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Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

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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.


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.


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.


For other genetic causes of these phenotypes see Differential 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 multigene 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 multigene 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 multigene 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 are likely to change over time. (2) ) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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 multigene 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 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
CAPN3 Sequence analysis 3>95% 4, 5
Gene-targeted deletion/duplication analysis 6<5% 7

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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.


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].


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].


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.


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].


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.


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.


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]. Multigene 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.

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.


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.


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 in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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.

Autosomal Recessive Inheritance – 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.
  • 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 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.

Autosomal Dominant Inheritance – Risk to Family Members

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/preimplantatin genetic 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).

Prenatal Testing and Preimplantation Genetic Testing

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 testing are possible. Prenatal testing for calpainopathy has been requested from heterozygous couples who previously had an affected child [Restagno et al 1996].


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
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • Muscular Dystrophy Association (MDA) - USA
    Phone: 800-572-1717
    Email: ResourceCenter@mdausa.org
  • Muscular Dystrophy UK
    United Kingdom
    Phone: 0800 652 6352

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
CAPN3 15q15​.1 Calpain-3 CAPN3 homepage - Leiden Muscular Dystrophy pages CAPN3 CAPN3

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

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.Ala45Thr NM_000070​.2
c.347C>A 2p.Ala116Asp

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

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


Variant designation that does not conform to current naming conventions


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.


