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Calpainopathy

Synonyms: Limb-Girdle Muscular Dystrophy Type 2A, LGMD2A

, MD and , PhD.

Author Information
, MD
Department of Neurosciences
University of Padova
Padova, Italy
, PhD
Department of Neurosciences
University of Padova
Padova, Italy

Initial Posting: ; Last Update: November 26, 2014.

Summary

Clinical characteristics.

Calpainopathy is characterized by symmetric and progressive weakness of proximal (limb-girdle) muscles. The age at onset of muscle weakness ranges from two to 40 years. The phenotype shows intra- and interfamilial variability ranging from mild to severe. Three calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset:

  • Pelvifemoral limb-girdle muscular dystrophy (LGMD) (Leyden-Möbius LGMD) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle, with onset before age 12 years or after age 30 years
  • Scapulohumeral LGMD (Erb LGMD) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle
  • HyperCKemia, usually observed in children or young individuals, in which asymptomatic individuals have only high serum creatine kinase (CK) concentrations

Clinical findings include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Other findings include symmetric weakness of proximal more than distal muscles in the limbs, trunk, and periscapular area; laxity of the abdominal muscles; Achilles tendon shortening; scoliosis; and joint contractures. Affected individuals typically do not have cardiac involvement or intellectual disability.

Diagnosis/testing.

The diagnosis of calpainopathy, which is suggested by clinical findings and elevated serum CK concentration, is either confirmed by detection of biallelic pathogenic variants in CAPN3 (encoding proteolytic enzyme calpain-3) or (if genetic data are unavailable) highly suspected on detection of a severe deficiency of calpain-3 protein on muscle biopsy tissue.

Management.

Treatment of manifestations: Physical therapy and stretching exercises to promote mobility and prevent contractures; aids such as canes, walkers, orthotics, and wheelchairs to help maintain independence; surgery for foot deformities, scoliosis, and Achilles tendon contractures as needed; respiratory aids to treat chronic respiratory insufficiency in late stages of the disease.

Surveillance: Monitoring of muscle strength, joint range of motion, respiratory function, and orthopedic complications.

Agents/circumstances to avoid: Strenuous and excessive muscle exercise; obesity and excessive weight loss; physical trauma, bone fractures, and immobility.

Genetic counseling.

Calpainopathy is inherited in an autosomal recessive manner. At conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the CAPN3 pathogenic variants in the family are known.

GeneReview Scope

Calpainopathy: Included Disorders 1
  • Pelvifemoral limb-girdle muscular dystrophy (Leyden-Möbius LGMD)
  • Scapulohumeral limb-girdle muscular dystrophy (Erb LGMD)
  • HyperCKemia

For synonyms and outdated names see Nomenclature.

1. Forms of disorders associated with genes other than CAPN3 are not addressed in this GeneReview.

Diagnosis

Suggestive Findings

Calpainopathy (also known as limb-girdle muscular dystrophy 2A, or LGMD2A) should be suspected in individuals with the following clinical findings and test results:

Clinical findings

  • Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age <12 years), adult onset, or late onset (age >30 years)
  • Atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [Fardeau et al 1996].
  • Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine)
  • Waddling gait; tip-toe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair
  • Sparing of facial, ocular, tongue, and neck muscles
  • Asymptomatic elevated creatine kinase (CK) concentrations, especially in childhood or adolescence
  • Absence of cardiomyopathy and intellectual disability
  • Family history consistent with autosomal recessive inheritance

Preliminary Testing

Serum creatine kinase (CK) concentration is always elevated (5-80 times normal) from early infancy on, particularly during the active stage of the disease. Serum CK concentration decreases with disease progression, as muscles become more and more atrophic [Urtasun et al 1998].

Muscle imaging

Electromyogram (EMG) pattern is typically myopathic (showing small polyphasic potentials), although a normal EMG can also be observed in presymptomatic individuals. Myotonia and spontaneous discharges are not present.

