Multiminicore Disease

Mendelian MONDO:0018948 Pathograph 5 Show in embeddings browser

Multiminicore disease (MmD), also called multi-minicore disease, minicore myopathy, or multicore myopathy, is a genetically heterogeneous, recessively inherited congenital myopathy defined by the presence of multiple "minicores" on skeletal muscle biopsy. Minicores are multifocal, well-circumscribed areas of reduced oxidative enzyme activity that extend only a short distance along the longitudinal axis of the muscle fiber and show sarcomeric disorganization with a paucity of mitochondria on electron microscopy. The classic phenotype is characterized by a clinical triad of axial muscle weakness, spinal rigidity with early scoliosis, and respiratory impairment that is often disproportionate to limb weakness. MmD is most commonly caused by biallelic variants in SELENON (SEPN1), which underlie the classic rigid-spine / respiratory phenotype, and in RYR1, which underlie a broader phenotypic spectrum that frequently includes external ophthalmoplegia and overlaps histologically with central core disease. Rarer cases are associated with TTN and MYH7.

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5
Pathophys.
12
Phenotypes
5
Pathograph
4
Genes
7
Medical Actions
3
Subtypes
1
Trials
2
References
1
Deep Research
◆

Subtypes

3
SELENON (SEPN1)-related, classic MmD
Autosomal recessive inheritance
The classic multiminicore phenotype caused by biallelic SELENON (SEPN1) variants. It is the most instantly recognizable form, characterized by early axial weakness, spinal rigidity, early-onset scoliosis and severe respiratory insufficiency that is disproportionate to relatively preserved limb strength. Multi-minicores are the most common biopsy lesion. This is the form historically equated with "rigid spine muscular dystrophy" (RSMD1).
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene"
Jungbluth review defines the classic SELENON/SEPN1-related MmD subtype.
RYR1-related, ophthalmoplegic / CCD-overlap MmD
Autosomal recessive inheritance Autosomal dominant inheritance
A clinically broader multiminicore form caused (most often recessively) by RYR1 variants. It encompasses a wider range of features including external ophthalmoplegia, distal weakness and wasting, or predominant hip-girdle involvement resembling central core disease (CCD). There may be a histopathologic continuum with CCD due to dominant RYR1 mutations. Malignant hyperthermia susceptibility is an important anesthetic consideration in RYR1-associated disease.
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD)"
Jungbluth review defines the RYR1-related MmD subtype with its broader phenotype and ophthalmoplegia.
Other rare genetic forms (TTN, MYH7)
A small minority of multiminicore / multicore myopathy cases are associated with variants in other sarcomeric or contractile-apparatus genes, principally TTN (titin) and MYH7 (beta-myosin heavy chain). These are far less common than SELENON- and RYR1-related disease.
⚙

Pathophysiology

5
SELENON loss of function
Biallelic SELENON (SEPN1) variants cause loss of functional selenoprotein N (SelN), a redox-active selenoprotein resident in the endoplasmic reticulum (ER) / sarcoplasmic reticulum (SR) membrane. SelN participates in oxidative and calcium homeostasis and is implicated in regulation of the ryanodine receptor. Loss of SelN is the initiating molecular lesion in the classic rigid-spine / respiratory form of MmD.
Skeletal muscle fiber CL:0000188 Skeletal muscle satellite cell CL:0000594
ER calcium and redox regulation GO:0055074
Downstream
ER stress and oxidative dysregulation Loss of SelN dysregulates ER redox state and calcium handling, leading to ER stress and oxidative stress in muscle.
Show evidence (3 references)
PMID:22527882 SUPPORT Human Clinical
"Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1-related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and..."
Castets review establishes SelN deficiency as the cause of the SEPN1-related myopathy spectrum including classic MmD features.
PMID:22527882 SUPPORT Other
"SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity"
Establishes the redox- and calcium-handling role of SelN, including ryanodine receptor regulation.
PMID:22527882 SUPPORT Model Organism
"SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans"
Supports involvement of satellite cells in SELENON-related muscle pathology.
ER stress and oxidative dysregulation
SelN deficiency dysregulates ER redox state and calcium handling. SEPN1 interacts with the ER-stress-induced oxidoreductase ERO1A; both are enriched in mitochondria-associated membranes (MAMs) and govern redox regulation of proteins. Loss of SEPN1 produces ER stress, perturbed ER calcium, and impaired ER-mitochondria coupling, with ERO1A overexpression observed in patient muscle biopsies.
Endoplasmic reticulum unfolded protein response GO:0030968 Response to oxidative stress GO:0006979
Downstream
Mitochondrial bioenergetic defect and muscle weakness ER stress and disrupted MAM/calcium homeostasis impair mitochondrial bioenergetics, contributing to muscle weakness, especially of the diaphragm.
Show evidence (2 references)
PMID:38402623 SUPPORT In Vitro
"Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins."
Germani et al. establish the SEPN1-ERO1A interaction in ER redox regulation.
PMID:38402623 SUPPORT Human Clinical
"muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression"
Demonstrates ERO1A overexpression in patient muscle, linking ER stress to human disease.
Mitochondrial bioenergetic defect and muscle weakness
Impaired ER-mitochondria coupling and disrupted MAM/calcium homeostasis in SELENON-related disease compromise mitochondrial bioenergetics in muscle. TUDCA, which rescues the SEPN1-null phenotype, improves bioenergetics in patient-derived primary myoblasts, supporting a bioenergetic defect as an intermediary that converges with RYR1-related disease on the common minicore lesion.
Skeletal muscle fiber CL:0000188
Mitochondrial ATP synthesis-coupled electron transport GO:0042775 ↓ DECREASED
Downstream
Minicore formation and oxidative depletion Bioenergetic compromise and disrupted oxidative metabolism contribute to focal loss of oxidative enzyme activity and mitochondrial paucity (minicores), converging with the RYR1-related pathway.
Show evidence (1 reference)
PMID:38402623 SUPPORT In Vitro
"TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics"
Germani et al. show the ER-stress inhibitor TUDCA improves mitochondrial bioenergetics in patient-derived myoblasts, supporting a bioenergetic defect downstream of SEPN1-related ER stress.
RYR1 dysfunction and abnormal SR calcium release
RYR1 encodes the type 1 ryanodine receptor (RyR1), the sarcoplasmic reticulum calcium release channel that mediates excitation-contraction coupling in skeletal muscle. In RYR1-related MmD, RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, loss of RyR1-calstabin1 association, and oxidative stress disrupt calcium homeostasis. This abnormal SR calcium handling is thought to drive core/minicore formation with focal loss of oxidative activity and mitochondrial depletion.
Skeletal muscle fiber CL:0000188
SR calcium ion release GO:0014808 ↕ DYSREGULATED Skeletal muscle contraction GO:0003009 ↓ DECREASED
Downstream
Minicore formation and oxidative depletion Abnormal SR calcium release produces focal areas of reduced oxidative enzyme activity and mitochondrial paucity (minicores).
Show evidence (3 references)
PMID:38318125 SUPPORT Human Clinical
"RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis."
Todd et al. summarize the RyR1 calcium-handling defects underlying RYR1-related myopathy pathogenesis.
PMID:38318125 SUPPORT Human Clinical
"Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies"
Documents SR calcium leak and altered channel regulation in RYR1-RM patient muscle.
PMID:17631035 SUPPORT Human Clinical
"Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis"
Jungbluth review attributes RYR1-related MmD to altered excitability and calcium homeostasis.
Minicore formation and oxidative depletion
The histopathologic hallmark of MmD is the minicore: multifocal, well-circumscribed areas of reduced oxidative staining that extend only a short distance along the longitudinal axis of the fiber and show myofibrillar disruption and a paucity of mitochondria on electron microscopy. Both SELENON- and RYR1-related disease converge on this lesion, which is the common diagnostic substrate of the disease.
Oxidative phosphorylation GO:0006119 ↓ DECREASED
Show evidence (2 references)
PMID:17631035 SUPPORT Human Clinical
"characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy"
Defines the minicore-on-biopsy hallmark that characterizes MmD as a congenital myopathy.
PMID:17365175 SUPPORT Human Clinical
"characterized by the presence of small cores or areas lacking oxidative enzymes, in skeletal muscle fibres"
Zorzato review describes the oxidative-enzyme-depleted minicore lesion in muscle fibers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Multiminicore Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Metabolism 1
Malignant hyperthermia susceptibility Malignant hyperthermia HP:0002047
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"the possibility of malignant hyperthermia susceptibility in RYR1-related forms"
Jungbluth review identifies MH susceptibility as an anesthetic risk requiring management in RYR1-related MmD.
Musculoskeletal 4
Spinal rigidity VERY_FREQUENT Spinal rigidity HP:0003306
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment"
Jungbluth review identifies spinal rigidity as a defining feature of classic MmD.
Scoliosis VERY_FREQUENT Scoliosis HP:0002650
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:32796131 SUPPORT Human Clinical
"spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years)"
Villar-Quiles cohort quantifies scoliosis frequency (86.1%) supporting VERY_FREQUENT.
Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:17631035 PARTIAL Human Clinical
"multiple cores on muscle biopsy and clinical features of a congenital myopathy"
Indirect citation. The Jungbluth review establishes MmD as a congenital myopathy; hypotonia is the characteristic early manifestation of this disease class but is not named verbatim in the cited abstract, so this evidence supports hypotonia only inferentially via the congenital-myopathy classification.
Reduced bone mineral density VERY_FREQUENT Reduced bone mineral density HP:0004349
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures"
Bouman study quantifies reduced BMD in 80% of SELENON-RM patients.
Respiratory 1
Respiratory insufficiency VERY_FREQUENT Respiratory insufficiency HP:0002093
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:32796131 SUPPORT Human Clinical
"All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant."
Villar-Quiles cohort documents universal respiratory failure, supporting VERY_FREQUENT.
Constitutional 1
Fatigue Fatigue HP:0012378
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"Questionnaires revealed impaired quality of life, pain and problematic fatigue."
Bouman study documents problematic fatigue as a prominent patient-reported symptom.
Other 5
Axial muscle weakness VERY_FREQUENT Axial muscle weakness HP:0003327
Show evidence (1 reference)
PMID:32796131 SUPPORT Human Clinical
"The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis"
Villar-Quiles cohort (n=132) confirms severe axial weakness as a marked feature.
Nocturnal hypoventilation Nocturnal hypoventilation HP:0002877
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age."
Bouman cross-sectional study documents age-independent diaphragm/respiratory impairment underlying nocturnal hypoventilation.
External ophthalmoplegia Ophthalmoplegia HP:0000602
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia"
Jungbluth review links external ophthalmoplegia to RYR1-related MmD.
Minicores on muscle biopsy VERY_FREQUENT Minicore myopathy HP:0003789
Show evidence (1 reference)
PMID:32796131 SUPPORT Human Clinical
"Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions."
Villar-Quiles cohort confirms multi-minicores as the predominant biopsy lesion.
Subclinical cardiac abnormalities VERY_FREQUENT Abnormal EKG HP:0003115
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%"
Bouman cross-sectional study documents subclinical cardiac dysfunction (impaired LV GLS 43%, QRS fragmentation 80%) in SELENON-RM; authors recommend routine cardiorespiratory surveillance.
🧬

