# 254110

MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 8; LGMDR8


Alternative titles; symbols

MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2H; LGMD2H
MUSCULAR DYSTROPHY, HUTTERITE TYPE
SARCOTUBULAR MYOPATHY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
9q33.1 Muscular dystrophy, limb-girdle, autosomal recessive 8 254110 AR 3 TRIM32 602290
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Face
- Facial muscle weakness
- 'Flat smile'
Neck
- Neck flexor muscle weakness
MUSCLE, SOFT TISSUES
- Waddling gait
- Pelvic girdle muscle weakness
- Pelvic girdle muscle atrophy
- Quadriceps muscle weakness
- Shoulder girdle muscle weakness
- Shoulder girdle muscle atrophy
- 'Winged' scapulae
- Positive Gowers sign
- Exercise-induced weakness
- Exercise-induced muscle pain
- Pectoralis muscles may be less involved, leading to inward shrugging posture
- Calf muscle pseudohypertrophy
- Facial muscle weakness
- Myopathic changes seen on EMG
- Increased echo intensity in affected muscles
- Dystrophic changes seen on muscle biopsy
- Centralized nuclei
- Increased fiber size variation
- Atrophic fibers
- Small, membrane-bound vacuoles predominantly in type 2 fibers
- Vacuole membranes show ATPase reactivity consistent with origin from the sarcoplasmic reticulum
NEUROLOGIC
Peripheral Nervous System
- Hyporeflexia
- Areflexia
LABORATORY ABNORMALITIES
- Increased serum creatine kinase
MISCELLANEOUS
- Highly variable phenotype and severity
- Onset usually in childhood (1 to 9 years of age)
- Slowly progressive
- High frequency in Hutterite population
MOLECULAR BASIS
- Caused by mutation in the tripartite motif-containing protein 32 gene (TRIM32, 602290.0001)
Muscular dystrophy, limb-girdle, autosomal recessive - PS253600 - 30 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p34.1 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 AR 3 613157 POMGNT1 606822
1q25.2 ?Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures AR 3 617072 TOR1AIP1 614512
2p13.2 Muscular dystrophy, limb-girdle, autosomal recessive 2 AR 3 253601 DYSF 603009
2q14.3 ?Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue AR 3 616827 LIMS2 607908
2q31.2 Muscular dystrophy, limb-girdle, autosomal recessive 10 AR 3 608807 TTN 188840
3p22.1 Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 AR 3 618135 POMGNT2 614828
3p21.31 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 AR 3 613818 DAG1 128239
3p21.31 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 AR 3 615352 GMPPB 615320
3q13.33 Muscular dystrophy, limb-girdle, autosomal recessive 21 AR 3 617232 POGLUT1 615618
4q12 Muscular dystrophy, limb-girdle, autosomal recessive 4 AR 3 604286 SGCB 600900
4q35.1 Muscular dystrophy, limb-girdle, autosomal recessive 18 AR 3 615356 TRAPPC11 614138
5q13.3 Muscular dystrophy, limb-girdle, autosomal recessive 28 AR 3 620375 HMGCR 142910
5q33.2-q33.3 Muscular dystrophy, limb-girdle, autosomal recessive 6 AR 3 601287 SGCD 601411
6q21 Muscular dystrophy, limb-girdle, autosomal recessive 25 AR 3 616812 BVES 604577
6q21 Muscular dystrophy, limb-girdle, autosomal recessive 26 AR 3 618848 POPDC3 605824
6q22.33 Muscular dystrophy, limb-girdle, autosomal recessive 23 AR 3 618138 LAMA2 156225
7p21.2 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7 AR 3 616052 CRPPA 614631
8q24.3 Muscular dystrophy, limb-girdle, autosomal recessive 17 AR 3 613723 PLEC1 601282
9q31.2 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 AR 3 611588 FKTN 607440
9q33.1 Muscular dystrophy, limb-girdle, autosomal recessive 8 AR 3 254110 TRIM32 602290
9q34.13 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 AR 3 609308 POMT1 607423
11p14.3 Muscular dystrophy, limb-girdle, autosomal recessive 12 AR 3 611307 ANO5 608662
13q12.12 Muscular dystrophy, limb-girdle, autosomal recessive 5 AR 3 253700 SGCG 608896
14q24.3 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 AR 3 613158 POMT2 607439
14q32.33 Muscular dystrophy, limb-girdle, autosomal recessive 27 AR 3 619566 JAG2 602570
15q15.1 Muscular dystrophy, limb-girdle, autosomal recessive 1 AR 3 253600 CAPN3 114240
17q12 Muscular dystrophy, limb-girdle, autosomal recessive 7 AR 3 601954 TCAP 604488
17q21.33 Muscular dystrophy, limb-girdle, autosomal recessive 3 AR 3 608099 SGCA 600119
19q13.32 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 AR 3 607155 FKRP 606596
21q22.3 Ullrich congenital muscular dystrophy 1A AD, AR 3 254090 COL6A1 120220

TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-8 (LGMDR8) is caused by homozygous mutation in the gene encoding tripartite motif-containing protein-32 (TRIM32; 602290) on chromosome 9q33.

For a discussion of genetic heterogeneity of autosomal recessive LGMD, see LGMDR1 (253600).


Nomenclature

At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2H was renamed LGMDR8.


Clinical Features

Jerusalem et al. (1973) reported 2 brothers from an inbred Hutterite colony with a disorder they termed 'sarcotubular myopathy.' Nonprogressive muscular weakness was present from infancy. Muscle biopsy showed selective involvement of type II fibers with changes that were vacuolar in transverse section and segmental on longitudinal section. The spaces were membrane-bound on electron microscopy. Cytochemical markers indicated that the delimiting membranes were reactive for the sarcoplasmic reticulum-associated ATPase.

In a geographically isolated Hutterite population in Manitoba, Shokeir and Kobrinsky (1976) described a slowly progressive proximal muscular dystrophy with facial features. Eleven persons were known to be affected. In 1 case an affected male had 9 unaffected children, and another affected male had 8 unaffected children. Onset was between 1 and 9 years of age, in the quadriceps and pelvic girdle musculature. Patients show a waddling gait and difficulty rising from the squatting position as well as a 'flat smile.' EMG and muscle biopsy showed a muscular dystrophy.

Weiler et al. (1998) considered individuals affected if they showed signs and symptoms of proximal muscle weakness and had creatine kinase (CK) levels more than 4 times the upper limit of normal. Other features included signs and symptoms of proximal muscle weakness, and electromyogram or muscle biopsy consistent with a myopathic disorder. Asymptomatic patients with extremely elevated CK levels (more than 15 times the upper limit of normal) were also considered affected. Eighteen (11 males and 7 females) of 40 studied individuals in 4 related nuclear Hutterite families were classified as LGMD patients.

Muller-Felber et al. (1999) reported 2 German brothers with sarcotubular myopathy who had very different clinical courses. The older patient developed exercise-induced muscle weakness and pain at age 6 years. He had slow progression and was wheelchair-bound by his late twenties. He also had scapular winging, moderate hypertrophy of the calves, absent deep tendon reflexes, and increased serum creatine kinase. Skeletal muscle biopsy showed rounded muscle fibers with centralized nuclei and small membrane-bound vacuoles. The younger brother developed exercise-induced myalgia at age 32 years with little progression and disability. Skeletal muscle biopsy was similar to his brother's. The parents were unaffected.

Frosk et al. (2005) compared the clinical features of Hutterites with LGMD2H with those of Hutterites with LGMD2I (LGMDR9; 607155) caused by an L276I mutation in the FKRP gene (606596.0004). The FKRP L276I mutation also occurs in non-Hutterite patients with LGMD from Europe, Canada, and Brazil, and appears to be a founder mutation dispersed among populations of European origin. Hutterite LGMD2I patients had an earlier age at diagnosis, a more severe course, and higher serum creatine kinase than LGMD2H patients. In addition, some of the LGMD2I patients showed calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia; none of these features were present among LGMD2H patients.

Saccone et al. (2008) reported 2 unrelated non-Hutterite European patients with LGMD2H. A 44-year-old Croatian woman had slowly progressive proximal muscle weakness and wasting, respiratory weakness, and chronic keratitis. EMG showed myopathic and neurogenic changes. An unrelated man with LGMD2H reported disease onset in the third decade with weakness and paresthesias. He had marked proximal weakness and atrophy as well as respiratory weakness, and lost the ability to walk at age 64 after prolonged immobility for other causes.

