About Limb-Girdle Muscular Weakness (LGMW)

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.

Incidence

  • 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

Inheritance

  • 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

Program Eligibility

The Lantern Project* is for individual patients with:

  1. Symptoms suggestive of a limb-girdle muscular dystrophy, or
  2. 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.

About the Test

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

Testing algorithm:

  1. NGS gene panel will be performed. Patients with 2 GAA variants (whether pathogenic, likely pathogenic or variants of uncertain significance) will reflex to:
  2. acid α-glucosidase enzyme assay

Focused Neuromuscular Disease Panel

  • Dried blood spots (DBS) are preferred, but whole blood (EDTA) is also acceptable. Note that saliva cannot be used to reflex to acid a-glucosidase enzyme testing for Pompe disease.

Acid alpha-glucosidase Enzyme Assay

  • Dried blood spots are preferred, but whole blood (EDTA) is also acceptable.

Bundled Testing (Sequencing panel with reflex to enzyme testing)

  • Dried blood spots (DBS) are preferred, but whole blood (EDTA) is also acceptable. Note that saliva cannot be used to reflex to acid a-glucosidase enzyme testing for Pompe disease.

Click Here for detailed sample instructions and required quantities.

Gene Sequencing Assay

  • Focused Neuromuscular Disease Panel is performed using NGS and analysis of all coding exons and 10bp of flanking intronic regions. This assay cannot detect variants in regions of the exome that are not covered, such as deep intronic, promoter, and enhancer regions, areas containing large numbers (>2000) of tandem repeats. Of note, this assay is designed to detect the following variants in the GAA gene if present: exon 18 deletion [c.2481 + 102_2646 + 31del (p.Gly828_Asn882del)] and the intronic mutation c.-32-13T > G. Copy number variation (CNV) of three exons or more is reported. Single exon CNVs can also be predicted, but reported after follow-up confirmation is performed.
  • A full list of genes included on this panel can be found here.
  • For a complete list of genes included as well as associated conditions please Click Here
Enzyme Assay
  • Acid α-glucosidase activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS).

Focused Neuromuscular Disease Panel: 3 weeks

Acid α-glucosidase Enzyme Assays: 3 days

Ordering Instructions

Select the correct test for your patient, and fill out The Lantern Project Requisition Form.

  1. Obtain a sample for testing from the patient using one of the provided PerkinElmer Genomics test packs. If you do not have a kit available in your office, please contact us here and we can have one sent out to your office.
    • Ensure that the patient sample is labeled with the patient name and date of birth.
    • Please note that all biochemical assays require a dried blood spot sample or whole blood. Step-by-step instructions for collecting a DBS sample can be found here.
    • Samples may be submitted without a collection kit by following the guidelines for specimen requirements and completing the requisition form.
  2. Package the patient sample, informed consent form, and test requisition form back into the test kit, and utilize the included pre-paid shipping label to return the kit to PerkinElmer Genomics for processing.
    • As a patient’s clinical presentation is an essential part of fully interpreting genetic test results, we ask that you kindly include any applicable medical records or clinical notes with the sample at the time of test submission.

Once PerkinElmer receives the sample, you will receive phone call to report abnormal findings, with a written report to follow within the established turnaround time for the ordered test. Bundled tests will be reported together in one comprehensive result.

Other Conditions in the Lantern Project

  • To learn more about The Lantern Project, Click Here
  • To learn more about Fabry disease, Click Here
  • To learn more about Pompe disease, Click Here
  • To learn more about Gaucher disease and Niemann-Pick Type A/B (ASMD), Click Here
  • To learn more about Mucopolysaccharidosis I (MPS I) and Other MPS Disorders, Click Here

References

  1. Narayanaswami P, Weiss M, Selcen D, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies. Neurology. 2014;83:1453-1463.
  2. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) Summary of evidence-based guideline for clinicians. Evidence-based guideline: diagnosis and treatment of limb-girdle and distal muscular dystrophies. 2014. American Academy of Neurology. https://www.aan.com/Guidelines/home/GetGuidelineContent/672 Accessed July 28, 2018.
  3. Murphy AP, Straub V. The classification, natural history and treatment of the limb girdle muscular dystrophies. Journal of Neuromuscular Diseases. 2015;2:S7-S19.
  4. Pegoraro E, Hoffman EP. Limb-Girdle muscular dystrophy overview. NCBI Bookshelf. 2012;1-31. (need to remove this reference) add in this one instead: Corrado Angelini, Laura Giaretta & Roberta Marozzo (2018): An update on diagnostic options and considerations in limb girdle dystrophies, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2018.1508997
  5. Werneck, Lineu Cesar, Lorenzoni, Paulo José, Kay, Cláudia Suemi Kamoi, & Scola, Rosana Herminia. (2013). Muscle biopsy in Pompe disease. Arquivos de Neuro-Psiquiatria, 71(5), 284-289. https://dx.doi.org/10.1590/0004-282X20130022