Genetic Associations

4
SELENON (Causative)
Gene: SELENON hgnc:15999
Autosomal recessive
Show evidence (2 references)
PMID:32796131 SUPPORT Human Clinical
"Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017)."
Villar-Quiles cohort establishes the SEPN1 mutational spectrum and genotype-phenotype correlation.
PMID:17631035 SUPPORT Human Clinical
"is due to recessive mutations in the selenoprotein N (SEPN1) gene"
Jungbluth review confirms recessive SEPN1 mutations cause the classic phenotype.
RYR1 (Causative)
Gene: RYR1 hgnc:10483
Autosomal recessive Autosomal dominant
Show evidence (2 references)
PMID:17631035 SUPPORT Human Clinical
"recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features"
Jungbluth review confirms recessive RYR1 mutations cause the broader MmD spectrum.
PMID:17631035 SUPPORT Human Clinical
"there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background"
Documents dominant RYR1 mutations and the CCD histopathologic continuum.
TTN (Causative)
Gene: TTN hgnc:12403
MYH7 (Causative)
Gene: MYH7 hgnc:7577
💊

Medical Actions

7
Noninvasive ventilation
Action: noninvasive ventilation MAXO:0000506
Nocturnal and later daytime noninvasive ventilation is a mainstay of supportive care given near-universal respiratory failure, often required while patients are still ambulant. Respiratory impairment is the most important prognostic factor.
Show evidence (2 references)
PMID:32796131 SUPPORT Human Clinical
"All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant."
Villar-Quiles cohort documents the need for assisted ventilation, supporting noninvasive ventilation as standard care.
PMID:17631035 SUPPORT Human Clinical
"Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD"
Jungbluth review establishes supportive respiratory management as the core of treatment.
Scoliosis / spinal surgery
Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Scoliosis is frequent and often progressive; spinal stabilization surgery (arthrodesis) is commonly performed in adolescence to stabilize scoliosis.
Show evidence (1 reference)
PMID:32796131 SUPPORT Human Clinical
"spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years)"
High frequency of early progressive scoliosis underpins the need for orthopedic/spinal surgical management.
Physical therapy and rehabilitation
Action: physical therapy MAXO:0000011
Rehabilitation and physical therapy, alongside interventions targeting pain and fatigue, are recommended to support function and quality of life.
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"We recommend management interventions to reduce pain and fatigue."
Bouman study recommends management interventions for pain and fatigue, including rehabilitation.
Bone health management
Action: vitamin D supplementation MAXO:0000110
Given frequent low bone mineral density and fragility fractures in SELENON-related myopathy, vitamin D supplementation and optimization of calcium intake are recommended.
Show evidence (1 reference)
PMID:37807786 SUPPORT Human Clinical
"we advise vitamin D supplementation and optimization of calcium intake to improve bone quality"
Bouman study explicitly recommends vitamin D supplementation and calcium optimization.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling and cascade testing are recommended after molecular diagnosis, given the predominantly autosomal recessive inheritance.
Show evidence (1 reference)
PMID:17631035 SUPPORT Human Clinical
"Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis"
Jungbluth review establishes molecular genetic testing of RYR1/SEPN1 as central to MmD diagnostic confirmation, supporting genetic counseling and cascade testing.
TUDCA (investigational, SELENON-related)
Action: Pharmacotherapy NCIT:C15986
Agent: tauroursodeoxycholic acid CHEBI:80774
Tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor / chemical chaperone, is an investigational candidate for SEPN1-related myopathy. In SEPN1 knockout mice it mirrored the rescue seen with ERO1A loss, and it improved bioenergetics in patient-derived primary myoblasts. Not an approved therapy.
Show evidence (2 references)
PMID:38402623 SUPPORT Model Organism
"The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss."
Germani et al. show TUDCA rescue in SEPN1 knockout mice, supporting it as an investigational candidate.
PMID:38402623 PARTIAL In Vitro
"TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics"
Patient-derived myoblast data support TUDCA's bioenergetic effect; human clinical efficacy not yet demonstrated.
ARM210 / Rycal S48168 (investigational, RYR1-related)
Action: Pharmacotherapy NCIT:C15986
ARM210 (Rycal S48168) is an investigational RyR1-stabilizing compound for RYR1-related myopathies. A phase 1, open-label, dose-escalation trial (NCT04141670) found it well tolerated over 29 days with exploratory improvements in fatigue and proximal strength at 200 mg/day. Not an approved therapy.
Show evidence (2 references)
PMID:38318125 SUPPORT Human Clinical
"S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile."
Todd et al. phase 1 trial demonstrates ARM210 safety and tolerability in RYR1-RM patients.
PMID:38318125 PARTIAL Human Clinical
"Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination."
Exploratory efficacy signals at 200 mg/day, supporting further controlled trials but not definitive efficacy.
🔬

Clinical Trials

1
NCT04141670 PHASE_I COMPLETED
First-in-patient, open-label, dose-escalation trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-related myopathies, evaluating safety, tolerability, pharmacokinetics, and exploratory motor and fatigue endpoints.
Target Phenotypes: Fatigue HP:0012378 Proximal muscle weakness HP:0003701
Show evidence (1 reference)
PMID:38318125 SUPPORT Human Clinical
"The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021."
Confirms NCT04141670 as the registered phase 1 ARM210 trial in RYR1-related myopathy.
{ }

