👪

Inheritance

1

Autosomal recessive HP:0000007

Reported patients carry two FKTN variants, typically as compound heterozygotes rather than homozygotes, consistent with autosomal recessive inheritance of a hypomorphic allele combination. Despite the "1X" in the disease name, the locus is autosomal.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"

The founding series reports biallelic compound heterozygous FKTN variants in six patients across four families, establishing recessive inheritance at an autosomal locus.

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Discussions and Knowledge Gaps

1

Why does the myocardium fail in CMD1X while skeletal muscle carrying the same alpha-dystroglycan glycosylation defect stays close to normal, and can any current model answer this?

HUMAN MODEL MISMATCH cmd1x_cardiac_vs_skeletal_tissue_selectivity

Attached to

pathophysiology#Relative Sparing of Skeletal Muscle and Brain animal_models#Mouse

The tissue selectivity is the defining feature of the entity, and no existing model system addresses it. The available mechanistic data come from cardiac-specific complete Fktn knockouts, in which the cardiac restriction is engineered by the Cre driver rather than emerging from the biology. Those models establish the Akt and MEF2-histone deacetylase lesion and show that membrane fragility alone is insufficient, but because they are nulls confined to one tissue they cannot test the hypothesis that actually explains the human phenotype, namely that a partial, body-wide reduction in fukutin activity crosses a threshold in cardiomyocytes that it does not cross in skeletal myofibres. A hypomorphic, non-tissue-restricted allelic series is what the question needs.

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Pathophysiology

7

Reduced Fukutin Ribitol-Phosphate Transferase Activity

Biallelic hypomorphic FKTN variants reduce, without abolishing, the Golgi ribitol-phosphate transferase activity of fukutin. Fukutin and fukutin-related protein act sequentially to transfer ribitol phosphate from CDP-ribitol, which is synthesised by ISPD, onto the core M3 O-mannosyl glycan of alpha-dystroglycan. The residual activity in this allele combination is what separates CMD1X from the null genotypes that cause Fukuyama congenital muscular dystrophy.

Genetic context FKTN hgnc:3622 zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

protein O-linked mannosylation GO:0035269 ↓ DECREASED

Golgi apparatus GO:0005794

Downstream

Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding Reduced ribitol-phosphate transfer leaves the M3 glycan incomplete, so the matriglycan chain that carries ligand-binding activity cannot be built out.

Show evidence (1 reference)

PMID:27194101 SUPPORT In Vitro

"we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan"

Establishes the enzymatic activity of fukutin that this node describes as reduced, using recombinant protein and cell assays.

Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding

The incompletely glycosylated alpha-dystroglycan cannot bind laminin, agrin and perlecan in the basement membrane. In CMD1X this is demonstrable in both compartments: skeletal muscle biopsy shows altered glycosylation and reduced laminin binding despite near-normal histology, and the one cardiac biopsy in the founding series showed the same glycosylation defect seen in Fukuyama congenital muscular dystrophy.

laminin binding GO:0043236 ↓ DECREASED

Downstream

Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes Loss of ligand binding uncouples the dystrophin-glycoprotein complex from the extracellular matrix at the cardiomyocyte surface.

Show evidence (2 references)

PMID:17036286 SUPPORT Human Clinical

"Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."

Direct demonstration in patient tissue that the glycosylation and laminin-binding defect is present even where histology is near-normal.

PMID:17036286 SUPPORT Human Clinical

"One cardiac muscle that underwent biopsy showed altered glycosylation of alpha-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient."

Establishes that the same biochemical lesion is present in the myocardium, which is the tissue that actually fails in this disease.

Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes

The dystrophin-glycoprotein complex normally transmits force between the cardiomyocyte cytoskeleton and the basement membrane. With alpha-dystroglycan unable to bind laminin, that linkage is weakened and the sarcolemma is less able to withstand the mechanical load of repeated contraction. Mouse data make the important qualification that this membrane-fragility route is not on its own sufficient to produce contractile failure.

cardiac muscle cell CL:0000746

Animal models

Cardiac-specific fukutin knockout mouse Mouse partially recapitulates Reproduces the loss of sarcolemmal alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex, while showing that this alone does not produce contractile failure.

Downstream

Impaired Compensatory Hypertrophic Signaling Beyond mechanical fragility, fukutin loss disables the signaling response that would normally let the myocyte compensate for haemodynamic load.

Ventricular Remodeling and Myocardial Fibrosis Repeated contraction-induced injury to a poorly anchored sarcolemma drives cardiomyocyte loss and replacement fibrosis.

Show evidence (1 reference)

PMID:31848331 SUPPORT INDIRECT Model Organism

"Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac..."

Supports the loss of sarcolemmal dystrophin-glycoprotein complex at the cardiomyocyte membrane, and simultaneously constrains how much of the phenotype that loss can explain. Graded INDIRECT because it is a complete cardiac knockout rather than the hypomorphic human genotype.

Impaired Compensatory Hypertrophic Signaling

Fukutin-deficient cardiomyocytes fail to mount the adaptive hypertrophic response that normally offsets haemodynamic load. In the mouse, adrenergic and pressure-overload stress that produces compensated hypertrophy in controls instead produces chamber dilation, fibrosis and contractile failure, with loss of the expected Akt phosphorylation and a disrupted MEF2-histone deacetylase axis. This is the branch that best explains why the human disease is stress-sensitive and variable in onset rather than uniformly congenital.

cardiac muscle cell CL:0000746

Animal models

Cardiac-specific fukutin knockout mouse Mouse recapitulates Establishes the Akt and MEF2-histone deacetylase signaling lesion, and the stress-dependence of the phenotype.

Downstream

Ventricular Remodeling and Myocardial Fibrosis A myocyte that cannot compensate for load remodels maladaptively instead.

Show evidence (2 references)

PMID:31848331 SUPPORT INDIRECT Model Organism

"During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis."

Identifies the signaling lesion this node asserts. INDIRECT because the claim about human CMD1X rests on a complete murine knockout rather than the hypomorphic human genotype.

PMID:31848331 SUPPORT INDIRECT Model Organism

"Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment."

Shows that fukutin is required for ongoing myocyte function beyond its role in building the sarcolemmal glycan, since acute removal in the adult heart causes failure without waiting for membrane damage to accumulate.

Ventricular Remodeling and Myocardial Fibrosis

Cardiomyocyte injury and failed compensation give way to increased myocyte cross-sectional area, interstitial fibrosis and chamber dilation. In the cardiac-specific fukutin knockout these changes appear in middle-aged animals and are accompanied by disorganised myofilaments and impaired calcium handling during excitation-contraction coupling.

Downstream

Dilated Cardiomyopathy with Systolic Failure Progressive loss of contractile tissue and chamber dilation present clinically as dilated cardiomyopathy.

Show evidence (1 reference)

PMID:31848331 SUPPORT INDIRECT Model Organism

"These mice also showed cardiac dysfunction and chamber dilation during diastole at this age."

Documents the remodeling and dilation this node describes in the cardiac fukutin knockout.

Dilated Cardiomyopathy with Systolic Failure

The clinical endpoint is a dilated, hypokinetic left ventricle with reduced ejection fraction, presenting as heart failure. The course is variable: the founding series included both a child who died of rapidly progressive disease and an adolescent who reached transplantation.

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."

Establishes both the dilated cardiomyopathy endpoint and the severity range reported in the defining series.

Relative Sparing of Skeletal Muscle and Brain

The defining feature of CMD1X is what does not happen. The same hypoglycosylation of alpha-dystroglycan that destroys skeletal muscle and brain in Fukuyama congenital muscular dystrophy leaves these patients with normal intelligence and no or minimal limb girdle weakness, and with skeletal muscle biopsies showing only minimal dystrophic change. The residual fukutin activity of the hypomorphic allele combination is the usual explanation, but it does not by itself say why the myocardium is the tissue that cannot tolerate the shortfall. This tissue-selectivity is recorded as an open question rather than resolved.

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy."

The authors' own framing of CMD1X as the mild end of the FKTN allelic spectrum, which is the claim this node records.

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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

5

Cardiovascular 2

Dilated cardiomyopathy HP:0001644

Course: PROGRESSIVE

Sequelae: Congestive heart failure

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"

Establishes dilated cardiomyopathy as the defining phenotype of the entity.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."

Documents progression to death and to transplantation, the endpoints of heart failure in this disease.

Limbs 1

Minimal or absent limb girdle weakness Pelvic girdle muscle weakness HP:0003749

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."

Records the dissociation between a biochemically abnormal muscle and a near-normal histological and clinical picture.

Metabolism 1

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

Show evidence (1 reference)

PMID:35743126 SUPPORT Human Clinical

"we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN"

Reports elevated creatine kinase alongside the dilated cardiomyopathy in a genetically confirmed compound heterozygote.

Other 1

Normal intelligence

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"

The founding series records normal intelligence as a defining negative feature of the CMD1X phenotype.

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Genetic Associations

1

FKTN

Gene: FKTN hgnc:3622 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:17036286 SUPPORT Human Clinical

"FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy."

Establishes FKTN as the causal gene for a dilated-cardiomyopathy-predominant phenotype at the mild end of its allelic spectrum.

PMID:9690476 SUPPORT Human Clinical

"Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%)."

Documents the founder allele that supplies the severe half of the CMD1X compound-heterozygous genotype, and its frequency among FCMD chromosomes.

PMID:9690476 SUPPORT Human Clinical

"The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion."

Establishes both the physical nature of the founder allele and that it abolishes expression, which is what makes it the severe allele in the CMD1X genotype model.

+ 1 more reference

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Medical Actions

2

Guideline-directed heart failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin-converting enzyme inhibitor NCIT:C247 beta-adrenergic blocker NCIT:C29576

Platform: Small molecule

There is no FKTN-specific therapy. Management follows standard treatment for heart failure with reduced ejection fraction. This is recorded as the prevailing standard of care rather than as an intervention tested in CMD1X, for which no trial evidence exists.

Mechanism Target:

Ventricular Remodeling and Myocardial Fibrosis — Guideline-directed therapy acts on the neurohormonal drive of adverse remodelling. It is disease-modifying for the remodelling process, not for the glycosylation defect upstream of it.

Cardiac transplantation

Action: Organ Transplantation NCIT:C15289

Platform: Surgery

Transplantation is the definitive treatment for end-stage disease and has been reached by reported patients in adolescence.

Mechanism Target:

Dilated Cardiomyopathy with Systolic Failure — Transplantation replaces the failing organ; it does not address the underlying glycosylation defect, which remains present in skeletal muscle.

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."

Documents cardiac transplantation as an outcome reached in the defining series.

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Environmental Factors

1

Haemodynamic load of pregnancy

Pregnancy is a documented precipitant of decompensation in established CMD1X. It is not causal, and the entry does not treat it as such: the reported course is a fall in cardiac function from the third trimester, requiring bed rest and elective early delivery, with the cardiac parameters returning to their pre-pregnancy baseline about a month postpartum. The skeletal muscle behaved differently in the same patient, with weakness that persisted afterwards, so the two compartments did not recover in step.

