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Myopathy, myofibrillar, 9, with early respiratory failure(MFM9)

MedGen UID:
350930
Concept ID:
C1863599
Disease or Syndrome
Synonyms: EDSTROM MYOPATHY; Hereditary myopathy with early respiratory failure; MFM9; Myopathy, distal, with early respiratory failure, autosomal dominant; MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT
SNOMED CT: MPRM - myopathy, proximal, with early respiratory muscle involvement (702373006); HMERF - hereditary myopathy with early respiratory failure (702373006); Hereditary myopathy with early respiratory failure (702373006); Hereditary proximal myopathy with early respiratory failure (702373006); Edstrom myopathy (702373006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
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.
 
Gene (location): TTN (2q31.2)
 
Monarch Initiative: MONDO:0011362
OMIM®: 603689
Orphanet: ORPHA178464

Disease characteristics

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s. [from GeneReviews]
Authors:
Gerald Pfeffer  |  Patrick F Chinnery   view full author information

Additional descriptions

From OMIM
Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by Pfeffer et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).  http://www.omim.org/entry/603689
From MedlinePlus Genetics
Hereditary myopathy with early respiratory failure (HMERF) is an inherited disease that affects muscles used for movement (skeletal muscles) and muscles that are needed for breathing (respiratory muscles).\n\nThe major signs and symptoms of HMERF usually appear in adulthood, often in the mid-thirties. Among the earliest signs of the condition are breathing problems and difficulty walking. Weakness of the respiratory muscles, particularly the diaphragm (the muscle that separates the organs in the abdomen from those in the chest), causes breathing problems. This weakness worsens over time and can lead to life-threatening respiratory failure. Some affected individuals have weakness of muscles of the lower leg and foot, which makes it difficult to lift the toes while walking, a condition known as foot drop. Other muscles that become weak in people with HMERF include those of the hips, thighs, upper arms, and neck.\n\nWhen viewed under a microscope, muscle fibers from affected individuals contain abnormal structures called cytoplasmic bodies. In many cases, the cytoplasmic bodies are arranged side-by-side in a ring inside the muscle fiber, resembling a necklace (necklace cytoplasmic bodies).  https://medlineplus.gov/genetics/condition/hereditary-myopathy-with-early-respiratory-failure

Clinical features

From HPO
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Elevated circulating creatine kinase concentration
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.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
Achilles tendon contracture
MedGen UID:
98052
Concept ID:
C0410264
Anatomical Abnormality
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Pelvic girdle muscle weakness
MedGen UID:
96534
Concept ID:
C0427064
Finding
Weakness of the muscles of the pelvic girdle (also known as the hip girdle), that is, lack of strength of the muscles around the pelvis.
Reduced vital capacity
MedGen UID:
141657
Concept ID:
C0476408
Finding
An abnormal reduction on the vital capacity, which is defined as the total lung capacity (volume of air in the lungs at maximal inflation) less the residual volume (i.e., volume of air in the lungs following maximal exhalation) of the lung.
Diaphragmatic weakness
MedGen UID:
101067
Concept ID:
C0521532
Finding
A decrease in the strength of the diaphragm.
Quadriceps muscle weakness
MedGen UID:
154367
Concept ID:
C0577655
Sign or Symptom
Weakness of the quadriceps muscle (that is, of the muscle fasciculus of quadriceps femoris).
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
The significant impairment of gas exchange within the lungs resulting in hypoxia, hypercarbia, or both, to the extent that organ tissue perfusion is severely compromised. Causes include chronic obstructive pulmonary disease, asthma, emphysema, acute respiratory distress syndrome, pneumonia, pulmonary edema, pneumothorax, and congestive heart failure. Treatment requires intubation and mechanical ventilation until the time the lungs recover sufficient function.
Muscle fiber splitting
MedGen UID:
322813
Concept ID:
C1836057
Finding
Fiber splitting or branching is a common finding in human and rat skeletal muscle pathology. Fiber splitting refers to longitudinal halving of the complete fiber, while branching originates from a regenerating end of a necrotic fiber as invaginations of the sarcolemma. In fiber branching, one end of the fiber remains intact as a single entity, while the other end has several branches.
Calf muscle hypertrophy
MedGen UID:
335868
Concept ID:
C1843057
Finding
Muscle hypertrophy affecting the calf muscles.
Neck flexor weakness
MedGen UID:
334801
Concept ID:
C1843637
Finding
Weakness of the muscles involved in neck flexion (sternocleidomastoid, longus capitus, longus colli, and scalenus anterior).
Nocturnal hypoventilation
MedGen UID:
375246
Concept ID:
C1843643
Finding
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.
Rimmed vacuoles
MedGen UID:
340089
Concept ID:
C1853932
Finding
Presence of abnormal vacuoles (membrane-bound organelles) in the sarcolemma. On histological staining with hematoxylin and eosin, rimmed vacuoles are popcorn-like clear vacuoles with a densely blue rim. The vacuoles are often associated with cytoplasmic and occasionally intranuclear eosinophilic inclusions.
Foot dorsiflexor weakness
MedGen UID:
356163
Concept ID:
C1866141
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
Myofibrillar myopathy
MedGen UID:
395532
Concept ID:
C2678065
Finding
Myofibrillar myopathy (MFM) describes a group of skeletal and cardiac muscle disorders, defined by the disintegration of myofibrils and aggregation of degradation products into intracellular inclusions, and is typically clinically characterized by slowly-progressive muscle weakness, which initially involves the distal muscles, but is highly variable and that can affect the proximal muscles as well as the cardiac and respiratory muscles in some patients.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMyopathy, myofibrillar, 9, with early respiratory failure
Follow this link to review classifications for Myopathy, myofibrillar, 9, with early respiratory failure in Orphanet.

Recent clinical studies

Diagnosis

Pfeffer G, Barresi R, Wilson IJ, Hardy SA, Griffin H, Hudson J, Elliott HR, Ramesh AV, Radunovic A, Winer JB, Vaidya S, Raman A, Busby M, Farrugia ME, Ming A, Everett C, Emsley HC, Horvath R, Straub V, Bushby K, Lochmüller H, Chinnery PF, Sarkozy A
J Neurol Neurosurg Psychiatry 2014 Mar;85(3):331-8. Epub 2013 Mar 13 doi: 10.1136/jnnp-2012-304728. PMID: 23486992Free PMC Article

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