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Autosomal recessive limb-girdle muscular dystrophy type 2A(LGMDR1)

MedGen UID:
358391
•Concept ID:
C1869123
•
Disease or Syndrome
Synonyms: Calpainopathy; Leyden-Moebius muscular dystrophy; LGMDR1; Limb-girdle muscular dystrophy type 2; Limb-girdle muscular dystrophy, type 2A; Muscular dystrophy, limb-girdle, type 2A, Amish; Muscular dystrophy, pelvofemoral
SNOMED CT: Autosomal recessive limb girdle muscular dystrophy type 2A (715341003); Primary calpainopathy (715341003); Calpain-3 deficiency limb girdle muscular dystrophy type 2A (715341003); Leyden-Möbius muscular dystrophy (715341003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): CAPN3 (15q15.1)
 
Monarch Initiative: MONDO:0009675
OMIM®: 253600
Orphanet: ORPHA267

Disease characteristics

Excerpted from the GeneReview: Calpainopathy
Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis. Affected individuals typically do not have cardiac involvement or intellectual disability. 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 is clinically variable, ranging from almost asymptomatic to wheelchair dependence after age 60 years in a few individuals; phenotype is generally milder than the recessive form. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Corrado Angelini   view full author information

Additional description

From OMIM
Autosomal recessive limb-girdle muscular dystrophy-1 affects primarily the proximal muscles, resulting in difficulty walking. The age at onset varies, but most patients show onset in childhood, and the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures (summary by Mercuri et al., 2005). Genetic Heterogeneity of Autosomal Recessive Limb-Girdle Muscular Dystrophy Autosomal recessive LGMD is genetically heterogeneous. LGMDR2 (253601), previously symbolized LGMD2B, is caused by mutation in the dysferlin gene (DYSF; 603009) on 2p13. LGMDR3 (608099), previously symbolized LGMD2D, is caused by mutation in the alpha-sarcoglycan gene (SGCA; 600119) on 17q21. LGMDR4 (604286), previously symbolized LGMD2E, is caused by mutation in the beta-sarcoglycan gene (SGCB; 600900) on 4q12. LGMDR5 (253700), previously symbolized LGMD2C, is caused by mutation in the gamma-sarcoglycan gene (SGCG; 608896) on 13q12. LGMDR6 (601287), previously symbolized LGMD2F, is caused by mutation in the delta-sarcoglycan gene (SGCD; 601411) on 5q33. LGMDR7 (601954), previously symbolized LGMD2G, is caused by mutation in the TCAP gene (604488) on 17q12. LGMDR8 (254110), previously symbolized LGMD2H, is caused by mutation in the TRIM32 gene (602290) on 9q33. LGMDR9 (607155), previously symbolized LGMD2I, is caused by mutation in the FKRP gene (606596) on 19q13. LGMDR10 (608807), previously symbolized LGMD2J, is caused by mutation in the titin gene (TTN; 188840) on 2q31. LGMDR11 (609308), previously symbolized LGMD2K, is caused by mutation in the POMT1 gene (607423) on 9q34. LGMDR12 (611307), previously symbolized LGMD2L, is caused by mutation in the ANO5 gene (608662) on 11p14. LGMDR13 (611588), previously symbolized LGMD2M, is caused by mutation in the FKTN gene (607440) on 9q31. LGMDR14 (613158), previously symbolized LGMD2N, is caused by mutation in the POMT2 gene (607439) on 14q24. LGMDR15 (613157), previously symbolized LGMD2O, is caused by mutation in the POMGNT1 gene (606822) on 1p34. LGMDR16 (613818), previously symbolized LGMD2P, is caused by mutation in the DAG1 gene (128239) on 3p21. LGMDR17 (613723), previously symbolized LGMD2Q, is caused by mutation in the PLEC1 gene (601282) on 8q24. LGMDR18 (615356), previously symbolized LGMD2S, is caused by mutation in the TRAPPC11 gene (614138) on 4q35. LGMDR19 (615352), previously symbolized LGMD2T, is caused by mutation in the GMPPB gene (615320) on 3p21. LGMDR20 (616052), previously symbolized LGMD2U, is caused by mutation in the ISPD gene (CRPPA; 614631) on 7p21. LGMDR21 (617232), previously symbolized LGMD2Z, is caused by mutation in the POGLUT1 gene (615618) on 3q13. Autosomal recessive Bethlem myopathy (see 158810) caused by any one of the collagen VI genes (120220, 120240, 120250) was designated LGMDR22. LGMDR23 (618138) is caused by mutation in the LAMA2 gene (156225) on 6q22. LGMDR24 (618135) is caused by mutation in the POMGNT2 gene (614828) on 3p22. LGMDR25 (616812), previously symbolized LGMD2X, is caused by mutation in the BVES gene (604577) on 6q21. LGMDR26 (618848) is caused by mutation in the POPDC3 gene (605824) on 6q21. LGMDR27 (619566) is caused by mutation in the JAG2 gene (602570) on 14q32. LGMDR28 (620375) is caused by mutation in the HMGCR gene (142910) on 5q13. LGMDR29 (620793) is caused by mutation in the SNUPN gene (607902) on chromosome 15q24. Some forms of autosomal recessive LGMD were reclassified by Straub et al. (2018). LGMD2R was reclassified as a form of myofibrillar myopathy (MFM1; 601419). For forms previously designated LGMD2W and LGMD2Y, see 616827 and 617072, respectively. For a discussion of autosomal dominant LGMD, see LGMDD1 (603511).  http://www.omim.org/entry/253600

