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Minicore myopathy

MedGen UID:
340597
Concept ID:
C1850674
Disease or Syndrome
Synonyms: Minicore myopathy with external ophthalmoplegia; MULTICORE MYOPATHY; Multicore myopathy with external ophthalmoplegia; Multiminicore disease with external ophthalmoplegia; MULTIMINICORE MYOPATHY MULTICORE MYOPATHY WITH EXTERNAL OPHTHALMOPLEGIA
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): RYR1 (19q13.2)
OMIM®: 255320
HPO: HP:0003789
Orphanet: ORPHA98905

Definition

Multiminicore disease (MMD) is an inherited neuromuscular disorder defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity running along a limited extent of the longitudinal axis of the muscle fiber, so-called 'minicores.' These regions show sarcomere disorganization and mitochondria depletion. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. MMD is a pathologic diagnosis and shows clinical and genetic heterogeneity. Affected individuals have clinical features of a congenital myopathy, including neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable (Ferreiro and Fardeau, 2002). Patients with recessive mutations in the RYR1 gene typically show severe congenital muscular dystrophy with ophthalmoplegia, although there is phenotypic variability. Some patients may present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations show variable features, including central cores (Jungbluth et al., 2007), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010). [from OMIM]

Additional description

From GHR
Multiminicore disease is a disorder that primarily affects muscles used for movement (skeletal muscles). This condition causes muscle weakness and related health problems that range from mild to life-threatening.Researchers have identified at least four forms of multiminicore disease, which can be distinguished by their characteristic signs and symptoms. The most common form, called the classic form, causes muscle weakness beginning in infancy or early childhood. This weakness is most noticeable in muscles of the trunk and neck (axial muscles) and is less severe in the arm and leg muscles. Muscle weakness causes affected infants to appear "floppy" (hypotonic) and can delay the development of motor skills such as sitting, standing, and walking. The disease causes muscles of the ribcage and spine to stiffen. When combined with weakness of the muscles needed for breathing, this stiffness leads to severe or life-threatening respiratory problems. Almost all children with multiminicore disease develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time.Other forms of multiminicore disease have different patterns of signs and symptoms. They are less common than the classic form, together accounting for about 25 percent of all cases. The atypical forms of the condition tend to be milder and cause few or no problems with breathing. The moderate form with hand involvement causes muscle weakness and looseness of the joints, particularly in the arms and hands. Another form of multiminicore disease, known as the antenatal form with arthrogryposis, is characterized by stiff, rigid joints throughout the body (arthrogryposis), distinctive facial features, and other birth defects. Paralysis of the eye muscles (external ophthalmoplegia) is a primary feature of another atypical form of multiminicore disease. This form of the condition also causes general muscle weakness and feeding difficulties that appear in the first year of life.Many people with multiminicore disease also have an increased risk of a developing a severe reaction to certain drugs used during surgery and other invasive procedures. This reaction is called malignant hyperthermia. Malignant hyperthermia occurs in response to some anesthetic gases, which are used to block the sensation of pain, and with a particular type of muscle relaxant. If given these drugs, people at risk for malignant hyperthermia may experience muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), a high fever, increased acid levels in the blood and other tissues (acidosis), and a rapid heart rate. The complications of malignant hyperthermia can be life-threatening unless they are treated promptly.Multiminicore disease gets its name from small, disorganized areas called minicores, which are found in muscle fibers of many affected individuals. These abnormal regions can only be seen under a microscope. Although the presence of minicores can help doctors diagnose multiminicore disease, it is unclear how they are related to muscle weakness and the other features of this condition.  https://ghr.nlm.nih.gov/condition/multiminicore-disease

Clinical features

Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
Drooping of the upper lid due to deficient development or paralysis of the levator palpebrae muscle.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
A condition of abnormally high AMNIOTIC FLUID volume, such as greater than 2,000 ml in the LAST TRIMESTER and usually diagnosed by ultrasonographic criteria (AMNIOTIC FLUID INDEX). It is associated with maternal DIABETES MELLITUS; MULTIPLE PREGNANCY; CHROMOSOMAL DISORDERS; and congenital abnormalities.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
A condition characterized by fluid accumulation in two or more anatomic compartments in the fetus.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed)
Scoliosis
MedGen UID:
21278
Concept ID:
C0037932
Finding
The presence of an abnormal lateral curvature of the spine.
Joint laxity
MedGen UID:
39439
Concept ID:
C0086437
Pathologic Function
Lack of stability of a joint.
External ophthalmoplegia
MedGen UID:
57662
Concept ID:
C0162292
Disease or Syndrome
Paralysis of the external ocular muscles.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
A finding indicating the complete absence of neurological reflexes.
Skeletal muscle atrophy
MedGen UID:
902598
Concept ID:
C0234958
Disease or Syndrome
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
A reduction in the strength of muscles in multiple anatomic sites.
Proximal muscle weakness
MedGen UID:
325534
Concept ID:
C1838869
Sign or Symptom
A lack of strength of the proximal muscles.
Axial muscle weakness
MedGen UID:
334472
Concept ID:
C1843697
Finding
Reduced strength of the axial musculature (i.e., of the muscles of the head and neck, spine, and ribs).
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Exercise-induced myalgia
MedGen UID:
340638
Concept ID:
C1850830
Sign or Symptom
The occurrence of an unusually high amount of muscle pain following exercise.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Facial palsy
MedGen UID:
346972
Concept ID:
C1858719
Finding
Muscular dystrophy
MedGen UID:
351199
Concept ID:
C1864711
Finding
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Increased connective tissue
MedGen UID:
400898
Concept ID:
C1866021
Finding
The presence of an abnormally increased amount of connective tissue.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Nemaline bodies
MedGen UID:
814369
Concept ID:
C3808039
Finding
Nemaline rods are abnormal bodies that can occur in skeletal muscle fibers. The rods can be observed on histological analysis of muscle biopsy tissue or upon electron microscopy, where they appear either as extensions of sarcomeric Z-lines, in random array without obvious attachment to Z-lines (often in areas devoid of sarcomeres) or in large clusters localized at the sarcolemma or intermyofibrillar spaces.
Type 1 and type 2 muscle fiber minicore regions
MedGen UID:
871103
Concept ID:
C4025568
Finding
Multiple small zones of sarcomeric disorganization and lack of oxidative activity (known as minicores) in type 1 and type 2 muscle fibers.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMinicore myopathy
Follow this link to review classifications for Minicore myopathy in Orphanet.

