3.3 kb) including a DUX4 gene, and it is expressed in germline cells but silenced in somatic tissues [103,106]. The silencing can be reversed as a result of DNA hypomethylation and consequent opening of the chromatin structure by the following two mechanisms. In facioscapulohumeral muscular dystrophy type 1 (FSHD1) accounting for 95% of cases, an internal contraction of D4Z4 repeats occurs, leading to a reduced number of repeats, 1 to 10 repeat units, while the unaffected individuals contain 11 to 100 D4Z4 units [106,107].

[15] A pediatric case report and literature review of facioscapulohumeral muscular dystrophy type1

Authors: Ting Xiao, Haiyang Yang, Siyi Gan, Liwen Wu
Year: 2021
Venue: Medicine
URL: https://www.semanticscholar.org/paper/d39bf2d0a9f15060d81e0f8a73cc4ca3e15083c8
DOI: 10.1097/MD.0000000000027907
PMID: 34964760
PMCID: 8615324
Citations: 6
Summary: The clinical characteristics of 2 patients with early-onset facial and shoulder brachial muscular dystrophy are reported to improve clinicians’ understanding of this particular condition and identify early identification and genetic diagnosis to improve patient prognosis.
Evidence snippets:
Snippet 1 (score: 0.514) > Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy. Currently, there are 2 genetically distinct types of FSHD, FSHD1, and FSHD2. [5] Facioscapulohumeral muscular dystrophy type 1 (FSHD1, OMIM: 158900) is an autosomal dominant genetic disease in which integral copies of the 3.3 kb tandem repeat unit D4Z4 are deleted in the subtelomere region of chromosome 4q35.41. [8] Some studies have shown that there is a negative correlation between the number of D4Z4 repetitions and the severity of FSHD. Therefore, studies have shown that very short alleles (1-3 D4Z4 repeats) are related to the most severe form of the disease. [7,8] The D4Z4 repeat sequence contains the DUX4 gene, which is abnormally expressed in skeletal muscle cells of FSHD patients. The abnormal expression of DUX4 leads to dysregulation of molecular pathways that are involved in muscle differentiation, oxidative stress responses, immune responses, and protein turnover. However, the precise mechanism leading to FSHD is still unknown. [3,9,10] acioscapulohumeral muscular dystrophy type 2 (FSHD2, OMIM: 158901) is associated with mutations of the structural maintenance of the chromosome flexible hinge domain-containing protein 1 [11] (SMCHD1) gene on chromosome 18p1143 or the DNA methyltransferase 3B [12] (DNMT3B) gene on chromosome 20q11 in the presence of a disease-permissive 4qA haplotype. Both types of mutations are associated with insufficient epigenetic repression of D4Z4 repeats, leading to aberrant expression of double homeobox protein 4 (DUX4) in skeletal muscles and consequently, disease progression. FSHD2 can present with autosomal dominant or recessive inheritance. [3,5]