Clinical features

From HPO
Scapular winging
MedGen UID:
66822
•Concept ID:
C0240953
•
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
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Lower limb muscle weakness
MedGen UID:
324478
•Concept ID:
C1836296
•
Finding
Weakness of the muscles of the legs.
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Clumsiness
MedGen UID:
66690
•Concept ID:
C0233844
•
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
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Gait disturbance
MedGen UID:
107895
•Concept ID:
C0575081
•
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
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Muscular dystrophy
MedGen UID:
44527
•Concept ID:
C0026850
•
Disease or Syndrome
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
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Flexion contracture
MedGen UID:
83069
•Concept ID:
C0333068
•
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
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Facial palsy
MedGen UID:
87660
•Concept ID:
C0376175
•
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
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Proximal amyotrophy
MedGen UID:
342591
•Concept ID:
C1850794
•
Disease or Syndrome
Amyotrophy (muscular atrophy) affecting the proximal musculature.
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Muscle eosinophilia
MedGen UID:
1670980
•Concept ID:
C4732805
•
Finding
Eosinophil infiltration of skeletal muscle.
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Eosinophilia
MedGen UID:
41824
•Concept ID:
C0014457
•
Disease or Syndrome
Increased count of eosinophils in the blood.
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Myositis disease
MedGen UID:
44564
•Concept ID:
C0027121
•
Disease or Syndrome
Idiopathic inflammatory myopathy is a group of disorders characterized by inflammation of the muscles used for movement (skeletal muscles). Idiopathic inflammatory myopathy usually appears in adults between ages 40 and 60 or in children between ages 5 and 15, though it can occur at any age.\n\nThe primary symptom of idiopathic inflammatory myopathy is muscle weakness, which develops gradually over a period of weeks to months or even years. Other symptoms include joint pain and general tiredness (fatigue).\n\nThere are several forms of idiopathic inflammatory myopathy, including polymyositis, dermatomyositis, and sporadic inclusion body myositis.\n\nPolymyositis and dermatomyositis involve weakness of the muscles closest to the center of the body (proximal muscles), such as the muscles of the hips and thighs, upper arms, and neck. People with these forms of idiopathic inflammatory myopathy may find it difficult to climb stairs, get up from a seated position, or lift items above their head. In some cases, muscle weakness may make swallowing or breathing difficult.\n\nIn sporadic inclusion body myositis, the muscles most affected are those of the wrists and fingers and the front of the thigh. Affected individuals may frequently stumble while walking and find it difficult to grasp items. As in dermatomyositis and polymyositis, swallowing can be difficult.\n\nPolymyositis and dermatomyositis have similar symptoms, but dermatomyositis is distinguished by a reddish or purplish rash on the eyelids, elbows, knees, or knuckles. Sometimes, abnormal calcium deposits form hard, painful bumps under the skin (calcinosis).
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Elevated circulating creatine kinase concentration
MedGen UID:
69128
•Concept ID:
C0241005
•
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Autosomal recessive limb-girdle muscular dystrophy type 2A in Orphanet.

Professional guidelines

PubMed

Unmet needs and evolving treatment for limb girdle muscular dystrophies.
Pozsgai E, Griffin D, Potter R, Sahenk Z, Lehman K, Rodino-Klapac LR, Mendell JR
Neurodegener Dis Manag 2021 Oct;11(5):411-429. Epub 2021 Sep 2 doi: 10.2217/nmt-2020-0066. PMID: 34472379
Mutational Spectrum of CAPN3 with Genotype-Phenotype Correlations in Limb Girdle Muscular Dystrophy Type 2A/R1 (LGMD2A/LGMDR1) Patients in India.
Pathak P, Sharma MC, Jha P, Sarkar C, Faruq M, Jha P, Suri V, Bhatia R, Singh S, Gulati S, Husain M
J Neuromuscul Dis 2021;8(1):125-136. doi: 10.3233/JND-200547. PMID: 33337384

Recent clinical studies

Diagnosis

Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay.
Krahn M, Pécheux C, Chapon F, Béroud C, Drouin-Garraud V, Laforet P, Romero NB, Penisson-Besnier I, Bernard R, Urtizberea JA, Leturcq F, Lévy N
Clin Genet 2007 Dec;72(6):582-92. Epub 2007 Nov 1 doi: 10.1111/j.1399-0004.2007.00906.x. PMID: 17979987

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