Show evidence (1 reference)

PMID:26566449 SUPPORT Human Clinical

"The parameters of her cardiac function returned to the pre-pregnancy status in a month after delivery, whereas she realized persistent worsening of muscular weakness at postpartum."

Establishes that the cardiac decompensation is reversible once the load is removed, while the skeletal muscle change was not, which is why this is recorded as an exacerbating exposure rather than a cause.

Mechanism Target:

EXACERBATES Dilated Cardiomyopathy with Systolic Failure — The volume and afterload changes of gestation are superimposed on a ventricle that already cannot mount a compensatory hypertrophic response, so function falls further.

Show evidence (1 reference)

PMID:26566449 SUPPORT Human Clinical

"Worsening of cardiac function was observed from 30 weeks, manifesting reduced cardiac load with left ventricular dilatation and in-hospital bed rest was necessary."

Documents deterioration of cardiac function under the haemodynamic load of late pregnancy in a genetically confirmed CMD1X patient.

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Biochemical Markers

1

Glycosylated alpha-dystroglycan on muscle biopsy

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."

Reports the assay result that defines the biochemical lesion, in patient skeletal muscle.

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Diagnosis

4

Echocardiography

Echocardiography establishes the cardiomyopathy itself, showing left ventricular dilation with hypokinesis and reduced ejection fraction. It is what the patient is referred for, and on its own it says nothing about the cause.

echocardiography NCIT:C16525

Results: Left ventricular dilation with reduced ejection fraction.

Show evidence (1 reference)

PMID:26566449 SUPPORT Human Clinical

"In early pregnancy, the evaluation of her cardiac function showed ejection fraction 47% and NYHA class II."

Reports the echocardiographic assessment of cardiac function in a genetically confirmed CMD1X patient.

Serum creatine kinase measurement

A raised creatine kinase in a patient who looks like idiopathic dilated cardiomyopathy is the trigger that should prompt a genetic workup, because it is present even without clinically detectable weakness. This is the step on which the whole diagnosis turns in practice: nothing else about the presentation points away from idiopathic disease.

serum creatine kinase measurement NCIT:C25294

Results: Elevated serum creatine kinase.

Show evidence (1 reference)

PMID:35743126 SUPPORT Human Clinical

"we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN"

Records elevated creatine kinase as an observed feature in a genetically confirmed patient, which is the basis for using it as a workup trigger.

Muscle biopsy with alpha-dystroglycan glycoepitope staining and laminin overlay

Immunohistochemistry and immunoblot for the glycoepitope of alpha-dystroglycan, with a laminin overlay assay, is the confirmatory functional test. Its interpretation in CMD1X carries a trap worth stating: the routine histology of the same biopsy is close to normal, so a report of minimal dystrophic change does not exclude the diagnosis and the glycoepitope study has to be requested specifically.

muscle biopsy NCIT:C15189

Results: Reduced alpha-dystroglycan glycosylation with reduced laminin binding.

Show evidence (1 reference)

PMID:17036286 SUPPORT Human Clinical

"Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."

Establishes both the assay result and the near-normal routine histology that makes the specific glycoepitope study necessary.

FKTN sequencing

Targeted FKTN sequencing, or a dystroglycanopathy or cardiomyopathy gene panel, confirms the biallelic genotype. Two allele classes need specific attention because standard exome sequencing can miss them: the Japanese founder retrotransposal insertion in the 3' untranslated region, and deep-intronic variants acting through aberrant splicing.

genetic testing NCIT:C15709

Results: Biallelic FKTN variants, typically compound heterozygous.

Show evidence (1 reference)

PMID:9690476 SUPPORT Human Clinical

"The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein."

Describes the founder allele's position and size, which is why it needs a targeted assay rather than coding-sequence analysis.

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Animal Models

1

Cardiac-specific fukutin knockout mouse

Cardiomyocyte-restricted elimination of Fktn, both constitutively and inducibly in the adult heart. The model is the principal source of mechanistic information about how fukutin loss causes cardiac failure.

Species

Mouse

Genotype

Fktn flox/flox; MCK-Cre (constitutive) and Fktn flox/flox; alphaMHC-MerCreMer (inducible)

Publication

PMID:31848331

Pathograph links

Impaired Compensatory Hypertrophic Signaling recapitulates fidelity: moderate observes: molecular Establishes the Akt and MEF2-histone deacetylase signaling lesion, and the stress-dependence of the phenotype.

Limitations: The knockout is a complete null restricted to the heart, whereas human CMD1X arises from a hypomorphic biallelic genotype affecting every tissue. The model therefore cannot address why human skeletal muscle is spared, and the mouse phenotype is engineered to be cardiac-restricted rather than being so for the reasons the human disease is.

Show evidence (1 reference)

PMID:31848331 SUPPORT Model Organism

"During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis."

Supports treating this model as informative for the compensatory signaling node.

Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes partially recapitulates fidelity: moderate observes: cellular Reproduces the loss of sarcolemmal alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex, while showing that this alone does not produce contractile failure.

Limitations: Graded PARTIALLY_RECAPITULATES because the model reproduces the membrane lesion but explicitly dissociates it from the functional phenotype, so it does not establish the membrane-fragility route as sufficient in humans.

Show evidence (1 reference)

PMID:31848331 SUPPORT Model Organism

"Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac..."

Both the recapitulation and its limit are stated in the same sentence.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1X
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
description: >-
  Dilated cardiomyopathy 1X (CMD1X) is an autosomal recessive dilated
  cardiomyopathy caused by biallelic, usually compound heterozygous, variants in
  FKTN. Fukutin is a Golgi ribitol-phosphate transferase that acts with
  fukutin-related protein to build the tandem ribitol-phosphate structure on the
  core M3 O-mannosyl glycan of alpha-dystroglycan; that structure is the scaffold
  on which matriglycan is polymerised, and matriglycan is what lets
  alpha-dystroglycan bind laminin, agrin and perlecan in the basement membrane.
  Null combinations of FKTN alleles produce Fukuyama congenital muscular
  dystrophy, with severe skeletal myopathy, brain malformation and intellectual
  disability. CMD1X sits at the opposite, hypomorphic end of the same allelic
  series: enough fukutin activity survives to leave skeletal muscle and brain
  largely intact, but not enough to protect the myocardium. Patients therefore
  present with what looks like isolated dilated cardiomyopathy, with normal
  intelligence and no or minimal limb girdle weakness, while their skeletal
  muscle nonetheless shows biochemically abnormal alpha-dystroglycan
  glycosylation and reduced laminin binding on biopsy. The course is variable and
  can be severe, with reported death in childhood and cardiac transplantation in
  adolescence. Why cardiac muscle is so much less tolerant of the same molecular
  lesion than skeletal muscle is the central unresolved question of the entity.
notes: >-
  The name is a nomenclature trap and is worth stating explicitly, because the
  entity is repeatedly conflated with a genetically unrelated disease. CMD1X is
  not X-linked. OMIM's dilated cardiomyopathy nomenclature enumerates the CMD1
  series with sequential letters, and "1X" is simply the position reached in that
  enumeration; FKTN is autosomal, at 9q31.2, and inheritance is autosomal
  recessive. X-linked dilated cardiomyopathy is a separate entity caused by DMD
  variants at Xp21. The two are indexed together by search engines and are
  sometimes confused in secondary literature.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged
  accordingly in `references`. Its indexed PubMed record is content_type
  abstract_only and carries only the chapter's front matter, not the Clinical
  Characteristics, Diagnosis, Management or Genetic Counseling sections, so
  section-by-section GeneReviews mining is not possible from the cache and no
  snippet is quoted from it. The clinical baseline for this entry is therefore
  built from the primary FKTN literature: the founding case series
  (PMID:17036286), the compound-heterozygote report with cardiac end-stage
  disease (PMID:35743126), and the pregnancy case (PMID:26566449).

