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Limb-Girdle muscular dystrophy

(last modified December 10, 2006)

Content

Introduction
LGMD's
Tabular overview
Frequency LGMD's
- sarcoglycanopathies

CMD / LGMD

The Congenital Muscular Dystrophies (CMD) and the Limb-Girdle Muscular Dystrophies (LGMD) are common forms of highly heterogeneous muscular dystrophies which can be distinguished by their age at onset. In CMD, onset of symptoms is at birth or within the first 6 months of life; in LGMD onset of symptoms is in late childhood, adolescence or even adult life. Inheritance in LGMD can be autosomal dominant (LGMD type 1) or autosomal recessive (LGMD type 2), CMD is always recessively inherited. Recent data show that CMD and LGMD can overlap both clinically and genetically, which suggests that the underlying pathology may follow similar pathways. Several of the phenotypically similar but genetically distinct LGMDs have been shown to be caused by abnormalities of the plasma membrane of the muscle fiber, destroying the so called dystrophin-associated glycoprotein complex (DGC).

LGMD

ENMC - diagnostic criteria for LGMD
entry in GeneTests - GeneClinics

Type 1 - autosomal dominant

LGMD-1A seems due to changes in the TTID-gene (myotilin).
LGMD-1B is caused by changes in the gene encoding lamin A/C (LMNA). Changes in LMNA have been related to a range of other disorders, including CMD1A (OMIM 115200), CMT2B1 (OMIM 605588), EDMD2 (OMIM 181350), EDMD3 (OMIM 604929), FPLD (OMIM 151660), HGPS (OMIM 176670), LDHPC (OMIM 608056), MAD (OMIM 248370), WRN (OMIM 277700).
LGMD-1C is caused by changes in the caveolin-3 gene (CAV3). Changes in CAV3 are also involved in hyperCKemia (OMIM 123320) and rippling muscle disease (RMD, OMIM 06072)
LGMD-1D (OMIM 603511) maps to chromosome 7q (Speer et al. [1999]). The gene involved has not yet been identified.
LGMD-1E (or CMD1F, OMIM 602067) has been mapped to chromosome 6q22 (Messina et al [1997]). The gene involved has not yet been identified.
LGMD-1F (not in OMIM) maps to chromosome 7q31.1 (Palenzuela et al. [2003]). The gene involved has not yet been identified.
LGMD-1G (not in OMIM) maps to chromosome 4p21 (Starling et al. [2004]). The gene involved has not yet been identified.

Type 2 - autosomal recessive

Autosomal recessive inheritance with heterogeneous clinical features. In severe form, onset at age 3 to 5 years (SCARMD). In mild forms onset in the first, second or third decade of life. There is a significant variability of clinical features in unrelated patients and within families.

LGMD-2A is caused by changes in the calpain-3 gene (CAPN3, Richard et al [1995])
LGMD-2B and Miyoshi myopathy are caused by changes in the dysferlin gene (DYSF, Bashir et al. [1998] / Liu et al. [1998])
sarcoglycanopathies
- LGMD-2C is caused by changes in the gamma-sarcoglycan gene (SGCG, Noguchi et al. [1995])
- LGMD-2D is caused by changes in the alpha-sarcoglycan gene (SGCA, Roberds et al. [1994])
- LGMD-2E is caused by changes in the betaa-sarcoglycan gene (SGCB, Lim et al. [1995] / Bönnemann et al [1995])
- LGMD-2F and CMD1L (OMIM ...)are caused by changes in the delta-sarcoglycan gene (SGCD, Nigro et al. [1996] / Nigro et al. [1996])
LGMD-2G is caused by changes in the telethonin gene (TCAP, Moreira et al. [2000])
LGMD-2H is caused by changes in the TRIM32 gene (TRIM32, Frosk et al. [2002])
LGMD-2I (OMIM 607155) maps to 19q13.3 and is caused by changes in the fukutin-related protein gene (FKRP, Brockington et al. [2001]). Changes in the same gene cause MDC-1C (OMIM 606612), MEB (OMIM 253280) and WWS (OMIM 236670)
LGMD-2J (OMIM 608807) maps to 2q24.3 and is caused by changes in the titin gene (TTN, Hackman et al. [2002]) The difficulty lies in identifying changes in this 363-exon 295 kb gene encoding a protein of over 38,000 amino acids.
LGMD-2K (OMIM 609308) maps to 9q34.1 and is caused by changes in the protein O-mannosyltransferase-1 gene (POMT1, Balci et al. [2005])

Tabular overview

Disease (OMIM link)	Chromosomal location	Gene (LocusLink)	Age at onset	CK level	Distinctive feature	At these pages
LGMD-1A	5q31.2	TTID	20-40y	normal - 10x	dysarthria	*TTID / TTID variation DB*
LGMD-1B	1q22	LMNA	<10y	normal - 20x	contractures	*LMNA / LMNA variation DB*
LGMD-1C	3p25.3	CAV3	<10y	2 - 25x	mounding / rippling	*CAV3 / CAV3 variation DB*
LGMD-1D	7q	?	15-50y	normal - 4x	cardiomyopathy
LGMD-1E	6q22	?	30-50y	normal - 10x	-
LGMD-1F (not in OMIM)	7q31.1	?
LGMD-1F (not in OMIM)	4p21	?
LGMD-2A	15q15.2	CAPN3	5-40y	normal - 50x	adductor weakness	*CAPN3 / CAPN3 variation DB*
LGMD-2B, MM	2p13.2	DYSF	10-30y	10 - 150x	distal leg weakness	*DYSF / DYSF variation DB*
LGMD-2C	13q12	SGCG	3-20y	5 - 120x	-	*SGCG / SGCG variation DB*
LGMD-2D	17q21.33	SGCA				*SGCA / SGCA variation DB*
LGMD-2E	4q11	SGCB				*SGCB / SGCB variation DB*
LGMD-2F	5q33.3	SGCD				*SGCD / SGCD variation DB*
LGMD-2G	17q12	TCAP	2-15y	2 - 30x	in Brazilians	*TCAP / TCAP variation DB*
LGMD-2H	9q33.1	TRIM32	15-30y	normal - 20x	in Hutterite	*TRIM32 / TRIM32 variation DB*
LGMD-2I	19q13.32	FKRP	1-40y	5 - 40x	respiratory dysfunction	*FKRP / FKRP variation DB*
LGMD-2J (not in OMIM)	2q24.3-31	TTN	5-20y	normal - 2x	in Finns

Most data are as reported by Wicklund et al. (2003)

Frequency of LGMD's

Duggan et al. (1997) reported that in a set of 263 patients with a dystrophinopathy-like disorder (DLMD or LGMD) and normal dystrophin, 25 (10%) showed a complete and 29 (11%) a partial alpha-sarcoglycan deficiency in muscle biopsy samples. In a group of 38 autosomal recessive Turkish LGMD families Dincer et al. (2000) detected 7 CAPN3, 3 DYSF, 2 SGCA, 7 SGCB, 5 SGCG, 1 SGCD and 2 LAMA2 deficiencies. Two families showed an EMD-like phenotype and 9 had preserved sarcoglycans and no linkage to LGMD2A-F loci.

Sarcoglycanopathies

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