Establishing the Diagnosis

The diagnosis of calpainopathy is confirmed by detection of biallelic pathogenic variants in CAPN3 (encoding proteolytic enzyme calpain-3) (Table 1); if molecular genetic testing is not available or does not identify CAPN3 pathogenic variants, the diagnosis is highly suspected on detection of severe deficiency of calpain-3 protein on muscle biopsy tissue.

Molecular genetic testing approaches can include the following:

  • Sequence analysis of CAPN3 [Nigro et al 2011] which is expected to identify pathogenic variants in fewer than 40% of individuals with clinically defined LGMD (of which calpainopathy is the most common form) in non-consanguineous populations [Kawai et al 1998, Chou et al 1999, Zatz et al 2000, Bushby & Beckmann 2003, Guglieri et al 2008, Fanin et al 2009a]. If only one or no CAPN3 pathogenic variant is identified, deletion/duplication analysis is performed.
  • Use of a multi-gene panel that includes CAPN3 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
  • Consideration of genomic testing if single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of calpainopathy. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

    Notes regarding WMitoSeq. (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively

Table 1.

Summary of Molecular Genetic Testing Used in Calpainopathy

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
CAPN3Sequence analysis 284% 3, 4
Deletion/duplication analysis 5Unknown 6
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

The probability of identifying a pathogenic variant is about 84% in patients with immunoblot confirmation [Fanin et al 2004].

4.

In about 20%-30% of individuals with calpainopathy, only one CAPN3 pathogenic variant was found [Richard et al 1999, De Paula et al 2002, Saenz et al 2005, Krahn et al 2006a, Groen et al 2007] possibly because the second pathogenic variants are located in genomic regions outside the coding exons (e.g., introns or promoter) or are large genomic rearrangements.

5.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

Large genomic rearrangements involving CAPN3 have been recognized as causative of calpainopathy [Richard et al 1999], including the frame-shift deletion of exons 2-8 (c.309+4469_c.1116-1204del) [Krahn et al 2007, Todorova et al 2007] and the frame-shift deletion of exons 2-6 [Ginjaar et al 2008].

Muscle biopsy

Histopathology. A variety of morphologic changes and variable muscle involvement may be observed, irrespective of the age of the individual at the time of biopsy. Wide variability can be observed among individuals who are homozygous for the same missense mutation [Chae et al 2001, Fanin et al 2003].

Specialized studies

Calpain-3 immunoblot analysis is useful in the diagnosis of calpainopathy [Pollitt et al 2001, Fanin et al 2009a] and highly specific when calpain-3 protein is absent or severely reduced [Fanin et al 2004, Luo et al 2012]. Approximately 80% of individuals with mutation of CAPN3 show a complete loss or a severe reduction of calpain-3 protein and 20%-30% have a normal amount of protein (but with loss of protein function) [Talim et al 2001, Fanin et al 2004, Groen et al 2007, Milic et al 2007, Fanin et al 2009b, Perez et al 2010].

Note: The results of calpain-3 immunoblot analysis need to be interpreted with caution, as the analysis is neither completely specific (i.e., it can yield false positive results) nor completely sensitive (i.e., it can yield false negative results). Furthermore, the results must be considered in the context of other muscle proteins [Anderson & Davison 1999] and optimal tissue preservation.

Clinical Characteristics

Clinical Description

Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. The age at onset of muscle weakness ranges from two to 40 years. Early motor milestones are usually normal. Intra- and interfamilial clinical variability ranges from severe to mild [Richard et al 1999].

Three calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset:

  • Pelvifemoral LGMD (Leyden-Möbius LGMD) phenotype, the most frequently observed calpainopathy phenotype. Muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle. Onset can be early (age <12 years), adult (age 12-30 years), or late (age >30 years). Individuals with early onset and rapid disease course usually have pelvifemoral LGMD.
  • Scapulohumeral LGMD (Erb LGMD) phenotype. Muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle. Early onset is infrequent; the disease course is variable, but usually milder than that in the pelvifemoral phenotype.
  • HyperCKemia. Asymptomatic individuals have high serum CK concentrations only. HyperCKemia may be considered a presymptomatic stage of calpainopathy, as it is usually observed in young persons [Fanin et al 2009a, Kyriakides et al 2010].

