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Calpainopathy

, MD and , PhD.

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Initial Posting: ; Last Update: August 3, 2017.

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 severe to mild.

Three autosomal recessive 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 that may occur as early as before age 12 years or as late as 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 individuals are asymptomatic and have high serum creatine kinase (CK) concentrations

The autosomal dominant form of calpainopathy shows a variability of clinical phenotype, ranging from almost asymptomatic to wheelchair dependence after age 60 years in few cases with a generally milder phenotype than the recessive form.

Clinical findings of calpainopathy 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 established by identification of biallelic pathogenic variants in CAPN3 (encoding proteolytic enzyme calpain-3) or a dominantly acting heterozygous pathogenic variant for the CAPN3 21-bp deletion (c.643_663del21) by molecular genetic testing. If such testing is not available or not conclusive, muscle biopsy with protein immuno-analysis should be used for diagnostic confirmation.

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 prolonged immobility.

Genetic counseling.

Calpainopathy is typically inherited in an autosomal recessive manner. Less commonly, calpainopathy is inherited in an autosomal dominant manner. In the autosomal recessive form, 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. To date, all individuals diagnosed with autosomal dominant calpainopathy have inherited a pathogenic CAPN3 variant from a heterozygous parent. Testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the CAPN3 pathogenic variant(s) in the family are known.

GeneReview Scope

Calpainopathy: Included Phenotypes 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.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Calpainopathy is a form of limb-girdle muscular dystrophy (LGMD).

Suggestive Findings

Calpainopathy 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)
  • Symmetric 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
  • Elevated creatine kinase (CK) concentrations, especially in childhood or adolescence, with or without overt muscle symptoms
  • Absence of cardiomyopathy and intellectual disability
  • Back pain and myalgia; present in 50% of individuals with dominantly inherited calpainopathy [Vissing et al 2016]

Clinical testing

  • Serum creatine kinase (CK) concentration is always elevated (5-80x 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]. In the dominant form of calpainopathy, some individuals presented normal CK levels [Vissing et al 2016].
  • 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 established in a proband by identification of biallelic pathogenic variants in CAPN3 (encoding proteolytic enzyme calpain-3) or a dominantly acting heterozygous pathogenic variant for the CAPN3 21-bp deletion (c.643_663del21) by molecular genetic testing (Table 1). Molecular genetic testing approaches can include use of a multi-gene panel, more comprehensive genomic testing, and single-gene testing.

For calpainopathy, after the initial clinical workup and exclusion of the more common conditions with overlapping phenotypes, many experts recommend the use of a multi-gene panel or more comprehensive testing as the immediate next step (see Thompson & Straub [2016]). If the process generates a clear result (biallelic pathogenic variants or a dominantly acting heterozygous pathogenic variant), no further diagnostic laboratory workup is required; if the result is unclear, imaging studies and muscle biopsy with protein immuno-analysis come into play. See Muscle Biopsy.

Molecular Genetic Testing

A multi-gene panel that includes CAPN3 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Note: (1) As compared to direct sequencing, more comprehensive genome testing was able to improve the detection rate of calpainopathy [Ghaoui et al 2015, Savarese et al 2016, Magri et al 2017]. (2) Many studies have revealed that this type of testing could be a time- and cost-effective method of diagnosing calpainopathy [Bushby 2009, Piluso et al 2011, Nigro & Piluso 2012, Nigro & Savarese 2014, Ghaoui et al 2015, Fadaee et al 2016, Kuhn et al 2016, Monies et al 2016, Seong et al 2016, Fattahi et al 2017, Magri et al 2017, Reddy et al 2017].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Single-gene testing may be recommended if a multi-gene panel and/or more comprehensive genomic testing is not available and calpainopathy appears to be a likely diagnosis based on clinical findings. Sequence analysis of CAPN3 is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Targeted analysis for specific pathogenic variants can be performed first in individuals from certain populations/backgrounds. See Molecular Genetics.

Table 1.

