ORPHA: 258, 565837;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q22.33 | Muscular dystrophy, limb-girdle, autosomal recessive 23 | 618138 | Autosomal recessive | 3 | LAMA2 | 156225 |
A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by homozygous or compound heterozygous mutation in the LAMA2 gene (156225) on chromosome 6q22.
Biallelic mutation in the LAMA2 gene can also cause congenital muscular dystrophy (MDC1A; 607855), which has overlapping but more severe features.
Autosomal recessive limb-girdle muscular dystrophy-23 is characterized by slowly progressive proximal muscle weakness primarily affecting the lower limbs and resulting in gait difficulties. Age at onset generally ranges from childhood to mid-adulthood. Additional features include white matter abnormalities on brain imaging, increased serum creatine kinase, and dystrophic features, with partial LAMA2 deficiency on muscle biopsy. Some patients may have additional neurologic features, including executive deficits, seizures, and peripheral neuropathy. Patients remain ambulatory well into adulthood (summary by Gavassini et al., 2011 and Chan et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Gavassini et al. (2011) reported 5 patients from 4 families with LGMDR23. The phenotype was highly variable, but all patients remained ambulant between 17 and 65 years of age. Four patients had normal motor development, whereas 1 patient had delayed walking at 2 years of age. The age at onset was reported to be between 10 and 59 years, but 1 patient had onset at age 14 months. Features included proximal muscle weakness in the upper and lower limbs, difficulty climbing stairs and running, waddling gait, Gowers sign, and muscle cramps, as well as increased serum creatine kinase. Three patients had calf hypertrophy. Neurologic involvement was also variable: all patients had nonprogressive diffuse white matter abnormalities on brain imaging, 3 had deficits in executive function or cognition, 2 had controlled seizures, and 2 had possible seizures. Muscle biopsy showed partial and variably decreased immunostaining for LAMA2 as well as increased immunostaining for LAMA5 (601033).
Chan et al. (2014) reported an 11-year-old girl with LGMDR23. She had normal early motor development, but had transient unilateral ptosis in early childhood. At age 5, she was noted to be clumsy and slow, and later showed difficulty running, jumping, climbing stairs and lifting heavy objects, but remained ambulatory. Her initial assessment, including electrophysiologic studies, was consistent with a demyelinating sensorimotor peripheral neuropathy. Physical examination showed proximal weakness of the upper and lower limbs, areflexia, distal hand wasting, Gowers sign, elbow contractures, and mild kyphosis. Sensation, proprioception, and vibration sensation were intact. She had decreased nerve conduction velocities as well as signs of chronic reinnervation and axonal degeneration. Muscle biopsy showed dystrophic features, including increased fiber size variation, increased fat and connective tissue, and internal nuclei. Immunostaining of skeletal muscle sample showed partial LAMA2 deficiency in both muscle fibers and intramuscular motor nerves. Serum creatine kinase was increased, and brain imaging showed white matter abnormalities.
Lokken et al. (2015) reported 1 new patient (patient 7) with LGMDR23. This woman showed delayed motor development before 1 year of age, but presented with LGMD at age 32. She was able to walk and run and remained ambulatory as an adult, but she had a positive Gowers sign. Serum creatine kinase was increased, and muscle biopsy showed mild dystrophic and myopathic changes as well as partial LAMA2 deficiency. Brain imaging showed white matter abnormalities; cognition was normal.
The transmission pattern of LGMDR23 in the families reported by Gavassini et al. (2011) was consistent with autosomal recessive inheritance.
In 5 patients from 4 families with LGMDR23, Gavassini et al. (2011) identified homozygous or compound heterozygous mutations in the LAMA2 gene (see, e.g., 156225.0016 and 156225.0017). There were 4 missense mutations, 1 splice site mutation, and 1 in-frame deletion. The mutations were located in both the globular and the rod-like domains of the protein. Functional studies of the variants were not performed, but the splice site mutation was confirmed to result in a frameshift in patient cells. Muscle biopsy showed partial LAMA2 deficiency in all patients.
In a girl with LGMDR23, Chan et al. (2014) identified compound heterozygous mutations in the LAMA2 gene (Q131X, 156225.0018 and A1496V, 156225.0019). The mutations segregated with the disorder in the family. Functional studies of the variants were not performed.
In a patient with LGMDR23, Lokken et al. (2015) identified compound heterozygous missense mutations in the LAMA2 gene (L12R and L1253R). Functional studies of the variants were not performed.
In a comprehensive mutation update on LAMA2 mutations, Oliveira et al. (2018) stated that the most frequently reported genotypes are variants that create premature termination codons (PTC) in both disease alleles, are associated with complete deficiency of laminin in muscle biopsy, and cause a severe, congenital muscular dystrophy (MDC1A). In contrast, missense variants, which are present in a smaller number of cases, usually correlate with partial laminin deficiency in muscle biopsy, and cause a milder, later-onset disorder (LGMDR23).
Chan, S. H. S., Foley, R., Phadke, R., Mathew, A. A., Pitt, M., Sewry, C., Muntoni, F. Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy. Neuromusc. Disord. 24: 677-683, 2014. [PubMed: 24957499] [Full Text: https://doi.org/10.1016/j.nmd.2014.05.008]
Gavassini, B. F., Carboni, N., Nielsen, J. E., Danielsen, E. R, Thomsen, C., Svenstrup, K., Bello, L. Maioli, M. A., Marrosu, G., Ticca, A. F., Mura, M., Marrosu, M. G., Soraru, G., Angelini, C., Vissing, J., Pegoraro, E. Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations. Muscle Nerve 44: 703-709, 2011. [PubMed: 21953594] [Full Text: https://doi.org/10.1002/mus.22132]
Lokken, N., Born, A. P., Duno, M., Vissing, J. LAMA2-related myopathy: frequency among congenital and limb-girdle muscular dystrophies. Muscle Nerve 52: 547-553, 2015. [PubMed: 25663498] [Full Text: https://doi.org/10.1002/mus.24588]
Oliveira, J., Gruber, A., Cardoso, M., Taipa, R., Fineza, I., Goncalves, A., Laner, A., Winder, T. L., Schroeder, J., Rath, J., Oliveira, M. E., Vieira, E., and 11 others. LAMA2 gene mutation update: toward a more comprehensive picture of the laminin-alpha-2 variome and its related phenotypes. Hum. Mutat. 39: 1314-1337, 2018. [PubMed: 30055037] [Full Text: https://doi.org/10.1002/humu.23599]