Literature Cited

  • Anderson LV, Davison K, Moss JA, Richard I, Fardeau M, Tome FM, Hubner C, Lasa A, Colomer J, Beckmann JS. Characterization of monoclonal antibodies to calpain 3 and protein expression in muscle from patients with limb-girdle muscular dystrophy type 2A. Am J Pathol. 1998;153:1169–79. [PMC free article: PMC1853046] [PubMed: 9777948]
  • Anderson LV, Harrison RM, Pogue R, Vafiadaki E, Pollitt C, Davison K, Moss JA, Keers S, Pyle A, Shaw PJ, Mahjneh I, Argov Z, Greenberg CR, Wrogemann K, Bertorini T, Goebel HH, Beckmann JS, Bashir R, Bushby KM. Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies). Neuromusc Disord. 2000;10:553–9. [PubMed: 11053681]
  • Anderson LVB, Davison K. Multiplex western blotting system for the analysis of muscular dystrophy proteins. Am J Pathol. 1999;154:1017–22. [PMC free article: PMC1866550] [PubMed: 10233840]
  • Angelini C, Nardetto L, Borsato C, Padoan R, Fanin M, Nascimbeni AC, Tasca E. The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B). Neurol Res. 2010;32:41–6. [PubMed: 20092694]
  • Ankala A, Kohn JN, Dastur R, Gaitonde P, Khadilkar SV, Hegde MR. Ancestral founder mutations in calpain-3 in the Indian Agarwal community: historical, clinical, and molecular perspective. Muscle Nerve. 2013;47:931–7. [PubMed: 23666804]
  • Arikawa E, Hoffman EP, Kaido M, Nonaka I, Sugita H, Arahata K. The frequency of patients with dystrophin abnormalities in a limb-girdle patient population. Neurology. 1991;41:1491–6. [PubMed: 1842672]
  • Awater C, Zerres K, Rudnik-Schöneborn S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur J Obstet Gynecol Reprod Biol. 2012;162:153–9. [PubMed: 22459654]
  • Baghdiguian S, Martin M, Richard I, Pons F, Astier C, Bourg N, Hay RT, Chemaly R, Halaby G, Loiselet J, Anderson LV, Lopez de Munain A, Fardeau M, Mangeat P, Beckmann JS, Lefranc G. Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IkappaB alpha/NF-kappaB pathway in limb-girdle muscular dystrophy type 2A. Nat Med. 1999;5:503–11. [PubMed: 10229226]
  • Baghdiguian S, Richard I, Martin M, Coopman P, Beckmann JS, Mangeat P, Lefranc G. Pathophysiology of limb girdle muscular dystrophy type 2A: hypothesis and new insights into the IkappaB alpha/NF-kappaB survival pathway in skeletal muscle. J Mol Med. 2001;79:254–61. [PubMed: 11485017]
  • Balci B, Aurino S, Haliloglu G, Talim B, Erdem S, Akcoren Z, Tan E, Caglar M, Richard I, Nigro V, Topaloğlu H, Dinçer P. Calpain-3 mutations in Turkey. Eur J Pediatr. 2006;165:293–8. [PubMed: 16411092]
  • Bartoli M, Negre P, Wein N, Bourgeois P, Pecheux C, Levy N, Krahn M. Validation of comparative genomic hybridization arrays for the detection of genomic rearrangements of the calpain-3 and dysferlin genes. Clin Genet. 2012;81:99–101. [PubMed: 22150418]
  • Beckmann JS, Richard I, Hillaire D, Broux O, Antignac C, Bois E, Cann H, Cottingham RW Jr, Feingold N, Feingold J, et al. A gene for limb-girdle muscular dystrophy maps to chromosome 15 by linkage. C R Acad Sci III. 1991;312:141–8. [PubMed: 1901754]
  • Beckmann JS, Spencer M. Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance. Neuromusc Disord. 2008;18:913–21. [PMC free article: PMC2614824] [PubMed: 18974005]
  • Benayoun B, Baghdiguian S, Lajmanovich A, Bartoli M, Daniele N, Gicquel E, Bourg N, Raynaud F, Pasquier MA, Suel L, Lochmuller H, Lefranc G, Richard I. NF-kB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. FASEB J. 2008;22:1521–9. [PubMed: 18073330]
  • Blázquez L, Aiastui A, Goicoechea M, Martins de Araujo M, Avril A, Beley C, García L, Valcárcel J, Fortes P, López de Munain A. In vitro correction of a pseudoexon-generating deep intronic mutation in LGMD2A by antisense oligonucleotides and modified small nuclear RNAs. Hum Mutat. 2013;34:1387–95. [PubMed: 23864287]
  • Blázquez L, Azpitarte M, Sáenz A, Goicoechea M, Otaegui D, Ferrer X, Illa I, Gutierrez-Rivas E, Vilchez JJ, López de Munain A. Characterization of novel CAPN3 isoforms in white blood cells: an alternative approach for limb-girdle muscular dystrophy 2A diagnosis. Neurogenetics. 2008;9:173–82. [PubMed: 18563459]
  • Borsato C, Padoan R, Stramare R, Fanin M, Angelini C. Limb-girdle muscular dystrophies type 2A and 2B: clinical and radiological aspects. Basic Appl Myol. 2006;16:17–25.
  • Brown RH Jr, Amato A. Calpainopathy and eosinophilic myositis. Ann Neurol. 2006;59:875–7. [PubMed: 16718709]
  • Burke G, Hillier C, Cole J, Sampson M, Bridges L, Bushby K, Barresi R, Hammans SR. Calpainopathy presenting as foot drop in a 41 year old. Neuromusc Disord. 2010;20:407–10. [PubMed: 20580976]
  • Bushby K. Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol. 2009;9:314–23. [PubMed: 19923111]
  • Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain. 1999;122:1403–20. [PubMed: 10430828]
  • Bushby KM, Beckmann JS (2003) The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies, Naarden, April 12-14, 2002. Neuromusc Disord 13:80-90.
  • Canki-Klain N, Milic A, Kovac B, Trlaja A, Grgicevic D, Zurak N, Fardeau M, Leturcq F, Kaplan JC, Urtizberea JA, Politano L, Piluso G, Feingold J. Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia. Am J Med Genet A. 2004;125A:152–6. [PubMed: 14981715]
  • Chae J, Minami N, Jin Y, Nakagawa M, Murayama K, Igarashi F, Nonaka I. Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy. Neuromusc Disord. 2001;11:547–55. [PubMed: 11525884]
  • Chou FL, Angelini C, Daentl D, Garcia C, Greco C, Hausmanowa-Petrusewicz I, Fidzianska A, Wessel H, Hoffman EP. Calpain III mutation analysis of a heterogeneous limb-girdle muscular dystrophy population. Neurology. 1999;52:1015–20. [PubMed: 10102422]