Molecular Genetic Testing Used in Calpainopathy

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
CAPN3Sequence analysis 3>95% 4, 5
Gene-targeted deletion/duplication analysis 6<5% 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

In individuals showing a severe calpain-3 protein deficiency in muscle biopsy, the probability of identifying pathogenic variants is about 84% [Fanin et al 2004].

5.

In approximately 20%-30% of individuals with calpainopathy, only one CAPN3 pathogenic variant was found, 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 [Fanin & Angelini 2015].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Large genomic rearrangements involving CAPN3 have been recognized as causative of calpainopathy [Richard et al 1999], including out-of-frame deletion of exons 2-8 [Joncourt et al 2003, Krahn et al 2007, Todorova et al 2007, Ginjaar et al 2008, Nascimbeni et al 2010], of exons 2-6 [Ginjaar et al 2008], or of the entire gene [Jaka et al 2014].

Muscle Biopsy

Muscle biopsy should be used when molecular genetic analysis is not conclusive, or for diagnostic confirmation.

Note: For this disorder, the results of the specialized studies are much more useful for diagnosis than the routine histopathology of muscle biopsy.

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

  • 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 (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [Vainzof et al 2003, Hermanová et al 2006, Keira et al 2007, Luo et al 2011].
  • The extent of muscle regeneration is less than is typically observed in other LGMDs [Fanin et al 2007a, Sáenz et al 2008, Hauerslev et al 2012, Rosales et al 2013].
  • Eosinophilic myositis can be an early and transient feature of calpainopathy, which has been reported in individuals with increased CK levels and is not present in muscle from older affected individuals with typical calpainopathy [Brown & Amato 2006, Krahn et al 2006b, Oflazer et al 2009, Krahn et al 2011].
  • There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [Fanin et al 2013] and is significantly higher in affected males than affected females [Fanin et al 2014].
  • Muscle biopsies from individuals with dominant calpainopathy show mild myopathic changes (including increased internal nuclei and fiber size variability, occasional necrotic fibers, ring fibers and fibrosis), which however do not reach in severity the level seen in individuals with autosomal recessive calpainopathy [Vissing et al 2016].

Specialized studies: calpain-3 immunoblot analysis. Calpain-3 immunoblot testing 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, Krahn et al 2006a, Fanin et al 2009b, Luo et al 2012]. Approximately 80% of individuals with pathogenic variants in 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 depends on phenotype and genotype and 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, Fanin & Angelini 2015].

Three phenotypes of autosomal recessive calpainopathy 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. HyperCKemia may be considered a presymptomatic stage of calpainopathy, as it is usually observed in children or in young persons with recessive calpainopathy [Fanin et al 2009a, Kyriakides et al 2010]. Asymptomatic individuals, who are identified as affected following genetic studies, may develop symptoms of muscle weakness later.

The autosomal dominant form of calpainopathy shows a variability of clinical phenotype, ranging from almost asymptomatic to wheelchair dependent after age 60 years in a small number of cases [Vissing et al 2016]. A prominent feature of such individuals is back pain and myalgia (present in >50% of the heterozygotes for the CAPN3 c.643_663del21 pathogenic variant). The onset of muscle weakness is on average at age 34 years –16 years later than British and Danish individuals with autosomal recessive calpainopathy. Unquestionably, the clinical phenotype of the dominant calpainopathy is generally milder than in recessive calpainopathy.

The first clinical findings of calpainopathy are usually:

  • The tendency to walk on tiptoe
  • Difficulty in running
  • Scapular winging

Early stage of the disorder

  • The following are frequently observed:
  • Variable findings include:
  • Muscle pain, exercise intolerance, and excessive lactate production in some individuals similar to that seen in a pseudo-metabolic myopathy [Pénisson-Besnier et al 1998, Pollitt et al 2001];
  • Eosinophilic myositis, an early and transient feature, with increased CK level; it is not present in older individuals [Brown & Amato 2006, Krahn et al 2006b, Krahn et al 2011];
  • Significant atrophy of the calf muscle or more rarely, calf hypertrophy;
  • Rhabdomyolysis (and/or myoglobinuria) triggered by physical exercise; occasionally observed in asymptomatic individuals or in individuals with mild muscle involvement [Lahoria & Milone 2016].

