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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: July 5, 2012.

Summary

Disease 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 dystrophies (LGMDs) (Leyden-Möbius) 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) 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; and
  • 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 tiptoes, 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. Serum CK concentration is elevated (5-80 times normal). Muscle biopsy in individuals with severe disease reveals an active dystrophic process. CAPN3, which encodes proteolytic enzyme calpain-3, is the only gene known to be associated with calpainopathy. Approximately 80% of individuals with CAPN3 mutations show variable levels of calpain-3 protein deficiency. Although CAPN3 mutations are distributed throughout the length of the gene, most are clustered in a limited number of exons; mutation scanning of these regions detects approximately 90% of causative mutations. Sequence analysis of the entire coding region detects approximately 99% of mutations.

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 disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

Calpainopathy (also known as limb-girdle muscular dystrophy 2A, or LGMD2A) is suspected in individuals with the following:

  • Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age <12 years), adult onset, or late onset (age >30 years)
  • Atrophy of limb and trunk muscles; possible calf hypertrophy
  • 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

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.

Muscle CT scan or MRI

  • Wasting of muscles predominantly from the posterior compartment of the limbs, evident on clinical examination, is observed by muscle CT scan [Fardeau et al 1996]. The difference in distribution of muscle involvement between calpainopathy and other limb-girdle muscular dystrophies (LGMDs) (i.e., sarcoglycanopathies and dysferlinopathies) makes CT scan analysis an important element in clinical diagnosis (see Differential Diagnosis).
  • MRI scan confirms this selective involvement [Mercuri et al 2005] and shows in some cases edema-like changes [Fischer et al 2005, Borsato et al 2006, Degardin et al 2010, Stramare et al 2010, Wattjes et al 2010]. Muscle MRI is a useful tool in characterizing the degree of muscle atrophy and in some cases also the severity of the disease.

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.

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. Most individuals have the typical features of an active dystrophic process (increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers); others have mild and nonspecific myopathic features (increased central nuclei, fiber splitting, lobulated fibers, type 1 fiber predominance) [Luo et al 2011]. The extent of muscle regeneration is less than is typically observed in other LGMDs [Fanin et al 2007a, Saenz et al 2008, Hauerslev et al 2012]. Eosinophilic myositis is an early and transient feature of calpainopathy, which has been reported in individuals with increased CK levels [Brown & Amato 2006, Krahn et al 2006b, Oflazer et al 2009, Krahn et al 2011] and is not present in muscle from older affected individuals with typical calpainopathy. Wide variability can be observed among individuals who are homozygous for the same missense mutation [Chae et al 2001, Fanin et al 2003].

  • Calpain-3 immunohistochemical analysis. Absent immunohistochemical reaction was reported in muscle from affected individuals in whom the absent protein had previously been detected by immunoblotting [Kolski et al 2008, Charlton et al 2009]. This method appears however less sensitive than immunoblotting in detecting partial protein reduction.
  • Calpain-3 immunoblot analysis of muscle biopsy is the most useful diagnostic tool in calpainopathy. Approximately 80% of individuals with CAPN3 mutations show variable levels of calpain-3 protein deficiency (~58% of affected individuals have no detectable calpain-3 protein; 22% have partial reduction of the amount of protein) and 20% have a normal amount of protein (but with loss of protein function) [Fanin et al 2004, Groen et al 2007, Fanin et al 2009a].

Note: The results of calpain-3 immunoblot analysis need to be interpreted with caution, as the analysis is neither completely sensitive (i.e., it can yield false negative results) nor completely specific (i.e., it can yield false positive results). In particular, calpain-3 protein levels can be partially reduced in other muscular dystrophies such as dysferlinopathy and Udd muscular dystrophy (titinopathy) [Anderson et al 2000, Fanin et al 2001, Haravuori et al 2001]. Moreover, although calpain-3 protein is extremely stable in human muscle over time [Anderson et al 1998], the amount of protein can be partially reduced by the degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (especially partial thawing and exposure to moisture) [Anderson et al 1998, Fanin et al 2003]. The probability that an individual has calpainopathy (LGMD2A) is very high (84%) if calpain immunoblotting testing shows complete calpain-3 deficiency; the probability progressively decreases with the amount of protein detected [Fanin et al 2004, Fanin et al 2009a].

  • Assay of calpain-3 autolytic function in muscle is better than conventional immunoblot analysis in identifying those affected individuals in whom CAPN3 mutations affect the autolytic function of calpain-3 protein rather than the quantity of calpain-3 protein [Fanin et al 2007b].