  • Chrobáková T, Hermanová M, Kroupová I, Vondrácek P, Maríková T, Mazanec R, Zámecník J, Stanek J, Havlová M, Fajkusová L. Mutations in Czech LGMD2A patients revealed by analysis of calpain3 mRNA and their phenotypic outcome. Neuromusc Disord. 2004;14:659–65. [PubMed: 15351423]
  • Dadali EL, Shagina OA, Ryzhkova OP, Rudenskaia GE, Fedotov VP, Poliakov AV. Clinical-genetic characteristics of limb girdle-muscular dystrophy type 2A. Zh Nevrol Psikhiatr Im S S Korsakova. 2010;110:79–83.
  • D'Angelo MG, Romei M, Lo Mauro A, Marchi E, Gandossini S, Bonato S, Comi GP, Magri F, Turconi AC, Pedotti A, Bresolin N, Aliverti A. Respiratory pattern in an adult population of dystrophic patients. J Neurol Sci. 2011;306:54–61. [PubMed: 21529845]
  • Degardin A, Morillon D, Lacour A, Cotten A, Vermersch P, Stojkovic T. Morphologic imaging in muscular dystrophies and inflammatory myopathies. Skeletal Radiol. 2010;39:1219–27. [PubMed: 20449587]
  • de Paula F, Vainzof M, Passos-Bueno MR, de Cássia M, Pavanello R, Matioli SR, Anderson L, Nigro V, Zatz M. Clinical variability in calpainopathy: what makes the difference? Eur J Hum Genet. 2002;10:825–32. [PubMed: 12461690]
  • De Tullio R, Stifanese R, Salamino F, Pontremoli S, Melloni E. Characterization of a new p94-like calpain form in human lymphocytes. Biochem J. 2003;375:689–96. [PMC free article: PMC1223710] [PubMed: 12882647]
  • Díaz-Manera J, Llauger J, Gallardo E, Illa I. Muscle MRI in muscular dystrophies. Acta Myol. 2015;34:95–108. [PMC free article: PMC4859076] [PubMed: 27199536]
  • Dinçer P, Leturcq F, Richard I, Piccolo F, Yalnizoglu D, de Toma C, Akçören Z, Broux O, Deburgrave N, Brenguier L, Roudaut C, Urtizberea JA, Jung D, Tan E, Jeanpierre M, Campbell KP, Kaplan JC, Beckmann JS, Topaloğlu H. A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey. Ann Neurol. 1997;42:222–9. [PubMed: 9266733]
  • Dirik E, Aydin A, Kurul S, Sahin B. Limb girdle muscular dystrophy type 2A presenting with cardiac arrest. Pediatr Neurol. 2001;24:235–7.
  • Dorobek M, Ryniewicz B, Kabzinska D, Fidzianska A, Styczynska M, Hausmanowa-Petrusewicz I. The frequency of c.550delA mutation of the CAPN3 gene in the Polish LGMD2A population. Genet Test Mol Biomarkers. 2015;19:637–40. [PubMed: 26484845]
  • Duguez S, Bartoli M, Richard I. Calpain 3: a key regulator of the sarcomere? FEBS J. 2006;273:3427–36. [PubMed: 16884488]
  • Duno M, Sveen ML, Schwartz M, Vissing J. cDNA analyses of CAPN3 enhance mutation detection and reveal a low prevalence of LGMD2A patients in Denmark. Eur J Hum Genet. 2008;16:935–40. [PubMed: 18337726]
  • Eagle M. Report on the muscular dystrophy campaign workshop: exercise in neuromuscular diseases. Newcastle, January 2002. Neuromusc Disord. 2002;12:975–83. [PubMed: 12467755]
  • Eggers S, Zatz M. Social adjustment in adult males affected with progressive muscular dystrophy. Am J Med Genet. 1998;81:4–12. [PubMed: 9514580]
  • Ermolova N, Kudryashova E, DiFranco M, Vergara J, Kramerova I, Spencer MJ. Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3. Hum Mol Genet. 2011;20:3331–45. [PMC free article: PMC3153300] [PubMed: 21624972]
  • Fadaee M, Kariminejad A, Fattahi Z, Nafissi S, Reza Godarzi H, Beheshtian M, Vazehan R, Reza Akbari M, Kahrizi K, Najmabadi H. report of limb girdle muscular dystrophy type 2A in six Iranian patients, one with a novel deletion in CAPN3 gene. Neuromusc Disord. 2016;26:277–82. [PubMed: 27020652]
  • Fanin M, Angelini C. Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: the yield and the pitfalls. Muscle Nerve. 2015;52:163–73. [PubMed: 25900067]
  • Fanin M, Benedicenti F, Fritegotto C, Nascimbeni A, Peterle E, Stanzial F, Cristofoletti A, Castellan C, Angelini C. An intronic mutation causes severe LGMD2A in a large inbred family belonging to a genetic isolate in the Alps. Clin Genet. 2012;82:601–2. [PubMed: 22486197]
  • Fanin M, Fulizio L, Nascimbeni AC, Spinazzi M, Piluso G, Ventriglia VM, Ruzza G, Siciliano G, Trevisan CP, Politano L, Nigro V, Angelini C. Molecular diagnosis in LGMD2A: mutation analysis or protein testing? Hum Mutat. 2004;24:52–62. [PubMed: 15221789]
  • Fanin M, Nardetto L, Nascimbeni AC, Tasca E, Spinazzi M, Padoan R, Angelini C. Correlations between clinical severity, genotype and muscle pathology in limb girdle muscular dystrophy type 2A. J Med Genet. 2007a;44:609–14. [PMC free article: PMC2597960] [PubMed: 17526799]
  • Fanin M, Nascimbeni AC, Angelini C. Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations. J Med Genet. 2007b;44:38–43. [PMC free article: PMC2597906] [PubMed: 16971480]
  • Fanin M, Nascimbeni AC, Angelini C. Gender difference in limb-girdle muscular dystrophy: a muscle fiber morphometric study in 101 patients. Clin Neuropathol. 2014;33:179–85. [PubMed: 24618072]
  • Fanin M, Nascimbeni AC, Angelini C. Muscle atrophy in limb girdle muscular dystrophy 2A: a morphometric and molecular study. Neuropathol Appl Neurobiol. 2013;39:762–71. [PubMed: 23414389]
  • Fanin M, Nascimbeni AC, Aurino S, Tasca E, Pegoraro E, Nigro V, Angelini C. Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes. Neurology. 2009a;72:1432–5. [PubMed: 19380703]
  • Fanin M, Nascimbeni AC, Fulizio L, Angelini C. The frequency of limb girdle muscular dystrophy 2A in northeastern Italy. Neuromusc Disord. 2005;15:218–24. [PubMed: 15725583]
  • Fanin M, Nascimbeni AC, Fulizio L, Trevisan CP, Meznaric-Petrusa M, Angelini C. Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression. Am J Pathol. 2003;163:1929–36. [PMC free article: PMC1892408] [PubMed: 14578192]
  • Fanin M, Nascimbeni AC, Tasca E, Angelini C. How to tackle the diagnosis of limb-girdle muscular dystrophy 2A. Eur J Hum Genet. 2009b;17:598–603. [PMC free article: PMC2986267] [PubMed: 18854869]