Advanced stage of the disorder

  • Commonly observed:
  • The inability to climb stairs, to rise up from a chair, to lift weights, or to get up from the floor
  • Joint contractures (in the hips, knees, elbows, and fingers)
  • Occasionally observed:
  • Uncommon: Cardiomyopathy. In most individuals cardiac symptoms that precede cardiac morbidity (including chest pain, lower limb oedema, palpitations) are not present, and cardiac abnormalities may be identified by echocardiography or electrocardiography. A systematic evaluation of heart involvement in a group of affected individuals using cardiovascular magnetic resonance showed the lack of cardiac involvement in this disorder, even in individuals with advanced age and greater disorder severity [Quick et al 2015]. A few individuals have presented with non-life-threatening cardiac abnormalities [Richard et al 2016], atrial fibrillation, or variably impaired left ventricular function [Groen et al 2007, Okere et al 2013, Mori-Yoshimura et al 2017].

Note: Neither intellectual disability nor macroglossia is associated with this disorder.

Progression and variability. The asymptomatic stage may be relatively long in some affected individuals, especially in females. In some individuals with calpainopathy, the onset of symptoms or the worsening of symptoms may be influenced by environmental factors, such as infectious disease, strenuous physical exercise, drug treatment, a traumatic event, or pregnancy [Sáenz et al 2005].

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, Sáenz et al 2005, Angelini et al 2010, Gallardo et al 2011, Richard et al 2016]. In general, loss of independent ambulation occurs earlier in individuals with infantile onset of the disease [Gallardo et al 2011].

A more rapid progression of the disease was observed in males than in females [de Paula et al 2002, Zatz et al 2003, Piluso et al 2005, Richard et al 2016]. In a natural history clinical study of affected individuals, a higher proportion of women were still walking as compared to men (72% versus 48% in men) [Richard et al 2016]. Males are more susceptible to muscle fiber atrophy than females and more affected by the consequent muscle weakness and clinical disability [Fanin et al 2014].

Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variant the age at onset and the clinical course can vary considerably [Schessl et al 2008], suggesting the influence of genetic background and environmental factors in determining the course of the disease.

Genotype-Phenotype Correlations

There is no consistent genotype-phenotype correlation in calpainopathy, although null homozygous variants are generally associated with a severe phenotype and absent calpain-3 protein in muscle [Richard et al 1999].

A single heterozygous in-frame c.643_663del21 pathogenic variant in CAPN3 results in a dominantly inherited form of calpainopathy [Vissing et al 2016].

Penetrance

Nearly full penetrance is observed in adulthood. Some individuals remain asymptomatic until adulthood. Serum CK concentration is usually increased until the advanced stage of the disease.

Nomenclature

Calpainopathy was originally called LGMD2A because it was the first form of autosomal recessive LGMD to be mapped [Beckmann et al 1991], but in recently revised nomenclature the designation LGMDR1 has been proposed (LGMDR refers to genetic types of LGMD showing autosomal recessive inheritance).

Vissing et al [2016] proposed that the recently characterized autosomal dominant form of calpainopathy associated with the c.643_663del21 pathogenic variant be designated LGMD1I in the current nomenclature (LGMD1 refers to genetic types of LGMD showing dominant inheritance), and designated LGMDD3 in revised nomenclature (LGMDD refers to genetic types of LGMD showing autosomal dominant inheritance).

As both recessive and dominant forms are associated with calpain-3 abnormality, calpainopathy is the preferred term for this disorder.