Neri et al. (2013) reported a 35-year-old Italian woman with LGMDR8 who presented with muscle weakness and muscle pain predominantly of the lower limbs. She had normal motor development but was unable to run as fast as her peers in childhood. She first experience progressive muscle weakness and difficulty climbing stairs at age 25 years. On examination she had marked hypotrophy and weakness of the pelvic girdle muscles, especially the glutei, but no evidence of calf hypertrophy. Her cardiac examination and EKG were normal. Her CK levels were 2 times normal and an electromyography of her biceps brachialis and tibialis muscles showed a myopathic pattern with decrease in duration of the action potential.

Nectoux et al. (2015) reported 2 patients with LGMDR8. The first patient experienced progressive muscle weakness, scapular winging, and a waddling gait beginning at age 30 years. When he was seen 10 years later, he had frequent falls, moderately elevated CK levels, and a myogenic pattern on electromyography. On muscle biopsy, a nonspecific myopathy pattern was seen. The second patient, who was first seen at age 41 years, described difficulties with jumping and rope climbing since the age of 10 years. Difficulties with climbing stairs began at age 30, and the patient became wheelchair bound by the age of 50. The patient had a pure atrophic presentation with the quadriceps muscles being the most affected. CK levels were normal and an electromyogram showed myogenic impairment. A muscle biopsy of the biceps brachialis muscle was compatible with a dystrophic process. An echocardiogram at age 50 showed moderate hypertrophy of both ventricular walls, without left ventricular dysfunction. The patient also developed mild progressive cognitive impairment.


Mapping

Weiler et al. (1997) found that autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites was not linked to any of the 7 known LGMD loci or to any of 3 other candidate genes. They studied 4 related sibships with a total of 21 patients with a mild form of autosomal recessive LGMD. Weiler et al. (1998) used a genome scan of pooled DNA in the large Hutterite kindred to demonstrate linkage between limb-girdle muscular dystrophy of a mild autosomal recessive form and chromosomal region 9q31-q34.1. The FKTN gene (607440), which is responsible for Fukuyama congenital muscular dystrophy (FCMD), now designated muscular dystrophy-dystroglycanopathy type A4 (MDDGA4; 253800), maps to this region, but haplotype analysis revealed 5 recombinations that placed the LGMD locus distal to the FCMD locus. On the basis of an inferred ancestral recombination, the gene, symbolized LGMD2H, may lie in a 300-kb region between D9S302 and D9S934.

Frosk et al. (2002) narrowed the candidate LGMD2H region to 560 kb, flanked by D9S1126 and D9S737 and containing 4 genes.


Cytogenetics

Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified 2 patients with LGMDR8 with homozygous or compound heterozygous mutations in the TRIM32 gene. In the first patient, one allele had a frameshift mutation (602290.0006), confirmed by Sanger sequencing, and the other allele had a 124.4-kb deletion that included the entire TRIM32 gene. The second patient, born to nonconsanguineous parents, had a homozygous 336-kb deletion including the TRIM32 gene. The deletions in both patients, which were confirmed by quantitative PCR, included part of the ASTN2 gene (612856). Analysis of the breakpoints showed that the 5-prime boundaries of both deletions were located within regions enriched with genomic repeats, possibly making rearrangements and deletions more likely to occur. Parents were not available for study for either patient.


Inheritance

The transmission pattern of LGMD2H in the families reported by Frosk et al. (2002) and Schoser et al. (2005) was consistent with autosomal recessive inheritance.


Molecular Genetics

In Hutterite patients with LGMD2H, Frosk et al. (2002) identified a homozygous asp487-to-asn mutation in the TRIM32 gene (D487N; 602290.0001).

Schoser et al. (2005) identified the homozygous D487N mutation in the TRIM32 gene in the patients reported by Jerusalem et al. (1973) and Muller-Felber et al. (1999), confirming that they had LGMD2H. In addition, haplotype analysis showed that all LGMD2H patients shared the same haplotype, suggesting that the mutation arose before the emergence of the Hutterite religion in central Europe in the 16th century. Schoser et al. (2005) noted the phenotypic variability caused by the same mutation.

Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the LGMD2H-related TRIM32 mutation, D487N, and the LGMD2I-related FKRP mutation, L276I (606596.0004). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression. The grandfather of the boys was the proband originally reported by Shokeir and Kobrinsky (1976).