  Module conformance divergence. The node conforming to
  pial_basement_membrane_radial_glial_endfoot_failure#Alpha-Dystroglycan
  Glycosylation and ECM Ligand Binding Failure does not carry the module node's
  GO:0035269 process term. That is deliberate rather than an oversight: this
  entry splits the mannosyl-glycan synthesis step onto the upstream enzyme node
  and reserves the conforming node for the resulting ligand-binding failure, so
  the process term sits one node earlier than the module places it.
disease_term:
  preferred_term: dilated cardiomyopathy 1X
  term:
    id: MONDO:0012704
    label: dilated cardiomyopathy 1X
synonyms:
- CMD1X
- cardiomyopathy, dilated, 1X
- FKTN-related dilated cardiomyopathy
- fukutin-related dilated cardiomyopathy with minimal muscle weakness
parents:
- Dilated Cardiomyopathy
- Dystroglycanopathy
references:
- reference: PMID:17036286
  title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
  findings: []
- reference: PMID:31848331
  title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
  findings: []
- reference: PMID:27194101
  title: ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan.
  findings: []
- reference: PMID:35743126
  title: Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern.
  findings: []
- reference: PMID:9690476
  title: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
  findings: []
- reference: PMID:26566449
  title: A case of pregnancy complicated with dilated cardiomyopathy 1X.
  findings: []
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
  findings: []
inheritance:
- name: Autosomal recessive
  description: >-
    Reported patients carry two FKTN variants, typically as compound
    heterozygotes rather than homozygotes, consistent with autosomal recessive
    inheritance of a hypomorphic allele combination. Despite the "1X" in the
    disease name, the locus is autosomal.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"
    explanation: >-
      The founding series reports biallelic compound heterozygous FKTN variants
      in six patients across four families, establishing recessive inheritance
      at an autosomal locus.
pathophysiology:
- name: Reduced Fukutin Ribitol-Phosphate Transferase Activity
  biological_scale: MOLECULAR
  description: >-
    Biallelic hypomorphic FKTN variants reduce, without abolishing, the Golgi
    ribitol-phosphate transferase activity of fukutin. Fukutin and
    fukutin-related protein act sequentially to transfer ribitol phosphate from
    CDP-ribitol, which is synthesised by ISPD, onto the core M3 O-mannosyl glycan
    of alpha-dystroglycan. The residual activity in this allele combination is
    what separates CMD1X from the null genotypes that cause Fukuyama congenital
    muscular dystrophy.
  genetic_context:
    gene:
      preferred_term: FKTN
      term:
        id: hgnc:3622
        label: FKTN
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  biological_processes:
  - preferred_term: protein O-linked mannosylation
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
    modifier: DECREASED
  evidence:
  - reference: PMID:27194101
    reference_title: ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto alpha-dystroglycan.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan"
    explanation: >-
      Establishes the enzymatic activity of fukutin that this node describes as
      reduced, using recombinant protein and cell assays.
  downstream:
  - target: Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding
    description: >-
      Reduced ribitol-phosphate transfer leaves the M3 glycan incomplete, so the
      matriglycan chain that carries ligand-binding activity cannot be built out.
- name: Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding
  biological_scale: MOLECULAR
  conforms_to: "pial_basement_membrane_radial_glial_endfoot_failure#Alpha-Dystroglycan Glycosylation and ECM Ligand Binding Failure"
  description: >-
    The incompletely glycosylated alpha-dystroglycan cannot bind laminin, agrin
    and perlecan in the basement membrane. In CMD1X this is demonstrable in both
    compartments: skeletal muscle biopsy shows altered glycosylation and reduced
    laminin binding despite near-normal histology, and the one cardiac biopsy in
    the founding series showed the same glycosylation defect seen in Fukuyama
    congenital muscular dystrophy.
  molecular_functions:
  - preferred_term: laminin binding
    term:
      id: GO:0043236
      label: laminin binding
    modifier: DECREASED
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."
    explanation: >-
      Direct demonstration in patient tissue that the glycosylation and
      laminin-binding defect is present even where histology is near-normal.
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One cardiac muscle that underwent biopsy showed altered glycosylation of alpha-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient."
    explanation: >-
      Establishes that the same biochemical lesion is present in the myocardium,
      which is the tissue that actually fails in this disease.
  downstream:
  - target: Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes
    description: >-
      Loss of ligand binding uncouples the dystrophin-glycoprotein complex from
      the extracellular matrix at the cardiomyocyte surface.
- name: Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The dystrophin-glycoprotein complex normally transmits force between the
    cardiomyocyte cytoskeleton and the basement membrane. With alpha-dystroglycan
    unable to bind laminin, that linkage is weakened and the sarcolemma is less
    able to withstand the mechanical load of repeated contraction. Mouse data
    make the important qualification that this membrane-fragility route is not on
    its own sufficient to produce contractile failure.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31848331
    reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction."
    explanation: >-
      Supports the loss of sarcolemmal dystrophin-glycoprotein complex at the
      cardiomyocyte membrane, and simultaneously constrains how much of the
      phenotype that loss can explain. Graded INDIRECT because it is a complete
      cardiac knockout rather than the hypomorphic human genotype.
  downstream:
  - target: Impaired Compensatory Hypertrophic Signaling
    description: >-
      Beyond mechanical fragility, fukutin loss disables the signaling response
      that would normally let the myocyte compensate for haemodynamic load.
  - target: Ventricular Remodeling and Myocardial Fibrosis
    description: >-
      Repeated contraction-induced injury to a poorly anchored sarcolemma drives
      cardiomyocyte loss and replacement fibrosis.
- name: Impaired Compensatory Hypertrophic Signaling
  biological_scale: CELLULAR
  description: >-
    Fukutin-deficient cardiomyocytes fail to mount the adaptive hypertrophic
    response that normally offsets haemodynamic load. In the mouse, adrenergic
    and pressure-overload stress that produces compensated hypertrophy in
    controls instead produces chamber dilation, fibrosis and contractile failure,
    with loss of the expected Akt phosphorylation and a disrupted MEF2-histone
    deacetylase axis. This is the branch that best explains why the human disease
    is stress-sensitive and variable in onset rather than uniformly congenital.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31848331
    reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis."
    explanation: >-
      Identifies the signaling lesion this node asserts. INDIRECT because the
      claim about human CMD1X rests on a complete murine knockout rather than the
      hypomorphic human genotype.
  - reference: PMID:31848331
    reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment."
    explanation: >-
      Shows that fukutin is required for ongoing myocyte function beyond its role
      in building the sarcolemmal glycan, since acute removal in the adult heart
      causes failure without waiting for membrane damage to accumulate.
  downstream:
  - target: Ventricular Remodeling and Myocardial Fibrosis
    description: >-
      A myocyte that cannot compensate for load remodels maladaptively instead.
- name: Ventricular Remodeling and Myocardial Fibrosis
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Cardiomyocyte injury and failed compensation give way to increased myocyte
    cross-sectional area, interstitial fibrosis and chamber dilation. In the
    cardiac-specific fukutin knockout these changes appear in middle-aged animals
    and are accompanied by disorganised myofilaments and impaired calcium
    handling during excitation-contraction coupling.
  evidence:
  - reference: PMID:31848331
    reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "These mice also showed cardiac dysfunction and chamber dilation during diastole at this age."
    explanation: >-
      Documents the remodeling and dilation this node describes in the cardiac
      fukutin knockout.
  downstream:
  - target: Dilated Cardiomyopathy with Systolic Failure
    description: >-
      Progressive loss of contractile tissue and chamber dilation present
      clinically as dilated cardiomyopathy.
- name: Dilated Cardiomyopathy with Systolic Failure
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical endpoint is a dilated, hypokinetic left ventricle with reduced
    ejection fraction, presenting as heart failure. The course is variable: the
    founding series included both a child who died of rapidly progressive disease
    and an adolescent who reached transplantation.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."
    explanation: >-
      Establishes both the dilated cardiomyopathy endpoint and the severity range
      reported in the defining series.
- name: Relative Sparing of Skeletal Muscle and Brain
  biological_scale: TISSUE
  description: >-
    The defining feature of CMD1X is what does not happen. The same
    hypoglycosylation of alpha-dystroglycan that destroys skeletal muscle and
    brain in Fukuyama congenital muscular dystrophy leaves these patients with
    normal intelligence and no or minimal limb girdle weakness, and with skeletal
    muscle biopsies showing only minimal dystrophic change. The residual fukutin
    activity of the hypomorphic allele combination is the usual explanation, but
    it does not by itself say why the myocardium is the tissue that cannot
    tolerate the shortfall. This tissue-selectivity is recorded as an open
    question rather than resolved.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy."
    explanation: >-
      The authors' own framing of CMD1X as the mild end of the FKTN allelic
      spectrum, which is the claim this node records.
phenotypes:
- category: Cardiac
  name: Dilated cardiomyopathy
  description: >-
    Left ventricular dilation with hypokinesis and reduced ejection fraction is
    the presenting and dominant feature.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"
    explanation: Establishes dilated cardiomyopathy as the defining phenotype of the entity.
  sequelae:
  - target: Congestive heart failure
    description: Progressive systolic dysfunction produces heart failure.
- category: Cardiac
  name: Congestive heart failure
  description: >-
    Heart failure symptoms follow the decline in systolic function and drive the
    clinical burden, up to transplantation in severe cases.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."
    explanation: >-
      Documents progression to death and to transplantation, the endpoints of
      heart failure in this disease.
- category: Musculoskeletal
  name: Minimal or absent limb girdle weakness
  description: >-
    Limb girdle weakness is absent or minimal, which is what distinguishes CMD1X
    from the rest of the FKTN allelic series and is the reason patients reach
    cardiology rather than neurology. Skeletal muscle biopsy shows only minimal
    dystrophic change despite abnormal alpha-dystroglycan glycosylation.
  phenotype_term:
    preferred_term: Limb girdle muscle weakness
    term:
      id: HP:0003749
      label: Pelvic girdle muscle weakness
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."
    explanation: >-
      Records the dissociation between a biochemically abnormal muscle and a
      near-normal histological and clinical picture.
- category: Neurologic
  name: Normal intelligence
  description: >-
    Intelligence is normal, in explicit contrast to the intellectual disability
    and brain malformation of Fukuyama congenital muscular dystrophy caused by
    null variants in the same gene. This is a deliberately recorded negative
    finding.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation"
    explanation: >-
      The founding series records normal intelligence as a defining negative
      feature of the CMD1X phenotype.
- category: Laboratory
  name: Elevated serum creatine kinase
  description: >-
    Creatine kinase is raised even in patients without clinically detectable
    weakness, which is what makes it the practical discriminator in this disease:
    it is the finding that converts an apparently idiopathic dilated
    cardiomyopathy workup into a genetic one.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:35743126
    reference_title: Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN"
    explanation: >-
      Reports elevated creatine kinase alongside the dilated cardiomyopathy in a
      genetically confirmed compound heterozygote.
genetic:
- name: FKTN
  notes: >-
    FKTN, at 9q31.2, encodes fukutin, a 461-amino-acid Golgi ribitol-phosphate
    transferase. The allelic architecture is the explanation for why CMD1X exists
    as an entity distinct from Fukuyama congenital muscular dystrophy rather than
    being a mild case of it, and it is worth stating explicitly.

    The Japanese founder allele is a roughly 3 kb retrotransposal insertion of
    tandemly repeated sequence in the FKTN 3' untranslated region, carried by 87
    per cent of FCMD chromosomes, and it abolishes expression in patients who
    carry it. Two null alleles of this kind give Fukuyama congenital muscular
    dystrophy. CMD1X patients are compound heterozygotes who carry one severe
    allele in trans with a milder allele that retains partial enzyme function.
    Missense alleles reported in the cardiac-predominant phenotype include
    p.Ser299Arg and p.Asn442Ser. Deep-intronic alleles acting through aberrant
    splicing are also described in this gene.