The first clinical findings of calpainopathy are usually the tendency to walk on tiptoe, difficulty in running, and scapular winging. Waddling gait and slight hyperlordosis are frequently observed in the early stage of the disease. Symmetric weakness of proximal more than distal muscles is evident in the limbs, trunk, and periscapular area. Scapular winging is frequently present. Marked laxity of the abdominal muscles is frequently seen [Bushby 1999, Pollitt et al 2001]. The gluteus maximus, thigh adductors, and posterior compartment of the limbs are severely affected early in the disease course [Fardeau et al 1996, Van der Kooi et al 1996, Dincer et al 1997, Topaloglu et al 1997, Urtasun et al 1998]. Early Achilles tendon shortening and scoliosis may be present.

Some individuals report muscle pain, exercise intolerance, and excessive lactate production similar to that seen in a pseudo-metabolic myopathy [Penisson-Besnier et al 1998, Pollitt et al 2001]. Another early and transient feature in calpainopathy is eosinophilic myositis, which has been reported in patients with increased CK level and is not present in older patients [Krahn et al 2006b, Krahn et al 2011, Brown & Amato 2006]. Calf hypertrophy can be rarely observed, and in a number of cases, significant atrophy is observed. With rare exceptions, muscle involvement is symmetric [Matsubara et al 2007]. Facial and neck muscles are usually spared. Macroglossia has not been described.

In the advanced stage of the disease, the inability to climb stairs, to rise up from a chair, to lift weights, or to get up from the floor is common. Joint contractures (in the hips, knees, elbows, and fingers) are common; rigid spine is occasionally observed [Pollitt et al 2001]. Foot drop may occasionally be present [Burke et al 2010]. Because of a deficiency in diaphragmatic function and weakness in thoracic and abdominal muscles, respiratory insufficiency with reduced lung vital capacity to 30%-50% may be present [Fardeau et al 1996]. Cardiomyopathy is uncommon. Intelligence is normal.

The asymptomatic stage may be relatively long in some affected individuals, especially in females. The disease is invariably progressive and loss of ambulation occurs approximately ten to 30 years after the onset of symptoms (between ages 10 and 48 years) [Richard et al 1999, Zatz et al 2003, Saenz et al 2005, Angelini et al 2010].

A more rapid progression of the disease was observed in male than in female patients [Piluso et al 2005, De Paula et al 2002, Zatz et al 2003]. Male patients are more susceptible to muscle fiber atrophy than females and more affected by the consequent muscle weakness and clinical disability.

Genotype-Phenotype Correlations

Genotype-phenotype correlation in calpainopathy is complex and often complicated by the fact that most individuals are compound heterozygotes for two different pathogenic variants in CAPN3.

Null homozygous variants are generally associated with a severe phenotype and absent calpain-3 protein in muscle [Richard et al 1999].

Although it has been suggested that homozygous missense variants are usually associated with a milder phenotype than null variants [Fardeau et al 1996, Anderson et al 1998, Richard et al 1999, Chae et al 2001], the phenotypic consequences of homozygous missense variants are more difficult to predict [Richard et al 1997, Bushby 1999, De Paula et al 2002, Saenz et al 2011].

Wide clinical variability has been described among individuals homozygous for the same missense variant, even within the same family [Fardeau et al 1996, Kawai et al 1998, Penisson-Besnier et al 1998, Richard et al 1999, Fanin et al 2004, Saenz et al 2005, Schessl et al 2008].

No direct correlations have been observed between the severity of the phenotype and the amount of calpain-3 protein detected by calpain-3 immunoblot analysis [Anderson et al 1998, Zatz et al 2003, Gallardo et al 2011]. Affected individuals with either no detectable protein or normal amounts of protein have varying severity of the clinical phenotype [De Paula et al 2002, Fanin et al 2004]. Whereas null variants are usually associated with a lack of detectable protein, missense variants have variable and unpredictable consequences, which depend at least partially on the quantity of protein.