Source YAML

click to show 
name: Multiminicore Disease
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
  Multiminicore disease (MmD), also called multi-minicore disease, minicore
  myopathy, or multicore myopathy, is a genetically heterogeneous, recessively
  inherited congenital myopathy defined by the presence of multiple "minicores"
  on skeletal muscle biopsy. Minicores are multifocal, well-circumscribed areas
  of reduced oxidative enzyme activity that extend only a short distance along
  the longitudinal axis of the muscle fiber and show sarcomeric disorganization
  with a paucity of mitochondria on electron microscopy. The classic phenotype
  is characterized by a clinical triad of axial muscle weakness, spinal
  rigidity with early scoliosis, and respiratory impairment that is often
  disproportionate to limb weakness. MmD is most commonly caused by biallelic
  variants in SELENON (SEPN1), which underlie the classic rigid-spine /
  respiratory phenotype, and in RYR1, which underlie a broader phenotypic
  spectrum that frequently includes external ophthalmoplegia and overlaps
  histologically with central core disease. Rarer cases are associated with
  TTN and MYH7.
disease_term:
  preferred_term: Multiminicore Disease
  term:
    id: MONDO:0018948
    label: multiminicore myopathy

references:
  - reference: PMID:17631035
    title: "Multi-minicore Disease."
  - reference: PMID:22009146
    title: "Clinical utility gene card for: Multi-minicore disease."

has_subtypes:
- name: SELENON
  display_name: SELENON (SEPN1)-related, classic MmD
  description: >
    The classic multiminicore phenotype caused by biallelic SELENON (SEPN1)
    variants. It is the most instantly recognizable form, characterized by
    early axial weakness, spinal rigidity, early-onset scoliosis and severe
    respiratory insufficiency that is disproportionate to relatively preserved
    limb strength. Multi-minicores are the most common biopsy lesion. This is
    the form historically equated with "rigid spine muscular dystrophy" (RSMD1).
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene"
    explanation: Jungbluth review defines the classic SELENON/SEPN1-related MmD subtype.
- name: RYR1
  display_name: RYR1-related, ophthalmoplegic / CCD-overlap MmD
  description: >
    A clinically broader multiminicore form caused (most often recessively) by
    RYR1 variants. It encompasses a wider range of features including external
    ophthalmoplegia, distal weakness and wasting, or predominant hip-girdle
    involvement resembling central core disease (CCD). There may be a
    histopathologic continuum with CCD due to dominant RYR1 mutations.
    Malignant hyperthermia susceptibility is an important anesthetic
    consideration in RYR1-associated disease.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD)"
    explanation: Jungbluth review defines the RYR1-related MmD subtype with its broader phenotype and ophthalmoplegia.
- name: Other
  display_name: Other rare genetic forms (TTN, MYH7)
  description: >
    A small minority of multiminicore / multicore myopathy cases are associated
    with variants in other sarcomeric or contractile-apparatus genes,
    principally TTN (titin) and MYH7 (beta-myosin heavy chain). These are far
    less common than SELENON- and RYR1-related disease.

pathophysiology:
- name: SELENON loss of function
  description: >
    Biallelic SELENON (SEPN1) variants cause loss of functional selenoprotein N
    (SelN), a redox-active selenoprotein resident in the endoplasmic reticulum
    (ER) / sarcoplasmic reticulum (SR) membrane. SelN participates in oxidative
    and calcium homeostasis and is implicated in regulation of the ryanodine
    receptor. Loss of SelN is the initiating molecular lesion in the classic
    rigid-spine / respiratory form of MmD.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Skeletal muscle satellite cell
    term:
      id: CL:0000594
      label: skeletal muscle satellite cell
  biological_processes:
  - preferred_term: ER calcium and redox regulation
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  evidence:
  - reference: PMID:22527882
    reference_title: "Selenoprotein N in skeletal muscle: from diseases to function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1-related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency."
    explanation: Castets review establishes SelN deficiency as the cause of the SEPN1-related myopathy spectrum including classic MmD features.
  - reference: PMID:22527882
    reference_title: "Selenoprotein N in skeletal muscle: from diseases to function."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity"
    explanation: Establishes the redox- and calcium-handling role of SelN, including ryanodine receptor regulation.
  - reference: PMID:22527882
    reference_title: "Selenoprotein N in skeletal muscle: from diseases to function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans"
    explanation: Supports involvement of satellite cells in SELENON-related muscle pathology.
  downstream:
  - target: ER stress and oxidative dysregulation
    description: Loss of SelN dysregulates ER redox state and calcium handling, leading to ER stress and oxidative stress in muscle.
    causal_link_type: DIRECT
- name: ER stress and oxidative dysregulation
  description: >
    SelN deficiency dysregulates ER redox state and calcium handling. SEPN1
    interacts with the ER-stress-induced oxidoreductase ERO1A; both are enriched
    in mitochondria-associated membranes (MAMs) and govern redox regulation of
    proteins. Loss of SEPN1 produces ER stress, perturbed ER calcium, and
    impaired ER-mitochondria coupling, with ERO1A overexpression observed in
    patient muscle biopsies.
  biological_processes:
  - preferred_term: Endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  - preferred_term: Response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:38402623
    reference_title: "SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins."
    explanation: Germani et al. establish the SEPN1-ERO1A interaction in ER redox regulation.
  - reference: PMID:38402623
    reference_title: "SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression"
    explanation: Demonstrates ERO1A overexpression in patient muscle, linking ER stress to human disease.
  downstream:
  - target: Mitochondrial bioenergetic defect and muscle weakness
    description: ER stress and disrupted MAM/calcium homeostasis impair mitochondrial bioenergetics, contributing to muscle weakness, especially of the diaphragm.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Mitochondrial bioenergetic defect and muscle weakness
  description: >
    Impaired ER-mitochondria coupling and disrupted MAM/calcium homeostasis in
    SELENON-related disease compromise mitochondrial bioenergetics in muscle.
    TUDCA, which rescues the SEPN1-null phenotype, improves bioenergetics in
    patient-derived primary myoblasts, supporting a bioenergetic defect as an
    intermediary that converges with RYR1-related disease on the common minicore
    lesion.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Mitochondrial ATP synthesis-coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:38402623
    reference_title: "SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics"
    explanation: Germani et al. show the ER-stress inhibitor TUDCA improves mitochondrial bioenergetics in patient-derived myoblasts, supporting a bioenergetic defect downstream of SEPN1-related ER stress.
  downstream:
  - target: Minicore formation and oxidative depletion
    description: Bioenergetic compromise and disrupted oxidative metabolism contribute to focal loss of oxidative enzyme activity and mitochondrial paucity (minicores), converging with the RYR1-related pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: RYR1 dysfunction and abnormal SR calcium release
  description: >
    RYR1 encodes the type 1 ryanodine receptor (RyR1), the sarcoplasmic
    reticulum calcium release channel that mediates excitation-contraction
    coupling in skeletal muscle. In RYR1-related MmD, RyR1 sub-conductance,
    SR calcium leak, reduced RyR1 expression, loss of RyR1-calstabin1
    association, and oxidative stress disrupt calcium homeostasis. This abnormal
    SR calcium handling is thought to drive core/minicore formation with focal
    loss of oxidative activity and mitochondrial depletion.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: SR calcium ion release
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DYSREGULATED
  - preferred_term: Skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis."
    explanation: Todd et al. summarize the RyR1 calcium-handling defects underlying RYR1-related myopathy pathogenesis.
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies"
    explanation: Documents SR calcium leak and altered channel regulation in RYR1-RM patient muscle.
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis"
    explanation: Jungbluth review attributes RYR1-related MmD to altered excitability and calcium homeostasis.
  downstream:
  - target: Minicore formation and oxidative depletion
    description: Abnormal SR calcium release produces focal areas of reduced oxidative enzyme activity and mitochondrial paucity (minicores).
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Minicore formation and oxidative depletion
  description: >
    The histopathologic hallmark of MmD is the minicore: multifocal,
    well-circumscribed areas of reduced oxidative staining that extend only a
    short distance along the longitudinal axis of the fiber and show myofibrillar
    disruption and a paucity of mitochondria on electron microscopy. Both
    SELENON- and RYR1-related disease converge on this lesion, which is the
    common diagnostic substrate of the disease.
  biological_processes:
  - preferred_term: Oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy"
    explanation: Defines the minicore-on-biopsy hallmark that characterizes MmD as a congenital myopathy.
  - reference: PMID:17365175
    reference_title: "Functional effects of mutations identified in patients with multiminicore disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by the presence of small cores or areas lacking oxidative enzymes, in skeletal muscle fibres"
    explanation: Zorzato review describes the oxidative-enzyme-depleted minicore lesion in muscle fibers.

