Limb Girdle Muscular Dystrophy

Transcription

1 Limb Girdle Muscular Dystrophy Reza Shervin Badv MD, Pediatric Neurologist Children s Medical Center Pediatrics Center of Excellence Tehran University of Medical Sciences

2 Limb-girdle muscular dystrophies(lgmd) are a large group of genetic diseases in which there is muscle weakness and wasting (muscular dystrophy). Prevalence estimates range from 1 in 14,500 to 1 in 123,000 individuals. A meta-analysis study estimates the overall prevalence of the LGMDs at 1.63 (CI, 0.94 to 2.81) per 100,000.

3 The term LGMD was first formally introduced in the 1950s to include the category of a larger group of patients with muscle weakness that could not be recognized under the major MD groups identified at the time, such as X-linked Duchenne s muscular dystrophy(dmd) or fascioscapulohumeral dystrophy (FSHD)

4 LGMD is defined as an MD presenting with predominantly proximal weakness, sparing facial, extraocular, and distal extremity muscles (at least early in the course of the disease).

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13 Classification Type 1 LGMDs : Dominantly inherited Type 2 LGMDs : Recessively inherited

14 Type 1 LGMDs(AD) LGMD1A (MYOT mutation) LGMD1B (LMNA mutation) LGMD1C (CAV3 mutation) LGMD1D (DNAJB6 mutation) LGMD1E (DES mutation) LGMD1F (TNP03 mutation)

15 Type 2 LGMDs (AR) LGMD2A (CAPN3 mutations) LGMD2B (DYSF mutations) LGMD2C, also called SCARMD1 (SGCG mutations) LGMD2D, also called SCARMD2 (SGCA mutations) LGMD2E (SGCB mutations) LGMD2F (SGCD mutations) LGMD2G (TCAP mutations) LGMD2H (TRIM32 mutations) LGMD2I (FKRP mutations) LGMD2J (TTN mutations) LGMD2K (POMT1 mutations) LGMD2L (ANO5 mutations)

16 Type 2 LGMDs (AR) cont LGMD2M (FKTN mutations) LGMD2N (POMT2 mutations) LGMD2O (POMGnT1 mutations) LGMD2P (DAG1 mutations) LGMD2Q (PLEC1 mutations) LGMD2R (DES mutations) LGMD2S (TRAPPC11 mutations) LGMD2T (GMPPB mutations) LGMD2U (ISPD mutations) LGMD2V (GAA mutations) LGMD2W (LIMS2 mutations) LGMD2X (BVES mutations) LGMD2Y (TOR1A1P1 mutations)

17 Some LGMD subtype names Calpainopathy (CAPN3 mutations; recessive; LGMD2A) Desmin myopathy (DES mutation; dominant; LGMD1E / DES mutation; recessive; LGMD2R) Dysferlinopathy (DYSF mutations; recessive; LGMD2B) Sarcoglycanopathies (SGCG, SGCA, SGCB, SGCD mutations; recessive; LGMD2C, LGMD2D, LGMD2E, LGMD2F) ZASP-related myopathy (ZASP mutation; dominant; a form of myofibrillar myopathy)

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22 The most common limb girdle muscular dystrophy subtypes reported nowadays in Brazil are calpainopathy (LGMD2A) 32%, sarcoglycanopathy (LGMD2C, LGMD2D, LGMD2E, LGMD2F) 32%, dysferlinopathy (LGMD2B) 22%, fukutin related proteinopathy or FKRPathy (LGMD2I) 11%, and telethoninopathy (LGMD2G) 3%.

23 Classic autosomal-recessive LGMDs Sarcoglycanopathies (LGMD 2C-F) Calpainopathy (LGMD 2A) Dysferlinopathy (LGMD 2B).

24 SARCOGLYCANOPATHIES Of the sarcoglycan mutations, αsarcoglycanopathies are likely the most common type in Europe, North America, and Brazil, accounting for more than 50% of genetically proven sarcoglycanopathies

25 Clinical features of the four genetically distinct sarcoglycanopathies overlap significantly with little difference among the different types. They predominantly affect young children with a median age of onset around 6 to 8 years

26 The first symptoms generally relate to pelvic muscle weakness,evidenced by a waddling gait, which limits activities such as running, getting up from the floor, or climbing stairs. Primary toe walking may be present in some children.

27 In later stages and similar to DMD, neck flexor weakness may occur. Loss of independent ambulation may occur around 12 to 16 years of age. Cardiac involvement clearly occurs in sarcoglycanopathies(clinically overt dilated cardiomyopathy is only seen in a minority of patients).

28 AR-LGMD

29 AD-LGMD

30 Diagnostic algorithms for limb-girdle muscular dystrophy. (Reproduced from Narayanaswami P, Weiss M, Selcen D, et al). 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 Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 2014;83: )

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