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Myofibrillar myopathy, BAG3-related(MFM6)

MedGen UID:
414119
Concept ID:
C2751831
Disease or Syndrome
Synonyms: MFM6; MYOPATHY, MYOFIBRILLAR, 6
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): BAG3 (10q26.11)
OMIM®: 612954
Orphanet: ORPHA199340

Definition

Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419). [from OMIM]

Additional description

From GHR
Myofibrillar myopathy is part of a group of disorders called muscular dystrophies that affect muscle function and cause weakness. Myofibrillar myopathy primarily affects skeletal muscles, which are muscles that the body uses for movement. In some cases, the heart (cardiac) muscle is also affected.The signs and symptoms of myofibrillar myopathy vary widely among affected individuals, typically depending on the condition's genetic cause. Most people with this disorder begin to develop muscle weakness (myopathy) in mid-adulthood. However, features of this condition can appear anytime between infancy and late adulthood. Muscle weakness most often begins in the hands and feet (distal muscles), but some people first experience weakness in the muscles near the center of the body (proximal muscles). Other affected individuals develop muscle weakness throughout their body. Facial muscle weakness can cause swallowing and speech difficulties. Muscle weakness worsens over time.Other signs and symptoms of myofibrillar myopathy can include a weakened heart muscle (cardiomyopathy), muscle pain (myalgia), loss of sensation and weakness in the limbs (peripheral neuropathy), and respiratory failure. Individuals with this condition may have skeletal problems including joint stiffness (contractures) and abnormal side-to-side curvature of the spine (scoliosis). Rarely, people with this condition develop clouding of the lens of the eyes (cataracts).  https://ghr.nlm.nih.gov/condition/myofibrillar-myopathy

Clinical features

Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
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)
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Complete or severe weakness of the muscles of respiration. This condition may be associated with MOTOR NEURON DISEASES; PERIPHERAL NERVE DISEASES; NEUROMUSCULAR JUNCTION DISEASES; SPINAL CORD DISEASES; injury to the PHRENIC NERVE; and other disorders.
Scoliosis
MedGen UID:
21278
Concept ID:
C0037932
Finding
The presence of an abnormal lateral curvature of the spine.
Elevated serum creatine phosphokinase
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase, CPK; EC 2.7.3.2) in the blood. CPK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
demyelinating neuropathy
MedGen UID:
82859
Concept ID:
C0270922
Disease or Syndrome
Demyelinating neuropathy is characterized by slow nerve conduction velocities with reduced amplitudes of sensory/motor nerve conduction and prolonged distal latencies.
Knee flexion contracture
MedGen UID:
98042
Concept ID:
C0409355
Finding
A bent (flexed) knee joint that cannot be straightened actively or passively.
Nasal speech
MedGen UID:
107884
Concept ID:
C0566620
Finding
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Axonal loss
MedGen UID:
316962
Concept ID:
C1832338
Finding
A reduction in the number of axons in the peripheral nervous system.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Spinal rigidity
MedGen UID:
346721
Concept ID:
C1858025
Finding
Reduced ability to move the vertebral column with a resulting limitation of neck and trunk flexion.
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.
Myofibrillar myopathy
MedGen UID:
395532
Concept ID:
C2678065
Finding
Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.
EMG: myopathic abnormalities
MedGen UID:
867362
Concept ID:
C4021726
Pathologic Function
The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.

Term Hierarchy

Follow this link to review classifications for Myofibrillar myopathy, BAG3-related in Orphanet.

Recent clinical studies

Etiology

Konersman CG, Bordini BJ, Scharer G, Lawlor MW, Zangwill S, Southern JF, Amos L, Geddes GC, Kliegman R, Collins MP
Neuromuscul Disord 2015 May;25(5):418-22. Epub 2015 Feb 4 doi: 10.1016/j.nmd.2015.01.009. PMID: 25728519
Lee HC, Cherk SW, Chan SK, Wong S, Tong TW, Ho WS, Chan AY, Lee KC, Mak CM
Clin Genet 2012 Apr;81(4):394-8. Epub 2011 Apr 4 doi: 10.1111/j.1399-0004.2011.01659.x. PMID: 21361913

Diagnosis

Konersman CG, Bordini BJ, Scharer G, Lawlor MW, Zangwill S, Southern JF, Amos L, Geddes GC, Kliegman R, Collins MP
Neuromuscul Disord 2015 May;25(5):418-22. Epub 2015 Feb 4 doi: 10.1016/j.nmd.2015.01.009. PMID: 25728519
Lee HC, Cherk SW, Chan SK, Wong S, Tong TW, Ho WS, Chan AY, Lee KC, Mak CM
Clin Genet 2012 Apr;81(4):394-8. Epub 2011 Apr 4 doi: 10.1111/j.1399-0004.2011.01659.x. PMID: 21361913

Prognosis

Lee HC, Cherk SW, Chan SK, Wong S, Tong TW, Ho WS, Chan AY, Lee KC, Mak CM
Clin Genet 2012 Apr;81(4):394-8. Epub 2011 Apr 4 doi: 10.1111/j.1399-0004.2011.01659.x. PMID: 21361913

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