phenotypes:
- name: Axial muscle weakness
  category: Phenotypic
  description: >
    Marked weakness of axial (trunk and neck) muscles is a defining feature of
    classic MmD, typically disproportionate to relatively preserved limb
    strength.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis"
    explanation: Villar-Quiles cohort (n=132) confirms severe axial weakness as a marked feature.
- name: Spinal rigidity
  category: Phenotypic
  description: >
    Rigidity of the spine with limitation of spinal flexion is a hallmark of the
    classic SELENON-related form ("rigid spine" phenotype), typically of early
    onset.
  phenotype_term:
    preferred_term: Spinal rigidity
    term:
      id: HP:0003306
      label: Spinal rigidity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment"
    explanation: Jungbluth review identifies spinal rigidity as a defining feature of classic MmD.
- name: Scoliosis
  category: Phenotypic
  description: >
    Early-onset, frequently progressive scoliosis is common, often requiring
    spinal stabilization surgery in adolescence. In the SEPN1 cohort it occurred
    in 86.1% with a mean onset of 8.9 years.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years)"
    explanation: Villar-Quiles cohort quantifies scoliosis frequency (86.1%) supporting VERY_FREQUENT.
- name: Respiratory insufficiency
  category: Phenotypic
  description: >
    Respiratory impairment is a major determinant of morbidity and prognosis and
    is often disproportionate to limb weakness. In the SEPN1 cohort all patients
    developed respiratory failure (from 10.1 years), with 81.7% requiring
    ventilation while still ambulant.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant."
    explanation: Villar-Quiles cohort documents universal respiratory failure, supporting VERY_FREQUENT.
- name: Nocturnal hypoventilation
  category: Phenotypic
  description: >
    Respiratory impairment frequently manifests first as nocturnal
    hypoventilation, detected by polysomnography, before overt daytime
    respiratory failure. Diaphragm dysfunction is prominent across all ages.
  phenotype_term:
    preferred_term: Nocturnal hypoventilation
    term:
      id: HP:0002877
      label: Nocturnal hypoventilation
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age."
    explanation: Bouman cross-sectional study documents age-independent diaphragm/respiratory impairment underlying nocturnal hypoventilation.
- name: Hypotonia
  category: Phenotypic
  description: >
    Generalized hypotonia is a typical early presenting feature of this
    congenital myopathy, often noted in infancy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple cores on muscle biopsy and clinical features of a congenital myopathy"
    explanation: Indirect citation. The Jungbluth review establishes MmD as a congenital myopathy; hypotonia is the characteristic early manifestation of this disease class but is not named verbatim in the cited abstract, so this evidence supports hypotonia only inferentially via the congenital-myopathy classification.
- name: External ophthalmoplegia
  category: Phenotypic
  subtype: RYR1
  description: >
    External ophthalmoplegia (ophthalmoparesis) is a characteristic feature of
    the RYR1-related form of MmD and helps distinguish it from the classic
    SELENON-related phenotype.
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia"
    explanation: Jungbluth review links external ophthalmoplegia to RYR1-related MmD.
- name: Malignant hyperthermia susceptibility
  category: Phenotypic
  subtype: RYR1
  description: >
    RYR1-related multiminicore disease carries a risk of malignant hyperthermia
    susceptibility (MHS), an important anesthetic consideration. Volatile
    anesthetic agents and depolarizing muscle relaxants should be avoided, and
    patients and families should be counseled about this risk before any
    surgical procedure.
  phenotype_term:
    preferred_term: Malignant hyperthermia susceptibility
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the possibility of malignant hyperthermia susceptibility in RYR1-related forms"
    explanation: Jungbluth review identifies MH susceptibility as an anesthetic risk requiring management in RYR1-related MmD.
- name: Minicores on muscle biopsy
  category: Histopathologic
  description: >
    Multiple minicores on skeletal muscle biopsy are the defining pathologic
    feature: multifocal areas of reduced oxidative enzyme activity with
    sarcomeric disruption and mitochondrial paucity. Multi-minicores were the
    most common lesion (59.5%) in the SEPN1 cohort.
  phenotype_term:
    preferred_term: Minicore myopathy
    term:
      id: HP:0003789
      label: Minicore myopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions."
    explanation: Villar-Quiles cohort confirms multi-minicores as the predominant biopsy lesion.
- name: Reduced bone mineral density
  category: Phenotypic
  subtype: SELENON
  description: >
    Decreased bone mineral density is common in SELENON-related myopathy, with
    associated fragility long-bone fractures, supporting routine bone-health
    surveillance.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures"
    explanation: Bouman study quantifies reduced BMD in 80% of SELENON-RM patients.
- name: Fatigue
  category: Phenotypic
  subtype: SELENON
  description: >
    Problematic fatigue, alongside pain and impaired quality of life, was a
    prominent patient-reported outcome in SELENON-related myopathy.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Questionnaires revealed impaired quality of life, pain and problematic fatigue."
    explanation: Bouman study documents problematic fatigue as a prominent patient-reported symptom.
- name: Subclinical cardiac abnormalities
  category: Phenotypic
  subtype: SELENON
  description: >
    Despite preserved left ventricular systolic ejection fraction, subclinical
    cardiac dysfunction is common in SELENON-related myopathy: abnormal LV global
    longitudinal strain in 43% of patients and QRS fragmentation in 80% on
    electrocardiography. Routine cardiorespiratory follow-up is recommended for
    all patients.
  phenotype_term:
    preferred_term: Abnormal EKG
    term:
      id: HP:0003115
      label: Abnormal EKG
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%"
    explanation: Bouman cross-sectional study documents subclinical cardiac dysfunction (impaired LV GLS 43%, QRS fragmentation 80%) in SELENON-RM; authors recommend routine cardiorespiratory surveillance.

genetic:
- name: SELENON
  gene_term:
    preferred_term: SELENON
    term:
      id: hgnc:15999
      label: SELENON
  association: Causative
  subtype: SELENON
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >
    Biallelic SELENON (SEPN1) variants cause the classic rigid-spine /
    respiratory form of MmD. In a 132-patient cohort, 65 SEPN1 mutations were
    identified (32 novel, including the first pathogenic copy-number variant),
    with exon 1 as the main mutational hotspot; biallelic null mutations were
    significantly associated with disease severity.
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017)."
    explanation: Villar-Quiles cohort establishes the SEPN1 mutational spectrum and genotype-phenotype correlation.
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is due to recessive mutations in the selenoprotein N (SEPN1) gene"
    explanation: Jungbluth review confirms recessive SEPN1 mutations cause the classic phenotype.
- name: RYR1
  gene_term:
    preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  association: Causative
  subtype: RYR1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >
    RYR1 variants (most often recessive in MmD) cause the broader phenotypic
    form including external ophthalmoplegia and CCD-overlap. A histopathologic
    continuum with central core disease can occur with dominant RYR1 mutations.
    Malignant hyperthermia susceptibility is an important anesthetic risk.
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features"
    explanation: Jungbluth review confirms recessive RYR1 mutations cause the broader MmD spectrum.
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background"
    explanation: Documents dominant RYR1 mutations and the CCD histopathologic continuum.
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  association: Causative
  subtype: Other
  notes: >
    TTN (titin) variants are a rarer cause of multicore/minicore myopathy. Listed
    here as an established but uncommon genetic subtype; specific cohort-level
    evidence within the retrieved deep-research sources was limited.
- name: MYH7
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  association: Causative
  subtype: Other
  notes: >
    MYH7 (beta-myosin heavy chain) variants are a rarer cause of
    multicore/minicore myopathy. Listed here as an established but uncommon
    genetic subtype; specific cohort-level evidence within the retrieved
    deep-research sources was limited.

