Clinical Guidance

There are no consistent genotype-phenotype correlations in calpainopathy, although null homozygous variants are generally associated with a severe phenotype and absent calpain-3 protein in muscle . Individuals who are compound heterozygous for CAPN3 variant c.1746-20CG and another variant consistently present with a phenotype of mild-to-moderate severity. This variant is most frequently identified in individuals from northern and western regions of Russia and may originate from this region . CAPN3 variants in proximity to the calmodulin-binding site, which are predicted to interfere with proteolytic activation, are associated with autosomal dominant calpainopathy .

Source: GeneReviews — "Calpainopathy"

Penetrance

Nearly full penetrance is observed by adulthood. Serum CK concentration is usually increased until the advanced stage of the disease.

Source: GeneReviews — "Calpainopathy"

Diagnostic Criteria

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

Suggestive Findings

Calpainopathy should be suspected in individuals with the following clinical, laboratory, imaging, and electromyogram (EMG) findings.

Clinical findings

Source: GeneReviews — "Calpainopathy"

Differential Diagnosis

Table 2. Genes of Interest in the Differential Diagnosis of Calpainopathy

Management Guidelines

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 limb-girdle muscular dystrophy (LGMD) as described by , , and , and revised by the Committee of the American Academy of Neurology .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with calpainopathy, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Calpainopathy

System/Concern | Evaluation | Comment

Neurologic

| Complete neurologic eval incl:

• Grading of muscle strength in single upper, lower, proximal, distal muscles

• Analysis of several functional performances (e.g., 6MWT, GSGC)

|

Orthopedics/ physical medicine rehab/ PT eval | To incl assessment of:

• Gross motor skills

• Gait, mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills)

Pulmonary

| Pulmonary function testing (incl forced vital capacity measurement) |

Cardiac

| • Cardiac eval

• Echocardiogram

|

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of calpainopathy to facilitate medical personal decision making

Source: GeneReviews — "Calpainopathy"

Clinical Guidance

Strenuous and excessive 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 instances this may result in rhabdomyolysis and myoglobinuria , which may lead to severe complications such as acute kidney 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.

Source: GeneReviews — "Calpainopathy"

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. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Calpainopathy"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in are recommended.

Table 5.

Recommended Surveillance for Individuals with Calpainopathy

System/Concern | Evaluation | Frequency

Neurologic

| Assess muscle strength joint range of motion. | Annually

Orthopedic

| Monitor for orthopedic complications (foot deformities, scoliosis, Achilles tendon contractures).

Pulmonary

| Assess for signs/symptoms of nocturnal hypoventilation (sleep disturbances, early morning headache, daytime drowsiness).

• Pulmonary eval (incl pulmonary function tests) in those w/nocturnal hypoventilation1

• Note: Forced vital capacity should be measured in sitting supine position.

| As needed

Cardiac

| Exam of cardiac function in advanced stage of disease (although it is not frequently compromised)2

Family/Community

| Assess need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning). | At each visit

1.

2. ,

Source: GeneReviews — "Calpainopathy"