Saccone et al. (2008) identified homozygous mutations in the TRIM32 gene (see, e.g., 602290.0003; 602290.0004) in non-Hutterite patients with LGMD2H. A 73-year-old man with a milder phenotype was found to be heterozygous for 1 of the mutations.


Population Genetics

The Hutterites are divided into several main groups (tribes or demes) (Hostetler, 1985). The cases reported by Shokeir and Kobrinsky (1976) were from the Schmiedeleut Hutterites of Manitoba Province in Canada. Shokeir and Rozdilsky (1985) described the same type of muscular dystrophy in a Dariusleut kindred of Saskatchewan Province. They cited personal communications indicating the occurrence of the same muscular dystrophy in the Lehrerleut Hutterites of Alberta Province, as well.

The Hutterites, also called Hutterite Brethren, live on farming colonies predominantly in the Prairie Province and Great Plains of the U.S., and constitute a religious and genetic isolate. The ancestry of the overwhelming majority of the Hutterites can be traced back to 89 ancestors (Nimgaonkar et al., 2000). The history and social structure of the Hutterite Brethren were described by Hostetler (1985).

Among 1,493 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 228 heterozygotes and 9 homozygotes for the D487N mutation in the TRIM32 gene (rs111033570; 602290.0001), for a frequency of 0.153, or 1 in 6.5. The carrier frequency in other populations was unknown, with only 2 non-Hutterite cases having been reported (Schoser et al., 2005). The 9 homozygous individuals ranged in age from 10 to 42 years, and were unaware of their status.

Using comparative genomic hybridization (CGH) and sequencing of the TRIM32 gene in a 35-year-old Italian woman with LGMDR8, Neri et al. (2013) identified compound heterozygous mutations: a nonsense mutation (R316X; 602290.0005) in the C-terminal NHL domain of TRIM32 on one allele and a deletion including the entire TRIM32 gene on the other allele. The precise breakpoints of the deletion could not be defined.

Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified a patient with LGMDR8 who had a frameshift mutation in the TRIM32 gene (c.160delC; 602290.0006), confirmed by Sanger sequencing, and a 124.4-kb deletion that included the entire TRIM32 gene and part of the ASTN2 gene (612856); see CYTOGENETICS. The deletion was confirmed by quantitative PCR. The parents were not available for study.


Animal Model

Kudryashova et al. (2009) generated a Trim32-null mouse model of human muscular dystrophy phenotypes. Histologic analysis of Trim32-null skeletal muscles revealed mild myopathic changes. Electron microscopy showed areas with Z-line streaming and a dilated sarcotubular system with vacuoles, replicating the phenotypes of LGMD2H and sarcotubular myopathy. The level of Trim32 expression in normal mouse brain exceeded that observed in skeletal muscle by more than 100-fold. Analysis of Trim32-null neural tissue revealed a decreased concentration of neurofilaments and a reduction in myelinated motor axon diameters. The axonal changes suggested a shift toward a slower motor unit type. Trim32-null soleus muscle expressed an elevated type I slow myosin isotype with a concomitant reduction in the type II fast myosin. Kudryashova et al. (2009) suggested that muscular dystrophy due to TRIM32 mutation may involve both neurogenic and myogenic characteristics.


REFERENCES

  1. Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120, images, related citations] [Full Text]

  2. Frosk, P., Del Bigio, M. R., Wrogemann, K., Greenberg, C. R. Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. Europ. J. Hum. Genet. 13: 978-982, 2005. [PubMed: 15886712, related citations] [Full Text]

  3. Frosk, P., Greenberg, C. R., Tennese, A. A. P., Lamont, R., Nylen, E., Hirst, C., Frappier, D., Roslin, N. M., Zaik, M., Bushby, K., Straub, V., Zatz, M., de Paula, F., Morgan, K., Fujiwara, T. M., Wrogemann, K. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum. Mutat. 25: 38-44, 2005. [PubMed: 15580560, related citations] [Full Text]

  4. Frosk, P., Weiler, T., Nylen, E., Sudha, T., Greenberg, C. R., Morgan, K., Fujiwara, T. M., Wrogemann, K. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am. J. Hum. Genet. 70: 663-672, 2002. [PubMed: 11822024, images, related citations] [Full Text]

  5. Hostetler, J. A. History and relevance of the Hutterite population for genetic studies. Am. J. Med. Genet. 22: 453-462, 1985. [PubMed: 3904447, related citations] [Full Text]

