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Congenital multicore myopathy with external ophthalmoplegia(CMYP1B)

MedGen UID:
340597
Concept ID:
C1850674
Disease or Syndrome
Synonyms: CONGENITAL MYOPATHY 1B, AUTOSOMAL RECESSIVE; Minicore myopathy with external ophthalmoplegia; MULTICORE MYOPATHY; Multicore myopathy with external ophthalmoplegia; Multiminicore disease with external ophthalmoplegia
 
Gene (location): RYR1 (19q13.2)
 
Monarch Initiative: MONDO:0009712
OMIM®: 255320
Orphanet: ORPHA98905

Definition

Congenital myopathy-1B (CMYP1B) is an autosomal recessive disorder of skeletal muscle characterized by severe hypotonia and generalized muscle weakness apparent soon after birth or in early childhood with delayed motor development, generalized muscle weakness and atrophy, and difficulty walking or running. Affected individuals show proximal muscle weakness with axial and shoulder girdle involvement, external ophthalmoplegia, and bulbar weakness, often resulting in feeding difficulties and respiratory insufficiency. Orthopedic complications such as joint laxity, distal contractures, hip dislocation, cleft palate, and scoliosis are commonly observed. Serum creatine kinase is normal. The phenotype is variable in severity (Jungbluth et al., 2005; Bharucha-Goebel et al., 2013). Some patients show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. The most severely affected patients 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 can show variable features, including multiminicores (Ferreiro and Fardeau, 2002), central cores (Jungbluth et al., 2002), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

Additional description

From MedlinePlus Genetics
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 forms of multiminicore disease are the classic form, the progressive form with hand involvement, the antenatal form with arthrogryposis, and the ophthalmoplegic form.

The classic form accounts for about 75 percent of cases of multiminicore disease. This form causes muscle weakness beginning in infancy or early childhood. The muscles of the torso and neck (axial muscles) are most affected with arm and leg muscles less so. Muscle weakness causes affected infants to appear "floppy" (hypotonic) and they may have feeding problems early in life. Muscle weakness can delay the development of motor skills such as sitting, standing, and walking. In this form, the muscles of the ribcage and spine become stiff. In addition, the muscles needed for breathing are weak. This combination of muscle weakness and stiffness leads to severe or life-threatening respiratory problems. Almost all children with the classic form develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time.

The progressive form with hand involvement causes muscle weakness and looseness of the joints (joint laxity) in the arms and hands. Individuals with this form may experience muscle pain (myalgia) or extreme fatigue in response to physical activity (exercise intolerance). This form accounts for about 10 percent of cases of multiminicore disease.

The antenatal form with arthrogryposis is characterized by stiff, rigid joints throughout the body (arthrogryposis) and distinctive facial features. Weakness in the muscles needed for breathing can result in breathing problems for affected individuals. This form also accounts for about 10 percent of cases of multiminicore disease.

The ophthalmoplegic form of multiminicore disease is characterized by paralysis of the eye muscles (external ophthalmoplegia). This can lead to abnormal eye movements and droopy eyelids (ptosis). This form of the condition can also cause weakness in the muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. The ophthalmoplegic form accounts for 5 to 10 percent of cases of multiminicore disease.

Many people with multiminicore disease also have an increased risk of 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, either given alone or in combination with a muscle relaxant that is used to temporarily paralyze a person during a surgical procedure. If given these drugs, people at risk of malignant hyperthermia may experience a rapid increase in heart rate (tachycardia) and body temperature (hyperthermia), abnormally fast breathing (tachypnea), muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). 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 skeletal muscle cells of many affected individuals. These abnormal regions can only been seen when muscle tissue is viewed under a microscope. Minicores are often present in cells with few or no mitochondria, which are the energy-producing centers within cells. 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://medlineplus.gov/genetics/condition/multiminicore-disease

Clinical features

From HPO
Exercise-induced myalgia
MedGen UID:
340638
Concept ID:
C1850830
Sign or Symptom
The occurrence of an unusually high amount of muscle pain following exercise.
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.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
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.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
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
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Centrally nucleated skeletal muscle fibers
MedGen UID:
330782
Concept ID:
C1842170
Finding
An abnormality in which the nuclei of sarcomeres take on an abnormally central localization (or in which this feature is found in an increased proportion of muscle cells).
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.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
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.
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.
Minicore myopathy
MedGen UID:
961596
Concept ID:
CN279271
Disease or Syndrome
Multiple small zones of sarcomeric disorganization and lack of oxidative activity (known as minicores) in muscle fibers.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
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.
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.
Abnormal circulating creatine kinase concentration
MedGen UID:
868058
Concept ID:
C4022449
Finding
Any deviation from the normal circulating creatine kinase concentration.
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).
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.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
External ophthalmoplegia
MedGen UID:
57662
Concept ID:
C0162292
Disease or Syndrome
Paralysis of the external ocular muscles.

