Calpainopathy

Clinical characteristics.

Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. The age at onset of muscle weakness ranges from two to 40 years. The phenotype shows intra- and interfamilial variability ranging from severe to mild.

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

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

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

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

Diagnosis/testing.

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

Management.

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

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

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

Genetic counseling.

Calpainopathy is typically inherited in an autosomal recessive manner. Less commonly, calpainopathy is inherited in an autosomal dominant manner. In the autosomal recessive form, at conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. To date, all individuals diagnosed with autosomal dominant calpainopathy have inherited a pathogenic CAPN3 variant from a heterozygous parent. Testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the CAPN3 pathogenic variant(s) in the family are known.

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
  • CT reveals early and striking wasting of muscles predominantly from the posterior compartment of the thighs (but also hip adductors and quadriceps), which is also evident on clinical examination [Fardeau et al 1996, Urtasun et al 1998], with sparing of the sartorius and gracilis muscles. The difference in distribution of muscle involvement between calpainopathy and other LGMDs (i.e., sarcoglycanopathies and dysferlinopathies) makes muscle imaging analysis an important element in clinical diagnosis [ten Dam et al 2012] (see Differential Diagnosis).
  • MRI shows this selective muscle involvement and in some cases reveals edema-like changes on STIR sequences [Fischer et al 2005, Mercuri et al 2005, Borsato et al 2006, Degardin et al 2010, Stramare et al 2010, Wattjes et al 2010, Kana et al 2014]. Muscle MRI is a useful tool in characterizing the degree of muscle atrophy and in some cases also the severity of the disease [Straub et al 2012, Díaz-Manera et al 2015].
  • In the dominant form of calpainopathy, the paraspinal muscles were almost completely lost and replaced by fat [Vissing et al 2016, Prahm et al 2017].
• 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.

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:

• Waddling gait and slight hyperlordosis
• Symmetric weakness [Matsubara et al 2007] of proximal more than distal muscles in the limbs, trunk, and periscapular area. In particular, the gluteus maximus, thigh adductors, and posterior compartment of the limbs may be severely affected [Fardeau et al 1996, van der Kooi et al 1996, Dinçer et al 1997, Topaloğlu et al 1997, Urtasun et al 1998] and facial and neck muscles are usually spared.
• Scapular winging
• Marked laxity of the abdominal muscles [Bushby 1999, Pollitt et al 2001]
• Early Achilles tendon shortening and scoliosis

• 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:

• Rigid spine [Pollitt et al 2001]
• Foot drop [Burke et al 2010]
• Respiratory insufficiency with reduced lung vital capacity to 30%-50% due to deficiency in diaphragmatic function, weakness in thoracic and abdominal muscles, and scoliosis [Fardeau et al 1996, Urtasun et al 1998]. Compromised respiratory function was observed in 11% of individuals showing forced vital capacity lower than 50% [Richard et al 2016]. Some of those with severe respiratory insufficiency required the use of respiratory aids [Mori-Yoshimura et al 2017].

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

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

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

The disease is invariably progressive and loss of ambulation occurs approximately ten to 30 years after the onset of symptoms (between ages 10 and 48 years) [Richard et al 1999, Zatz et al 2003, Sáenz et al 2005, Angelini et al 2010, Gallardo et al 2011, Richard et al 2016]. In general, loss of independent ambulation occurs earlier in individuals with infantile onset of the disease [Gallardo et al 2011].

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

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

Genotype-Phenotype Correlations

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

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

Penetrance

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

Nomenclature

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

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

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

Prevalence

Calpainopathy is considered the most common form of LGMD [Bushby & Beckmann 2003, Guglieri et al 2008], representing approximately 30% of LGMD cases, depending on the geographic region [Chou et al 1999, Zatz et al 2000]. Estimates based on molecular data indicate that the frequency of calpainopathy ranges from 6%-8% of all LGMD in Australia, Korea, and Germany [Hanisch et al 2007, Shin et al 2007, Lo et al 2008, Ghaoui et al 2015, Seong et al 2016], to 4%-12% in the USA [Chou et al 1999, Moore et al 2006, Reddy et al 2017], 13% in Denmark [Duno et al 2008], 16% in Saudi Arabia [Monies et al 2016], 17%-18% in Mexico and northern China [Gómez-Díaz et al 2012, Mahmood et al 2013], 21% in the Netherlands [van der Kooi et al 2007], 21%-26% in Japan and Lithuania [Kawai et al 1998, Minami et al 1999, Luo et al 2011, Inashkina et al 2016], 24% in Iran [Fattahi et al 2017], 25%-35% in Italy, Germany, and northern England [Piluso et al 2005, Guglieri et al 2008, Fanin et al 2009a, Norwood et al 2009, Kuhn et al 2016, Magri et al 2017], 32% in Brazil [Zatz et al 2000], 33% in Czech Republic [Stehlíková et al 2014], 40%-50% in France, Turkey, Spain, India, Slovenia, and Bulgaria [Dinçer et al 1997, Richard et al 1997, Meznaric-Petrusa et al 2002, Georgieva et al 2005, Sáenz et al 2005, Balci et al 2006, Todorova et al 2007, Pathak et al 2010], and 80% in Basque country, Russia, and Poland [Urtasun et al 1998, Pogoda et al 2000, Dadali et al 2010, Dorobek et al 2015].