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 6%-8% of all LGMD in Australia, Korea, and Germany [Hanisch et al 2007, Shin et al 2007, Lo et al 2008, Ghaoui et al 2015, Seong et al 2016], to 4%-12% in the USA [Chou et al 1999, Moore et al 2006, Reddy et al 2017], 13% in Denmark [Duno et al 2008], 16% in Saudi Arabia [Monies et al 2016], 17%-18% in Mexico and northern China [Gómez-Díaz et al 2012, Mahmood et al 2013], 21% in the Netherlands [van der Kooi et al 2007], 21%-26% in Japan and Lithuania [Kawai et al 1998, Minami et al 1999, Luo et al 2011, Inashkina et al 2016], 24% in Iran [Fattahi et al 2017], 25%-35% in Italy, Germany, and northern England [Piluso et al 2005, Guglieri et al 2008, Fanin et al 2009a, Norwood et al 2009, Kuhn et al 2016, Magri et al 2017], 32% in Brazil [Zatz et al 2000], 33% in Czech Republic [Stehlíková et al 2014], 40%-50% in France, Turkey, Spain, India, Slovenia, and Bulgaria [Dinçer et al 1997, Richard et al 1997, Meznaric-Petrusa et al 2002, Georgieva et al 2005, Sáenz et al 2005, Balci et al 2006, Todorova et al 2007, Pathak et al 2010], and 80% in Basque country, Russia, and Poland [Urtasun et al 1998, Pogoda et al 2000, Dadali et al 2010, Dorobek et al 2015].

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].

Higher prevalence rates have been calculated in small and genetically isolated communities; the prevalence of the disease has been estimated at 48 per million in the Reunion Island [Fardeau et al 1996], 69 per million in Basque country [Urtasun et al 1998], 1900 per million in the Mòcheni community in the Alps [Fanin et al 2012], 4300 per million in the Tlaxcala village in central Mexico (with a carrier frequency of 1:11) [Pantoja-Melendez et al 2017], and 13000 per million in the Amish population of Indiana [Young et al 1992, Richard et al 1995].

Three general population screening studies of the most common CAPN3 pathogenic variant (c.550delA) in Lithuania, Croatia, and Poland resulted in the identification of healthy carriers, corresponding to estimated carrier frequencies of 1:175, 1:133, and 1:124 respectively [Canki-Klain et al 2004, Dorobek et al 2015, Inashkina et al 2016].

Differential Diagnosis

Other forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2 or LGMDR in revised nomenclature; see OMIM Phenotypic Series: Muscular dystrophy, limb-girdle, autosomal recessive) 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 pathogenic variants and confirm a diagnosis of a specific form 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, Sacconi et al 2012] in which muscle weakness with onset in the shoulder girdle, scapular winging, elevated serum CK concentration, and nonspecific myopathic changes on muscle biopsy can be seen. However, facial muscle weakness and asymmetric scapular muscle involvement, which can be observed in FSHD, are uncommon in calpainopathy. Inheritance is autosomal dominant; although some controversy remains, FSHD is likely caused by inappropriate expression of the double homeobox-containing gene DUX4 in muscle cells.

In a few cases, both a contracted D4Z4 fragment (DUX4) and a heterozygous pathogenic variant in CAPN3 have been identified in association with limb-girdle and facioscapulohumeral muscular dystrophy-like phenotype [Pastorello et al 2012, Simeoni et al 2015].

Dystrophinopathy. The dystrophinopathies include a spectrum of muscle disease caused by pathogenic variants in DMD, which encodes the protein dystrophin. Dystrophinopathy was diagnosed in about 17% of individuals 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.

Becker muscular dystrophy (BMD), muscle disease at the mild end of the dystrophinopathy spectrum, 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. An X-linked pattern of inheritance or the presence of heart involvement (mainly dilated cardiomyopathy), distinguish BMD from calpainopathy [Shaboodien et al 2015].

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 [Pénisson-Besnier et al 1998, Pollitt et al 2001]. In metabolic myopathies muscle weakness can be either distal (e.g., glycogenosis type 3) or proximal (e.g., glycogenosis type 2) and may be transitory (e.g., CPT-2 deficiency) or permanent (e.g., glycogenosis type 2 and glycogenosis type 5). Metabolic myopathies are also different from calpainopathy because of vacuolar muscle biopsy histopathologic features (e.g., glycogen storage).