Term Hierarchy

Follow this link to review classifications for Congenital multicore myopathy with external ophthalmoplegia in Orphanet.

Professional guidelines

Curated

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

Topaloglu H
Acta Myol 2020 Dec;39(4):266-273. Epub 2020 Dec 1 doi: 10.36185/2532-1900-029. PMID: 33458581Free PMC Article
Fusto A, Moyle LA, Gilbert PM, Pegoraro E
Dis Model Mech 2019 Dec 19;12(12) doi: 10.1242/dmm.041368. PMID: 31874912Free PMC Article
Ge L, Fu X, Zhang W, Wang D, Wang Z, Yuan Y, Nonaka I, Xiong H
Neuromuscul Disord 2019 May;29(5):350-357. Epub 2019 Mar 14 doi: 10.1016/j.nmd.2019.03.007. PMID: 31053406
Alkhunaizi E, Shuster S, Shannon P, Siu VM, Darilek S, Mohila CA, Boissel S, Ellezam B, Fallet-Bianco C, Laberge AM, Zandberg J, Injeyan M, Hazrati LN, Hamdan F, Chitayat D
Am J Med Genet A 2019 Mar;179(3):386-396. Epub 2019 Jan 16 doi: 10.1002/ajmg.a.61025. PMID: 30652412

Diagnosis

Ogasawara M, Nishino I
Neuromuscul Disord 2021 Oct;31(10):968-977. Epub 2021 Sep 17 doi: 10.1016/j.nmd.2021.08.015. PMID: 34627702
Topaloglu H
Acta Myol 2020 Dec;39(4):266-273. Epub 2020 Dec 1 doi: 10.36185/2532-1900-029. PMID: 33458581Free PMC Article
Zhang H, Ma Y, Lv Y, Wan Y, Zhao Q, Gai Z, Liu Y
Stem Cell Res 2020 May;45:101775. Epub 2020 Mar 20 doi: 10.1016/j.scr.2020.101775. PMID: 32272370
Alkhunaizi E, Shuster S, Shannon P, Siu VM, Darilek S, Mohila CA, Boissel S, Ellezam B, Fallet-Bianco C, Laberge AM, Zandberg J, Injeyan M, Hazrati LN, Hamdan F, Chitayat D
Am J Med Genet A 2019 Mar;179(3):386-396. Epub 2019 Jan 16 doi: 10.1002/ajmg.a.61025. PMID: 30652412
Kazamel M, Milone M
J Clin Neurosci 2019 Apr;62:238-239. Epub 2019 Jan 3 doi: 10.1016/j.jocn.2018.12.024. PMID: 30612914

Therapy

Takeuchi N, Ohkusu M, Hishiki H, Fujii K, Hotta M, Murata S, Ishiwada N
J Infect Chemother 2020 Jul;26(7):749-751. Epub 2020 May 12 doi: 10.1016/j.jiac.2020.02.009. PMID: 32409019

Prognosis

Kazamel M, Milone M
J Clin Neurosci 2019 Apr;62:238-239. Epub 2019 Jan 3 doi: 10.1016/j.jocn.2018.12.024. PMID: 30612914

Clinical prediction guides

Witherspoon JW, Vuillerot C, Vasavada RP, Waite MR, Shelton M, Chrismer IC, Jain MS, Meilleur KG
Muscle Nerve 2019 Jul;60(1):80-87. doi: 10.1002/mus.26491. PMID: 31004442Free PMC Article
Kazamel M, Milone M
J Clin Neurosci 2019 Apr;62:238-239. Epub 2019 Jan 3 doi: 10.1016/j.jocn.2018.12.024. PMID: 30612914
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

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