Calpainopathy

Last updated
Calpainopathy
Other namesLGMDR1, LMGD2A
Calpainopathy Overview.png
Calpainopathy overview
Specialty Neurology, neuromuscular medicine
Symptoms proximal muscle weakness, scapular winging
Usual onset2 - 40 years of age
DurationLong term
TypesPelvifemoral, scapulohumeral, hyperCKemia, autosomal dominant
CausesGenetic (inherited or new mutation)
Diagnostic method Genetic testing
Differential diagnosis Other LGMD2, facioscapulohumeral muscular dystrophy, dystrophinopathy, Metabolic myopathy [1]
ManagementPhysical therapy, bracing, orthopedic surgery
Frequency1-9/100,000

Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). [2] It preferentially affects the muscles of the hip girdle and shoulder girdle.

Contents

No disease modifying pharmaceuticals have been developed as of 2019, although physical therapy, lifestyle modification, and orthopedic surgery can address symptoms.

Signs and symptoms

Disease severity varies greatly, even between family members with identical mutations. [1] Age of onset is highly variable, although symptoms usually appear between 8 and 15 years of age. [3] Patients usually lose the ability to ambulate 10 – 20 years after symptoms appear. [3] Milder forms present with symptoms other than weakness, such as muscle aches, cramps, or exercise intolerance, and people in this group can retain ambulation beyond age 60. [3] Weakness is symmetric, progressive, and proximal (on or close to the torso), usually affecting the hip girdle and shoulder girdle muscles. [1] [3] Hip weakness can manifest as a waddling gate. [1] Shoulder weakness can manifest as winged scapulas. [1] Muscle contractures, especially of the Achilles tendon, and scoliosis can also occur. [1]

Heart function and intelligence are generally not affected. [1] Additionally, the muscles of the face, eye, tongue, and neck are spared. [1]

Subtypes

Three subtypes of the autosomal recessive form have been described

There is a less common, autosomal dominant form, which is milder than the autosomal recessive forms, ranging from no symptoms to wheel chair dependence after age 60. [1]

Genetics

Mutation in the gene CAPN3 , which encodes the protein calpain-3 (CAPN3), is the cause of calpainopathy. [1] As of 2019, more than 480 CAPN3 mutations have been reported, some of which can be associated with severe or benign disease course. [3] Usually, the disease follows an autosomal recessive inheritance pattern, requiring both CAPN3 alleles to be mutated for disease to occur. [1] However, there can be CAPN3 mutations that follow an autosomal dominant inheritance pattern. [1]

Pathophysiology

Diagram of calpainopathy pathophysiology, showing calcium dysregulation to play a central role. Calpainopathy pathophysiology.png
Diagram of calpainopathy pathophysiology, showing calcium dysregulation to play a central role.
Schematic representation of CAPN3 structure. Regions specific to CAPN3 are shown in blue (NS, IS1, and IS2). Regions shared with similar proteins are protease core domains (PC1 and PC2), a calpain-type b-sandwich domain (CBSW), and a penta E-F hand domain (PEF) that binds four calcium ions. Calpainopathy Structure.png
Schematic representation of CAPN3 structure. Regions specific to CAPN3 are shown in blue (NS, IS1, and IS2). Regions shared with similar proteins are protease core domains (PC1 and PC2), a calpain-type β-sandwich domain (CBSW), and a penta E-F hand domain (PEF) that binds four calcium ions.

As of 2019, the pathophysiology is largely not understood, although it is increasingly becoming accepted that calcium dysregulation plays a role. [3]

Calpain 3 is unique from other calpain proteases in that it is relatively specific to muscle. [4] Calpain 3 is both a protease and a structural protein. [4] As a protease, it cleaves proteins of the sarcomere and cytoskeleton, designating them to be degraded by proteasomes, a part of muscle remodeling. [4] The structural role of calpain 3 is stabilization of the triad protein complexes. [4] A triad protein complex plays a role converting electrical excitation into calcium release, and it is composed of two calcium channels, the ryanodine receptor (RYR1), and the dihydropyridine receptor (DHPR). [4]

With calpain 3 mutation, proteins typically found at the triad are reduced, including CaMKII (Ca2+/calmodulin-dependent protein kinase II). [4] Decreased CaMKII activity impairs induction of slow oxidative gene expression, which in turn impairs genes involving the mitochondria and lipid metabolism. [4]

Diagnosis

Photomicrograph of muscle affected by calpainopathy. Seen in these views are endomysial fibrosis (black asterisks), central nuclei (black arrows), fiber splitting (yellow triangle), necrosis (black triangles), atrophic fibers (yellow arrows), and increased variation in size and shape. Scale bar: 25um Calpainopathy Muscle Biopsy.png
Photomicrograph of muscle affected by calpainopathy. Seen in these views are endomysial fibrosis (black asterisks), central nuclei (black arrows), fiber splitting (yellow triangle), necrosis (black triangles), atrophic fibers (yellow arrows), and increased variation in size and shape. Scale bar: 25µm

Genetic testing is the most definitive test. [1]

If genetic testing is not available, a muscle biopsy with protein immunoanalysis can be used. [1] Biopsy shows general dystrophic features, such as areas of muscle death, variability in muscle size, nuclei in the center of muscle fibers, and disorganized muscle fibers within muscle cells. [3]

Serum creatine kinase, a nonspecific marker of muscle damage, can be elevated early in the disease. [3]

Facioscapulohumeral muscular dystrophy (FSHD) can present similarly, although facial weakness and asymetrical weakness is common in FSHD.