Molecular Genetic Testing

Gene. CAPN3, which encodes proteolytic enzyme calpain-3, is the only gene in which mutations are known to cause calpainopathy.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Calpainopathy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CAPN3Sequence analysis of genomic or cDNA 4Sequence variants 5~99% 6
Deletion/duplication analysis 7Partial- and whole-gene deletions/duplicationsUnknown 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Sequence analysis of cDNA (from muscle or blood) may be more efficient than exon-by-exon genomic sequencing [Richard & Beckmann 1995]; functional consequences of variants detected in non-coding regions and deep-intronic mutations have been reported [Krahn et al 2007, Blazquez et al 2008, Nascimbeni et al 2010].

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Although CAPN3 mutations are distributed throughout the length of the gene [Richard et al 1999], in some populations most mutant alleles are clustered in a limited numbers 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]. (see also Molecular Genetics). Some laboratories serving a specific population may offer targeted mutation analysis of a mutation panel.

7. Testing that identifies deletions/duplications not readily 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.

8. Large genomic mutations [Richard et al 1999] including the frame-shift deletion of exons 2-8 [Todorova et al 2007] are a cause of calpainopathy.

Testing Strategy

To confirm/establish the diagnosis in a proband. The testing strategy used in the diagnosis of calpainopathy in a proband differs depending on the availability of diagnostic muscle biopsy. Elements of the diagnostic approach are summarized in Figure 1.

Figure 1

Figure

Figure 1. Diagnostic algorithm when calpainopathy (LGMD2A) is suspected

  • Individuals for whom muscle biopsy is available. Diagnostic muscle biopsy allows screening by western blot of multiple proteins that are responsible for different forms of LGMD. After exclusion of other protein defects (i.e., sarcoglycans, dystrophin, dysferlin, caveolin), calpain-3 protein immunoblot remains the most useful strategy in the diagnosis of calpainopathy [Pollitt et al 2001, Fanin et al 2009b].

    The subsequent steps, aimed at identifying gene mutations, vary according to the findings obtained from protein analysis:
    • In individuals with immunoblot-confirmed calpain-3 deficiency, the detection rate for one or two pathogenic CAPN3 mutations is approximately 84%. If two mutant alleles are identified, the genetic diagnosis is confirmed.
    • In individuals with immunoblot-confirmed calpain-3 protein deficiency and no identified CAPN3 mutations, genetic diagnosis of calpainopathy can neither be established nor excluded.
    • In individuals with normal amounts of calpain-3 protein on immunoblot analysis of muscle biopsy tissue, the diagnosis of calpainopathy appears unlikely but cannot be excluded because of possible functional enzyme defects. Such individuals have a residual risk of calpainopathy of approximately 9%. In these individuals, sequencing of CAPN3 can be pursued but the yield will be low.
  • Individuals for whom muscle biopsy is unavailable. Sequence analysis of CAPN3 is the optimal diagnostic step in these individuals [Nigro et al 2011].
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having calpainopathy is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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) 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, or late (age >30 years). Individuals with early onset and rapid disease course usually have pelvifemoral LGMD.
  • Scapulohumeral LGMD (Erb) 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 children or young individuals [Fanin et al 2009b, Kyriakides et al 2010].

The first clinical findings of calpainopathy are usually the tendency to walk on tiptoes, 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. 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 most affected [Fardeau 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 and exercise intolerance [Penisson-Besnier et al 1998]. In some individuals, eosinophilic myositis was also found [Krahn et al 2006b]. Calf hypertrophy is rarely observed, and in a number of cases, significant atrophy is observed. 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, 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]. Respiratory insufficiency with reduced lung vital capacity may be present. 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].

Genotype-Phenotype Correlations

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

Null homozygous mutations are generally associated with a severe phenotype.

Although it has been suggested that homozygous missense mutations are usually associated with a milder phenotype than null mutations [Fardeau et al 1996, Anderson et al 1998, Richard et al 1999, Chae et al 2001], the phenotypic consequences of homozygous missense mutations 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 mutation, even among individuals 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 mutations are usually associated with a lack of detectable protein, missense mutations 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.

Anticipation

Anticipation has not been described.