Penetrance

Nearly full penetrance is observed in adulthood. Some individuals remain asymptomatic until adulthood. Serum CK concentration is always increased.

Nomenclature

Calpainopathy was originally called LGMD2A because it was the first form of autosomal recessive LGMD to be mapped [Beckmann et al 1991].

Prevalence

Calpainopathy is considered the most common form of LGMD [Bushby & Beckmann 2003, Guglieri et al 2008], representing approximately 30% of LGMD cases, depending on the geographic region [Chou et al 1999, Zatz et al 2000]. Estimates based on molecular data indicate that the frequency of calpainopathy ranges from 10% of all LGMD in a white population from the US and in Mexico [Chou et al 1999, Moore et al 2006, Gomez-Diaz et al 2012], to 13% in Denmark [Duno et al 2008], 21% in the Netherlands [van der Kooi et al 2007], 21%-26% in Japan [Kawai et al 1998, Minami et al 1999, Luo et al 2011], 25%-28% in Italy [Guglieri et al 2008, Fanin et al 2009a], 33% in Czech Republic [Stehlikova et al 2014], 40%-50% in Turkey, India, and Bulgaria [Dincer et al 1997, Balci et al 2006, Pathak et al 2010, Todorova et al 2007], and 80% in the Basque country and Russia [Urtasun et al 1998, Pogoda et al 2000, Dadali et al 2010].

A genetic epidemiologic study in northeastern Italy estimated that calpainopathy has a prevalence of approximately 1:100,000 inhabitants (corresponding to a carrier frequency of ~1:160) [Fanin et al 2005]. Another study in southern Italy estimated the prevalence of calpainopathy at 1:42,700 inhabitants (corresponding to a carrier frequency of ~1:103) [Piluso et al 2005]. A general population screening of the most common CAPN3 gene mutation in Croatia (c.550delA) resulted in the identification of four healthy carriers, corresponding to an estimated carrier frequency of 1:133 [Canki-Klain et al 2004]. The prevalence of the disease has been estimated at 48 per million in the Reunion Island [Fardeau et al 1996], 69 per million in the Basque country [Urtasun et al 1998], and 1900 per million in the Mòcheni community in the Alps [Fanin et al 2012].

Differential Diagnosis

Other forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2) (i.e., LGMD2B – LGMD2L) cannot be distinguished from calpainopathy on clinical grounds, although calpainopathy generally has a later onset and is relatively mild, particularly by comparison with sarcoglycanopathies [Nigro & Savarese 2014]. Multi-gene panels are increasingly used to identify the causative mutations and the diagnosis of LGMD. If this approach is not available, immunoblot analysis of muscle biopsy for candidate proteins (sarcoglycans, dysferlin, telethonin, titin) can help establish the correct diagnosis. (See Limb-Girdle Muscular Dystrophy Overview.)

Facioscapulohumeral muscular dystrophy (FSHD) shares some clinical and laboratory features with Erb LGMD (one of the calpainopathy phenotypes) [Leidenroth et al 2012]: muscle weakness with onset in the shoulder girdle, scapular winging, elevated serum CK concentration, and nonspecific myopathic changes on muscle biopsy. However, facial muscle weakness and asymmetric scapular muscle involvement, which can be observed in FSHD, are uncommon in calpainopathy. Inheritance is autosomal dominant.

Becker muscular dystrophy (BMD) should be considered in males with clinical and laboratory features that are in common with calpainopathy: onset of weakness in the lower girdle muscles in adolescence or adulthood, and elevated serum CK concentrations. However, an X-linked recessive pattern of inheritance or the presence of heart involvement (mainly dilated cardiomyopathy), distinguish BMD from calpainopathy.

Dystrophinopathy was diagnosed in about 17% of patients with a clinical diagnosis of LGMD (31% of males and 13% of females) [Arikawa et al 1991], emphasizing the clinical overlap between LGMD and dystrophinopathy.