The association between rhabdomyolysis and LGMD is less recognized than the association between rhabdomyolysis and metabolic myopathies (i.e. CPT2 deficiency); this often leads to misdiagnosis or delayed diagnosis. Some individuals with calpainopathy presented rhabdomyolytic episodes, mild muscle weakness, and persistent elevation of CK levels even at distance from a myoglobinuric episode (whereas in metabolic myopathies CK levels between myoglobinuric episodes is usually normal) [Lahoria & Milone 2016].

Myopathy with contractures. The phenotype of calpainopathy may include muscle weakness with severe tendon contractures [Pollitt et al 2001, Gallardo et al 2011, Richard et al 2016], raising the possibility of Emery-Dreifuss muscular dystrophy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with calpainopathy, the following evaluations are recommended if they have not already been completed:

  • 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
  • When walking ability is compromised, an evaluation for physical therapy and orthoses, especially in later stages of the disease
  • Baseline pulmonary function testing (including forced vital capacity measurement)
  • Baseline cardiac evaluation including echocardiogram
  • Consultation with a clinical geneticist and/or genetic counselor

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], and revised by the Committee of the American Academy of Neurology [Narayanaswami et al 2014]:

  • A passive physical therapy program [Oygard et al 2011] and stretching exercises should be instituted early after diagnosis to promote mobility, prolong walking, and slow the disease progression, in particular by maintaining joint flexibility. Individuals usually benefit from strengthening and gentle [Sveen et al 2013], low-impact aerobic exercise (swimming, stationary bicycling) with a supervised sub-maximal effort, which improves cardiovascular performance, increases muscle efficiency, and lessens muscle fatigue. Although there are no specific reports on supportive care, physical and occupational therapies are important [Eagle 2002].
  • Avoidance of prolonged immobility is recommended.
  • Technical aids can also compensate for the loss of certain motor abilities; canes, walkers, orthotics, and wheelchairs enable individuals to regain independence. The use of knee-ankle-foot orthoses at bedtime is recommended to prevent contractures. Scoliosis occurs mainly after wheelchair dependence and attention should be paid to seating [Norwood et al 2007].
  • 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 [Pollitt et al 2001, Norwood et al 2007, D’Angelo et al 2011, Richard et al 2016, Mori-Yoshimura et al 2017].
    • Individuals should be monitored for signs of nocturnal hypoventilation (sleep disturbances, early morning headache, daytime drowsiness).
    • Overnight pulse oxymetry is recommended if forced vital capacity is lower than 60% and the demonstration of nocturnal hypoventilation should lead to noninvasive nocturnal ventilation [Norwood et al 2007].
    • Intervention in the form of nocturnal ventilator assistance for respiratory failure (by noninvasive positive pressure ventilation, NIV, by nasal masks) may be life saving in severely affected individuals [Dirik et al 2001, Hashiguchi et al 2014, Mori-Yoshimura et al 2017].
    • Wheelchair-bound individuals may also develop weak cough efforts, placing them at risk of atelectasia, pneumonia, progressive mismatch, and respiratory failure.
    • Annual influenza vaccination and prompt treatment for chest and respiratory infections should be eventually addressed using a mechanical in-ex-sufflator [Mori-Yoshimura et al 2017].
  • 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].
  • Clinicians should anticipate and facilitate decision-making for affected individuals and their families as the disease progresses, including decisions regarding loss of mobility and need of assistance with activities of daily living, medical complications, and end-of-life care [Narayanaswami et al 2014].