    That one-severe-plus-one-hypomorphic model is what the entry's
    functional_impact_category of PARTIAL_LOSS_OF_FUNCTION asserts at the level of
    the enzyme, and it is the reason the phenotype stops at the myocardium instead
    of extending to brain and skeletal muscle.
  gene_term:
    preferred_term: FKTN
    term:
      id: hgnc:3622
      label: FKTN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy."
    explanation: >-
      Establishes FKTN as the causal gene for a dilated-cardiomyopathy-predominant
      phenotype at the mild end of its allelic spectrum.
  - reference: PMID:9690476
    reference_title: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%)."
    explanation: >-
      Documents the founder allele that supplies the severe half of the CMD1X
      compound-heterozygous genotype, and its frequency among FCMD chromosomes.
  - reference: PMID:9690476
    reference_title: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion."
    explanation: >-
      Establishes both the physical nature of the founder allele and that it
      abolishes expression, which is what makes it the severe allele in the
      CMD1X genotype model.
  - reference: PMID:35743126
    reference_title: Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN"
    explanation: >-
      Names two of the missense alleles reported in the cardiac-predominant
      phenotype and confirms the compound heterozygous configuration.
diagnosis:
- name: Echocardiography
  description: >-
    Echocardiography establishes the cardiomyopathy itself, showing left
    ventricular dilation with hypokinesis and reduced ejection fraction. It is
    what the patient is referred for, and on its own it says nothing about the
    cause.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  results: Left ventricular dilation with reduced ejection fraction.
  evidence:
  - reference: PMID:26566449
    reference_title: A case of pregnancy complicated with dilated cardiomyopathy 1X.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In early pregnancy, the evaluation of her cardiac function showed ejection fraction 47% and NYHA class II."
    explanation: >-
      Reports the echocardiographic assessment of cardiac function in a
      genetically confirmed CMD1X patient.
- name: Serum creatine kinase measurement
  description: >-
    A raised creatine kinase in a patient who looks like idiopathic dilated
    cardiomyopathy is the trigger that should prompt a genetic workup, because it
    is present even without clinically detectable weakness. This is the step on
    which the whole diagnosis turns in practice: nothing else about the
    presentation points away from idiopathic disease.
  diagnosis_term:
    preferred_term: serum creatine kinase measurement
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: Elevated serum creatine kinase.
  evidence:
  - reference: PMID:35743126
    reference_title: Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN"
    explanation: >-
      Records elevated creatine kinase as an observed feature in a genetically
      confirmed patient, which is the basis for using it as a workup trigger.
- name: Muscle biopsy with alpha-dystroglycan glycoepitope staining and laminin overlay
  description: >-
    Immunohistochemistry and immunoblot for the glycoepitope of
    alpha-dystroglycan, with a laminin overlay assay, is the confirmatory
    functional test. Its interpretation in CMD1X carries a trap worth stating:
    the routine histology of the same biopsy is close to normal, so a report of
    minimal dystrophic change does not exclude the diagnosis and the glycoepitope
    study has to be requested specifically.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  results: Reduced alpha-dystroglycan glycosylation with reduced laminin binding.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."
    explanation: >-
      Establishes both the assay result and the near-normal routine histology that
      makes the specific glycoepitope study necessary.
- name: FKTN sequencing
  description: >-
    Targeted FKTN sequencing, or a dystroglycanopathy or cardiomyopathy gene
    panel, confirms the biallelic genotype. Two allele classes need specific
    attention because standard exome sequencing can miss them: the Japanese
    founder retrotransposal insertion in the 3' untranslated region, and
    deep-intronic variants acting through aberrant splicing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Biallelic FKTN variants, typically compound heterozygous.
  evidence:
  - reference: PMID:9690476
    reference_title: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein."
    explanation: >-
      Describes the founder allele's position and size, which is why it needs a
      targeted assay rather than coding-sequence analysis.
biochemical:
- name: Glycosylated alpha-dystroglycan on muscle biopsy
  notes: >-
    Immunohistochemistry and immunoblot for the glycoepitope of
    alpha-dystroglycan show reduced or aberrant signal, with reduced laminin
    binding on overlay assay. This is the confirmatory functional assay, and in
    CMD1X it is abnormal in skeletal muscle whose histology is close to normal.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability."
    explanation: >-
      Reports the assay result that defines the biochemical lesion, in patient
      skeletal muscle.
treatments:
- name: Guideline-directed heart failure pharmacotherapy
  description: >-
    There is no FKTN-specific therapy. Management follows standard treatment for
    heart failure with reduced ejection fraction. This is recorded as the
    prevailing standard of care rather than as an intervention tested in CMD1X,
    for which no trial evidence exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin-converting enzyme inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-adrenergic blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Ventricular Remodeling and Myocardial Fibrosis
    description: >-
      Guideline-directed therapy acts on the neurohormonal drive of adverse
      remodelling. It is disease-modifying for the remodelling process, not for
      the glycosylation defect upstream of it.
- name: Cardiac transplantation
  description: >-
    Transplantation is the definitive treatment for end-stage disease and has
    been reached by reported patients in adolescence.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Dilated Cardiomyopathy with Systolic Failure
    description: >-
      Transplantation replaces the failing organ; it does not address the
      underlying glycosylation defect, which remains present in skeletal muscle.
  evidence:
  - reference: PMID:17036286
    reference_title: Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old."
    explanation: >-
      Documents cardiac transplantation as an outcome reached in the defining
      series.
environmental:
- name: Haemodynamic load of pregnancy
  description: >-
    Pregnancy is a documented precipitant of decompensation in established CMD1X.
    It is not causal, and the entry does not treat it as such: the reported course
    is a fall in cardiac function from the third trimester, requiring bed rest and
    elective early delivery, with the cardiac parameters returning to their
    pre-pregnancy baseline about a month postpartum. The skeletal muscle behaved
    differently in the same patient, with weakness that persisted afterwards, so
    the two compartments did not recover in step.
  review_notes: >-
    No ECTO exposure term is bound. ECTO covers chemical, dietary and
    environmental exposures; the physiological haemodynamic load of pregnancy is
    not an exposure in that sense, and binding a chemical-exposure term here would
    be worse than leaving it unbound.
  influences_mechanisms:
  - target: Dilated Cardiomyopathy with Systolic Failure
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      The volume and afterload changes of gestation are superimposed on a ventricle
      that already cannot mount a compensatory hypertrophic response, so function
      falls further.
    evidence:
    - reference: PMID:26566449
      reference_title: A case of pregnancy complicated with dilated cardiomyopathy 1X.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Worsening of cardiac function was observed from 30 weeks, manifesting reduced cardiac load with left ventricular dilatation and in-hospital bed rest was necessary."
      explanation: >-
        Documents deterioration of cardiac function under the haemodynamic load of
        late pregnancy in a genetically confirmed CMD1X patient.
  evidence:
  - reference: PMID:26566449
    reference_title: A case of pregnancy complicated with dilated cardiomyopathy 1X.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The parameters of her cardiac function returned to the pre-pregnancy status in a month after delivery, whereas she realized persistent worsening of muscular weakness at postpartum."
    explanation: >-
      Establishes that the cardiac decompensation is reversible once the load is
      removed, while the skeletal muscle change was not, which is why this is
      recorded as an exacerbating exposure rather than a cause.
animal_models:
- name: Cardiac-specific fukutin knockout mouse
  species: Mouse
  genotype: Fktn flox/flox; MCK-Cre (constitutive) and Fktn flox/flox; alphaMHC-MerCreMer (inducible)
  publication: PMID:31848331
  description: >-
    Cardiomyocyte-restricted elimination of Fktn, both constitutively and
    inducibly in the adult heart. The model is the principal source of
    mechanistic information about how fukutin loss causes cardiac failure.
  modeled_mechanisms:
  - target: Impaired Compensatory Hypertrophic Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Establishes the Akt and MEF2-histone deacetylase signaling lesion, and the
      stress-dependence of the phenotype.
    limitations: >-
      The knockout is a complete null restricted to the heart, whereas human
      CMD1X arises from a hypomorphic biallelic genotype affecting every tissue.
      The model therefore cannot address why human skeletal muscle is spared, and
      the mouse phenotype is engineered to be cardiac-restricted rather than
      being so for the reasons the human disease is.
    evidence:
    - reference: PMID:31848331
      reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis."
      explanation: >-
        Supports treating this model as informative for the compensatory
        signaling node.
  - target: Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the loss of sarcolemmal alpha-dystroglycan glycosylation and
      dystrophin-glycoprotein complex, while showing that this alone does not
      produce contractile failure.
    limitations: >-
      Graded PARTIALLY_RECAPITULATES because the model reproduces the membrane
      lesion but explicitly dissociates it from the functional phenotype, so it
      does not establish the membrane-fragility route as sufficient in humans.
    evidence:
    - reference: PMID:31848331
      reference_title: Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction."
      explanation: >-
        Both the recapitulation and its limit are stated in the same sentence.
discussions:
- discussion_id: cmd1x_cardiac_vs_skeletal_tissue_selectivity
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why does the myocardium fail in CMD1X while skeletal muscle carrying the same
    alpha-dystroglycan glycosylation defect stays close to normal, and can any
    current model answer this?
  rationale: >-
    The tissue selectivity is the defining feature of the entity, and no existing
    model system addresses it. The available mechanistic data come from
    cardiac-specific complete Fktn knockouts, in which the cardiac restriction is
    engineered by the Cre driver rather than emerging from the biology. Those
    models establish the Akt and MEF2-histone deacetylase lesion and show that
    membrane fragility alone is insufficient, but because they are nulls confined
    to one tissue they cannot test the hypothesis that actually explains the
    human phenotype, namely that a partial, body-wide reduction in fukutin
    activity crosses a threshold in cardiomyocytes that it does not cross in
    skeletal myofibres. A hypomorphic, non-tissue-restricted allelic series is
    what the question needs.
  attaches_to:
  - pathophysiology#Relative Sparing of Skeletal Muscle and Brain
  - animal_models#Mouse

📚

References & Deep Research

References

7

PMID:17036286

Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.

No top-level findings curated for this source.

PMID:31848331

Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.

No top-level findings curated for this source.

PMID:27194101

ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan.

No top-level findings curated for this source.

PMID:35743126

Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern.

No top-level findings curated for this source.

PMID:9690476

An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.

No top-level findings curated for this source.

PMID:26566449

A case of pregnancy complicated with dilated cardiomyopathy 1X.

No top-level findings curated for this source.

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Dilated Cardiomyopathy 1X (MONDO:0012704, FKTN) · 2026-09-04T02:57:03Z · View source

New entry for CMD1X, curated as a standalone Disease rather than a has_subtypes row on Dystroglycanopathy. MONDO places MONDO:0012704 directly under MONDO:0700335 (familial isolated dilated cardiomyopathy), and the causal chain from the FKTN lesion to heart failure stays in the heart rather than running through the skeletal-muscle and pial-basement-membrane routes that Dystroglycanopathy.yaml curates. Deep research: one run with the claude_code provider (research/Dilated_Cardiomyopathy_1X-deep-research-claude_code.md). Its reference validation was clean (8/8 references resolved, 0 unresolved, 2/2 quoted claims found in source). Its term validation was materially useful and changed two bindings: HP:0001635 is Congestive heart failure, not Dilated cardiomyopathy, so the dilated cardiomyopathy phenotype is bound to HP:0001644 and HP:0001635 is used for the heart failure phenotype instead; and HP:0003749 is canonically Pelvic girdle muscle weakness, which is the label recorded. GO:0006486 was flagged obsolete and was not used. The single most important thing the research corrected is the disease name. CMD1X is NOT X-linked: the X is the position reached in OMIM's sequential lettering of the CMD1 series, FKTN is autosomal at 9q31.2, and inheritance is autosomal recessive through compound heterozygous hypomorphic alleles. The claim issue body and the first-pass draft both implied X-linkage. The entry now carries a top-level notes block stating this explicitly, because the entity is routinely conflated with DMD-related X-linked dilated cardiomyopathy at Xp21. Pathograph: seven nodes from reduced fukutin ribitol-phosphate transferase activity through alpha-dystroglycan hypoglycosylation, weakened sarcolemma-to-basement-membrane linkage, impaired compensatory hypertrophic signalling, ventricular remodelling, to dilated cardiomyopathy with systolic failure, plus a node recording the relative sparing of skeletal muscle and brain. Conformance declared to pial_basement_membrane_radial_glial_endfoot_failure#Alpha-Dystroglycan Glycosylation and ECM Ligand Binding Failure (checked first that this node is written generically and names FKTN, rather than being brain-scoped) and to three nodes of cardiomyopathy_maladaptive_remodeling. Mouse evidence is graded MODEL_ORGANISM with directness INDIRECT throughout, and the cardiac-specific Fktn knockout is recorded as an animal model with two modeled_mechanisms links, one RECAPITULATES and one PARTIALLY_RECAPITULATES with limitations. A HUMAN_MODEL_MISMATCH discussion records that no current model can address the defining question, because the available models are complete nulls made cardiac-restricted by a Cre driver rather than hypomorphic alleles acting body-wide. Also added Dilated Cardiomyopathy 1X as a member of kb/groupings/Familial_Dilated_Cardiomyopathy.yaml with a differentiating_mechanisms entry, and updated that grouping's rationale from five to six mechanistic classes, FKTN being the only member whose failing component lies outside the myocyte. Checked before adding that the grouping already admits a member with skeletal muscle involvement (CMD1A/LMNA), so CMD1X's minimal extracardiac involvement does not breach the isolated clause. just check-groupings reports CMD1X SATISFIED on both necessary criteria. Not done: no environmental entry for pregnancy as a decompensation trigger, although the research reports a case, because the source was available only as a PMC identifier and could not be fetched into the reference cache as a citable PMID. No prevalence record, because the entity is known only from case reports and no population rate can be honestly stated. No clinical trials. Validation: just validate, just validate-terms, just count-verified-snippets (19/19 verified), just check-duplicate-keys, just check-entity-refs, just check-causal-targets, just check-qualifier-terms, just check-enum-values, just validate-grouping and just check-groupings all pass.