The correct diagnosis can be established in most affected individuals by molecular genetic testing of DMD. (See Dystrophinopathies.)

Metabolic myopathy. Calpainopathy has been reported in individuals with asthenia, myalgias, exercise intolerance, lower-limb proximal muscle weakness, and excessive lactate production after aerobic exercise [Penisson-Besnier et al 1998]. Such individuals may be difficult to diagnose.

Myopathy with contractures. The phenotype of calpainopathy may include muscle weakness with severe tendon contractures [Pollitt et al 2001], raising the possibility of Emery-Dreifuss muscular dystrophy.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with calpainopathy, the following evaluations are recommended:

  • Complete physical evaluation including the grading of muscle strength in single upper, lower, proximal, and distal muscles and the analysis of several functional performances
  • Orthopedic examination when gait is severely impaired
  • Monitoring of pulmonary function (including forced vital capacity measurement) in the advanced stage of disease
  • Examination of cardiac function in the advanced stage of disease (although it is not frequently compromised) [Dirik et al 2001, Okere et al 2013]
  • Medical genetics consultation

Treatment of Manifestations

Appropriate management, tailored to each individual, can improve quality of life and prolong survival. The general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995], Bushby [1999], and Norwood et al [2007]:

  • Physical therapy [Oygard et al 2011] and stretching exercises can promote mobility, prolong walking, and slow the disease progression, in particular by maintaining joint flexibility. Although there are no specific reports on supportive care, physical and occupational therapies are important [Eagle 2002]. In accordance with guidelines for other muscular dystrophies, gentle exercise [Sveen et al 2013] and avoidance of prolonged immobility would be recommended.
  • Technical aids can also compensate for the loss of certain motor abilities; canes, walkers, orthotics, and wheelchairs enable individuals to regain independence.
  • Surgical intervention may be required for correction of orthopedic complications including foot deformities, scoliosis, and Achilles tendon contractures. Occasionally, scapular fixation may be required for particularly problematic scapular winging.
  • In the late stage of the disease, chronic respiratory insufficiency may occur [D’Angelo et al 2011] and the use of respiratory aids may be indicated to prolong survival [Norwood et al 2007]. Patients should be monitored for signs of hypoventilation and for chest infections, to which they have an increased susceptibility. Intervention in the form of nocturnal ventilator assistance for respiratory failure may be life saving in severely affected patients.
  • Social and emotional support help to improve the quality of life, to maximize a sense of social involvement and productivity, and to reduce the sense of social isolation [Eggers & Zatz 1998].

Prevention of Secondary Manifestations

There are a number of measures that reverse disease manifestations in a symptomatic patient: control of weight gain, prevention of joint contractures by means of physical therapy and stretching exercises, and in the advanced stage, control of respiratory insufficiency. Physical therapy and stretching exercises can help to slow disease progression; therefore, a physical therapy program should be instituted early after diagnosis.

Surveillance

Annual monitoring of muscle strength, joint range of motion, and respiratory function is recommended.

Monitoring for orthopedic complications, such as foot deformities, scoliosis, and Achilles tendon contractures, is recommended.

Agents/Circumstances to Avoid

Strenuous and eccentric muscle exercise should be discouraged as it exacerbates muscle necrosis and could precipitate the onset of weakness or accelerate muscle wasting.

Body weight should be controlled to avoid obesity as well as excessive weight loss (atrophy of muscles can be accelerated by loss of muscle proteins).

Physical trauma, bone fractures, and immobility can induce disuse atrophy and thus should be avoided.

Although no association of the disease with malignant hyperthermia is reported, the use of succinylcholine and halogenated anesthetic agents should be avoided when possible. (See Malignant Hyperthermia Susceptibility.)

While the specific mechanism whereby cholesterol-lowering agents (e.g., statins) may produce muscle lesions is unknown, such drugs should be avoided when possible.