Prevention of Secondary Manifestations

There are a number of measures that decrease disease manifestations in a symptomatic individual: 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

The following are appropriate:

  • Annual monitoring of muscle strength, joint range of motion, and respiratory function:
    • Monitoring for orthopedic complications, such as foot deformities, scoliosis, and Achilles tendon contractures
    • Referral for pulmonary evaluation (eventually including pulmonary function tests) when there are complaints of excessive daytime somnolence, non-restorative sleep, early morning headache [Narayanaswami et al 2014]. Measurement of forced vital capacity should be made in sitting and supine position.
  • Examination of cardiac function in the advanced stage of disease (although it is not frequently compromised) [Dirik et al 2001, Okere et al 2013].

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. Although individuals with minimal muscle weakness and functional limitation may be able to perform strenuous exercise, in some cases this may result in rhabdomyolysis and myoglobinuria [Lahoria & Milone 2016] which may lead to severe complications such as acute renal failure and compartment syndrome.

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 prolonged 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 damage causing pain or weakness is unknown, such drugs should be avoided when possible.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the CAPN3 pathogenic variant in the family in order to identify as early as possible those who would benefit from initiation of evaluation and subsequent surveillance. With the associated intrafamilial phenotype variability, the possibility of calpainopathy should not be excluded in sibs on the basis of absence of symptoms alone.

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 individuals with LGMD [Awater et al 2012]. Epidural blockade can be difficult in those 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 typically inherited in an autosomal recessive manner. Less commonly, calpainopathy is inherited in an autosomal dominant manner.

Risk to Family Members – Autosomal Recessive Inheritance

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

Carrier (heterozygote) detection

  • Carrier testing for at-risk family members requires prior identification of the CAPN3 pathogenic variants in the family.
  • If the reproductive partner of an affected individual (or known carrier) belongs to the same genetic isolate and is therefore at an increased risk of being a carrier of an CAPN3 pathogenic variant (see Prevalence), carrier testing may be requested and is generally done by sequence analysis.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • If a parent of the proband is affected and/or is known to be heterozygous for the CAPN3 pathogenic variant, the risk to sibs is 50%. Intrafamilial clinical variability ranging from asymptomatic to wheelchair dependence has been observed [Vissing et al 2016].
  • If the CAPN3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
  • If both parents are clinically unaffected but have not been tested for the CAPN3 pathogenic variant, the sibs of a proband are still at increased risk for calpainopathy because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant calpainopathy has a 50% chance of inheriting the CAPN3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CAPN3 pathogenic variant, his or her family members may be at risk.

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 and Preimplantation Genetic Diagnosis

Once the CAPN3 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. Prenatal diagnosis for calpainopathy has been requested from heterozygous couples, who previously had an affected child [Restagno et al 1996].

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 UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CAPN315q15​.1Calpain-3CAPN3 homepage - Leiden Muscular Dystrophy pagesCAPN3CAPN3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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].

Muscle tissue expresses only one isoform (the full-length transcript), whereas leukocytes express four different transcripts (produced by alternative splicing of exons 6,15,16), all of which lack exon 15. Since peripheral blood instead of muscle tissue has increasingly been used to obtain mRNA for cDNA sequencing, the results of the two analyses could be discordant in some cases [Blázquez et al 2008]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. According to the Leiden Muscular Dystrophy Mutation Database, more than 490 pathogenic variants have been reported; they are distributed throughout CAPN3 [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 abnormal alleles are missense variants; the remaining are a variety of loss-of-function variants (small deletions or insertions causing frameshift and premature stop codon, nonsense, and splice site variants) [Richard et al 1999].

About 25% of pathogenic variants in CAPN3 are located at exon-intron boundaries and cause aberrant splicing [Krahn et al 2007, Blázquez et al 2008, Nascimbeni et al 2010].

Many deep intronic pathogenetic variants that disrupt the correct splicing can be overlooked by sequencing of genomic DNA [Krahn et al 2007]; their identification may require the sequencing of cDNA obtained from muscle or blood tissues [Krahn et al 2006a, Blázquez et al 2008, Nascimbeni et al 2010].