[16] Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

Authors: Alexander Mensch, S. Zierz
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/22b8c2f84f84b8479f611e296ca9b32813c3bf6c
DOI: 10.3390/ijms21165830
PMID: 32823799
PMCID: 7461575
Citations: 15
Summary: This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases and relevant therapeutic approaches that aim to abrogate defects of cellular Stress response in muscular disorders are outlined.
Evidence snippets:
Snippet 1 (score: 0.513) > Muscular dystrophies are a phenotypically and genotypically heterogeneous group of inherited muscular disorders that share common histopathologic features, including degeneration/necrosis, regeneration, and endo-and perimysial fibrosis, as well as increased adipose tissue [121]. Causative gene mutations leading to individual muscular dystrophies reflect a broad spectrum of cellular functions, including extracellular matrix proteins, members of the dystrophin-glycoprotein complex, nuclear envelope proteins, and mitochondrial membrane proteins, amongst others [122]. Beside the pathogenetic consequences arising from individual gene mutations, additional aggrieving mechanisms have been identified that are not causally related to the gene product primarily affected in the individual muscular dystrophy. In this regard, ER-stress has been identified as a relevant source of muscular damage in several muscular dystrophies. The individual muscular dystrophies that show a deregulated ER-stress response/UPR can be found in Table 1. As for the underlying cause of ER-stress in muscular dystrophies, there has been a variety of suggestions. Hypotheses discussed include accumulation of misfolded protein due to the respective mutation in structural proteins and altered protein folding capacity because of oxidative stress and ROS production, as well as changes in calcium homeostasis. However, specific experimental evidence is missing to a great extent [13,17]. > Dystrophinopathies are the most prevalent forms of muscular dystrophies. While Duchenne muscular dystrophy (DMD) is a devastating muscle disease leading to rapid progression of muscular weakness, early loss of ambulation and premature death, Becker muscular dystrophy (BMD) usually shows a milder phenotype. The causative DMD gene encodes for the dystrophin protein, a core component of the dystrophin-glycoprotein complex that connects the muscle cell to the extracellular matrix [123]. Due to its prone function in muscle cell structure, the primary pathogenetic mechanism appears to be a disintegration of muscle cell organization and reduced resistance to mechanical stress.

[17] Serum miRNAs as biomarkers for the rare types of muscular dystrophy.

Authors: A. Koutsoulidou, Demetris Koutalianos, K. Georgiou, Andrea C. Kakouri, A. Oulas et al.
Year: 2022
Venue: Neuromuscular disorders : NMD
URL: https://www.semanticscholar.org/paper/66fe911cc2daff3c136f30d6771b2ec4807cfed9
DOI: 10.1016/j.nmd.2022.03.003
PMID: 35393236
Citations: 11
Influential citations: 2
Summary: New evidence is provided that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies, as well as identifying manymiRNAs that associate with muscular dystrophy patients compared to controls.
Evidence snippets:
Snippet 1 (score: 0.511) > Muscular dystrophies are a group of disorders which share similar clinical and pathological characteristics including progressive weakness, wasting and degeneration [1] . More than 50 distinct types of muscular dystrophies were identified which are caused by different mutations in various genes ascribing for the phenotype of each muscular dystrophy [2] . Several clinical phenotypes characterize each type of muscular dystrophy, including the groups of primarily affected muscles, the degree of weakness, the time of onset and the rate of progression. Currently, there is an increasing interest for the development of biomarkers for this family of disorders either for monitoring the disease progress or the response to new therapeutic interventions. In particular, emphasis has been placed on the research for identifying biomarkers for Duchene Muscular Dystrophy (DMD) which is the most common childhood onset muscular dystrophy with very severe symptoms in the affected boys [3][4][5][6] . A large number of circulating miRNAs and protein biomarkers have been identified for DMD, some of which were correlated to the disease severity and clinical assessments of the patients, suggesting that they can be used as monitoring biomarkers for the disorder [7][8][9][10][11] . Furthermore, miRNAs have been suggested as potential biomarkers for Myotonic Dystrophy type 1 (DM1), the most common muscular dystrophy in adults [12][13][14][15] . Importantly, four musclespecific miRNAs, miR-1, miR-133a, miR-133b and miR-206, were found to be correlated with muscle wasting in DM1 patients and were therefore suggested as monitoring biomarkers for the disease progression [ 12 , 13 ]. Regarding the other types of muscular dystrophies, very limited information exists for the presence of circulating biomarkers, especially for the rare types of muscular dystrophies such as Facioscapulohumeral muscular dystrophy (FSHD), Limb-Girdle Muscular dystrophy (LGMD) and Myotonic Dystrophy type 2 (DM2). > FSHD is