  • Fanin M, Pegoraro E, Matsuda-Asada C, Brown RH Jr, Angelini C. Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology. 2001;56:660–5. [PubMed: 11245721]
  • Fanin M, Tasca E, Nascimbeni AC, Angelini C. Sarcolemmal neuronal nitric oxide synthase defect in limb girdle muscular dystrophy: an adverse modulating factor in the disease course? J Neuropathol Exp Neurol. 2009c;68:383–90. [PubMed: 19287313]
  • Fardeau M, Hillaire D, Mignard C, Feingold N, Feingold J, Mignard D, de Ubeda B, Collin H, Tome FM, Richard I, Beckmann J. Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion Island. Brain. 1996;119:295–308. [PubMed: 8624690]
  • Fattahi Z, Kalhor Z, Fadaee M, et al. Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population. Clin Genet. 2017;91:386–402. [PubMed: 27234031]
  • Fischer D, Walter MC, Kesper K, Petersen JA, Aurino S, Nigro V, Kubisch C, Meindl T, Lochmüller H, Wilhelm K, Urbach H, Schröder R. Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs. J Neurol. 2005;252:538–47. [PubMed: 15726252]
  • Gallardo E, Sáenz A, Illa I. Limb-girdle muscular dystrophy 2A. Handb Clin Neurol. 2011;101:97–110. [PubMed: 21496626]
  • Georgieva B, Todorova A, Kremensky I, Tournev I, Mines V, Plageras P. 550delA mutation in the calpain 3 (CAPN3) gene: DMD/BMD, SMA, or LGMD2A clinically misdiagnosed cases. Am J Med Genet. 2005;136A:399–400. [PubMed: 16001438]
  • Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O’Grady G, Kaur S, Ong R, Davis M, Sue CM, Liang NG, North KN, MacArthur DG, Clarke NF. Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy. Outcomes and lessons learned. JAMA Neurol. 2015;72:1424–32. [PubMed: 26436962]
  • Ginjaar I, Tuit S, Frankhuizen W, van der Kooi A, Doorn P, Sival D, Bakker E. MLPA analysis of the CAPN3 gene detects large deletions in LGMD2A patients. Neuromuscul Disord. 2008;18:816A.
  • Gómez-Díaz B, Rosas-Vargas H, Roque-Ramirez B, Meza-Espinoza P, Ruano-Calderon LA, Fernandez-Valverde F, Escalante-Bautista D, Escobar-Cedillo RE, Sanchez-Chapul L, Vargas-Canas S, Lopez-Hernandez LB, Bahena-Martinez E, Luna-Angulo AB, Canto P, Coral-Vazquez RM. Immunodetection analysis of muscular dystrophies in Mexico. Muscle Nerve. 2012;45:338–45. [PubMed: 22334167]
  • Groen EJ, Charlton R, Barresi R, Anderson LV, Eagle M, Hudson J, Koref MS, Straub V, Bushby KMD. Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy. Brain. 2007;130:3237–49. [PubMed: 18055493]
  • Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, Cagliani R, Mora M, Fortunato F, Bordoni A, Del Bo R, Ghezzi S, Pagliarani S, Lucchiari S, Salani S, Zecca C, Lamperti C, Ronchi D, Aguennouz M, Ciscato P, Di Blasi C, Ruggieri A, Moroni I, Turconi A, Toscano A, Moggio M, Bresolin N, Comi GP. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mut. 2008;29:258–66. [PubMed: 17994539]
  • Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002;71:492–500. [PMC free article: PMC379188] [PubMed: 12145747]
  • Hanisch F, Müller CR, Grimm D, Xue L, Traufeller K, Merkenschlager A, Zierz S, Deschauer M. Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients. Clin Neuropathol. 2007;26:157–63. [PubMed: 17702496]
  • Haravuori H, Vihola A, Straub V, Auranen M, Richard I, Marchand S, Voit T, Labeit S, Somer H, Peltonen L, Beckmann JS, Udd B. Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology. 2001;56:869–77. [PubMed: 11294923]
  • Hashiguchi S, Adachi K, Arii Y, Kashiwagi S, Sato M, Kagawa N, Kawai H. A clinic-pathological investigation of two autopsy cases of calpainopathy (LGMD2A). Brain Nerve. 2014;66:1097–102. [PubMed: 25200581]
  • Hauerslev S, Sveen ML, Duno M, Angelini C, Vissing J, Krag TO. Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies. BMC Musculoskelet Disord. 2012;13:43. [PMC free article: PMC3338386] [PubMed: 22443334]
  • Herasse M, Ono Y, Fougerousse F, Kimura E, Stockholm D, Beley C, Montarras D, Pinset C, Sorimachi H, Suzuki K, Beckmann JS, Richard I. Expression and functional characteristics of calpain 3 isoforms generated through tissue-specific transcriptional and posttranscriptional events. Mol Cell Biol. 1999;19:4047–55. [PMC free article: PMC104364] [PubMed: 10330145]
  • Hermanová M, Zapletalová E, Sedlácková J, Chrobáková T, Letocha O, Kroupová I, Zámecník J, Vondrácek P, Mazanec R, Maríková T, Vohánka S, Fajkusová L. Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients. Muscle Nerve. 2006;33:424–32. [PubMed: 16372320]
  • Inashkina I, Jankevics E, Stavusis J, Vasiljeva I, Viksne K, Micule I, Strautmanis J, Naudina MS, Cimbalistiene L, Kucinskas V, Krumina A, Utkus A, Burnyte B, Matuleviciene A, Lace B. Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies. BMC Musculoskelet Disord. 2016;17:200. [PMC free article: PMC4855345] [PubMed: 27142102]
  • Jaka O, Azpitarte M, Paisan-Ruiz C, Zulaika M, Casas-Fraile L, Sanz R, Trevisiol N, Levy N, Bartoli M, Krahn M, Lopez de Munain A, Sáenz A. Entire CAPN3 gene deletion in a patient with limb girdle muscular dystrophy type 2A. Muscle Nerve. 2014;50:448–53. [PubMed: 24715573]
  • Joncourt F, Burgunder J, Steinlin M, Gallati S. LGMD2A caused by a large deletion: clinical, histochemical and molecular analysis. Eur J Hum Genet. 2003;11(S1):667A.
  • Kana V, Kellenberger CJ, Klein A. Muscle magnetic resonance imaging of the lower limbs: valuable diagnostic tool in the investigation of childhood neuromuscular disorders. Neuropediatrics. 2014;45:278–88. [PubMed: 25025777]
  • Kawabata Y, Hata S, Ono Y, Ito Y, Suzuki K, Abe K, Sorimachi H. Newly identified exons encoding novel variants of p94/calpain-3 are expressed ubiquitously and overlap the alpha-glucosidase C gene. FEBS Lett. 2003;555:623–30. [PubMed: 14675785]