Claude Code ▸

Dilated Cardiomyopathy 1X (CMD1X): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-09-04T02:46:42.496123

Dilated Cardiomyopathy 1X (CMD1X): Comprehensive Research Report

1. Disease Information

Overview

Dilated Cardiomyopathy 1X (CMD1X) is a rare, genetically defined form of dilated cardiomyopathy (DCM) caused by biallelic (typically compound heterozygous, occasionally homozygous) pathogenic variants in the FKTN gene (fukutin), which sits within the broader secondary alpha-dystroglycanopathy spectrum. It is clinically distinctive because it presents with prominent, sometimes isolated cardiac muscle involvement with minimal or absent limb-girdle skeletal myopathy and normal intelligence — a striking dissociation from the severe, multisystem phenotype (brain malformation, eye anomalies, profound muscle weakness) classically associated with FKTN mutations in Fukuyama congenital muscular dystrophy (FCMD). The original description characterized six patients from four families with "dilated cardiomyopathy with no or minimal limb girdle muscle involvement" (Murakami et al., Annals of Neurology 2006;60(5):597-602, PMID:17036286).

Important nomenclature note: Despite the "X" suffix, CMD1X is not X-linked. OMIM's dilated cardiomyopathy series uses sequential letters after "CMD1" (autosomal dominant/undetermined series) — CMD1A through CMD1BB and beyond — purely as an enumeration; "1X" is simply the 24th letter reached in that numbering scheme, not a locus designation. This is a genuine, well-documented curator pitfall: FKTN is autosomal (chromosome 9q31.2), and inheritance is autosomal recessive. (True X-linked dilated cardiomyopathy caused by DMD/dystrophin mutations is a separate entity, OMIM designated CMD3B/#302045, which should not be conflated with CMD1X.)

Key Identifiers

Database	ID
OMIM (phenotype)	#611615 — CARDIOMYOPATHY, DILATED, 1X; CMD1X
OMIM (gene)	*607440 — FUKUTIN; FKTN
MONDO	MONDO:0012704
Orphanet	ORPHA:154 (subsumed under the alpha-dystroglycanopathy/Fukuyama spectrum entries)
MedGen	C1969024
Gene	FKTN, HGNC:3622, chromosome 9q31.2
Inheritance	Autosomal recessive
Related allelic disorders (same gene, MDDG spectrum)	MDDGA4 (severe, congenital, brain/eye anomalies — includes classic Fukuyama CMD, Walker-Warburg syndrome, muscle-eye-brain disease; OMIM #253800), MDDGB4 (intermediate, congenital, no brain/eye involvement), MDDGC4/LGMD2M/LGMDR13 (limb-girdle form, OMIM #611588)

Sources: OMIM #611615 (via search), NCBI GTR C1969024, OMIM #253800, OMIM #611588

Synonyms

CMD1X
Cardiomyopathy, dilated, 1X
FKTN-related dilated cardiomyopathy
Fukutin-associated dilated cardiomyopathy with minimal muscle weakness

Evidence basis

The condition is characterized almost entirely from aggregated case-series and case-report literature (not large cohort/EHR registries) — the founding series (n=6, 4 families), subsequent single-patient reports from Europe (Italian, German cases), and a recent JACC case series pairing FKTN with LMNA-associated DCM. This is consistent with its rarity: it is an "orphan" subtype even within the rare-disease space of genetic DCM.

2. Etiology

Disease Causal Factors

CMD1X is caused by biallelic loss-of-function/hypomorphic variants in FKTN, encoding fukutin, a Golgi-resident ribitol-5-phosphate transferase required for functional glycosylation of alpha-dystroglycan (α-DG). The mechanism is genetic/enzymatic (a glycosylation defect), not environmental or infectious in origin, though pregnancy and hemodynamic stress can precipitate decompensation in an already-compromised heart (see below).

Genetic Risk Factors

Causal variants: Point mutations (missense, nonsense) and small indels in FKTN, typically as compound heterozygotes, with the cardiac-restricted phenotype associated with hypomorphic (partial function-retaining) alleles rather than the severe null combinations seen in Fukuyama CMD or Walker-Warburg syndrome.
The originally reported German/European compound heterozygote carried p.Ser299Arg and p.Asn442Ser (PMC9223741, MDPI Int J Mol Sci 2022).
A separate Chinese case reported a de novo p.Asp3368Gly-type dystrophin variant in a different gene context (this is a DMD-XLDC case, illustrating how the two entities are frequently co-indexed in literature searches and must be disambiguated).
The Japanese founder allele — a ~3-kb SVA-type retrotransposal insertion in the 3′-UTR of FKTN — is the classic severe Fukuyama-associated allele (present in ~87% of FCMD alleles in Japan); CMD1X patients typically carry this founder allele in trans with a second, milder point mutation, producing a "compound heterozygote with one hypomorphic and one severe allele" genotype-phenotype pattern that under-expresses the severe brain/eye phenotype while sparing enough fukutin activity to avoid overt limb-girdle myopathy but not enough to protect the heart.
A deep-intronic variant of FKTN has also been reported as a prevalent point-mutation-class allele in Japanese FCMD/dystroglycanopathy patients (J Hum Genet 2017).
Susceptibility/modifier genes: None specifically established for CMD1X; however, the JACC case-series literature (2026) documents co-occurring or phenocopy overlap with LMNA-associated DCM/LGMD in the differential for "cardiomyopathy-first" presentations later found to have limb-girdle disease.
Founder effects: Strong founder effect in the Japanese population via the FCMD retrotransposal insertion (age estimated at ~102 generations by haplotype analysis); most published CMD1X cases are of Japanese ancestry, though European cases have now been reported.

Environmental / Non-genetic Risk Factors

Pregnancy is a well-documented precipitant of clinical decompensation in patients with pre-existing CMD1X, due to the hemodynamic volume/afterload burden of gestation (see Section 8/Case report below) — this is a secondary exacerbating factor, not a causal one.
No toxin, occupational, infectious, or lifestyle causal factor has been established; standard DCM risk-modifying exposures (alcohol, cardiotoxic chemotherapy) are not part of the CMD1X literature and would represent phenocopies/comorbid triggers rather than part of the primary mechanism.

Protective Factors

None specifically reported for FKTN-related disease. General DCM disease-modifying factors (guideline-directed medical therapy adherence) apply once diagnosed but are not preventive at the genetic level.

Gene-Environment Interactions

The clearest documented interaction is the cardiac hemodynamic stress of pregnancy unmasking or worsening subclinical/mild CMD1X (see pregnancy case report, PMC4630494), analogous to peripartum cardiomyopathy but genetically determined rather than idiopathic.

3. Phenotypes

Cardiac phenotype (primary)

Dilated cardiomyopathy — left ventricular dilatation with hypokinesis/reduced ejection fraction (HP:0001635 Dilated cardiomyopathy)
Reported LVEF as low as 47% at presentation in the pregnancy case, with LV diastolic dimension (LVDd) of 53 mm (PMC4630494)
Progressive over time in most cases; two originally reported patients died (age 12, rapid progression) or required cardiac transplantation (age 18)
Congestive heart failure / reduced NYHA functional class (HP:0001635 / HP:0001642 Reduced left ventricular ejection fraction) — NYHA class II reported at baseline in the pregnancy case, worsening with hemodynamic stress
Arrhythmia (HP:0011675 Arrhythmia) — a general dystroglycanopathy-cardiac feature, though the primary literature emphasizes pump failure over primary electrical disease
Cardiomegaly (HP:0001640)

Skeletal muscle phenotype (minimal/mild — defining feature distinguishing CMD1X from the rest of the FKTN spectrum)

Mild or absent limb-girdle muscle weakness (HP:0003749 Limb-girdle muscle weakness) — present in some but not all patients; several index patients had no clinically detectable weakness
Elevated serum creatine kinase (CK) (HP:0003236 Elevated CK) — a laboratory abnormality frequently present even in the absence of overt weakness; broader FKTN-dystroglycanopathy literature documents serial CK from 298–11,900 U/L
Minimal dystrophic changes on skeletal muscle biopsy — histologically near-normal or minimally dystrophic muscle despite biochemically abnormal (hypoglycosylated) α-dystroglycan and reduced laminin-binding activity (Murakami et al. 2006)

CNS/cognitive phenotype

Normal intelligence (explicitly documented as a distinguishing negative finding — contrasts with the mental retardation/brain malformation of classic FCMD)
No history of seizures (explicit negative finding in the founding case series)

Phenotype characteristics

Age of onset: Variable — pediatric/adolescent onset (one fatal case at age 12) through young adulthood (transplant at 18; a 25-year-old diagnosed at 19 in the pregnancy case; a JACC-reported 22-year-old woman with biallelic FKTN requiring transplant)
Severity: Highly variable, from indolent/subclinical disease unmasked by pregnancy to rapidly progressive fatal disease in childhood
Progression: Generally progressive; some patients stable for years before decompensation under physiologic stress (pregnancy, illness)
Frequency data: Not established at a population level — this is an ultra-rare entity known chiefly from case reports/small series, so phenotype frequencies (e.g., "X% have LGMD features") are not quantifiable with confidence; qualitative descriptors ("mildest," "no or minimal") are used in the literature rather than percentages.

Quality of life impact

Not formally studied with QoL instruments (EQ-5D/SF-36) in the literature identified; qualitatively, the disease burden is dominated by heart-failure symptoms and, for a subset, progressive limb-girdle weakness postpartum (one patient reported "persistent worsening of muscular weakness" after delivery, PMC4630494).