treatments:
- name: Noninvasive ventilation
  description: >
    Nocturnal and later daytime noninvasive ventilation is a mainstay of
    supportive care given near-universal respiratory failure, often required
    while patients are still ambulant. Respiratory impairment is the most
    important prognostic factor.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: MAXO:0000506
      label: noninvasive ventilation
  therapeutic_modality: DEVICE
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant."
    explanation: Villar-Quiles cohort documents the need for assisted ventilation, supporting noninvasive ventilation as standard care.
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD"
    explanation: Jungbluth review establishes supportive respiratory management as the core of treatment.
- name: Scoliosis / spinal surgery
  description: >
    Scoliosis is frequent and often progressive; spinal stabilization surgery
    (arthrodesis) is commonly performed in adolescence to stabilize scoliosis.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:32796131
    reference_title: "The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years)"
    explanation: High frequency of early progressive scoliosis underpins the need for orthopedic/spinal surgical management.
- name: Physical therapy and rehabilitation
  description: >
    Rehabilitation and physical therapy, alongside interventions targeting pain
    and fatigue, are recommended to support function and quality of life.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend management interventions to reduce pain and fatigue."
    explanation: Bouman study recommends management interventions for pain and fatigue, including rehabilitation.
- name: Bone health management
  description: >
    Given frequent low bone mineral density and fragility fractures in
    SELENON-related myopathy, vitamin D supplementation and optimization of
    calcium intake are recommended.
  treatment_term:
    preferred_term: vitamin D supplementation
    term:
      id: MAXO:0000110
      label: vitamin D supplementation
  evidence:
  - reference: PMID:37807786
    reference_title: "SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we advise vitamin D supplementation and optimization of calcium intake to improve bone quality"
    explanation: Bouman study explicitly recommends vitamin D supplementation and calcium optimization.
- name: Genetic counseling
  description: >
    Genetic counseling and cascade testing are recommended after molecular
    diagnosis, given the predominantly autosomal recessive inheritance.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:17631035
    reference_title: "Multi-minicore Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis"
    explanation: Jungbluth review establishes molecular genetic testing of RYR1/SEPN1 as central to MmD diagnostic confirmation, supporting genetic counseling and cascade testing.
- name: TUDCA (investigational, SELENON-related)
  description: >
    Tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor / chemical
    chaperone, is an investigational candidate for SEPN1-related myopathy. In
    SEPN1 knockout mice it mirrored the rescue seen with ERO1A loss, and it
    improved bioenergetics in patient-derived primary myoblasts. Not an approved
    therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tauroursodeoxycholic acid
      term:
        id: CHEBI:80774
        label: tauroursodeoxycholic acid
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:38402623
    reference_title: "SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss."
    explanation: Germani et al. show TUDCA rescue in SEPN1 knockout mice, supporting it as an investigational candidate.
  - reference: PMID:38402623
    reference_title: "SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics"
    explanation: Patient-derived myoblast data support TUDCA's bioenergetic effect; human clinical efficacy not yet demonstrated.
- name: ARM210 / Rycal S48168 (investigational, RYR1-related)
  description: >
    ARM210 (Rycal S48168) is an investigational RyR1-stabilizing compound for
    RYR1-related myopathies. A phase 1, open-label, dose-escalation trial
    (NCT04141670) found it well tolerated over 29 days with exploratory
    improvements in fatigue and proximal strength at 200 mg/day. Not an approved
    therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile."
    explanation: Todd et al. phase 1 trial demonstrates ARM210 safety and tolerability in RYR1-RM patients.
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination."
    explanation: Exploratory efficacy signals at 200 mg/day, supporting further controlled trials but not definitive efficacy.

clinical_trials:
- name: NCT04141670
  phase: PHASE_I
  status: COMPLETED
  description: >
    First-in-patient, open-label, dose-escalation trial of Rycal S48168 (ARM210)
    in ambulatory adults with genetically confirmed RYR1-related myopathies,
    evaluating safety, tolerability, pharmacokinetics, and exploratory motor and
    fatigue endpoints.
  target_phenotypes:
    - preferred_term: Fatigue
      term:
        id: HP:0012378
        label: Fatigue
    - preferred_term: Proximal muscle weakness
      term:
        id: HP:0003701
        label: Proximal muscle weakness
  evidence:
    - reference: PMID:38318125
      reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021."
      explanation: Confirms NCT04141670 as the registered phase 1 ARM210 trial in RYR1-related myopathy.

datasets: []
📚

References & Deep Research

References

2
PMID:17631035
Multi-minicore Disease.
No top-level findings curated for this source.
PMID:22009146
Clinical utility gene card for: Multi-minicore disease.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Multiminicore Disease (MmD) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 31 citations 2026-06-05T15:39:50.851539

Multiminicore Disease (MmD) — Comprehensive Disease Characteristics Report

Scope note. “Multiminicore disease” is a muscle-biopsy-defined congenital myopathy phenotype characterized by multiple “core-like” lesions (“minicores”) and is genetically heterogeneous; in practice, many modern sources treat classic MmD largely within the spectrum of SELENON (SEPN1)-related myopathy and RYR1-related myopathies. Evidence below therefore covers MmD as a clinicopathologic entity and highlights the two best-supported genetic subtypes. (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 1-2)

1. Disease Information

1.1 Definition and current understanding

Multiminicore disease (MmD) is an inherited congenital myopathy defined by the presence of multiple “minicores” on skeletal muscle biopsy. Minicores are “multifocal, well-circumscribed areas” with reduced oxidative staining that “extend only for a short distance along the longitudinal axis of the muscle,” and on electron microscopy show “myofibrillar disruption and paucity of mitochondria.” (jungbluth2007multiminicoredisease pages 5-7)

The “classic” MmD phenotype is commonly described by the clinical triad of axial weakness, spinal rigidity/early scoliosis, and respiratory impairment (often disproportionate to limb weakness). (jungbluth2007multiminicoredisease pages 2-3, jungbluth2007multiminicoredisease pages 1-2)

1.2 Key identifiers (available from retrieved evidence)

  • OMIM / MIM disease IDs mentioned in retrieved evidence: MmD (MIM #255320); additional MmD-related OMIM numbers listed in a clinical utility gene card: #117000 and #607552. (lillis2012clinicalutilitygene pages 1-2, zorzato2007functionaleffectsof pages 1-3)
  • Gene OMIM IDs mentioned in retrieved evidence:
  • RYR1 (*180901) (lillis2012clinicalutilitygene pages 1-2)
  • SEPN1 / SELENON (*606210) (lillis2012clinicalutilitygene pages 1-2, zorzato2007functionaleffectsof pages 1-3)

Not found in the retrieved sources: MONDO ID, ICD-10/ICD-11 codes, MeSH term IDs, and Orphanet ORPHA identifiers were not explicitly present in the accessible full text excerpts; therefore they cannot be cited here. (jungbluth2007multiminicoredisease pages 1-2, lillis2012clinicalutilitygene pages 1-2)

1.3 Synonyms / alternative names

Synonyms reported include minicore myopathy, multicore myopathy, and minicore myopathy with external ophthalmoplegia (a recognized clinical presentation particularly in RYR1-related disease). (jungbluth2007multiminicoredisease pages 1-2)

1.4 Evidence source type

The information summarized here is derived from aggregated disease-level resources (reviews/gene cards) and aggregated cohorts (international and national observational studies), rather than EHR-only single-center data. (jungbluth2007multiminicoredisease pages 1-2, villarquiles2020theclinicalhistologic pages 1-2, bouman2023selenonrelatedmyopathyacross pages 1-3)

2. Etiology

2.1 Primary causal factors

MmD is primarily a genetic disorder (Mendelian), with major subtypes: - SELENON (SEPN1)-related MmD / SELENON-related myopathy: classically associated with a consistent phenotype including early spinal rigidity/scoliosis and prominent respiratory involvement. (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3) - RYR1-related MmD: phenotypically broader; ophthalmoparesis/external ophthalmoplegia is common; malignant hyperthermia risk is an anesthetic consideration in RYR1-associated disease. (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3)

2.2 Risk factors

  • Genetic risk is driven by biallelic pathogenic variants in causal genes (most often SELENON/SEPN1 for the classic rigid-spine/respiratory phenotype, and RYR1 for other multicore/minicore phenotypes). (jungbluth2007multiminicoredisease pages 2-3, zorzato2007functionaleffectsof pages 1-3)
  • In the largest SEPN1/SELENON cohort (n=132), bi-allelic null mutations were associated with higher disease severity (p=0.017). (villarquiles2020theclinicalhistologic pages 1-2)

Environmental risk factors: no specific toxin/lifestyle exposures were identified as causes in the retrieved primary sources. However, clinical deterioration can be influenced by management-related factors (e.g., untreated nocturnal hypoventilation and scoliosis progression), which act as modifiable determinants of severity. (villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 4-5)

2.3 Protective factors and gene–environment interactions

No specific protective variants or validated environmental protective factors were identified in the retrieved evidence for MmD itself. (villarquiles2020theclinicalhistologic pages 1-2)