  6. Jerusalem, F., Engel, A. G., Gomez, M. R. Sarcotubular myopathy. Neurology 23: 897-906, 1973. [PubMed: 4269389, related citations] [Full Text]

  7. Kudryashova, E., Wu, J., Havton, L. A., Spencer, M. J. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum. Molec. Genet. 18: 1353-1367, 2009. [PubMed: 19155210, images, related citations] [Full Text]

  8. Muller-Felber, W., Schlotter, B., Topfer, M., Ketelsen, U.-P., Muller-Hocker, J., Pongratz, D. Phenotypic variability in two brothers with sarcotubular myopathy. (Letter) J. Neurol. 246: 408-411, 1999. [PubMed: 10399877, related citations] [Full Text]

  9. Nectoux, J., de Cid, R., Baulande, S., Leturcq, F., Urtizberea, J. A., Penisson-Besnier, I., Nadaj-Pakleza, A., Roudaut, C., Criqui, A., Orhant, L., Peyroulan, D., Ben Yaou, R., and 11 others. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing. Europ. J. Hum. Genet. 23: 929-934, 2015. [PubMed: 25351777, images, related citations] [Full Text]

  10. Neri, M., Selvatici, R., Scotton, C., Trabanelli, C., Armaroli, A., De Grandis, D., Levy, N., Gualandi, F., Ferlini, A. A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation. Neuromusc. Disord. 23: 478-482, 2013. [PubMed: 23541687, related citations] [Full Text]

  11. Nimgaonkar, V. L., Fujiwara, T. M., Dutta, M., Wood, J., Gentry, K., Maendel, S., Morgan, K., Eaton, J. Low prevalence of psychoses among the Hutterites, an isolated religious community. Am. J. Psychiat. 157: 1065-1070, 2000. [PubMed: 10873912, related citations] [Full Text]

  12. Saccone, V., Palmieri, M., Passamano, L., Piluso, G., Meroni, G., Politano, L., Nigro, V. Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. Hum. Mutat. 29: 240-247, 2008. [PubMed: 17994549, related citations] [Full Text]

  13. Schoser, B. G. H., Frosk, P., Engel, A. G., Klutzny, U., Lochmuller, H., Wrogemann, K. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann. Neurol. 57: 591-595, 2005. [PubMed: 15786463, related citations] [Full Text]

  14. Shokeir, M. H. K., Kobrinsky, N. L. Autosomal recessive muscular dystrophy in Manitoba Hutterites. Clin. Genet. 9: 197-202, 1976. [PubMed: 1248180, related citations] [Full Text]

  15. Shokeir, M. H. K., Rozdilsky, B. Muscular dystrophy in Saskatchewan Hutterites. Am. J. Med. Genet. 22: 487-493, 1985. [PubMed: 4061485, related citations] [Full Text]

  16. Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862, related citations] [Full Text]

  17. Weiler, T., Greenberg, C. R., Nylen, E., Morgan, K., Fujiwara, T. M., Crumley, M. J., Zelinski, T., Halliday, W., Nickel, B., Triggs-Raine, B., Wrogemann, K. Limb girdle muscular dystrophy in Manitoba Hutterites does not map to any of the known LGMD loci. Am. J. Med. Genet. 72: 363-368, 1997. [PubMed: 9332671, related citations] [Full Text]

  18. Weiler, T., Greenberg, C. R., Zelinski, T., Nylen, E., Coghlan, G., Crumley, M. J., Fujiwara, T. M., Morgan, K., Wrogemann, K. A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus. Am. J. Hum. Genet. 63: 140-147, 1998. [PubMed: 9634523, related citations] [Full Text]