A genetic epidemiologic study in northeastern Italy estimated that calpainopathy has a prevalence of approximately 1:100,000 inhabitants (corresponding to a carrier frequency of ~1:160) [Fanin et al 2005]. Another study in southern Italy estimated the prevalence of calpainopathy at 1:42,700 inhabitants (corresponding to a carrier frequency of ~1:103) [Piluso et al 2005].

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

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

Evaluations Following Initial Diagnosis

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

• Complete physical evaluation including the grading of muscle strength in single upper, lower, proximal, and distal muscles and the analysis of several functional performances
• Orthopedic examination when gait is severely impaired
• When walking ability is compromised, an evaluation for physical therapy and orthoses, especially in later stages of the disease
• Baseline pulmonary function testing (including forced vital capacity measurement)
• Baseline cardiac evaluation including echocardiogram
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Appropriate management, tailored to each individual, can improve quality of life and prolong survival. The general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995], Bushby [1999], and Norwood et al [2007], and revised by the Committee of the American Academy of Neurology [Narayanaswami et al 2014]:

• A passive physical therapy program [Oygard et al 2011] and stretching exercises should be instituted early after diagnosis to promote mobility, prolong walking, and slow the disease progression, in particular by maintaining joint flexibility. Individuals usually benefit from strengthening and gentle [Sveen et al 2013], low-impact aerobic exercise (swimming, stationary bicycling) with a supervised sub-maximal effort, which improves cardiovascular performance, increases muscle efficiency, and lessens muscle fatigue. Although there are no specific reports on supportive care, physical and occupational therapies are important [Eagle 2002].
• Avoidance of prolonged immobility is recommended.
• Technical aids can also compensate for the loss of certain motor abilities; canes, walkers, orthotics, and wheelchairs enable individuals to regain independence. The use of knee-ankle-foot orthoses at bedtime is recommended to prevent contractures. Scoliosis occurs mainly after wheelchair dependence and attention should be paid to seating [Norwood et al 2007].
• Surgical intervention may be required for correction of orthopedic complications including foot deformities, scoliosis, and Achilles tendon contractures. Occasionally, scapular fixation may be required for particularly problematic scapular winging.
• In the late stage of the disease, chronic respiratory insufficiency may occur and the use of respiratory aids may be indicated to prolong survival [Pollitt et al 2001, Norwood et al 2007, D'Angelo et al 2011, Richard et al 2016, Mori-Yoshimura et al 2017].
  • Individuals should be monitored for signs of nocturnal hypoventilation (sleep disturbances, early morning headache, daytime drowsiness).
  • Overnight pulse oxymetry is recommended if forced vital capacity is lower than 60% and the demonstration of nocturnal hypoventilation should lead to noninvasive nocturnal ventilation [Norwood et al 2007].
  • Intervention in the form of nocturnal ventilator assistance for respiratory failure (by noninvasive positive pressure ventilation, NIV, by nasal masks) may be life saving in severely affected individuals [Dirik et al 2001, Hashiguchi et al 2014, Mori-Yoshimura et al 2017].
  • Wheelchair-bound individuals may also develop weak cough efforts, placing them at risk of atelectasia, pneumonia, progressive mismatch, and respiratory failure.
  • Annual influenza vaccination and prompt treatment for chest and respiratory infections should be eventually addressed using a mechanical in-ex-sufflator [Mori-Yoshimura et al 2017].
• Social and emotional support help to improve the quality of life, to maximize a sense of social involvement and productivity, and to reduce the sense of social isolation [Eggers & Zatz 1998].
• Clinicians should anticipate and facilitate decision-making for affected individuals and their families as the disease progresses, including decisions regarding loss of mobility and need of assistance with activities of daily living, medical complications, and end-of-life care [Narayanaswami et al 2014].

Prevention of Secondary Manifestations

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

Surveillance

The following are appropriate:

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

Agents/Circumstances to Avoid

Strenuous and eccentric muscle exercise should be discouraged as it exacerbates muscle necrosis and could precipitate the onset of weakness or accelerate muscle wasting. Although individuals with minimal muscle weakness and functional limitation may be able to perform strenuous exercise, in some cases this may result in rhabdomyolysis and myoglobinuria [Lahoria & Milone 2016] which may lead to severe complications such as acute renal failure and compartment syndrome.

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

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

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

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

Evaluation of Relatives at Risk

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

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

Pregnancy Management

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.