Please note as of February 28, 2020, the genes on this panel has been revised based on new data from the literature and the manner in which the panel was curated. This was done to better focus the subtypes of Limb-Girdle Muscular Weakness most likely to confer a diagnosis and to reduce the burden of variants of unknown significance reported in the test process, which require additional investigation by the provider. Please find the updated gene list here. As such any test request for this panel submitted after March 1, 2020 will be automatically converted to the new gene list.
Limb-girdle muscular weakness (LGMW) is a term describing the weakness pattern encompassing a group of diseases associated with weakness and wasting of predominantly proximal muscles of the pelvic and shoulder girdles. The limb-girdle muscular dystrophies (LGMDs) encompass a heterogeneous group of disorders that vary in severity and age of onset and can be classified into two main groups depending on the inheritance pattern.1
There are a variety of LGMD subtypes characterized by specific genetic mutations and distinguishing features but many are characterized by muscle weakness and wasting, proximal greater than distal. The clinical course is typically progressive, serum CK is usually elevated and muscle biopsy typically shows dystrophic changes especially in childhood onset cases.
Late Onset Pompe Disease (LOPD) shares considerable phenotypic overlap with the Limb Girdle Muscular Dystrophies, presenting with progressive proximal weakness (particularly pelvic girdle), scapular winging, and feeding/swallowing difficulties. CK is often elevated. Differentiating Pompe from other LGMDs can be guided by pulmonary function testing as Pompe presents with respiratory insufficiency. Muscle biopsy findings tend to show vacuolated, and PAS-positive fibers5, though muscle biopsies can be normal depending on the state of disease progression and site of biopsy. Pompe is an autosomal recessive disorder caused by mutations in the GAA gene. If Pompe disease is strongly suspected, enzyme assay for acid α-glucosidase is a more appropriate test and could be ordered in parallel.
Limb Girdle Muscular Dystrophy is clinically and genetically heterogenous thereby making it difficult for a physician to assign a definite genetic diagnosis based on the clinical presentation. This gene panel includes genes causative of overlapping clinical presentation for Limb Girdle Muscular Dystrophy, Congenital Muscular Dystrophy, Duchenne Muscular Dystrophy, and several myopathy and myasthenic syndromes.
- Most LGMDs are rare, with estimated prevalence ranging from 2.4-7.3 per 100,000 (Becker) to 0.07 per 100,000 (LGMD2D, E) to 0.43 per 100,000 (LGMD2I)
- Pompe disease overall incidence estimates for the United States for all forms is 1 in 40,0001
- Most subtypes of LGMD are autosomal recessive (LGMD2A-Q, Pompe)
- Several rare subtypes are autosomal dominant (LGMD1A-E)
- A few myopathies are X-linked (Becker, EGMD-X1, -X2)2
The Lantern Project* is for individual patients with:
- Symptoms suggestive of a limb-girdle muscular dystrophy, or
- Clinical diagnosis of an unspecified limb-girdle muscular dystrophy requiring genetic confirmation
*This testing program is not appropriate for carrier testing or for individuals with a family history of Pompe disease in whom a diagnosis of Pompe is considered. Also note that there is no age restriction on the use of this panel; the genes include disorders that encompass both pediatric and adult ages of onset. It is possible for pediatric patients to receive results that may not have immediate clinical implications. Patient/parental consent is highly recommended.
This panel contains genes including GAA, all of the LGMD genes, and genes associated with other myopathies and myasthenic syndromes. For a complete list of genes included as well as associated conditions please click here.
- NGS gene panel will be performed. Patients with 2 GAA variants (whether pathogenic, likely pathogenic or variants of uncertain significance) will reflex to:
- acid α-glucosidase enzyme assay