3. Phenotypes

3.1 Core phenotype set (classic MmD)

Key phenotype domains (with HPO term suggestions): - Axial muscle weakness (HP:0003323 Axial muscle weakness; also HP:0003798 Neck flexor weakness) (jungbluth2007multiminicoredisease pages 2-3, jungbluth2007multiminicoredisease pages 1-2) - Spinal rigidity / rigid spine (HP:0003301 Rigid spine) (villarquiles2020theclinicalhistologic pages 4-5) - Scoliosis (HP:0002650 Scoliosis) (villarquiles2020theclinicalhistologic pages 4-5) - Respiratory insufficiency / hypoventilation, often nocturnal first (HP:0002093 Respiratory insufficiency; HP:0002872 Sleep-related hypoventilation) (villarquiles2020theclinicalhistologic pages 4-5) - Ophthalmoparesis/external ophthalmoplegia in RYR1-related MmD subgroups (HP:0000602 Ophthalmoplegia) (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 1-2)

3.2 Phenotype frequencies and timing (SELENON/SEPN1 cohort)

In a large international retrospective cohort of 132 individuals with SEPN1/SELENON-related myopathy (age 2–58 years) followed for decades: - Scoliosis occurred in 86.1% (mean onset 8.9 ± 4 years). (villarquiles2020theclinicalhistologic pages 1-2) - Respiratory failure developed in 100% (mean onset 10.1 ± 6 years). (villarquiles2020theclinicalhistologic pages 1-2) - Assisted ventilation was required in 81.9%, often while still ambulant. (villarquiles2020theclinicalhistologic pages 4-5) - Rigid spine was common (~87.8% in one excerpted analysis). (villarquiles2020theclinicalhistologic pages 3-4) - Muscle biopsy: multi-minicores were the most common lesion (59.5%), with variable additional features (mild dystrophic changes; Mallory-like eosinophilic inclusions in 6.3%). (villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 5-7)

Disease severity in this cohort was classified as severe 28.4%, moderate 53.1%, and mild 18.5% (subset with detailed phenotyping). (villarquiles2020theclinicalhistologic pages 7-8)

3.3 Quality of life and symptom burden (recent quantitative data)

A Dutch cross-sectional “trial readiness” study of 11 genetically confirmed SELENON-RM patients (mean age 20±13 years; range 3–42) reported: - Mean MFM-20/32 total score 71.2 ± 15.1% (domain 1—standing/transfers—most affected). (bouman2023selenonrelatedmyopathyacross pages 1-3) - Problematic fatigue, pain, and impaired quality of life were prominent in patient-reported outcomes. (bouman2023selenonrelatedmyopathyacross pages 1-3, bouman2023selenonrelatedmyopathyacross pages 14-16) - Respiratory impairment in all patients with marked diaphragm dysfunction regardless of age. (bouman2023selenonrelatedmyopathyacross pages 1-3)

3.4 Suggested anatomical structures affected (UBERON) and cell types (CL)

  • Primary tissue: skeletal muscle (UBERON:0001134). (jungbluth2007multiminicoredisease pages 5-7)
  • Respiratory muscle involvement, especially diaphragm (UBERON:0001103), is a major determinant of morbidity. (bouman2023selenonrelatedmyopathyacross pages 10-13)
  • Relevant cell type emphasis for mechanism mapping: skeletal muscle fiber / myofiber (CL:0000187) and skeletal muscle satellite cell (CL:0000516; supported indirectly by SelN roles in muscle biology and disease mechanisms). (castets2012selenoproteinnin pages 7-8)

4. Genetic / Molecular Information

4.1 Causal genes (best-supported)

  • SELENON (SEPN1): autosomal recessive; classically associated with the rigid spine–scoliosis–respiratory phenotype of MmD/SELENON-related myopathy. (lillis2012clinicalutilitygene pages 1-2, villarquiles2020theclinicalhistologic pages 1-2)
  • RYR1: autosomal dominant or recessive across the RYR1-related myopathy spectrum; recessive forms commonly underlie MmD presentations and may overlap with central core disease. (jungbluth2007multiminicoredisease pages 2-3, todd2024rycals48168(arm210) pages 1-2)

4.2 Pathogenic variant spectrum and genotype–phenotype

In the SEPN1/SELENON international cohort (n=132), 65 SEPN1 mutations were identified (32 novel), including the first pathogenic copy-number variant, with exon 1 as a mutational hotspot; bi-allelic null variants correlated with greater severity. (villarquiles2020theclinicalhistologic pages 1-2)

4.3 Molecular functions (current mechanistic consensus)

  • SELENON/SelN is an ER/SR-localized, redox-active selenoprotein implicated in regulating oxidative stress and calcium handling, including interaction with ryanodine receptors; SelN deficiency increases oxidative stress in patient cells and reduces RyR function in biochemical assays. (castets2012selenoproteinnin pages 7-8)
  • SEPN1/SELENON is also described as an ER Ca2+-linked redox regulator that can activate SERCA in a redox-dependent manner (mechanistic model discussed in a 2024 thesis-derived excerpt). (germani2024chopero1apathwayof pages 17-21)

5. Environmental Information

No specific infectious triggers or environmental toxic exposures are implicated as primary causes in the retrieved literature. The clinically most relevant “environmental” aspects are perioperative/anesthetic exposures in RYR1-related disease because of malignant hyperthermia susceptibility; anesthetic precautions are recommended in RYR1-associated cases. (jungbluth2007multiminicoredisease pages 2-3)

6. Mechanism / Pathophysiology

6.1 Causal chain (SELENON/SEPN1-related)

A synthesis from mechanistic and translational studies supports this chain: 1. SELENON loss-of-function → dysregulated ER/SR redox and stress responses and impaired regulation of calcium-handling proteins (RyR and SERCA). (castets2012selenoproteinnin pages 7-8, germani2024chopero1apathwayof pages 17-21) 2. Increased ER stress and maladaptive UPR signaling can involve the CHOP/ERO1A axis, with ERO1A upregulation observed in SEPN1-RM models and patient biopsies. (germani2024sepn1relatedmyopathydepends pages 1-3, germani2024chopero1apathwayof pages 68-72) 3. Downstream consequences include impaired ER–mitochondria functional coupling and mitochondrial bioenergetics defects, contributing to muscle weakness and vulnerability of respiratory muscles (especially diaphragm). (germani2024sepn1relatedmyopathydepends pages 1-3, bouman2023selenonrelatedmyopathyacross pages 10-13)

6.2 Key 2024 development: ERO1A as a target and TUDCA as a candidate therapy

A 2024 Cell Reports Medicine study identified ERO1A as a disease-relevant factor in SEPN1-related myopathy and reported both genetic and pharmacologic rescue: - ERO1A depletion/knockout in SEPN1-loss contexts reduced ER stress and rescued Ca2+ handling and mitochondrial bioenergetics, reversing diaphragmatic weakness in mice. (germani2024sepn1relatedmyopathydepends pages 1-3) - Treatment with TUDCA (tauroursodeoxycholic acid), described as an ER-stress inhibitor/chemical chaperone, mirrored aspects of ERO1A-loss rescue in SEPN1 KO mice and improved bioenergetics in patient-derived myoblasts. (germani2024sepn1relatedmyopathydepends pages 1-3)

Ontology mapping suggestions (mechanism): - ER stress / unfolded protein response: GO:0030968 (endoplasmic reticulum unfolded protein response) - Oxidation–reduction / oxidative stress: GO:0055114 (oxidation-reduction process), GO:0006979 (response to oxidative stress) - Calcium ion homeostasis: GO:0055074 (calcium ion homeostasis) - Mitochondrial bioenergetics: GO:0006119 (oxidative phosphorylation)

6.3 RYR1-related MmD mechanisms

RYR1-related myopathies involve dysfunction of the skeletal muscle SR Ca2+ release channel central to excitation–contraction coupling. Reported pathophysiologic contributors include SR Ca2+ leak and altered channel regulation (e.g., reduced calstabin1 association, oxidative stress, altered open probability), providing a rationale for RyR1-stabilizing compounds (Rycals). (todd2024rycals48168(arm210) pages 1-2)

7. Anatomical Structures Affected

  • Primary organ/system: skeletal muscle (UBERON:0001134). (jungbluth2007multiminicoredisease pages 5-7)
  • Clinically dominant functional vulnerability: respiratory pump muscles, particularly the diaphragm (UBERON:0001103), reflected by severe reductions in forced vital capacity and large sitting-to-supine VC drops in SELENON-RM patients. (bouman2023selenonrelatedmyopathyacross pages 10-13)
  • Musculoskeletal system: spine with rigid spine phenotype and scoliosis; scoliosis frequently requires stabilization surgery in adolescence in SELENON-RM. (villarquiles2020theclinicalhistologic pages 5-7)