[18] Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

Authors: Yan-li Wei, Qisheng Su, Xiao-Hua Li
Year: 2022
Venue: Medicine
URL: https://www.semanticscholar.org/paper/270eedbe2a86196967455d575878a3326f57e676
DOI: 10.1097/MD.0000000000032603
PMID: 36596079
PMCID: 9803489
Citations: 4
Summary: SerPING1, F13A1, C1S, C 1R, and HLA-DPA1 may participate in the development of DMD by regulating innate immunity and inflammation, and they are expected to be a potential biomarker and novel therapeutic targets for DMD.
Evidence snippets:
Snippet 1 (score: 0.510) > Muscular dystrophy (MD) is a genetic disorder in which genetic abnormalities lead to abnormalities in a group of proteins that maintain stability of skeletal muscle cell structure and function. Chronic and progressive muscle weakness or muscle atrophy is the main clinical manifestation of MD. Common muscular dystrophy are Duchenne muscular dystrophy (DMD), Bekerer muscular dystrophy (BMD), myotonic muscular dystrophy (MD), congenital muscular dystrophy (CMD), limb girdle type Muscular dystrophy (LGMD), facial scapulohumeral muscular dystrophy (FSMD), distal muscular dystrophy, ophthalmopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), etc. Among them, DMD is an X-recessive genetic disease caused by mutations in the anti-atropin gene. It is the most common type of progressive muscular dystrophy and the most severe type in childhood. [1] Most of the patients with DMD were found to have disease at the age of 3 to 5 years, often accompanied by delayed motor development, progressive skeletal muscle atrophy, scoliosis, joint spasm, respiratory muscle weakness, and dilated heart disease. Most patients with DMD died of respiratory failure and heart failure around the age of 20. [2,3] At present, there are a lot of studies on DMD. Gene substitution with adenovirus and CRISPR gene editing are considered as potential therapeutic methods for DMD. [4] Some targets have been found to delay the development of DMD. p. 5] Although great progress has been made in the treatment of DMD, there is still much room for exploration. [7] We believe that exploring the molecular and mechanism involved in the occurrence and development of DMD may help to find new therapeutic targets for DMD, and may provide help for the treatment of DMD. > Weighted gene co-expression network analysis (WGCNA) is 1 way to identify gene modules and key genes related to phenotypic traits. [8]

[19] Immunohistochemical Characterization of FacioscapulohumeralMuscular Dystrophy Muscle Biopsies

Authors: J. Statland, K. Odrzywolski, Bharati Shah, D. Henderson, A. Fricke et al.
Year: 2015
Venue: Journal of Neuromuscular Diseases
URL: https://www.semanticscholar.org/paper/1783c8861ca01161de60ef8ace8851890ba7c39c
DOI: 10.3233/JND-150077
PMID: 26345300
PMCID: 4560242
Citations: 28
Influential citations: 1
Summary: Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD.
Evidence snippets:
Snippet 1 (score: 0.509) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common progressive muscular dystrophies (prevalence 1:15000) [1,2]. Recent studies have suggested that both Facioscapulohumeral muscular dystrophy (FSHD) types 1 and 2 operate through a common downstream genetic mechanism of de-repression of a retrogene DUX4, not normally expressed in somatic muscle tissue [3,4]. Gene expression profiling from FSHD muscle has shown altered regulation of large number of genes associated with myogenesis, increased susceptibility to oxidative stress, angiogenensis, vascular smooth muscle or endothelial cells, muscle isoenzymes, cholesterol metabolism, and the actin cytoskeleton [5][6][7][8]. Expression of DUX4 in vitro inhibits myogenesis, increases oxidative stress in myogenic precursors, and induces apoptosis [9][10][11]. DUX4 is a transcription factor normally expressed in the luminal cells of the testis, which activates genes involved in the germline and early stem cell development [12]. One line of thinking posits induction of a mitotic program in a post-mitotic cell results in apoptosis. Another line of thinking proposes DUX4 may affect satellite cell renewal. The muscle immunohistochemical correlates to these posited pathological mechanisms are unknown. A better understanding of the muscle pathology in FSHD can be important in two ways: 1) providing insights into the patho-mechanism in FSHD, and 2) providing potential biomarkers for proof of concept or early phase clinical studies. > Here we perform a retrospective cross-sectional histopathological study in genetically confirmed FSHD muscle biopsies. We quantify the apoptotic rates, satellite cell counts, and nuclear and capillary density and compare to healthy volunteers (CON) and myotonic dystrophy type 1 (DM1) as a disease control.