Management

As of 2019, no disease modifying pharmaceuticals are known. [3]

Both strength and aerobic exercise have shown to be beneficial, [3] although strenuous and excessive exercise should be avoided. [1]

Physical therapy can address contractures. [1]

Orthopedic surgery address foot deformities, scoliosis, Achilles tendon contractures, and winged scapula. Winged scapula can be addressed with either scapulopexy or scapulothoracic fusion. [1]

Circumstances to avoid include extremes of body weight, bone fractures, and prolonged immobility. [1]

Epidemiology

Prevalence ranges from 1 to 9 cases per 100,000 people. [3] LGMDR1 represents 30% of all LGMD cases. [3]

History

CAPN3 mutation was the first gene mutation linked to an LGMD. [4]

Research directions

Research is being done to identify the proteins cleaved by calpain-3. [5]

Gene therapy is being studied to replace the function of the calpain-3. Injection of plasmids containing CAPN3 into mouse models resulted in increased levels of calpain-3. [6]

Related Research Articles

Muscular dystrophy Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

Limb–girdle muscular dystrophy Medical condition

Limb–girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD usually has an autosomal pattern of inheritance. It currently has no known cure or treatment.

Duchenne muscular dystrophy Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms.

Becker muscular dystrophy Genetic muscle disorder

Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.

Oculopharyngeal muscular dystrophy Medical condition

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.

Fukuyama congenital muscular dystrophy Medical condition

Fukuyama congenital muscular dystrophy (FCMD) is a rare, autosomal recessive form of muscular dystrophy mainly described in Japan but also identified in Turkish and Ashkenazi Jewish patients; fifteen cases were first described on 1960 by Dr. Yukio Fukuyama.

Facioscapulohumeral muscular dystrophy Medical condition

Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin. Almost any skeletal muscle can be affected in severe disease. Abnormally positioned, or winged, scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years. FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.

Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

Calpain Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.

Dysferlin Protein encoded by the DYSF gene in humans

Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene.

Congenital muscular dystrophy Medical condition

Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.

Emery–Dreifuss muscular dystrophy Medical condition

Emery–Dreifuss muscular dystrophy (EDMD) is a type of muscular dystrophy, a group of heritable diseases that cause progressive impairment of muscles. EDMD affects muscles used for movement, causing atrophy, weakness and contractures. It almost always affects the heart, causing abnormal rhythms, heart failure, or sudden cardiac death. It is rare, affecting 0.39 per 100,000 people. It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.

Distal myopathy Medical condition

Distal myopathy is a group of rare genetic disorders that cause muscle damage and weakness, predominantly in the hands and/or feet. Mutation of many different genes can be causative. Many types involve dysferlin.

Bethlem myopathy Medical condition

Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a mutation in one of the three genes coding for type VI collagen. These include COL6A1, COL6A2, and COL6A3. Gower's sign, tiptoe-walking and contractures of the joints are typical signs and symptoms of the disease. Bethlem myopathy could be diagnosed based on clinical examinations and laboratory tests may be recommended. Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. Bethlem myopathy affects about 1 in 200,000 people.

Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.

Delta-sarcoglycan

Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.

SGCG

Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane.

Ullrich congenital muscular dystrophy Medical condition

Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated with this type of CMD. It is named after Otto Ullrich, who is also known for the Ullrich-Turner syndrome.

ANO5

Anoctamin 5 (ANO5) is a protein that in humans is encoded by the ANO5 gene.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Angelini, C; Fanin, M; Adam, MP; Ardinger, HH; Pagon, RA; Wallace, SE; Bean, LJH; Stephens, K; Amemiya, A (1993). "Calpainopathy". PMID   20301490.{{cite journal}}: Cite journal requires |journal= (help)
  2. Pollitt, C; Anderson, LV; Pogue, R; Davison, K; Pyle, A; Bushby, KM (April 2001). "The phenotype of calpainopathy: diagnosis based on a multidisciplinary approach". Neuromuscular Disorders. 11 (3): 287–96. doi:10.1016/s0960-8966(00)00197-8. PMID   11297944. S2CID   20081475.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Lasa-Elgarresta, J; Mosqueira-Martín, L; Naldaiz-Gastesi, N; Sáenz, A; López de Munain, A; Vallejo-Illarramendi, A (13 September 2019). "Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations". International Journal of Molecular Sciences. 20 (18): 4548. doi: 10.3390/ijms20184548 . PMC   6770289 . PMID   31540302.
  4. 1 2 3 4 5 6 7 8 Dowling, JJ; Weihl, CC; Spencer, MJ (November 2021). "Molecular and cellular basis of genetically inherited skeletal muscle disorders". Nature Reviews. Molecular Cell Biology. 22 (11): 713–732. doi:10.1038/s41580-021-00389-z. PMID   34257452. S2CID   235822532.
  5. Levy, Jennifer (21 January 2020). "Dufour Lab to investigate the biological role of calpain 3 in muscle". Coalition to Cure Calpain 3. Archived from the original on 6 May 2020. Retrieved 6 May 2020.
  6. Guha, TK; Pichavant, C; Calos, MP (13 December 2019). "Plasmid-Mediated Gene Therapy in Mouse Models of Limb Girdle Muscular Dystrophy". Molecular Therapy: Methods & Clinical Development. 15: 294–304. doi:10.1016/j.omtm.2019.10.002. PMC   6923511 . PMID   31890729.