  • Kawai H, Akaike M, Kunishige M, Inui T, Adachi K, Kimura C, Kawajiri M, Nishida Y, Endo I, Kashiwagi S, Nishino H, Fujiwara T, Okuno S, Roudaut C, Richard I, Beckmann JS, Miyoshi K, Matsumoto T. Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families. Muscle Nerve. 1998;21:1493–501. [PubMed: 9771675]
  • Keira Y, Noguchi S, Kurokawa R, Fujita M, Minami N, Hayashi YK, Kato T, Nishino I. Characterization of lobulated fibers in limb girdle muscular dystrophy type 2A by gene expression profiling. Neurosci Res. 2007;57:513–21. [PubMed: 17258832]
  • Keira Y, Noguchi S, Minami N, Hayashi YK, Nishino I. Localization of calpain 3 in human skeletal muscle and its alteration in limb-girdle muscular dystrophy 2A muscle. J Biochem. 2003;133:659–64. [PubMed: 12801918]
  • Khadilkar SV, Chaudhari CR, Dastur RS, Gaitonde PS, Yadav JG. Limb-girdle muscular dystrophy in the Agarwals: utility of founder mutations in CAPN3 gene. Ann Indian Acad Neurol. 2016;19:108–11. [PMC free article: PMC4782525] [PubMed: 27011640]
  • Kinbara K, Sorimachi H, Ishiura S, Suzuki K. Skeletal muscle specific calpain, p94: structure and physiological function. Biochem Pharmacol. 1998;56:415–20. [PubMed: 9763216]
  • Krahn M, Bernard R, Pecheux C, Hammouda EH, Lopez de Munain A, Cobo AM, Romero N, Urtizberea A, Leturcq F, Levy N. Screening of the CAPN3 gene in patients with possible LGMD2A. Clin Genet. 2006a;69:444–9. [PubMed: 16650086]
  • Krahn M, Goicoechea M, Hanisch F, Groen E, Bartoli M, Pécheux C, Garcia-Bragado F, Leturcq F, Jeannet PY, Lobrinus JA, Jacquemont S, Strober J, Urtizberea JA, Sáenz A, Bushby K, Lévy N, Lopez de Munain A. Eosinophilic infiltration related to CAPN3 mutations: a pathophysiological component of primary calpainopathy? Clin Genet. 2011;80:398–402. [PubMed: 21204801]
  • Krahn M, Lopez de Munain A, Streichenberger N, Bernard R, Pecheux C, Testard H, Pena-Segura JL, Yoldi E, Cabello A, Romero NB, Poza JJ, Bouillot-Eimer S, Ferrer X, Goicoechea M, Garcia-Bragado F, Leturcq F, Urtizberea JA, Levy N. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol. 2006b;59:905–11. [PubMed: 16607617]
  • Krahn M, Pécheux C, Chapon F, Béroud C, Drouin-Garraud V, Laforet P, Romero NB, Pénisson-Besnier I, Bernard R, Urtizberea JA, Leturcq F, Lévy N. Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay. Clin Genet. 2007;72:582–92. [PubMed: 17979987]
  • Kramerova I, Beckmann JS, Spencer MJ. Molecular and cellular basis of calpainopathy (limb girdle muscular dystrophy type 2A). Biochim Biophys Acta. 2007;1772:128–44. [PubMed: 16934440]
  • Kramerova I, Kudryashova E, Venkatraman G, Spencer MJ. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway. Hum Mol Genet. 2005;14:2125–34. [PubMed: 15961411]
  • Kramerova I, Kudryashova E, Wu B, Ottenheijm C, Granzier H, Spencer MJ. Novel role of calpain-3 in the triad-associated protein complex regulating calcium release in skeletal muscle. Hum Mol Genet. 2008;17:3271–80. [PMC free article: PMC2566524] [PubMed: 18676612]
  • Kuhn M, Glaser D, Joshi PR, Zierz S, Wenninger S, Schoser B, Deschauer M. Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy. J Neurol. 2016;263:743–750. [PubMed: 26886200]
  • Kyriakides T, Angelini C, Schaefer J, Sacconi S, Siciliano G, Vilchez JJ, Hilton-Jones D. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol. 2010;17:767–73. [PubMed: 20402744]
  • Lahoria R, Milone M. Rhabdomyolysis featuring muscular dystrophies. J Neurol Sci. 2016;361:29–33. [PubMed: 26810512]
  • Leidenroth A, Sorte HS, Gilfillan G, Ehrlich M, Lyle R, Hewitt JE. Diagnosis by sequencing: correction of misdiagnosis from FSHD2 to LGMD2A by whole-exome analysis. Eur J Hum Genet. 2012;20:999–1003. [PMC free article: PMC3421126] [PubMed: 22378277]
  • Lo HP, Cooper ST, Evesson FJ, Seto JT, Choitis AM, Tay V, Compton AG, Cairns AG, Corbett A, MacArthur DG, Yang N, Reardon K, North KN. Limb girdle muscular dystrophy: diagnostic evaluation, frequency and clues to pathogenesis. Neuromusc Disord. 2008;18:34–44. [PubMed: 17897828]
  • Luo SS, Xi JY, Lu JH, Zhao CB, Zhu WH, Lin J, Wang Y, Ren HM, Yin B, Urtizberea AJ. Clinical and pathological features in 15 Chinese patients with calpainopathy. Muscle Nerve. 2011;43:402–9. [PubMed: 21321956]
  • Luo SS, Xi JY, Zhu WH, Zhao CB, Lu JH, Lin J, Wang Y, Lu J, Qiao K. Genetic variability and clinical spectrum of Chinese patients with limb girdle muscular dystrophy type 2A. Muscle Nerve. 2012;46:723–9. [PubMed: 22926650]
  • Magri F, Nigro V, Angelini C, Mongini T, Mora M, Moroni I, et al. The Italian limb girdle muscular dystrophy registry: relative frequency, clinical fetaures, and differential diagnosis. Muscle Nerve. 2017;55:55–68. [PubMed: 27184587]
  • Mahmood OA, Jiang X, Zhang Q. Limb-girdle muscular dystrophy subtypes: first reported cohort from northeastern China. Neural Regen Res. 2013;8:1907–18. [PMC free article: PMC4145977] [PubMed: 25206500]
  • Matsubara E, Tsuchiya A, Minami N, Nishino I, Pappolla MA, Shoji M, Abe K. A unique case of limb girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene. Eur J Neurol. 2007;14:819–22. [PubMed: 17594342]
  • McDonald CM, Johnson ER, Abresch RT, Carter GT, Fowler WM, Kilmer DD. Profiles of neuromuscular diseases. Limb-girdle syndromes. Am J Phys Med Rehabil. 1995;74:S117–30. [PubMed: 7576419]
  • Mercuri E, Bushby K, Ricci E, Birchall D, Pane M, Kinali M, Allsop J, Nigro V, Sáenz A, Nascimbeni A, Fulizio L, Angelini C, Muntoni F. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromusc Disord. 2005;15:164–71. [PubMed: 15694138]