Suggested HP terms: HP:0001635 (Dilated cardiomyopathy), HP:0001644 (Dilated cardiomyopathy — note overlapping codes across HPO releases), HP:0003749 (Limb-girdle muscle weakness), HP:0003236 (Elevated CK), HP:0001639 (Hypertrophic cardiomyopathy — not applicable here but relevant to FKTN mutational screens that included HCM cohorts), HP:0001636 (Tachycardia), HP:0011675 (Arrhythmia).

4. Genetic/Molecular Information

Causal Gene

FKTN (fukutin), HGNC:3622, chromosome 9q31.2, OMIM gene entry *607440
Encodes a 461-amino-acid type II transmembrane, Golgi-resident enzyme

Pathogenic Variants

Variant types: Missense (e.g., p.Ser299Arg, p.Asn442Ser), the Japanese founder 3-kb retrotransposal (SVA-type) insertion in the 3′-UTR, deep-intronic variants affecting splicing, and other point mutations/small indels — heterogeneous across the allelic series
Classification: Reported ClinVar submissions for "Dilated cardiomyopathy 1X" include multiple FKTN variants (e.g., c.954T>A, c.2902C>T, c.1297A>G [p.Thr433Ala], c.1106del [p.Phe369fs], and the retrotransposal insertion c.4392_4393ins) — see ClinVar records cross-referenced above
Zygosity: Compound heterozygous in essentially all reported CMD1X cases (biallelic, two different variants) — consistent with autosomal recessive inheritance and the genotype-phenotype model of "one severe + one hypomorphic allele → cardiac-predominant phenotype"
Functional consequence: Loss/reduction of function — reduced ribitol-5-phosphate transferase activity, causing hypoglycosylation of α-dystroglycan and reduced laminin-binding capacity, demonstrable by Western blot with N-terminal dystrophin/glycosylated-α-DG-specific antibodies (e.g., IIH6) on muscle biopsy
Somatic vs. germline: Germline (Mendelian, autosomal recessive) — not a somatic/acquired disease

Modifier Genes

None formally established for CMD1X specifically; the 2026 JACC case series highlights that LMNA variants can produce an overlapping "DCM-first, LGMD-later" clinical trajectory, useful as a differential-diagnosis consideration rather than a true modifier of FKTN penetrance.

Molecular Pathway Context

FKTN operates in the CDP-ribitol / matriglycan biosynthesis pathway: - ISPD (isoprenoid synthase domain-containing protein) synthesizes CDP-ribitol - FKTN and FKRP (fukutin-related protein) sequentially transfer ribitol-5-phosphate (RboP) from CDP-ribitol onto the core M3 O-mannosyl glycan of α-dystroglycan, generating a tandem ribitol-phosphate unit essential for subsequent matriglycan polymerization by LARGE1 - This tandem RboP structure is required for α-DG to bind laminin-α2, agrin, and perlecan in the extracellular matrix - FKTN and FKRP are the only mammalian proteins bearing a bacterial-type LicD domain used for CDP-conjugate substrate chemistry

Primary sources: ISPD produces CDP-ribitol used by FKTN and FKRP (Nat Commun 2016, PMID:27194101)

Chromosomal Abnormalities

Not applicable — CMD1X is caused by sequence-level variants/indels/retrotransposal insertion, not large structural/chromosomal rearrangements.

Epigenetic Information

No disease-specific epigenetic (DNA methylation/histone) literature was identified for CMD1X; not a known mechanism in this disorder.

5. Environmental Information

Environmental factors: None causally implicated; this is a monogenic, autosomal recessive disorder.
Lifestyle factors: Not established as causal; standard cardiomyopathy comorbidity considerations (deconditioning, volume status) apply symptomatically but are not disease-causing.
Infectious agents: Not implicated.
Key modifiable physiologic stressor: Pregnancy, which is well-documented to precipitate/worsen decompensation (see Section 8) — this should be modeled as a triggering/exacerbating physiologic exposure rather than a classic toxin/infection.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic hypomorphic FKTN variants (typically compound heterozygous — one severe allele, e.g., the retrotransposal insertion, in trans with a milder missense allele) → reduces, but does not abolish, fukutin ribitol-5-phosphate transferase activity in the Golgi apparatus.
Reduced fukutin activity → impaired sequential transfer of ribitol-5-phosphate from CDP-ribitol (synthesized by ISPD) onto the core M3 O-mannosyl glycan of α-dystroglycan, in cooperation with FKRP → incomplete/aberrant tandem ribitol-phosphate glycan structure on α-dystroglycan. This step is directly demonstrated biochemically (Western blot with glycoepitope-specific antibodies such as IIH6 shows reduced/absent signal; PMID:27194101, PMC9223741).
Aberrant α-dystroglycan glycosylation → loss of downstream matriglycan polymerization and reduced α-dystroglycan binding affinity for laminin-α2, agrin, and perlecan in the extracellular matrix → weakened linkage between the sarcolemmal dystrophin-glycoprotein complex (DGC) and the basement membrane in cardiomyocytes and (to a lesser, tissue-dependent extent) skeletal myofibers. Demonstrated in patient muscle biopsy and cardiac Fktn-knockout mouse models (Murakami et al. 2006; Kanagawa/Beedle-type models reviewed via Nat Commun 2019, PMID:31848331).
Weakened DGC-ECM linkage in the myocardium → two convergent, partly dissociable downstream consequences, based on the cardiac-specific Fktn mouse knockout literature:
Branch A (membrane fragility route): reduced α-DG glycosylation and DGC protein content at the sarcolemma at all developmental stages → increased susceptibility to contraction-induced sarcolemmal microdamage, analogous to the mechanism in dystrophinopathy-associated cardiomyopathy — though the mouse data indicate this alone is not sufficient to cause overt dysfunction in early life, implying an inferred, only partially demonstrated causal step in humans.
Branch B (signaling/hypertrophic-stress route, better supported mechanistically): during young adulthood, Fktn-deficient cardiomyocytes show increased vulnerability to pathological hypertrophic stress, with downregulation of Akt signaling and disruption of the MEF2–histone deacetylase (HDAC) transcriptional axis → maladaptive hypertrophic/remodeling transcriptional program. Acute Fktn elimination in adult mouse hearts produces severe contractile dysfunction, disordered Golgi-microtubule networks, and accelerated mortality, indicating fukutin also has an ECM-glycosylation-independent role in myocyte structural/organellar integrity (Nat Commun 2019, PMID:31848331 — model-organism evidence; translational fidelity to the milder, chronic human CMD1X phenotype is not fully established and represents a genuine human-model gap).
Branch A + Branch B converge on progressive cardiomyocyte dysfunction, myocardial fibrotic remodeling, and chamber dilatation → clinical dilated cardiomyopathy with reduced ejection fraction, which in turn leads to → congestive heart failure symptoms, arrhythmia risk, and (in severe cases) death or need for cardiac transplantation.
In parallel, but largely uncoupled from the cardiac trajectory in CMD1X specifically (this dissociation is the entry's defining biological puzzle), the same glycosylation defect in skeletal muscle produces only minimal histological/dystrophic change, despite biochemically demonstrable hypoglycosylation and reduced laminin-binding — i.e., skeletal muscle appears more tolerant of the same molecular lesion than cardiac muscle in this genotype range, an unresolved cardiac-vs-skeletal-muscle tissue-vulnerability question in the literature.
Pregnancy-associated hemodynamic load (increased circulating volume, afterload/preload shifts) acts as an exacerbating step superimposed on the underlying structural cardiomyopathy (step 5) → acute-on-chronic decompensation, generally reversible postpartum for the cardiac component but sometimes associated with a step-change worsening of the skeletal myopathy (per the pregnancy case report), suggesting the hemodynamic stress event may also unmask/accelerate the peripheral muscle phenotype — a mechanistically unexplained observation, not yet causally dissected.

Molecular Pathways

CDP-ribitol/matriglycan biosynthesis pathway (ISPD → FKTN/FKRP → LARGE1) — see Section 4. Suggested GO terms: GO:0035269 (protein O-linked mannosylation), a fukutin-specific ribitol-phosphate transferase activity term, and GO:0007009 (plasma membrane organization) for downstream DGC effects.

Cellular Processes

Golgi glycosylation/protein trafficking dysfunction
Maladaptive cardiomyocyte hypertrophic signaling (Akt/MEF2-HDAC axis downregulation)
Sarcolemmal membrane fragility (secondary/contributory)

Protein Dysfunction

Loss-of-function/hypomorphic enzymatic activity of fukutin (a Golgi ribitol-5-phosphate transferase) — not a classic misfolding/aggregation disease.

Tissue Damage Mechanisms

Myocardial remodeling/fibrosis secondary to chronic contractile dysfunction and impaired ECM-cytoskeletal linkage; minimal comparable damage in skeletal muscle in the CMD1X-specific genotype range.

Cell types and biological processes involved

Suggested CL terms: CL:0000746 (cardiac muscle myocyte), CL:0000188 (skeletal muscle myoblast/fiber, for the milder, secondary skeletal involvement). Suggested GO: protein glycosylation (GO:0006486), O-mannosylation, and hypertrophic-signaling-related terms (PI3K-Akt signaling, GO:0043491).

Molecular Profiling / Advanced Technologies

No transcriptomic, proteomic, or single-cell datasets specific to human CMD1X myocardium were identified in this search; the mechanistic evidence base is predominantly (a) patient muscle-biopsy immunohistochemistry/Western blot and (b) mouse cardiac-specific Fktn knockout models (constitutive and inducible/acute), which is a model-organism evidence gap worth flagging for a HUMAN_MODEL_MISMATCH-type discussion: the mouse models capture the glycosylation defect and downstream Akt/MEF2 signaling faithfully but do not fully explain why human skeletal muscle is comparatively spared in the CMD1X allele combination.

7. Anatomical Structures Affected

Organ level

Primary organ: Heart (myocardium) — left ventricle predominantly, per echocardiographic dilatation/hypokinesis pattern
Secondary/minor organ involvement: Skeletal muscle (limb-girdle distribution), minimally
Body systems: Cardiovascular system (primary); musculoskeletal system (secondary, mild)
Not involved: Central nervous system (explicitly normal intelligence, no seizures) — distinguishing CMD1X from the rest of the FKTN/MDDG spectrum

Suggested UBERON terms: UBERON:0000948 (heart), UBERON:0002082 (cardiac ventricle), UBERON:0001630 (skeletal muscle tissue, limb-girdle group).

Tissue and cell level

Cardiomyocytes (CL:0000746) — primary affected population
Skeletal myofibers — secondarily, mildly affected
Extracellular matrix (basement membrane) surrounding both tissue types — site of the functional lesion (laminin-binding failure)

Subcellular level

Golgi apparatus — site of fukutin's enzymatic activity (GO Cellular Component: GO:0005794, Golgi apparatus)
Sarcolemma — site of the dystrophin-glycoprotein complex (DGC) whose ECM linkage is compromised
Microtubule/Golgi network — disrupted in the acute mouse knockout model

Localization

Bilateral, diffuse left ventricular involvement (not focal/segmental) per the echocardiographic description ("diffused left ventricular hypokinesis").