Conditions with this feature

Nemaline myopathy 7
MedGen UID:
343979
Concept ID:
C1853154
Disease or Syndrome
Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM). Amish NM. Intermediate congenital (20%). Typical congenital (46%). Childhood-onset (13%). Adult-onset (late-onset) (4%). Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk.

Professional guidelines

PubMed

Lillis S, Abbs S, Ferreiro A, Muntoni F, Jungbluth H
Eur J Hum Genet 2012 Feb;20(2) Epub 2011 Oct 19 doi: 10.1038/ejhg.2011.180. PMID: 22009146Free PMC Article

Recent clinical studies

Etiology

D'Amico A, Bertini E
Curr Neurol Neurosci Rep 2008 Jan;8(1):73-9. PMID: 18367042
Jungbluth H, Sewry CA, Muntoni F
Eur J Paediatr Neurol 2003;7(1):23-30. PMID: 12615171
Bönnemann CG, Thompson TG, van der Ven PF, Goebel HH, Warlo I, Vollmers B, Reimann J, Herms J, Gautel M, Takada F, Beggs AH, Fürst DO, Kunkel LM, Hanefeld F, Schröder R
J Neurol Sci 2003 Jan 15;206(1):71-8. PMID: 12480088
Galli L, Orrico A, Cozzolino S, Pietrini V, Tegazzin V, Sorrentino V
Cell Calcium 2002 Sep;32(3):143-51. PMID: 12208234
Jungbluth H, Sewry C, Brown SC, Manzur AY, Mercuri E, Bushby K, Rowe P, Johnson MA, Hughes I, Kelsey A, Dubowitz V, Muntoni F
Neuromuscul Disord 2000 Jun;10(4-5):264-73. PMID: 10838253

Diagnosis

Klaska C, Gonik B
Obstet Gynecol 2014 Feb;123(2 Pt 2 Suppl 2):438-40. doi: 10.1097/AOG.0000000000000003. PMID: 24413229
D'Amico A, Bertini E
Curr Neurol Neurosci Rep 2008 Jan;8(1):73-9. PMID: 18367042
Nadaj-Pakleza A, Fidziańska A, Ryniewicz B, Kostera-Pruszczyk A, Ferreiro A, Kwieciński H, Kamińska A
Folia Neuropathol 2007;45(2):56-65. PMID: 17594595
Gordon PH, Hays AP, Rowland LP, Dickoff DJ, Schotland DL, Rosenberg RN, Wolfe DE, Lange DJ, Lovelace RE
Arch Neurol 1996 Nov;53(11):1194-6. PMID: 8912497
Paljärvi L, Kalimo H, Lang H, Savontaus ML, Sonninen V
J Neurol Sci 1987 Jan;77(1):11-22. PMID: 3806134

Therapy

Gullotta F, Pavone L, La Rosa M, Grasso A
Klin Wochenschr 1982 Nov 2;60(21):1351-5. PMID: 7154615

Prognosis

Takayama K, Mitsuhashi S, Shin JY, Tanaka R, Fujii T, Tsuburaya R, Mukaida S, Noguchi S, Nonaka I, Nishino I
Neuromuscul Disord 2016 Sep;26(9):604-9. Epub 2016 Jun 10 doi: 10.1016/j.nmd.2016.06.005. PMID: 27460346
Lillis S, Abbs S, Ferreiro A, Muntoni F, Jungbluth H
Eur J Hum Genet 2012 Feb;20(2) Epub 2011 Oct 19 doi: 10.1038/ejhg.2011.180. PMID: 22009146Free PMC Article
Jungbluth H, Sewry C, Brown SC, Manzur AY, Mercuri E, Bushby K, Rowe P, Johnson MA, Hughes I, Kelsey A, Dubowitz V, Muntoni F
Neuromuscul Disord 2000 Jun;10(4-5):264-73. PMID: 10838253

Clinical prediction guides

Bánfai Z, Hadzsiev K, Pál E, Komlósi K, Melegh M, Balikó L, Melegh B
BMC Med Genet 2017 Sep 19;18(1):105. doi: 10.1186/s12881-017-0463-y. PMID: 28927399Free PMC Article
Galli L, Orrico A, Cozzolino S, Pietrini V, Tegazzin V, Sorrentino V
Cell Calcium 2002 Sep;32(3):143-51. PMID: 12208234
Jungbluth H, Sewry C, Brown SC, Manzur AY, Mercuri E, Bushby K, Rowe P, Johnson MA, Hughes I, Kelsey A, Dubowitz V, Muntoni F
Neuromuscul Disord 2000 Jun;10(4-5):264-73. PMID: 10838253

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