  • Meznaric-Petrusa MMP, Zidar J, Zupanic N, et al. Clinical, molecular and genetic features of calpainopathy in Slovenia. Neuromuscul Disord. 2002;12:73A.
  • Milic A, Canki-Klain N. Calpainopathy (LGMD2A) in Croatia: molecular and haplotype analysis. Croat Med J. 2005;46:657–63. [PubMed: 16100770]
  • Milic A, Daniele N, Lochmuller H, Mora M, Comi GP, Moggio M, Noulet F, Walter MC, Morandi L, Poupiot J, Roudaut C, Bittner RE, Bartoli M, Richard I. A third of LGMD2A biopsies have normal calpain-3 proteolytic activity as determined by an in-vitro assay. Neuromusc Disord. 2007;17:148–56. [PubMed: 17236769]
  • Minami N, Nishino I, Kobayashi O, Ikezoe K, Goto Y, Nonaka I. Mutations of calpain 3 gene in patients with sporadic limb girdle muscular dystrophy in Japan. J Neurol Sci. 1999;171:31–7. [PubMed: 10567047]
  • Monies D, Alhindi HN, Almuhaizea MA, Abouelhoda M, Alazami AM, Goljan E, Alyounes B, Jaroudi D, Allssa A, Alabdulrahman K, Subhani S, El-Kalioby M, Faquih T, Wakil SM, Altassan NA, Meyer BF, Bohlega S. A first-line diagnostic assy for limb-girdle muscular dystrophy and other myopathies. Hum Genomics. 2016;10:32. [PMC free article: PMC5037890] [PubMed: 27671536]
  • Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, Brown CA, Michele DE, Piccolo F, Winder TL, Stence A, Barresi R, King N, King W, Florence J, Campbell KP, Fenichel GM, Stedman HH, Kissel JT, Griggs RC, Pandya S, Mathews KD, Pestronk A, Serrano C, Darvish D, Mendell JR. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006;65:995–1003. [PubMed: 17021404]
  • Mori-Yoshimura M, Segawa K, Minami N, Oya Y, Komaki H, Nonaka I, Nishino I, Murata M. Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A. Muscle Nerve. 2017;55:465–9. [PMC free article: PMC5396288] [PubMed: 27500519]
  • Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, Wicklund M, Barohn RJ, Ensrud E, Griggs RC, Gronseth G, Amato AA. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies. Report of the guideline development subcommittee of the American Academy of Neurology and the practical issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2014;83:1453–63. [PMC free article: PMC4206155] [PubMed: 25313375]
  • Nascimbeni AC, Fanin M, Tasca E, Angelini C. Transcriptional and translational effects of intronic CAPN3 gene mutations. Hum Mutat. 2010;31:E1658–69. [PMC free article: PMC2966865] [PubMed: 20635405]
  • Nigro V, Piluso G. Next generation sequencing (NGS) strategies for the genetic testing of myopathies. Acta Myol. 2012;31:196–200. [PMC free article: PMC3631804] [PubMed: 23620651]
  • Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014;33:1–12. [PMC free article: PMC4021627] [PubMed: 24843229]
  • Norwood F, de Visser M, Eymard B, Lochmüller H, Bushby K. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol. 2007;14:1305–12. [PubMed: 18028188]
  • Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009;132:3175–86. [PMC free article: PMC4038491] [PubMed: 19767415]
  • Oflazer PS, Gundesli H, Zorludemir S, Sabuncu T, Dinçer P. Eosinophilic myositis in calpainopathy: could immunosuppression of the eosinophilic myositis alter the early natural course of the dystrophic disease? Neuromusc Disord. 2009;19:261–3. [PubMed: 19285864]
  • Okere A, Reddy SS, Gupta S, Shinnar M. A cardiomyopathy in a patient with limb girdle muscular dystrophy type 2A. Circ Heart Fail. 2013;6:e12–3. [PubMed: 23322878]
  • Ono Y, Ojima K, Torii F, Takaya E, Doi N, Nakagawa K, Hata S, Abe K, Sorimachi H. Skeletal muscle-specific calpain is an intracellular Na+-dependent protease. J Biol Chem. 2010;285:22986–98. [PMC free article: PMC2906292] [PubMed: 20460380]
  • Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K. Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A. J Biol Chem. 1998;273:17073–8. [PubMed: 9642272]
  • Oygard K, Haestad H, Jørgensen L. Physiotherapy, based on the Bobath concept, may influence the gait pattern in persons with limb-girdle muscle dystrophy: a multiple case series study. Physiother Res Int. 2011;16:20–31. [PubMed: 21110410]
  • Pantoja-Melendez CA, Miranda-Duarte A, Roque-Ramirez B, Zenteno JC. Epidemiological and molecular characterization of a Mexican population isolate with high prevalence of limb-girdle muscular dystrophy type 2A due to a novel Calpain-3 mutation. PLoS One. 2017;12(1):e0170280. [PMC free article: PMC5245889] [PubMed: 28103310]
  • Pastorello E, Cao M, Trevisan CP. Atypical onset in a series of 122 cases with facioscapulohumeral muscular dystrophy. Clin Neurol Neurosurg. 2012;114:230–4. [PMC free article: PMC3314982] [PubMed: 22079131]
  • Pathak P, Sharma MC, Sarkar C, Jha P, Suri V, Mohd H, Singh S, Bhatia R, Gulati S. Limb girdle muscular dystrophy type 2A in India: a study based on semi-quantitative protein analysis, with clinical and histopathological correlation. Neurol India. 2010;58:549–54. [PubMed: 20739790]
  • Pénisson-Besnier I, Richard I, Dubas F, Beckmann JS, Fardeau M. Pseudometabolic expression and phenotypic variability of calpain deficiency in two siblings. Muscle Nerve. 1998;21:1078–80. [PubMed: 9655129]
  • Perez F, Vital A, Martin-Negrier ML, Ferrer X, Sole G. Diagnostic procedure of limb girdle muscular dystrophies 2A or calpainopathies: French cohort from a neuromuscular center (Bordeaux). Rev Neurol. 2010;166:502–8. [PubMed: 20044116]
  • Piluso G, Dionisi M, Del Vecchio Blanco F, Torella A, Aurino S, Savarese M, Giugliano T, Bertini E, Terracciano A, Vainzof M, Criscuolo C, Politano L, Casali C, Santorelli FM, Nigro V. Motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. Clin Chem. 2011;57:1584–96. [PubMed: 21896784]