8. Temporal Development

Onset

Age of onset: Variable — pediatric (fatal case, age 12) through young adulthood (diagnosis at 19, transplant at 18 or 22); no neonatal/congenital cardiac presentation reported for the CMD1X subtype specifically (distinguishing it from the congenital MDDGA4/B4 forms)
Onset pattern: Insidious/subclinical in several reported cases, only unmasked by a physiologic stressor (pregnancy)

Progression

Disease course: Generally progressive dilated cardiomyopathy; rate is variable — from rapid/fatal in childhood to an indolent course persisting into adulthood
Stages: Not formally staged in a disease-specific system; general heart-failure staging (NYHA class) applies — NYHA II documented at baseline in the pregnancy case, with worsening under hemodynamic load
Duration: Chronic, lifelong once manifest; can require heart transplantation

Patterns

Reversibility: The pregnancy case demonstrated that pregnancy-associated cardiac decompensation (EF drop, LV dilatation) returned to baseline (pre-pregnancy) status approximately one month postpartum, indicating the cardiac component of an acute decompensation can be reversible even though the underlying cardiomyopathy is not cured; however, the skeletal myopathy in the same patient showed persistent worsening postpartum, suggesting differential reversibility between the cardiac and skeletal muscle compartments.
Critical period: Pregnancy is identified as a specific window of vulnerability requiring closer surveillance in known/suspected CMD1X patients.

9. Inheritance and Population

Epidemiology

Prevalence/incidence: Not established at a population level — CMD1X is known from isolated case reports and one small case series (6 patients/4 families in the founding report); it should be regarded as an ultra-rare subtype within the broader genetic-DCM landscape (general nonischemic DCM prevalence is estimated at roughly 1/2500, for context, but FKTN-attributable cases are a vanishingly small fraction of that).

Inheritance Pattern

Autosomal recessive (biallelic FKTN variants required) — not X-linked despite the "1X" name (see Section 1 nomenclature note).
Penetrance: Appears high for the cardiac phenotype once the specific hypomorphic compound-heterozygous genotype is present, though formal penetrance estimates are not available given the small case numbers.
Expressivity: Highly variable — ranging from asymptomatic-until-pregnancy to fatal childhood disease — consistent with the allelic-severity model (specific combination of the two inherited alleles determines phenotype across the whole FKTN/MDDG spectrum).
Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder in the classic sense, though the founder allele is itself a large insertion).
Founder effects: Strong — the ~3-kb SVA-type retrotransposal insertion in the FKTN 3′-UTR is a well-characterized Japanese founder mutation (present in ~87% of FCMD alleles; estimated age ~102 generations), and most published CMD1X patients are of Japanese descent, carrying this founder allele in trans with a second, milder FKTN variant. European cases (German, Italian) have since been reported with different, non-founder compound-heterozygous genotypes.
Carrier frequency: The FCMD founder allele carrier frequency in the Japanese population has been estimated in the range consistent with FCMD being the second most common muscular dystrophy in Japan (~1/90 carrier frequency has been cited historically for the founder insertion in the general Japanese population in FCMD literature, though this figure was not independently re-verified in this search and should be confirmed against a primary source before use in curation).
Consanguinity: Not specifically emphasized in the CMD1X case literature (compound heterozygosity, not homozygosity, is the predominant genotype reported).

Population Demographics

Affected populations: Predominantly Japanese (founder-allele-driven), with additional cases now reported in European (German, Italian) patients with non-founder genotypes — indicating the disorder is not population-restricted, only enriched by founder effect in Japan.
Sex ratio: No specific male:female skew has been established (consistent with autosomal recessive inheritance); both male and female patients are reported, including the female pregnancy case.
Age distribution: Concentrated in childhood-through-young-adult presentation in the literature identified.

10. Diagnostics

Clinical Tests

Echocardiography: Diagnostic mainstay for demonstrating LV dilatation, hypokinesis, and reduced EF (LVEF 47%, LVDd 53 mm reported in the pregnancy case)
Serum creatine kinase (CK): Frequently elevated even without overt weakness (broader FKTN-dystroglycanopathy literature: 298–11,900 U/L range); an important diagnostic clue prompting genetic workup in a patient presenting with "DCM plus unexplained CK elevation"
Muscle biopsy: Histopathology often shows only minimal dystrophic change in CMD1X (contrasting with more severe dystrophic histology in classic FCMD/LGMD2M), but immunohistochemistry/Western blot for glycosylated α-dystroglycan (e.g., using the IIH6 monoclonal antibody) reveals reduced/aberrant glycosylation and reduced laminin-binding — this is the key confirmatory functional assay
Cardiac biopsy: Abnormalities of cardiac dystrophin-associated glycoprotein complex demonstrable by Western blot with N-terminal antibodies in some reports, while skeletal muscle dystrophin/DGC remains comparatively preserved

Genetic Testing

Recommended approach: Targeted FKTN sequencing or a dystroglycanopathy/cardiomyopathy gene panel, given the clinical suspicion is usually raised by unexplained DCM plus mild CK elevation
Whole exome/genome sequencing: Appropriate when panel testing is non-diagnostic, given phenotypic overlap with other genetic DCM genes (LMNA, TTN, DMD, RPL3L, TNNC1, etc., all of which appear in the differential-diagnosis literature retrieved)
Japanese founder mutation testing: A specific, targeted clinical test exists for the FKTN 3′-UTR retrotransposal insertion (offered commercially, e.g., PreventionGenetics' "Fukuyama Congenital Muscular Dystrophy via the FKTN Japanese Founder Mutation Test"), relevant when one allele is suspected to be the founder insertion
Deep-intronic variant testing: A specific deep-intronic FKTN variant has been reported as a prevalent point-mutation-class cause of FKTN-related disease in Japan and may require specialized splicing-variant assays not captured by standard exome sequencing

Clinical Criteria

No CMD1X-specific consensus diagnostic criteria exist; diagnosis rests on the combination of (1) DCM phenotype, (2) absent/minimal overt myopathy, (3) elevated CK, (4) biallelic FKTN variants, and (5) confirmatory α-DG glycosylation studies on muscle biopsy where available.
Differential diagnosis: Other genetic DCM causes with occult skeletal myopathy — notably LMNA-associated DCM/LGMD (explicitly discussed as a mimicking/co-occurring entity in the 2026 JACC case series), X-linked dystrophinopathy-associated DCM (DMD gene — the entity often confused by name with CMD1X), TTN-truncating variant DCM, RPL3L-associated DCM, TNNC1-associated familial DCM, and idiopathic/peripartum cardiomyopathy (particularly relevant given the pregnancy-associated presentation).

Screening

No population or newborn screening program specific to CMD1X was identified; case-finding is reactive (via unexplained DCM + CK elevation workup) rather than proactive, given the extreme rarity.

11. Outcome/Prognosis

Survival/mortality: Highly variable — the founding case series documented one death at age 12 from rapidly progressive disease and one heart transplant at age 18; a more recent case series (JACC 2026) documents additional transplant cases (including a 22-year-old woman with biallelic FKTN variants). No population-level survival statistics (5-/10-year survival) exist given the rarity.
Morbidity: Dominated by heart-failure-related functional limitation; a subset of patients develop progressive limb-girdle weakness over time, sometimes accelerated by pregnancy.
Complications: Progression to end-stage heart failure requiring transplantation is a recurring theme across the literature; arrhythmia risk is presumed (general DCM risk) but not specifically quantified for this subtype.
Recovery potential: The cardiac component can show substantial reversibility after an acute precipitant (pregnancy) resolves, but the underlying cardiomyopathy and any skeletal myopathy are not curable and tend to persist/progress long-term.
Prognostic factors: Genotype severity (specific allele combination), presence/degree of skeletal muscle involvement, and physiologic stressors (pregnancy, intercurrent illness) appear to modulate short-term trajectory, though systematic prognostic-factor analysis has not been performed given small case numbers.

12. Treatment

No CMD1X-specific pharmacotherapy exists; management follows standard guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction, as used for genetic and non-genetic DCM broadly, per 2022 ACC/AHA/HFSA and 2023 ESC cardiomyopathy guidelines:

Pharmacotherapy

ACE inhibitors / ARBs / ARNI (sacubitril-valsartan) — NCIT:C15986 (Pharmacotherapy); sacubitril-valsartan shown superior to enalapril for reducing cardiovascular mortality/HF hospitalization in HFrEF generally
Beta-blockers — significant benefit on LVEF in nonischemic DCM management
Mineralocorticoid receptor antagonists (MRAs)
SGLT2 inhibitors — now part of standard 4-pillar HFrEF GDMT
Diuretics — symptomatic volume management

Device Therapy

Implantable cardioverter-defibrillator (ICD) for primary prevention — evidence nuanced in nonischemic DCM generally (DANISH trial: no overall mortality benefit, but reduced sudden cardiac death; younger patients <59 years showed mortality benefit) — NCIT term: device/procedure, not a drug-class NCIT clinical-action term (see dismech convention: bind the implantation procedure as the clinical action, with the device carried as a qualifier)

Advanced Therapeutics / Surgical

Cardiac transplantation — definitive treatment for end-stage disease; explicitly used in multiple reported CMD1X/FKTN-DCM patients (age 18 in the founding series; a 22-year-old in the JACC case series) — NCIT:C15289 (Organ Transplantation)
No gene therapy, cell therapy, or RNA-based therapy specific to FKTN-related cardiomyopathy was identified as approved or in trials; the ribitol-supplementation strategy explored for ISPD-related dystroglycanopathy (partial restoration of α-DG glycosylation with dietary ribitol in cell/mouse models) is a related experimental approach in the broader pathway but has not been specifically reported for FKTN-attributable disease in this search.

Supportive Care

Standard heart-failure supportive management; monitoring during pregnancy is specifically emphasized in the literature (elective early delivery, e.g., cesarean section at 35 weeks, was used in the reported case to preempt further cardiac deterioration)
Multidisciplinary cardiology–neuromuscular collaboration is explicitly recommended in the recent case-series literature once a dual cardiac/skeletal-muscle genetic diagnosis (FKTN or LMNA) is confirmed, to support transplant planning and lifelong neuromuscular surveillance

Experimental

No CMD1X-specific registered clinical trials (ClinicalTrials.gov/NCT) were identified in this search.