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of evaluation and subsequent surveillance.

  • If the CAPN3 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, clinical examination can be used to clarify the disease status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with calpainopathy do not have impaired uterine smooth muscle strength or function and typically have uncomplicated pregnancies. A higher incidence of abnormal fetal presentation was reported in wheelchair-bound patients with LGMD [Awater et al 2012]. Epidural blockade can be difficult in patients with severe spine deformities and appropriate general anaesthesia may be necessary. About half of persons with LGMD reported deterioration of clinical symptoms in pregnancy [Awater et al 2012].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Calpainopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one CAPN3 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a CAPN3 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • The offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant in CAPN3.
  • In populations with a high rate of consanguinity, the reproductive partner of an affected individual may be a carrier, in which case the risk to the offspring of being affected is 50%.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a CAPN3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible once the CAPN3 pathogenic variants have been identified in the family. Carrier testing for the reproductive partners of affected individuals and known carriers is possible and is generally done by sequence analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers (e.g., asymptomatic relatives of known affected individuals).

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the CAPN3 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@muscular-dystrophy.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Calpainopathy: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
LGMD2ACAPN315q15​.1Calpain-3CAPN3 homepage - Leiden Muscular Dystrophy pagesCAPN3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Calpainopathy (View All in OMIM)

114240CALPAIN 3; CAPN3
253600MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2A; LGMD2A

Gene structure. The longest CAPN3 transcript variant comprises 24 exons and covers a genomic region of 50 kb. It is expressed as a 3.5-kb transcript (2466 coding nucleotides). CAPN3 encodes a number of alternatively spliced transcripts [Herasse et al 1999]. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed [De Tullio et al 2003, Kawabata et al 2003]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A large number of benign CAPN3 allelic variants with no known or unknown pathogenic significance have been described [Richard et al 1999].

Pathogenic allelic variants. More than 480 pathogenic variants have been reported; they are distributed throughout CAPN3, although a few exons are more frequently involved [Anderson et al 1998, De Paula et al 2002, Zatz et al 2003, Fanin et al 2004].

Most pathogenic variants are single-nucleotide changes. Approximately 70% of mutant alleles have missense mutations; the remaining are a variety of null mutations (small deletions or insertions causing frameshift and premature stop codon, nonsense, and splice site mutations) [Richard et al 1999].

About 25% of causative mutations in CAPN3 are located at exon-intron boundaries and cause aberrant splicing [Krahn et al 2007, Blazquez et al 2008, Nascimbeni et al 2010]. Deep intronic mutations causing a pseudo-exonization of an intronic sequence have been reported [Blazquez et al 2008, Blazquez et al 2013], as well as large exonic deletions, the most frequent of which is a 31,012 bp deletion of exons 2-8 (c.309+4469_c.1116-1204del) [Richard et al 1999, Krahn et al 2007, Todorova et al 2007, Bartoli et al 2012].

Genomic rearrangements of Alu elements [Salem et al 2012], the entire CAPN3 gene deletion [Jaka et al 2014], and synonymous codon mutations [Richard & Beckmann 1995] have been occasionally reported.

In some populations most mutant alleles are clustered in a limited number of exons [Anderson et al 1998, De Paula et al 2002, Zatz et al 2003, Fanin et al 2004, Piluso et al 2005, Leiden Muscular Dystrophy Pages].

  • Approximately 80% of pathogenic variants reported in Brazil are clustered in exons 1, 2, 4, 5, 11, and 22 only [Zatz et al 2003].
  • Approximately 87% of pathogenic variants reported in Italy are found in exons 1, 4, 5, 8, 10, 11, and 21 [Fanin et al 2004].
  • Approximately 80% of pathogenic variants reported in France are clustered in exons 1, 4, 7, 10, 11, 13, 19, and 22 [Krahn et al 2006a].

Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele among individuals from different European countries [Richard et al 1999].

Pathogenic variants that recur in the following populations are most likely the result of a founder effect:

For more information, see Table A.

Table 2.