Nomenclature

Calpainopathy was formerly 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], 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 ranges from 10% of LGMD cases in a white population from the US [Chou et al 1999, Moore et al 2006], to 13% in Denmark [Duno et al 2008], 21% in the Netherlands [van der Kooi et al 2007], 25-28% in Italy [Guglieri et al 2008, Fanin et al 2009b], 26% in Japan [Kawai et al 1998], 50% in Turkey and India [Dincer et al 1997, Balci et al 2006, Pathak et al 2010], and 80% in the Basque country [Urtasun et al 1998] and Russia [Pogoda et al 2000]. In the latter countries and in consanguineous populations (La Reunion Island and the Old Order Amish community in North America), the disease can be ten times more common.

A founder effect for the 550delA mutation has been reported in Croatia [Milic & Canki-Klain 2005], Bulgaria [Todorova et al 2007], and Russia [Pogoda et al 2000].

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].

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. 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 muscular dystrophy (one of the calpainopathy phenotypes): muscle weakness with onset in the shoulder girdle, scapular winging, elevated serum CK concentration, and nonspecific myopathic changes on muscle biopsy. Facial muscle weakness and asymmetric 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:

  • Onset of weakness in the lower girdle muscles in adolescence or adulthood; and
  • Elevated serum CK concentrations; and
  • One of the following:
  • X-linked recessive pattern of inheritance (sometimes only resulting in elevated serum CK concentration in the proband's mother);
    • No family history of muscle disease;
    • Heart involvement (mainly dilated cardiomyopathy)

Diagnosis can be established by dystrophin immunoblot analysis on muscle biopsy or 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 Image SimulConsult.jpg, 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 in an individual diagnosed with calpainopathy, a complete physical evaluation including the grading of muscle strength in single muscles and the analysis of several functional performances is recommended.

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 and stretching exercises can promote mobility, prolong walking, slow the disease progression, in particular by maintaining joint flexibility.
  • 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 and the use of respiratory aids may be indicated to prolong survival. Affected individuals should be monitored for signs of hypoventilation and for chest infections, to which they have an increased susceptibility.
  • 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 person, i.e. 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

Relatives at risk (e.g., sibs of probands) should be clinically examined, especially if they may be affected. Molecular genetic testing can be offered to at-risk relatives when clinical findings suggest calpainopathy and the disease-causing mutations in the family are known.

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.

Therapies Under Investigation

The safety and efficacy of AAV-mediated calpain-3 gene transfer in a mouse model of calpainopthy has been reported [Bartoli et al 2006].

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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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 is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an affected individual are obligate heterozygotes (carriers) for a disease-causing mutation 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.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations 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 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 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

Normal allelic variants. 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].

Pathogenic allelic variants. More than 350 disease-causing mutations have been reported, most of which are private mutations. 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] (see Molecular Genetic Testing).

Most mutations 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]. Large genomic mutations [Richard et al 1999, Todorova et al 2007], synonymous codon mutations [Richard & Beckmann 1995], and intronic mutations causing aberrant splicing are further causes of calpainopathy [Krahn et al 2007, Blazquez et al 2008, Nascimbeni et al 2010].

In some populations most mutant alleles are clustered in a limited numbers 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 mutations reported in Brazil are clustered in exons 1, 2, 4, 5, 11, and 22 only [Zatz et al 2003].
  • Approximately 87% of mutations reported in Italy are found in exons 1, 4, 5, 8, 10, 11, and 21 [Fanin et al 2004].
  • Approximately 80% of mutations reported in France are clustered in exons 1, 4, 7, 10, 11, 13, 19, and 22 [Krahn et al 2006a].

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

Single mutations recur in the following populations, 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 Sequence
c.550delA p.Thr184ArgfsTer33NM_000070​.2
NP_000061​.1
c.946-1G>A
(IVS6-1G>A)
--
c.1193+6T>A--
c.1795_1796insA p.Thr599AsnfsTer30
c.2306G>A p.Arg769Gln
c.2362_2363delAGinsTCATCT
(2362AG>TCATCT)
p.Arg788SerfsTer13

Note on variant classification: Variants listed in the table have been provided by the author(s). 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]. 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]. Although 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 [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 mutations 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% to 30% of individuals, 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 2009a], even though calpain-3 may have lost its autocatalytic activity and may be functionally inactive [Fanin et al 2003, Fanin et al 2007b].

References

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Suggested Reading

  1. Kang PB, Kunkel LM. The muscular dystrophies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 216. New York, NY: McGraw-Hill. Available online. Accessed11-4-13.

Chapter Notes

Revision History

  • 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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