[20] LGMD phenotype due to a new gene and dysferlinopathy investigated by next-generation sequencing

Authors: C. Angelini
Year: 2015
Venue: Neurology: Genetics
URL: https://www.semanticscholar.org/paper/2c55b9718099ba1a33fa6f6ea43815046be1c557
DOI: 10.1212/NXG.0000000000000039
PMID: 27066575
PMCID: 4811386
Citations: 5
Summary: 3 cases of limb-girdle muscular dystrophy phenotype with mental retardation or hyperCKemia found by next-generation sequencing (NGS) to have a variant in the POMGNT2 gene, which has so far been recognized only as causing congenital muscular Dystrophy (CMD).
Evidence snippets:
Snippet 1 (score: 0.501) > The progression of muscle weakness is usually symmetrical and variable among individuals and genetic type. The term LGMD, used to molecularly classify the disease, is, however, inappropriate for many patients when it is used to describe the clinical severity. Indeed, these disorders present a wide spectrum of muscle involvement and wasting, spanning from very severe forms, such as those with childhood onset and rapid progression, to relatively benign forms with late onset. > The clinical phenotypes due to mutation in the LGMD genes include severe childhood-onset forms, distal and proximal myopathies, pseudometabolic myopathies, eosinophilic myositis, and hyperCKemia. Furthermore, patients with a clinically typical LGMD phenotype might carry mutations in the gene encoding emerin, which usually cause Emery-Dreifuss muscular dystrophy (EDMD) phenotype. Because there is a spectrum of phenotypes under the same genetic entity and a wide genetic heterogeneity under the same phenotype, it is crucial to identify suitable selection criteria to be used when screening patients for the proteins and genes responsible for LGMD. > As LGMD is relatively rare in most populations, other more likely diagnoses need to be excluded. Among these, dystrophinopathies (Duchenne dystrophy, Becker dystrophy, and female carriers of Duchenne dystrophy) are the most relevant, and these diagnoses can be ruled out based on dystrophin protein testing and/or DNA mutation analysis in the dystrophin gene. Another diagnosis that can usually be resolved by DNA analysis is facioscapulohumeral muscular dystrophy (FSHD): about 8% of patients with a diagnosis of LGMD may actually have FSHD, and the misdiagnosis can occur in families with autosomal dominant inheritance, especially when both pelvic and shoulder girdles are involved and facial weakness is minimal. Molecular investigation to exclude FSHD is worthwhile, especially in patients with a positive family history.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Facioscapulohumeral Muscular Dystrophy. Core disease mechanisms, molecular...

Relevant Papers

[1] Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

[2] Diagnosis, Pathogenesis and Treatment of Muscular Dystrophy

[3] Current Therapeutic Approaches in FSHD

[4] The Notch signaling pathway in skeletal muscle health and disease

[5] Meeting report: the 2021 FSHD International Research Congress

[6] Facioscapulohumeral Muscular Dystrophy.

[7] The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression

[8] Cellular and molecular mechanisms underlying muscular dystrophy

[9] Therapeutic advances in muscular dystrophy

[10] A Hypothesis for Mechanisms of Weakness Distribution in Muscular Dystrophies

[11] Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

[12] Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies

[13] The FSHD jigsaw: are we placing the tiles in the right position?

[14] Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

[15] A pediatric case report and literature review of facioscapulohumeral muscular dystrophy type1

[16] Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

[17] Serum miRNAs as biomarkers for the rare types of muscular dystrophy.

[18] Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

[19] Immunohistochemical Characterization of FacioscapulohumeralMuscular Dystrophy Muscle Biopsies

[20] LGMD phenotype due to a new gene and dysferlinopathy investigated by next-generation sequencing

Notes