8. Temporal Development

8.1 Onset

In the SEPN1/SELENON cohort, first signs occurred within the first 2 years in 84.7% (mean ~18 months), though presentations can vary. (villarquiles2020theclinicalhistologic pages 3-4)

8.2 Progression

SEPN1/SELENON-related myopathy is often considered slowly progressive but the large cohort emphasized it can be “more severe and progressive than previously thought,” with systematic functional decline from the end of the third decade, loss of ambulation in ~10%, and reduced lifespan even in mild cases. (villarquiles2020theclinicalhistologic pages 1-2)

9. Inheritance and Population

9.1 Inheritance

  • Classic MmD subtypes are commonly autosomal recessive, particularly SELENON/SEPN1-related disease; RYR1-related disease may be autosomal dominant or recessive depending on phenotype. (jungbluth2007multiminicoredisease pages 2-3, todd2024rycals48168(arm210) pages 1-2)

9.2 Epidemiology

  • An incidence estimate reported in a 2024 thesis excerpt: ~1.03 per million in France (country-specific; likely dependent on ascertainment and definitions). (germani2024chopero1apathwayof pages 17-21)

9.3 Prognostic factors and population modifiers

In the SEPN1/SELENON cohort, major determinants of severity/prognosis included scoliosis/respiratory management, SEPN1 genotype (including null variants), and body mass abnormalities. (villarquiles2020theclinicalhistologic pages 1-2)

10. Diagnostics

10.1 Clinical diagnostic concept

Clinical suspicion is raised by the classic triad (axial weakness + rigid spine/scoliosis + respiratory involvement) and confirmed by either: - Muscle biopsy demonstrating predominant minicores; and/or - Genetic confirmation of causal variants (increasingly the dominant approach). (jungbluth2007multiminicoredisease pages 5-7, lillis2012clinicalutilitygene pages 1-2)

10.2 Biopsy (histopathology)

  • Minicores: reduced oxidative staining lesions short along the fiber axis, with mitochondrial paucity and sarcomeric disruption. (jungbluth2007multiminicoredisease pages 5-7)
  • SELENON-related MmD: often numerous small, poorly defined minicores distributed throughout fibers. (lillis2012clinicalutilitygene pages 1-2)

10.3 Imaging and real-world implementation

Muscle MRI can support subtype discrimination and guide genetic testing; an Orphanet review provides MRI patterns and a subtype comparison table (images retrieved). (jungbluth2007multiminicoredisease media eac91681, jungbluth2007multiminicoredisease media f3b69ea4)

10.4 Respiratory testing

Because respiratory impairment can be disproportionate and may manifest first as nocturnal hypoventilation, polysomnography and upright/supine spirometry are clinically important; in the SEPN1/SELENON cohort, nocturnal hypoventilation was detected by polysomnography in 92.9%. (villarquiles2020theclinicalhistologic pages 4-5)

10.5 Differential diagnosis (evidence-supported highlights)

  • Other congenital myopathies with cores/minicores, including broader RYR1-related phenotypes and other genetically distinct congenital myopathies where multicore pathology can occur. (jungbluth2007multiminicoredisease pages 2-3, butterfield2019congenitalmusculardystrophy pages 14-15)

11. Outcomes / Prognosis

From the international SEPN1/SELENON cohort (n=132): - Respiratory failure is universal and a major determinant of prognosis; assisted ventilation was required in ~82% and often while ambulant. (villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 4-5) - Disease can be progressive with adulthood decline and reduced lifespan even in milder phenotypes. (villarquiles2020theclinicalhistologic pages 1-2)

From the Dutch cross-sectional study (n=11), additional clinically actionable morbidity signals include: - High prevalence of low bone mineral density (80%) and fragility long-bone fractures (55%). (bouman2023selenonrelatedmyopathyacross pages 1-3) - Subclinical cardiac abnormalities (abnormal global longitudinal strain in 43% and QRS fragmentation in 80%), despite preserved LVEF. (bouman2023selenonrelatedmyopathyacross pages 1-3)

12. Treatment

12.1 Current standard of care (supportive)

Evidence from cohort studies supports multi-domain supportive management: - Respiratory care: routine respiratory monitoring; many patients require nocturnal non-invasive ventilation; diaphragm dysfunction is common across ages in SELENON-RM. (villarquiles2020theclinicalhistologic pages 4-5, bouman2023selenonrelatedmyopathyacross pages 10-13) - Orthopedic/spine management: scoliosis is frequent and often progressive; spinal arthrodesis is commonly performed in adolescence and stabilizes scoliosis. (villarquiles2020theclinicalhistologic pages 5-7) - Bone health: vitamin D supplementation and calcium intake optimization recommended due to frequent low BMD and fractures. (bouman2023selenonrelatedmyopathyacross pages 1-3, bouman2023selenonrelatedmyopathyacross pages 13-14) - Symptom management: interventions targeting fatigue and pain, including rehabilitation/physical therapy and self-management approaches, were recommended in the Dutch cohort study. (bouman2023selenonrelatedmyopathyacross pages 13-14, bouman2023selenonrelatedmyopathyacross pages 14-16)

Suggested MAXO terms (treatment actions): - Noninvasive ventilation (MAXO:0000502 noninvasive ventilation) - Respiratory function monitoring (MAXO:0000470 respiratory function monitoring) - Physical therapy (MAXO:0000019 physical therapy) - Vitamin D supplementation (MAXO:0000752 vitamin D supplementation) - Calcium supplementation (MAXO:0000751 calcium supplementation)

12.2 Experimental / emerging therapeutics (2023–2024 priority)

A. TUDCA targeting ER stress in SEPN1/SELENON-related myopathy (2024) A translational mouse + patient-cell study suggests TUDCA may mitigate downstream ER-stress/bioenergetic defects and improve diaphragm weakness in SEPN1 deficiency models, nominating an actionable pathway (ERO1A/ER stress) and candidate therapy. (germani2024sepn1relatedmyopathydepends pages 1-3)

B. ARM210 (Rycal S48168) in RYR1-related myopathies (Phase 1, 2024) A phase 1, open-label, dose-escalation study (NCT04141670) reported ARM210 was well tolerated over 29 days and exploratory measures suggested improvements in fatigue and proximal strength in most participants at the 200 mg dose, supporting randomized proof-of-concept testing. (todd2024rycals48168(arm210) pages 1-2)

C. Gene editing proof-of-concept for RYR1 (Prime editing; 2023) Prime editing was used to correct a recessive RYR1 point mutation (T4709M) in human myoblasts with a reported 59% correction rate, demonstrating feasibility of precise editing strategies for RYR1-related myopathies. (godbout2023successfulcorrectionby pages 1-3)

13. Prevention

Primary prevention is not currently feasible for genetically determined MmD. Prevention in practice focuses on: - Genetic counseling and cascade testing after molecular diagnosis (implied by the strong autosomal recessive inheritance and genetic test-centric diagnosis). (villarquiles2020theclinicalhistologic pages 1-2) - Tertiary prevention of complications through proactive management of respiratory insufficiency, scoliosis, and bone health. (villarquiles2020theclinicalhistologic pages 4-5, bouman2023selenonrelatedmyopathyacross pages 13-14)

14. Other Species / Natural Disease

Evidence in the retrieved sources supports cross-species relevance primarily through experimental modeling: SelN/SELENON deficiency phenotypes have been reproduced in zebrafish (muscle disorganization resembling human multiminicore disease), supporting evolutionary conservation of key muscle pathways. (bellinger2009regulationandfunction pages 2-4)

15. Model Organisms

  • Mouse (SEPN1 KO) models: used to identify the ERO1A dependency and demonstrate pharmacologic rescue with TUDCA; diaphragm weakness was a key functional endpoint in vivo. (germani2024sepn1relatedmyopathydepends pages 1-3)
  • Mouse (RYR1 I4895T) models: described as developing core/minicore pathology and used to study UPR/ER-stress pathway involvement and modifiers (in thesis-derived mechanistic summary). (germani2024chopero1apathwayof pages 17-21, germani2024chopero1apathwayof pages 68-72)
  • Zebrafish SELENON knockdown: reported muscle fiber disorganization resembling human multiminicore disease. (bellinger2009regulationandfunction pages 2-4)