Deep intronic variants causing a pseudo-exonization of an intronic sequence have been reported [Blázquez et al 2008, Blázquez et al 2013], as well as large exon deletions, the most frequent of which is an out-of-frame 31,012-bp deletion of exons 2-8 (c.309+4469_c.1116-1204del) [Richard et al 1999, Joncourt et al 2003, Krahn et al 2007, Todorova et al 2007, Ginjaar et al 2008, Nascimbeni et al 2010, Piluso et al 2011, Bartoli et al 2012]. Since this deletion recurs in calpainopathy in individuals from different ethnic backgrounds, it is probably due to independent mutation events [Todorova et al 2007].

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

A single heterozygous in-frame c.643_663del21 pathogenic variant in CAPN3 results in a dominantly inherited form of calpainopathy [Vissing et al 2016]. Of note, this variant has been identified in compound heterozygosity with other pathogenic variants in CAPN3, including c.2362_2363delinsTCATCT, c.550delA, p.Ala45Thr, and p.Asp419Gly [Richard et al 1997, Groen et al 2007, Sáenz & López de Munain 2017].

Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele (accounting for up to 75% of abnormal alleles) 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 followed by genetic isolation; especially in small populations, the accumulation of specific pathogenic variants (also called “private mutations”) may be explained by consanguinity associated with historical, demographic, or cultural/religious factors:

For more information, see Table A.

Table 2.

Selected CAPN3 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.133G>Ap.Ala45ThrNM_000070​.2
NP_000061​.1
c.347C>A 2p.Ala116Asp
c.550delAp.Thr184ArgfsTer33
c.643_663del21p.Ser215_Gly221del
c.946-1G>A
(IVS6-1G>A)
--
c.1193+6T>A
c.1265A>Gp.Asp419Gly
c.1466G>Ap.Arg489Gln
c.1795_1796insAp.Thr599AsnfsTer30
c.2051-1G>T
c.2099-1G>T
c.2306G>Ap.Arg769Gln
c.2338G>Cp.Asp780His
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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

This variant was reported as c.348C>A; however, based on the sequencing trace in Pantoja-Melendez et al [2017] the correct naming of this variant is c.347C>A.

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) [Ono et al 1998]:

  • Domain I. Regulatory role
  • Domain II. Proteolytic module
  • Domain III. C2-like domain
  • Domain IV. Binds Ca++ ions [Ono et al 1998].
  • Sequence NS. Unknown function [Sorimachi & Suzuki 2001]
  • Sequence IS1. Three autocatalytic sites [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. Upon stimulation, calpain-3 both activates and inactivates itself rapidly through autocatalysis. In the sarcomeres, calpain-3 directly binds to titin [Keira et al 2003] and changes its localization from the M-lines to the NA2 regions as the sarcomeres extend. Calpain-3 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, Sáenz et al 2008, Fanin et al 2009c, Ono et al 2010, Ermolova et al 2011].

Abnormal gene product. The majority of CAPN3 pathogenic variants are loss-of-function variants and result in recessive disease. Most individuals with calpainopathy have complete or partial calpain-3 protein deficiency on muscle biopsy. In 10%-30% of individuals with calpainopathy, muscle biopsy shows 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 mobility of calpain-3 between the sarcomeric M-lines and the cytosol may have a key role in physical stress, and it is compromised in calpainopathy when its protease activity has been lost. An impairment of calpain proteolytic activity results in sarcomere remodeling by promoting ubiquitin-mediated degradation of sarcomeric proteins [Duguez et al 2006]. This 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]. 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 ubiquitin-proteasome system [Fanin et al 2013].

The mechanism by which CAPN3 pathogenic variants result in a dominant disease has been proposed to be a dominant-negative effect [Vissing et al 2016]. Since the active calpain-3 is a homodimer, the aberrant protein could polymerize with the wild type protein and render the complex inactive.

References

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Suggested Reading

  • 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). Chap 216. New York, NY: McGraw-Hill.

Chapter Notes

Revision History

  • 3 August 2017 (ha) 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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