13. Prevention

Primary prevention: Not applicable in the classic sense (monogenic recessive disorder); genetic counseling for carrier parents (both parents of an affected child are obligate carriers) is the relevant preventive intervention, with reproductive options including carrier testing of at-risk relatives and prenatal/preimplantation genetic diagnosis where familial variants are known — particularly salient given the Japanese founder-allele carrier population.
Secondary prevention: Early diagnostic suspicion in any patient with DCM plus unexplained CK elevation, enabling earlier initiation of GDMT and surveillance before advanced heart failure develops.
Tertiary prevention: Close cardiac surveillance during pregnancy in known female patients/carriers of the disease-causing genotype, given the demonstrated risk of pregnancy-associated decompensation; consideration of elective early delivery when cardiac function deteriorates in the third trimester (as performed in the reported case).
Genetic counseling: Standard autosomal recessive counseling — 25% recurrence risk for full siblings of an affected proband, carrier risk assessment for extended family, with special attention to the high carrier frequency of the FCMD founder allele in Japanese populations.

14. Other Species / Natural Disease

No naturally occurring FKTN-associated dilated cardiomyopathy has been reported in companion animals or wildlife (OMIA search not specifically performed for FKTN homologs in this pass, but no domestic-animal disease literature surfaced organically in this search).
Orthologous gene: Mouse Fktn (MGI:2179507), used extensively in engineered knockout/conditional-knockout models (see below) — this is the primary comparative-biology resource, not a naturally occurring veterinary disease.

15. Model Organisms

Mouse models

Cardiac-specific Fktn conditional/constitutive knockout mice — the key model system for CMD1X mechanism, described in "Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure" (Nat Commun 2019, PMID:31848331):
Constitutive cardiac Fktn elimination: markedly reduced α-DG glycosylation and DGC protein content at the sarcolemma at all developmental stages, but cardiac dysfunction manifests only in later adulthood — indicating membrane fragility alone is insufficient for the phenotype
Young-adult Fktn-deficient hearts: increased vulnerability to pathological hypertrophic stress, with downregulated Akt signaling and disrupted MEF2-HDAC transcriptional axis
Acute/inducible Fktn elimination in adult hearts: severe cardiac dysfunction and accelerated mortality, myocyte contractile dysfunction, disordered Golgi-microtubule networks
FKRP P448L mutant mice (a related dystroglycanopathy gene in the same pathway) — model progressive dystrophic pathology in diaphragm and impaired cardiac function, useful as a comparative dystroglycanopathy-cardiac model (PMC5053477)

Model Characteristics

Phenotype recapitulation: The mouse cardiac-specific knockout models faithfully reproduce the biochemical lesion (α-DG hypoglycosylation, DGC reduction) and capture a genuinely age-dependent, stress-sensitized cardiac dysfunction pattern broadly consistent with the human disease's variable-onset, stress-precipitated course (e.g., pregnancy).
Model limitations: The mouse constitutive/acute knockouts represent essentially complete loss of Fktn function, which more closely models the severe end of the FKTN allelic spectrum (Fukuyama/Walker-Warburg-type null combinations) rather than the specific hypomorphic compound-heterozygous genotype that produces the human CMD1X phenotype (cardiac-predominant, skeletal-muscle-sparing). This is a meaningful human-model fidelity gap: no current mouse model precisely recapitulates the tissue-selective (cardiac >> skeletal) vulnerability that defines CMD1X, since the knockouts used are typically complete nulls rather than partial-function hypomorphic alleles. This gap would be well-suited to a HUMAN_MODEL_MISMATCH discussion in a curated entry, since the mouse data support the general FKTN-cardiac-dysfunction mechanism (Akt/MEF2-HDAC pathway) but cannot yet explain the specific cardiac-vs-skeletal tissue dissociation central to the human phenotype.
Applications: These models have been used to dissect the relative contributions of membrane-fragility versus stress-signaling mechanisms in dystroglycanopathy-associated cardiomyopathy, and to identify the Akt/MEF2-HDAC axis as a candidate therapeutic target.

Resources

Mouse Genome Informatics: Fktn, MGI:2179507.

Summary Table of Suggested Ontology Bindings

Concept	Suggested term
Disease	MONDO:0012704 (Dilated cardiomyopathy 1X)
Gene	HGNC:3622 (FKTN)
Dilated cardiomyopathy phenotype	HP:0001635
Elevated CK	HP:0003236
Limb-girdle muscle weakness	HP:0003749
Cardiac muscle cell	CL:0000746
Heart	UBERON:0000948
Golgi apparatus (site of enzymatic defect)	GO:0005794
Protein O-linked mannosylation / glycosylation	GO:0035269 / GO:0006486
Organ transplantation (treatment)	NCIT:C15289
Pharmacotherapy (general)	NCIT:C15986

Notes on Evidence Gaps for Curation

No large cohort/registry data exist — all clinical characterization derives from case reports/small series (n≤6), so frequency/percentage-type claims (e.g., "X% have limb-girdle weakness") cannot be well supported and should be phrased qualitatively per the source language ("mild or no," "minimal").
Carrier frequency figure for the Japanese FCMD founder allele needs primary-source verification before inclusion in a KB entry (a commonly cited ~1/90 figure was not independently re-confirmed in this pass).
Human-model mismatch: mouse Fktn cardiac knockout models are complete nulls and do not recapitulate the hypomorphic, tissue-selective human CMD1X genotype-phenotype relationship — flag explicitly if citing the Nat Commun 2019 mouse mechanism data to support human pathophysiology claims.
Nomenclature disambiguation is critical: "CMD1X"/FKTN (autosomal recessive, chr9) must not be conflated with "X-linked dilated cardiomyopathy"/DMD (X-linked, Xp21, OMIM CMD3B #302045) — both terms appear interchangeably in search indices and even in some secondary literature, but they are genetically and mechanistically distinct entities.

Sources

Entry - #611615 - CARDIOMYOPATHY, DILATED, 1X; CMD1X - OMIM
Dilated cardiomyopathy 1X - NIH Genetic Testing Registry (GTR) - NCBI
Murakami T, et al. "Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness." Ann Neurol 2006;60(5):597-602. PubMed PMID:17036286
Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern - PMC9223741
A case of pregnancy complicated with dilated cardiomyopathy 1X - PMC4630494 / Oxford Medical Case Reports
Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure - Nature Communications (PMID:31848331)
ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan - Nature Communications (PMID:27194101)
Entry - *607440 - FUKUTIN; FKTN - OMIM
Entry - #253800 - MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 4; MDDGA4 - OMIM
Entry - #611588 - MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 4; MDDGC4 - OMIM
Fukuyama Congenital Muscular Dystrophy - GeneReviews - NCBI Bookshelf
Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan - Journal of Human Genetics
Dilated Cardiomyopathy and Later Onset Limb-Girdle Muscular Dystrophy Associated With Fukutin and Lamin A/C Mutations - JACC: Case Reports
Fukuyama Congenital Muscular Dystrophy via the FKTN Japanese Founder Mutation Test - PreventionGenetics
Progressive Dystrophic Pathology in Diaphragm and Impairment of Cardiac Function in FKRP P448L Mutant Mice - PMC5053477
Fktn MGI Mouse Gene Detail - MGI:2179507
X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy - PMC4491663 (context/disambiguation source for CMD3B/DMD-related XLDC, distinct from CMD1X)
Dilated Cardiomyopathy (DCM) Guidelines — Medscape: 2022 ACC/AHA/HFSA, 2023 ESC Cardiomyopathies
Current Management and Treatment - Dilated Cardiomyopathy - NCBI Bookshelf

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	8
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	25
Resolved	21
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	3
Terms whose name was checked	14
Terms named correctly	3
Terms named as a different term	4
Terms whose name is worth a second look	7

Terms the report names something else

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

MONDO:0012704 (2 mentions) - the report calls it "MONDO", "Dilated cardiomyopathy 1X"; MONDO calls it dilated cardiomyopathy 1X
HP:0001635 (4 mentions) - the report calls it "Dilated cardiomyopathy", "Dilated cardiomyopathy phenotype"; HP calls it Congestive heart failure
HP:0001639 (1 mention) - the report calls it "Hypertrophic cardiomyopathy — not applicable here but relevant to FKTN mutational screens that included HCM cohorts"; HP calls it Hypertrophic cardiomyopathy
HP:0001636 (1 mention) - the report calls it "Tachycardia"; HP calls it Tetralogy of Fallot

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006486 (obsolete protein glycosylation) (2 mentions) - replaced by GO:0009101

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0003749 (3 mentions) - the report calls it "Limb-girdle muscle weakness"; HP calls it Pelvic girdle muscle weakness, and lists "Hip girdle muscle weakness" among its other names
HP:0003236 (3 mentions) - the report calls it "Elevated CK"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated serum CPK" among its other names
HP:0001644 (1 mention) - the report calls it "Dilated cardiomyopathy — note overlapping codes across HPO releases"; HP calls it Dilated cardiomyopathy
CL:0000746 (3 mentions) - the report calls it "Cardiomyocytes", "Cardiac muscle cell"; CL calls it cardiac muscle cell, and lists "cardiomyocyte" among its other names
GO:0005794 (2 mentions) - the report calls it "Golgi apparatus (site of enzymatic defect)"; GO calls it Golgi apparatus
NCIT:C15986 (2 mentions) - the report calls it "Pharmacotherapy", "Pharmacotherapy (general)"; NCIT calls it Pharmacotherapy
NCIT:C15289 (2 mentions) - the report calls it "Organ Transplantation", "Organ transplantation (treatment)"; NCIT calls it Organ Transplantation

Terms named inconsistently

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

MONDO:0012704 - called "MONDO", "Dilated cardiomyopathy 1X"
HP:0001635 - called "Dilated cardiomyopathy", "Dilated cardiomyopathy phenotype"
CL:0000746 - called "Cardiomyocytes", "Cardiac muscle cell"
NCIT:C15986 - called "Pharmacotherapy", "Pharmacotherapy (general)"
NCIT:C15289 - called "Organ Transplantation", "Organ transplantation (treatment)"
MGI:2179507 - called "Fktn", "Orthologous gene*: Mouse Fktn"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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Dilated Cardiomyopathy 1X (CMD1X): Comprehensive Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms

Evidence basis

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental / Non-genetic Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Cardiac phenotype (primary)

Skeletal muscle phenotype (minimal/mild — defining feature distinguishing CMD1X from the rest of the FKTN spectrum)

CNS/cognitive phenotype

Phenotype characteristics

Quality of life impact

4. Genetic/Molecular Information

Causal Gene

Pathogenic Variants

Modifier Genes

Molecular Pathway Context

Chromosomal Abnormalities

Epigenetic Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Molecular Pathways

Cellular Processes

Protein Dysfunction

Tissue Damage Mechanisms

Cell types and biological processes involved

Molecular Profiling / Advanced Technologies

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Population Demographics

10. Diagnostics

Clinical Tests

Genetic Testing

Clinical Criteria

Screening

11. Outcome/Prognosis

12. Treatment

Pharmacotherapy

Device Therapy

Advanced Therapeutics / Surgical

Supportive Care

Experimental

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mouse models