Recent developments and real-world implementations (2023–2024 emphasis)

Trial-readiness and outcome measures in clinical care

  • Quantitative endpoints and monitoring: MFM-20/32, accelerometry, and muscle ultrasound were proposed as feasible measures for clinical trials and potentially for structured clinical follow-up in SELENON-RM. (bouman2023selenonrelatedmyopathyacross pages 1-3)
  • Cardiac and bone surveillance: The Dutch cross-sectional cohort recommended routine cardiorespiratory follow-up and emphasized the burden of low BMD and subtle cardiac abnormalities (GLS/QRS fragmentation), informing real-world multidisciplinary care. (bouman2023selenonrelatedmyopathyacross pages 1-3, bouman2023selenonrelatedmyopathyacross pages 13-14)

Key ongoing or recent studies (ClinicalTrials.gov)

  • NCT06157268 (READYCOM) — Natural history + fatigability study in congenital myopathies including MmD/CCD (Radboud UMC). Observational; recruiting; start 2024-03-28; primary outcome: MFM change over 24 months; includes endurance shuttle test for fatigability. (NCT06157268 chunk 1)
  • NCT04478981 (LAST STRONG) — Natural history of SELENON(SEPN1) or LAMA2 disease (Radboud UMC). Observational; completed; n=38; repeated assessments over 1.5 years; primary outcome: MFM change. (NCT04478981 chunk 1)
  • NCT00272883 — Boston Children’s Hospital congenital myopathy genetics and phenotyping program; observational; recruiting; target enrollment 4000; includes SELENON and RYR1 myopathy including MmD. (NCT00272883 chunk 1)
  • NCT06791369 — Prevalence of RYR1-related disease; observational; not yet recruiting; planned start 2025; aims to estimate prevalence and subgroup frequencies (including MmD) and establish genotype–phenotype correlations. (NCT06791369 chunk 1)

Visual evidence (muscle MRI and subtype comparison)

The Orphanet review provides a figure illustrating genotype-associated thigh muscle MRI patterns and a table comparing SEPN1-related vs RYR1-related MmD clinical and histopathologic features. (jungbluth2007multiminicoredisease media eac91681, jungbluth2007multiminicoredisease media f3b69ea4)

Summary tables

Subtype Disease names / synonyms Key identifiers mentioned in evidence Main causal genes / inheritance Hallmark clinical features Hallmark pathology / minicore definition Key 2023–2024 advances
General MmD Multi-minicore disease (MmD); multiminicore disease; minicore myopathy; multicore myopathy; minicore myopathy with external ophthalmoplegia MmD / MIM #255320; additional MmD-related OMIM numbers listed in gene card: #117000, #607552 (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 1-2, zorzato2007functionaleffectsof pages 1-3) Genetically heterogeneous congenital myopathy; major established subtypes are SELENON/SEPN1-related and RYR1-related; usually autosomal recessive in classic MmD (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3, zorzato2007functionaleffectsof pages 1-3) Classic triad: axial weakness, spinal rigidity/early scoliosis, respiratory impairment; early-onset but variable severity; some forms include feeding difficulty, facial weakness, high-arched palate, or ophthalmoplegia (jungbluth2007multiminicoredisease pages 2-3, jungbluth2007multiminicoredisease pages 1-2, zorzato2007functionaleffectsof pages 1-3) Histologic diagnosis: multiple small areas with reduced oxidative activity that extend only a short distance along the fiber axis; EM shows sarcomeric disorganization and paucity of mitochondria; diagnosis requires minicores as predominant biopsy feature plus compatible phenotype (jungbluth2007multiminicoredisease pages 5-7, zorzato2007functionaleffectsof pages 1-3) Field-level advances include better genotype-first diagnosis by exome/genome sequencing and trial-readiness studies in congenital myopathies (todd2024rycals48168(arm210) pages 1-2, bouman2023selenonrelatedmyopathyacross pages 1-3)
SELENON-related MmD SEPN1-related myopathy; SELENON-related myopathy; SEPN1-related MmD; classic multiminicore myopathy; rigid spine muscular dystrophy spectrum SEPN1 / SELENON MIM #606210; MmD MIM #255320 (lillis2012clinicalutilitygene pages 1-2, zorzato2007functionaleffectsof pages 1-3, villarquiles2020theclinicalhistologic pages 1-2) SELENON/SEPN1; autosomal recessive; exon 1 hotspot reported in large cohort; bi-allelic null variants associated with greater severity (villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 7-8) Consistent triad with marked axial weakness, spinal rigidity/early scoliosis, severe respiratory insufficiency often out of proportion to limb weakness; relatively preserved limb strength; possible cachexia/low BMI, contractures, fatigue, pain, and subtle cardiac strain abnormalities (lillis2012clinicalutilitygene pages 1-2, villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 5-7, bouman2023selenonrelatedmyopathyacross pages 1-3, bouman2023selenonrelatedmyopathyacross pages 10-13) Numerous small, often poorly defined minicores scattered through fibers; in the 132-patient cohort, multiminicores were the most common lesion (59.5%), often with mild dystrophic features; pathology can be variable/nonspecific (lillis2012clinicalutilitygene pages 1-2, villarquiles2020theclinicalhistologic pages 1-2, villarquiles2020theclinicalhistologic pages 5-7) 2024: ERO1A identified as a disease modifier/biomarker; genetic or pharmacologic targeting reduced ER stress and improved diaphragm/muscle bioenergetics in models; TUDCA showed rescue in mice and patient-derived cells (germani2024sepn1relatedmyopathydepends pages 1-3, germani2024chopero1apathwayof pages 68-72). 2023–2024 trial-readiness studies quantified respiratory, bone, fatigue, and cardiac surveillance needs (bouman2023selenonrelatedmyopathyacross pages 1-3, bouman2023selenonrelatedmyopathyacross pages 13-14, bouman2023selenonrelatedmyopathyacross pages 10-13)
RYR1-related MmD RYR1-related multiminicore disease; RYR1-related core myopathy with minicores; recessive RYR1-related MmD RYR1 *180901; MmD-related OMIMs listed in gene card include #117000 and #255320 (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3) RYR1; both dominant and recessive inheritance across RYR1-related myopathies, with MmD typically associated with recessive variants; broad phenotypic heterogeneity (todd2024rycals48168(arm210) pages 1-2, lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3) More variable than SELENON-related disease; axial/proximal weakness plus common ophthalmoparesis/external ophthalmoplegia; bulbar involvement may occur; respiratory involvement often milder than in classic SELENON-related MmD; malignant hyperthermia risk is important in RYR1-associated disease (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 2-3, jungbluth2007multiminicoredisease pages 1-2, jungbluth2007multiminicoredisease pages 3-5) Cores are often multiple, eccentric, and may be larger (“multicores”); overlaps with central core disease; RYR1 dysfunction disrupts SR calcium release / causes leak or uncoupling, contributing to minicore/core pathology (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 5-7, germani2024chopero1apathwayof pages 72-75, germani2024chopero1apathwayof pages 17-21) 2024: Phase 1 trial of Rycal S48168/ARM210 in RYR1-related myopathies showed tolerability, dose-dependent PK, and exploratory improvements in fatigue/proximal strength at 200 mg, supporting further trials (todd2024rycals48168(arm210) pages 1-2). 2023: prime editing corrected a pathogenic RYR1 mutation in human myoblasts (59% correction for T4709M), and 2025 follow-on work proposed a protective universal edit strategy (2023 evidence available here) (godbout2023successfulcorrectionby pages 1-3)

Table: This table summarizes the main Multiminicore disease subtypes, identifiers, causal genes, hallmark clinical and pathologic features, and notable 2023–2024 therapeutic advances. It is designed as a compact reference for knowledge-base population and downstream annotation.

Key limitations of this tool-based report

  • ICD-10/ICD-11, MeSH, ORPHA, and MONDO identifiers were not present in the retrieved full-text excerpts and therefore cannot be cited here. (lillis2012clinicalutilitygene pages 1-2, jungbluth2007multiminicoredisease pages 1-2)
  • Phenotype and management statistics are best-supported for SELENON/SEPN1-related myopathy (large cohort and recent trial-readiness work); equivalent large, genotype-stratified cohorts specifically labeled “RYR1-related multiminicore disease” were not retrieved in accessible form within this run. (villarquiles2020theclinicalhistologic pages 1-2, bouman2023selenonrelatedmyopathyacross pages 1-3)

References

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