Selected CAPN3 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.550delAp.Thr184ArgfsTer33NM_000070​.2
NP_000061​.1
c.946-1G>A
(IVS6-1G>A)
--
c.1193+6T>A--
c.1795_1796insAp.Thr599AsnfsTer30
c.2306G>Ap.Arg769Gln
c.2362_2363delAGinsTCATCT
(2362AG>TCATCT)
p.Arg788SerfsTer13

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Calpain-3 is an enzymatic protein of approximately 94 kd molecular weight (also called p94) composed of 821 amino acids. It is the muscle-specific member of a family of Ca++-activated neutral proteases, which cleave proteins into short polypeptides. Calpain-3 is a multidomain protein with three exclusive sequence inserts (NS, IS1, IS2); domain I has a regulatory role, domain II is the proteolytic module, domain III has a C2-like domain, and domain IV binds Ca++ ions [Ono et al 1998]. Sequence NS has an unknown function [Sorimachi & Suzuki 2001]. Sequence IS1 includes three sites that are involved in autocatalytic activity [Kinbara et al 1998]. Sequence IS2 contains a nuclear translocation signal, suggesting that calpain-3 may have a function in the nucleus, processing transcription factors. Calpain-3 is expressed predominantly in skeletal muscle, where it is localized either in the nucleus or in the cytoplasm (where it binds to the protein titin) [Keira et al 2003]. The physiologic role of calpain-3 is still under investigation; it is thought to process proteins involved in signaling pathways, transcription factors, calcium transport, and cytoskeletal proteins as part of a process called sarcomere remodeling, in which the synthesis of novel proteins is balanced by the degradation of misfolded proteins [Baghdiguian et al 1999, Baghdiguian et al 2001, Kramerova et al 2005, Duguez et al 2006, Kramerova et al 2007, Beckmann & Spencer 2008, Benayoun et al 2008, Kramerova et al 2008, Saenz et al 2008, Fanin et al 2009c, Ono et al 2010, Ermolova et al 2011].

Abnormal gene product. CAPN3 pathogenic variants have a loss-of-function effect on translated protein. Most individuals with calpainopathy have complete or partial calpain-3 protein deficiency on muscle biopsy as a result of premature truncating mutations or increased protein instability (when caused by missense mutations). In 10%-30% of individuals with calpainopathy, muscle biopsies have a normal amount of protein [Talim et al 2001, De Paula et al 2002, Fanin et al 2004, Groen et al 2007, Milic et al 2007, Fanin et al 2009b] even though calpain-3 may have lost its autocatalytic activity and may be functionally inactive [Fanin et al 2003, Fanin et al 2007b].

The pathogenetic mechanism in calpainopathy is related to an impairment of its proteolytic activity toward substrates, which finally results in sarcomere remodeling by promoting sarcomeric protein ubiquitination for their degradation by the ubiquitin-proteasome system (UPS) [Duguez et al 2006]. Since isolated proteasomes are unable to degrade intact myofibrils, the degradation process may depend on ubiquitous calpains in the initial stage, and on the UPS in the later stages [Kramerova et al 2005, Beckmann & Spencer 2008, Rajakumar et al 2013]. The impaired sarcomere remodeling would also affect myoblast fusion and repair, as well as the regenerative capacity of muscle in calpainopathy. The activation of the muscle atrophy process appears to depend mainly on the induction of the UPS system [Fanin et al 2013].

References

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Suggested Reading

  1. Kang PB, Kunkel LM. The muscular dystrophies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 216.

Chapter Notes

Revision History

  • 26 November 2014 (me) Comprehensive update posted live
  • 5 July 2012 (me) Comprehensive update posted live
  • 8 July 2010 (cd) Revision: deletion/duplication analysis available clinically
  • 3 December 2007 (me) Comprehensive update posted to live Web site
  • 15 December 2005 (ca) Revision: prenatal diagnosis available
  • 10 May 2005 (me) Review posted to live Web site
  • 29 November 2004 (ca) Original submission
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