Sonja A. Rasmussen - updated : 03/10/2022
Ada Hamosh - updated : 2/13/2013
George E. Tiller - updated : 11/10/2009
Cassandra L. Kniffin - updated : 3/6/2008
Cassandra L. Kniffin - updated : 4/27/2005
Cassandra L. Kniffin - updated : 2/16/2005
Victor A. McKusick - updated : 2/4/2005
Victor A. McKusick - updated : 3/21/2002
Victor A. McKusick - updated : 7/22/1998
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 03/26/2024
alopez : 03/21/2023
carol : 03/14/2022
carol : 03/10/2022
carol : 09/25/2018
carol : 03/27/2017
alopez : 02/13/2013
alopez : 2/13/2013
carol : 11/11/2010
wwang : 11/10/2009
wwang : 3/12/2008
ckniffin : 3/6/2008
wwang : 11/26/2007
wwang : 2/20/2006
ckniffin : 2/10/2006
tkritzer : 5/9/2005
ckniffin : 4/27/2005
carol : 2/16/2005
carol : 2/16/2005
ckniffin : 2/15/2005
terry : 2/4/2005
ckniffin : 12/27/2002
alopez : 3/27/2002
alopez : 3/27/2002
terry : 3/21/2002
carol : 10/12/1999
terry : 7/22/1998
mimman : 2/8/1996
supermim : 3/17/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988
reenie : 6/4/1986

# 254110

MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 8; LGMDR8


Alternative titles; symbols

MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2H; LGMD2H
MUSCULAR DYSTROPHY, HUTTERITE TYPE
SARCOTUBULAR MYOPATHY


SNOMEDCT: 240064008, 43226001;   ORPHA: 1878;   DO: 0110282;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
9q33.1 Muscular dystrophy, limb-girdle, autosomal recessive 8 254110 Autosomal recessive 3 TRIM32 602290

TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-8 (LGMDR8) is caused by homozygous mutation in the gene encoding tripartite motif-containing protein-32 (TRIM32; 602290) on chromosome 9q33.

For a discussion of genetic heterogeneity of autosomal recessive LGMD, see LGMDR1 (253600).


Nomenclature

At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2H was renamed LGMDR8.


Clinical Features

Jerusalem et al. (1973) reported 2 brothers from an inbred Hutterite colony with a disorder they termed 'sarcotubular myopathy.' Nonprogressive muscular weakness was present from infancy. Muscle biopsy showed selective involvement of type II fibers with changes that were vacuolar in transverse section and segmental on longitudinal section. The spaces were membrane-bound on electron microscopy. Cytochemical markers indicated that the delimiting membranes were reactive for the sarcoplasmic reticulum-associated ATPase.

In a geographically isolated Hutterite population in Manitoba, Shokeir and Kobrinsky (1976) described a slowly progressive proximal muscular dystrophy with facial features. Eleven persons were known to be affected. In 1 case an affected male had 9 unaffected children, and another affected male had 8 unaffected children. Onset was between 1 and 9 years of age, in the quadriceps and pelvic girdle musculature. Patients show a waddling gait and difficulty rising from the squatting position as well as a 'flat smile.' EMG and muscle biopsy showed a muscular dystrophy.

Weiler et al. (1998) considered individuals affected if they showed signs and symptoms of proximal muscle weakness and had creatine kinase (CK) levels more than 4 times the upper limit of normal. Other features included signs and symptoms of proximal muscle weakness, and electromyogram or muscle biopsy consistent with a myopathic disorder. Asymptomatic patients with extremely elevated CK levels (more than 15 times the upper limit of normal) were also considered affected. Eighteen (11 males and 7 females) of 40 studied individuals in 4 related nuclear Hutterite families were classified as LGMD patients.

Muller-Felber et al. (1999) reported 2 German brothers with sarcotubular myopathy who had very different clinical courses. The older patient developed exercise-induced muscle weakness and pain at age 6 years. He had slow progression and was wheelchair-bound by his late twenties. He also had scapular winging, moderate hypertrophy of the calves, absent deep tendon reflexes, and increased serum creatine kinase. Skeletal muscle biopsy showed rounded muscle fibers with centralized nuclei and small membrane-bound vacuoles. The younger brother developed exercise-induced myalgia at age 32 years with little progression and disability. Skeletal muscle biopsy was similar to his brother's. The parents were unaffected.

Frosk et al. (2005) compared the clinical features of Hutterites with LGMD2H with those of Hutterites with LGMD2I (LGMDR9; 607155) caused by an L276I mutation in the FKRP gene (606596.0004). The FKRP L276I mutation also occurs in non-Hutterite patients with LGMD from Europe, Canada, and Brazil, and appears to be a founder mutation dispersed among populations of European origin. Hutterite LGMD2I patients had an earlier age at diagnosis, a more severe course, and higher serum creatine kinase than LGMD2H patients. In addition, some of the LGMD2I patients showed calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia; none of these features were present among LGMD2H patients.

