Novel compound heterozygous mutations of LAMA2-limb–girdle muscular dystrophy: A case report and literature review

Abstract

The laminin α2 (LAMA2) gene pathogenic variants can lead to limb–girdle muscular dystrophy (known as LGMDR23), which is rarely reported and characterized by proximal weakness in the limbs. We present the case of a 52-year-old woman who gradually developed weakness in both lower extremities since the age of 32 years. Magnetic resonance imaging (MRI) brain showed symmetrical sphenoid wings-like white matter demyelination in bilateral lateral ventricles. Electromyography showed quadriceps muscle damage on the bilateral lower extremity. Next-generation sequencing (NGS) found two loci variations in the LAMA2 gene, i.e., c.2749 + 2dup and c.8689C>T. This case highlights the importance of considering LGMDR23 in patients presenting with weakness and white matter demyelination on MRI brain and further expands the gene variants spectrum of LGMDR23.

Identification of LAMA2 compound heterozygous variants: a case report

“…This variant was mainly detected in the compound heterozygous state ( 12 - 14 ). The c.2749 + 2dup is a splicing variant inherited from the mother and has been reported in previous studies ( 15 , 16 ). The splice donor site duplication (c.2749 + 2dup) may lead to splicing abnormalities.…”

“…Furthermore, diagnosis requires muscle biopsy, immunohistochemical staining, or genetic testing. It was reported that there was no merosin staining in MDC1A, but low levels of residual merosin can be detected in LGMDR23 ( 15 , 19 ). Unfortunately, muscle biopsy and immunohistochemistry staining had not been performed in this case.…”

“…GnomAD shows that the overall frequency of this variant in the population is 1/250,932 (with a frequency of 0/18,390 in the East Asian population), and it is not supported as a polymorphic locus. Results from a study by using spliceAI analysis suggest this variant may affect splicing ( 15 ), but it has not been experimentally investigated ( 17 ). Although this variant achieved a high spliceAI score of 0.99 for splice altering ( 15 ), it is also possible that the in frame/out of frame exon skips or the splice donor site changes to another location could lead to mild phenotypes in patients like this one ( 17 ).…”

“…Results from a study by using spliceAI analysis suggest this variant may affect splicing ( 15 ), but it has not been experimentally investigated ( 17 ). Although this variant achieved a high spliceAI score of 0.99 for splice altering ( 15 ), it is also possible that the in frame/out of frame exon skips or the splice donor site changes to another location could lead to mild phenotypes in patients like this one ( 17 ). This variant is not related to complete loss-of-function of the gene ( 16 ) and is consistent with the observed in our case.…”