  • Piluso G, Politano L, Aurino S, Fanin M, Ricci E, Ventriglia VM, Belsito A, Totaro A, Saccone V, Topaloğlu H, Nascimbeni AC, Fulizio L, Broccolini A, Canki-Klain N, Comi LI, Nigro G, Angelini C, Nigro V. Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. J Med Genet. 2005;42:686–93. [PMC free article: PMC1736133] [PubMed: 16141003]
  • Pogoda TV, Krakhmaleva IN, Lipatova NA, Shakhovskaya NI, Shishkin SS, Limborska SA. High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia. Hum Mutat. 2000;15:295.
  • Pollitt C, Anderson LV, Pogue R, Davison K, Pyle A, Bushby KM. The phenotype of calpainopathy: diagnosis based on a multidisciplinary approach. Neuromusc Disord. 2001;11:287–96. [PubMed: 11297944]
  • Prahm KP, Feldt-Rasmussen U, Vissing J. Human growth hormone stabilizes walking and improves strength in a patient with dominantly inherited calpainopathy. Neuromusc Disord. 2017;27:358–62. [PubMed: 28190647]
  • Quick S, Schaefer J, Waessnig N, Schultheiss T, Reuner U, Schoen S, Reichmann H, Strasser R, Speiser U. Evaluation of heart involvement in calpainopathy (LGMD2A) using cardiovascular magnetic resonance. Muscle Nerve. 2015;52:661–3. [PubMed: 26032656]
  • Rajakumar D, Alexander M, Oommen A. Oxidative stress, NF-kB and the ubiquitin proteasomal pathway in the pathology of calpainopathy. Neurochem Res. 2013;38:2009–18. [PubMed: 23846623]
  • Reddy HM, Cho KA, Lek M, Estrella E, Valkanas E, Jones MD, Mitsuhashi S, Darras BT, Amato AA, Lidov HGW, Brownstein CA, Margulies DM, Yu TW, Salih MA, Kunkel LM, MacArthur DG, Kang PB. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2017;62:243–52. [PMC free article: PMC5266644] [PubMed: 27708273]
  • Restagno G, Romero N, Richard I, Beckmann JS, Pagliano AM, Ferrone M, Carbonara A, Merlini L. Prenatal diagnosis of limb girdle muscular dystrophy type 2A. Neuromusc Disord. 1996;6:173–6. [PubMed: 8784805]
  • Richard I, Beckmann JS. How neutral are synonymous codon mutations? Nat Genet. 1995;10:259. [PubMed: 7670461]
  • Richard I, Brenguier L, Dinçer P, Roudaut C, Bady B, Burgunder JM, Chemaly R, Garcia CA, Halaby G, Jackson CE, Kurnit DM, Lefranc G, Legum C, Loiselet J, Merlini L, Nivelon-Chevallier A, Ollagnon-Roman E, Restagno G, Topaloğlu H, Beckmann JS. Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. Am J Hum Genet. 1997;60:1128–38. [PMC free article: PMC1712426] [PubMed: 9150160]
  • Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C, Hillaire D, Passos-Bueno MR, Zatz M, Tischfield JA, Fardeau M, Jackson CE, Cohen D, Beckmann JS. Mutations in the proteolytic enzyme calpain-3 cause limb girdle muscular dystrophy type 2A. Cell. 1995;81:27–40. [PubMed: 7720071]
  • Richard I, Roudaut C, Sáenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloğlu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, Beckmann JS. Calpainopathy-a survey of mutations and polymorphisms. Am J Hum Genet. 1999;64:1524–40. [PMC free article: PMC1377896] [PubMed: 10330340]
  • Richard I, Hogrel JY, Stockholm D, Payan CAM, Fougerousse F, Eymard B, Mignard C, Lopez de Munain A, Fardeau M, Urtizberea A. Natural history of LGMD2A for delineating outcome measures in clinical trials. Ann Clin Transl Neurol. 2016;3:248–65. [PMC free article: PMC4818744] [PubMed: 27081656]
  • Rosales XQ, Malik V, Sneh A, Chen L, Lewis S, Kota J, Gastier-Foster JM, Astbury C, Pyatt R, Reshmi S, Rodino-Klapac LR, Clark KR, Mendell JR, Sahenk Z. Impaired regeneration in LGMD2A supported by increased PAX7-positive satellite cell content and muscle-specific microRNA dysregulation. Muscle Nerve. 2013;47:731–9. [PMC free article: PMC3634894] [PubMed: 23553538]
  • Sacconi S, Camano P, de Greef JC, Lemmers RJ, Salviati L, Boileau P, Lopez de Munain A, van der Maarel SM, Desnuelle C. Patients with a phenotype consistent with facio scapulo humeral muscular dystrophy display genetic and epigenetic heterogeneity. J Med Genet. 2012;49:41–6. [PMC free article: PMC3560331] [PubMed: 21984748]
  • Sáenz A, Azpitarte M, Armananzas R, Leturcq F, Alzualde A, Inza I, García-Bragado F, De la Herran G, Corcuera J, Cabello A, Navarro C, De La Torre C, Gallardo E, Illa I, López de Munain A. Gene expression profiling in limb girdle muscular dystrophy 2A. PLoS One. 2008;3:e3750. [PMC free article: PMC2582180] [PubMed: 19015733]
  • Sáenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D, Camano P, Urtasun M, Vilchez J, Gutierrez-Rivas E, Emparanza J, Merlini L, Paisan C, Goicoechea M, Blázquez L, Eymard B, Lochmuller H, Walter M, Bonnemann C, Figarella-Branger D, Kaplan JC, Urtizberea JA, Marti-Masso JF, Lopez de Munain A. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain. 2005;128:732–42. [PubMed: 15689361]
  • Sáenz A, López de Munain A. Dominant LGMD2A: alternative diagnosis or hidden digenism? Brain. 2017;140:e7. [PubMed: 27818383]
  • Salem IH, Hsairi I, Mezghani N, Kenoun H, Triki C, Fakhfakh F. CAPN3 mRNA processing alterations caused by splicing mutation associated with novel genomic rearrangement of Alu elements. J Hum Genet. 2012;57:92–100. [PubMed: 22158424]
  • Savarese M, Di Fruscio G, Torella A, Fiorillo C, Magri F, Fanin M, Ruggiero L, Ricci G, Astrea G, Passamano L, Ruggieri A, Ronchi D, Tasca G, D'Amico A, Janssens S, Farina O, Mutarelli M, Marwah VS, Garofalo A, Giugliano T, Sanpaolo S, Del Vecchio Blanco F, Esposito G, Piluso G, D'Ambrosio P, Petillo R, Musumeci O, Rodolico C, Messina S, Evilä A, Hackman P, Filosto M, Di Iorio G, Siciliano G, Mora M, Maggi L, Minetti C, Sacconi S, Santoro L, Claes K, Vercelli L, Mongini T, Ricci E, Gualandi F, Tupler R, De Bleecker J, Udd B, Toscano A, Moggio M, Pegoraro E, Bertini E, Mercuri E, Angelini C, Santorelli FM, Politano L, Bruno C, Comi GP, Nigro V. The genetic basis of undiagnosed muscular dystrophies and myopathies. Neurology. 2016;87:71–6. [PMC free article: PMC4932234] [PubMed: 27281536]