Saccone et al. (2008) reported 2 unrelated non-Hutterite European patients with LGMD2H. A 44-year-old Croatian woman had slowly progressive proximal muscle weakness and wasting, respiratory weakness, and chronic keratitis. EMG showed myopathic and neurogenic changes. An unrelated man with LGMD2H reported disease onset in the third decade with weakness and paresthesias. He had marked proximal weakness and atrophy as well as respiratory weakness, and lost the ability to walk at age 64 after prolonged immobility for other causes.

Neri et al. (2013) reported a 35-year-old Italian woman with LGMDR8 who presented with muscle weakness and muscle pain predominantly of the lower limbs. She had normal motor development but was unable to run as fast as her peers in childhood. She first experience progressive muscle weakness and difficulty climbing stairs at age 25 years. On examination she had marked hypotrophy and weakness of the pelvic girdle muscles, especially the glutei, but no evidence of calf hypertrophy. Her cardiac examination and EKG were normal. Her CK levels were 2 times normal and an electromyography of her biceps brachialis and tibialis muscles showed a myopathic pattern with decrease in duration of the action potential.

Nectoux et al. (2015) reported 2 patients with LGMDR8. The first patient experienced progressive muscle weakness, scapular winging, and a waddling gait beginning at age 30 years. When he was seen 10 years later, he had frequent falls, moderately elevated CK levels, and a myogenic pattern on electromyography. On muscle biopsy, a nonspecific myopathy pattern was seen. The second patient, who was first seen at age 41 years, described difficulties with jumping and rope climbing since the age of 10 years. Difficulties with climbing stairs began at age 30, and the patient became wheelchair bound by the age of 50. The patient had a pure atrophic presentation with the quadriceps muscles being the most affected. CK levels were normal and an electromyogram showed myogenic impairment. A muscle biopsy of the biceps brachialis muscle was compatible with a dystrophic process. An echocardiogram at age 50 showed moderate hypertrophy of both ventricular walls, without left ventricular dysfunction. The patient also developed mild progressive cognitive impairment.


Mapping

Weiler et al. (1997) found that autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites was not linked to any of the 7 known LGMD loci or to any of 3 other candidate genes. They studied 4 related sibships with a total of 21 patients with a mild form of autosomal recessive LGMD. Weiler et al. (1998) used a genome scan of pooled DNA in the large Hutterite kindred to demonstrate linkage between limb-girdle muscular dystrophy of a mild autosomal recessive form and chromosomal region 9q31-q34.1. The FKTN gene (607440), which is responsible for Fukuyama congenital muscular dystrophy (FCMD), now designated muscular dystrophy-dystroglycanopathy type A4 (MDDGA4; 253800), maps to this region, but haplotype analysis revealed 5 recombinations that placed the LGMD locus distal to the FCMD locus. On the basis of an inferred ancestral recombination, the gene, symbolized LGMD2H, may lie in a 300-kb region between D9S302 and D9S934.

Frosk et al. (2002) narrowed the candidate LGMD2H region to 560 kb, flanked by D9S1126 and D9S737 and containing 4 genes.


Cytogenetics

Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified 2 patients with LGMDR8 with homozygous or compound heterozygous mutations in the TRIM32 gene. In the first patient, one allele had a frameshift mutation (602290.0006), confirmed by Sanger sequencing, and the other allele had a 124.4-kb deletion that included the entire TRIM32 gene. The second patient, born to nonconsanguineous parents, had a homozygous 336-kb deletion including the TRIM32 gene. The deletions in both patients, which were confirmed by quantitative PCR, included part of the ASTN2 gene (612856). Analysis of the breakpoints showed that the 5-prime boundaries of both deletions were located within regions enriched with genomic repeats, possibly making rearrangements and deletions more likely to occur. Parents were not available for study for either patient.


Inheritance

The transmission pattern of LGMD2H in the families reported by Frosk et al. (2002) and Schoser et al. (2005) was consistent with autosomal recessive inheritance.


Molecular Genetics

In Hutterite patients with LGMD2H, Frosk et al. (2002) identified a homozygous asp487-to-asn mutation in the TRIM32 gene (D487N; 602290.0001).

Schoser et al. (2005) identified the homozygous D487N mutation in the TRIM32 gene in the patients reported by Jerusalem et al. (1973) and Muller-Felber et al. (1999), confirming that they had LGMD2H. In addition, haplotype analysis showed that all LGMD2H patients shared the same haplotype, suggesting that the mutation arose before the emergence of the Hutterite religion in central Europe in the 16th century. Schoser et al. (2005) noted the phenotypic variability caused by the same mutation.

Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the LGMD2H-related TRIM32 mutation, D487N, and the LGMD2I-related FKRP mutation, L276I (606596.0004). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression. The grandfather of the boys was the proband originally reported by Shokeir and Kobrinsky (1976).

Saccone et al. (2008) identified homozygous mutations in the TRIM32 gene (see, e.g., 602290.0003; 602290.0004) in non-Hutterite patients with LGMD2H. A 73-year-old man with a milder phenotype was found to be heterozygous for 1 of the mutations.


Population Genetics

The Hutterites are divided into several main groups (tribes or demes) (Hostetler, 1985). The cases reported by Shokeir and Kobrinsky (1976) were from the Schmiedeleut Hutterites of Manitoba Province in Canada. Shokeir and Rozdilsky (1985) described the same type of muscular dystrophy in a Dariusleut kindred of Saskatchewan Province. They cited personal communications indicating the occurrence of the same muscular dystrophy in the Lehrerleut Hutterites of Alberta Province, as well.

The Hutterites, also called Hutterite Brethren, live on farming colonies predominantly in the Prairie Province and Great Plains of the U.S., and constitute a religious and genetic isolate. The ancestry of the overwhelming majority of the Hutterites can be traced back to 89 ancestors (Nimgaonkar et al., 2000). The history and social structure of the Hutterite Brethren were described by Hostetler (1985).

Among 1,493 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 228 heterozygotes and 9 homozygotes for the D487N mutation in the TRIM32 gene (rs111033570; 602290.0001), for a frequency of 0.153, or 1 in 6.5. The carrier frequency in other populations was unknown, with only 2 non-Hutterite cases having been reported (Schoser et al., 2005). The 9 homozygous individuals ranged in age from 10 to 42 years, and were unaware of their status.

Using comparative genomic hybridization (CGH) and sequencing of the TRIM32 gene in a 35-year-old Italian woman with LGMDR8, Neri et al. (2013) identified compound heterozygous mutations: a nonsense mutation (R316X; 602290.0005) in the C-terminal NHL domain of TRIM32 on one allele and a deletion including the entire TRIM32 gene on the other allele. The precise breakpoints of the deletion could not be defined.

Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified a patient with LGMDR8 who had a frameshift mutation in the TRIM32 gene (c.160delC; 602290.0006), confirmed by Sanger sequencing, and a 124.4-kb deletion that included the entire TRIM32 gene and part of the ASTN2 gene (612856); see CYTOGENETICS. The deletion was confirmed by quantitative PCR. The parents were not available for study.


Animal Model

Kudryashova et al. (2009) generated a Trim32-null mouse model of human muscular dystrophy phenotypes. Histologic analysis of Trim32-null skeletal muscles revealed mild myopathic changes. Electron microscopy showed areas with Z-line streaming and a dilated sarcotubular system with vacuoles, replicating the phenotypes of LGMD2H and sarcotubular myopathy. The level of Trim32 expression in normal mouse brain exceeded that observed in skeletal muscle by more than 100-fold. Analysis of Trim32-null neural tissue revealed a decreased concentration of neurofilaments and a reduction in myelinated motor axon diameters. The axonal changes suggested a shift toward a slower motor unit type. Trim32-null soleus muscle expressed an elevated type I slow myosin isotype with a concomitant reduction in the type II fast myosin. Kudryashova et al. (2009) suggested that muscular dystrophy due to TRIM32 mutation may involve both neurogenic and myogenic characteristics.


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Contributors:
Sonja A. Rasmussen - updated : 03/10/2022
Ada Hamosh - updated : 2/13/2013
George E. Tiller - updated : 11/10/2009
Cassandra L. Kniffin - updated : 3/6/2008
Cassandra L. Kniffin - updated : 4/27/2005
Cassandra L. Kniffin - updated : 2/16/2005
Victor A. McKusick - updated : 2/4/2005
Victor A. McKusick - updated : 3/21/2002
Victor A. McKusick - updated : 7/22/1998

Creation Date:
Victor A. McKusick : 6/4/1986

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