  • Schessl J, Walter MC, Schreiber G, Schara U, Müller CR, Lochmüller H, Bönnemann CG, Korinthenberg R, Kirschner J. Phenotypic variability in siblings with calpainopathy (LGMD2A). Acta Myol. 2008;27:54–8. [PMC free article: PMC2858935] [PubMed: 19364062]
  • Seong MW, Cho A, Park HW, Seo SH, Lim BC, Seol D, Cho SI, Park SS, Chae JH. Clinical application of next-generation sequencing-based gene panel in patients with muscular dystrophy: Korean experience. Clin Genet. 2016;89:484–8. [PubMed: 26060040]
  • Shaboodien G, Watkins DA, Pillay K, Beighton P, Heckmann JM, Mayosi BM. Limb girdle weakness in a marfanoid man: distinguishing calpainopathy from Becker’s muscular dystrophy. Pract Neurol. 2015;15:152–4. [PubMed: 25573340]
  • Shin JH, Kim HS, Lee CH, Kim CM, Park KH, Kim DS. Mutations of CAPN3 in Korean patients with limb girdle muscular dystrophy. J Korean Med Sci. 2007;22:463–9. [PMC free article: PMC2693639] [PubMed: 17596655]
  • Simeoni S, Russo V, Gigli GL, Scalise A. Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: "Double trouble" overlapping syndrome? J Neurol Sci. 2015;348:292–3. [PubMed: 25528007]
  • Sorimachi H, Suzuki K. The structure of calpain. J Biochem. 2001;129:653–64. [PubMed: 11328585]
  • Stehlíková K, Skálová D, Zídková J, Mrázová L, Vondráček P, Mazanec R, Voháňka S, Haberlová J, Hermanová M, Zámečník J, Souček O, Ošlejšková H, Dvořáčková N, Solařová P, Fajkusová L. Autosomal recessive limb girdle muscular dystrophies in the Czech Republic. BMC Neurology. 2014;14:154–62. [PMC free article: PMC4145250] [PubMed: 25135358]
  • Stramare R, Beltrame V, Dal Borgo R, Gallimberti L, Frigo AC, Pegoraro E, Angelini C, Rubaltelli L, Feltrin GP. MRI in the assessment of muscular pathology: a comparison between limb-girdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies. Radiol Med. 2010;115:585–99. [PubMed: 20177980]
  • Straub V, Carlier PG, Mercuri E. TREAT-NMD workshop: pattern recognition in genetic muscle diseases using muscle MRI. Neuromusc Disord. 2012;22:S42–53. [PubMed: 22980768]
  • Sveen ML, Andersen SP, Ingelsrud LH, Blichter S, Olsen NE, Jonck S, Krag TO, Vissing J. Resistance training in patients with limb girdle and Becker muscular dystrophies. Muscle Nerve. 2013;47:163–9. [PubMed: 23169433]
  • Talim B, Ognibene A, Mattioli E, Richard I, Anderson LV, Merlini L. Normal calpain expression in genetically confirmed limb-girdle muscular dystrophy type 2A. Neurology. 2001;56:692–3.
  • ten Dam L, van der Kooi AJ, Van Wattingen M, De Haan RJ, De Visser M. Reliability and accuracy of skeletal muscle imaging in limb girdle muscular dystrophies. Neurology. 2012;79:1716–23. [PubMed: 23035061]
  • Thompson R, Straub V. Limb girdle muscular dystrophies - international collaborations for translational research. Nat Rev Neurol. 2016;12:294–309. [PubMed: 27033376]
  • Todorova A, Georgieva B, Tournev I, Todorov T, Bogdanova N, Mitev V, Mueller CR, Kremensky I, Horst J. A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients. Neurogenetics. 2007;8:225–9. [PubMed: 17318636]
  • Topaloğlu H, Dinçer P, Richard I, Akçören Z, Alehan D, Ozme S, Cağlar M, Karaduman A, Urtizberea JA, Beckmann JS. Calpain-3 deficiency causes a mild muscular dystrophy in childhood. Neuropediatrics. 1997;28:212–6. [PubMed: 9309711]
  • Urtasun M, Sáenz A, Roudaut C, Poza JJ, Urtizberea JA, Cobo AM, Richard I, Garcia Bragado F, Leturcq F, Kaplan JC, Marti Masso JF, Beckmann JS, Lopez de Munain A. Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain). Brain. 1998;121:1735–47. [PubMed: 9762961]
  • Vainzof M, de Paula F, Tsanaclis AM, Zatz M. The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A. J Clin Pathol. 2003;56:624–6. [PMC free article: PMC1770017] [PubMed: 12890817]
  • van der Kooi AJ, Barth PG, Busch HF, de Haan R, Ginjaar HB, van Essen AJ, van Hooff LJ, Höweler CJ, Jennekens FG, Jongen P, Oosterhuis HJ, Padberg GW, Spaans F, Wintzen AR, Wokke JH, Bakker E, van Ommen GJ, Bolhuis PA, de Visser M. The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands. Brain. 1996;119:1471–80. [PubMed: 8931572]
  • van der Kooi AJ, Frankhuizen WS, Barth PG, Howeler CJ, Padberg GW, Spaans F, Wintzen AR, Wokke JH, van Ommen GJ, de Visser M, Bakker E, Ginjaar HB. Limb-girdle muscular dystrophy in the Netherlands: gene defect identified in half the families. Neurology. 2007;68:2125–8. [PubMed: 17562833]
  • Vissing J, Barresi R, Witting N, Van Ghelue M, Gammelgaard L, Bindoff LA, Straub V, Lochmüller H, Hudson J, Wahl CM, Arnardottir S, Dahlbom K, Jonsrud C, Duno M. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain. 2016;139:2154–63. [PubMed: 27259757]
  • Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol. 2010;20:2447–60. [PMC free article: PMC2940021] [PubMed: 20422195]
  • Young K, Foroud T, Williams P, Jackson CE, Beckmann JS, Cohen D, Conneally PM, Tischfield J, Hodes ME. Confirmation of linkage of limb-girdle muscular dystrophy, type 2, to chromosome 15. Genomics. 1992;13:1370–1. [PubMed: 1505977]
  • Zatz M, de Paula F, Starling A, Vainzof M. The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromusc Disord. 2003;13:532–44. [PubMed: 12921790]
  • Zatz M, Vainzof M, Passos-Bueno MR. Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes. Curr Opin Neurol. 2000;13:511–7. [PubMed: 11073356]

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 live
  • 15 December 2005 (ca) Revision: prenatal diagnosis available
  • 10 May 2005 (me) Review posted live
  • 29 November 2004 (ca) Original submission
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