Limb-Girdle Muscle Weakness Overview Limb-girdle muscle 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. Diagnosis is challenging as many symptoms, like progressive muscle weakness in the shoulders, pelvis, and lower limbs, as well as elevations in creatine kinase, can overlap.1 LGMW encompasses a heterogeneous group of disorders (limb-girdle muscular dystrophies (LGMDs), and other myopathies) that vary in severity and age of onset and can be classified into 2 main groups, depending on the inheritance pattern: LGMD1 is autosomal dominant, Incidence and LGMD2 is inherited in an autosomal recessive pattern.2 There are very few pathognomonic features of LGMDs • Estimated prevalence that clearly identify one from the other, or even from other diseases characterized by muscle weakness. ranging from 2.4-7.3 per 100 000 (Becker) to 0.07 per 100 000 Late Onset Pompe Disease (LOPD) shares considerable phenotypic overlap with the LGMDs, presenting with (LGMD2D, E) to 0.43 progressive proximal weakness (particularly pelvic girdle), scapular winging, feeding/swallowing difficulties and per 100 000 (LGMD2I)2 respiratory insufficiency. Pompe is an autosomal recessive disorder, caused by mutations in theGAA gene and • Pompe disease should be considered in the differential diagnosis of LGMDs.3,4 has an estimated incidence 1 in 40 0005 Diagnosis

When a diagnosis of LGMD is suspected, ruling out other diseases, such as Pompe disease, can shorten the diagnostic delay.2,4

The following evaluations may support a diagnosis of limb-girdle muscle weakness:

Clinical Findings • A medical history to determine age of onset and a family history, along with a physical examination can distinguish patterns of weakness specific to certain LGMD subtypes6

Laboratory Testing

• Serum creatine kinase levels are typically elevated secondary to muscle degeneration/regeneration6, 7 Inheritance • Next-generation sequencing (NGS) allows for the rapid sequencing of multiple genes in parallel and can more easily determine LGMD subtypes6 • Most subtypes of • Muscle biopsy3,6,7: Morphology, immunostaining/immunoblotting and biochemical testing may be helpful or LGMW are autosomal diagnostic, though many providers are electing to use NGS testing panels before more invasive testing recessive (LGMD2A-Q, Pompe)4

• Several rare subtypes are Other autosomal dominant (LGMD1A-E)4 • Electrophysiology and MRIs may be useful in the differential diagnosis and to rule out other neuromuscular diseases6 • A few myopothies • Electromyography (EMG) findings suggestive of LGMW include myotonic or pseudomyotonic discharges. are X-linked (Becker, EMG in LGMD may show short-duration, small-amplitude motor units with early recruitment in weak muscles; EGMD-X1, -X2)4 findings may be subtle in mild cases2 • Pulmonary function testing including spirometry and maximal inspiratory/expiratory force in the upright and supine positions may help narrow the differential diagnosis2

SGUSMA.PD.18.09.0536 Exp: 9/25/19 Sanofi Genzyme does not review or control the content of non-Sanofi Genzyme websites. These listings do not constitute an endorsement by Sanofi Genzyme of information provided by any other organizations. The following is a selection of laboratories offering gene panels for limb-girdle muscle weakness. There may be Testing Options for Limb-Girdle Muscle Weakness other gene panels appropriate for your patient and this is not an endorsement of any one lab. Consult each laboratory for a full range of options. Other testing options can be found at at www.concertgenetics.com or www.ncbi.nlm.nih.gov/gtr. Content is current at time of printing and tests may not be available in all states; please call laboratory to confirm test availability, sample shipping information, and all other logistics.

Available Mobile Lab Panel Sample Requirements Avg Genes Kits Billing Blood Contact Testing TAT Draw

ANO5, CAPN3, CAV3, COL6A1, COL6A2, COL6A3, DAG1, DES, DMD, DYSF, LGMD WB: 2-10 ml EDTA (lavender) Blood, P: 855-831-7447 EMD, FHL1, FKRP, FKTN, FLNC, GAA, GNE, ISPD, LMNA, MYOT, PLEC, Inst, Ins, EGL Genetics Sequencing tube (volume varies with 6 wks DBS, No E: [email protected] POMGNT1, POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, SMCHD1, SYNE1, Self-pay Panel age) Saliva W: www.egl-eurofins.com TCAP, TRIM32, TTN, VCP Blood, LGMD WB: 2-5 ml EDTA (lavender) ANO5, BVES, CAPN3, CAV3, DES, DMD, DNAJB6, DOK7, DYSF, FKRP, FKTN, P: 301-519-2100 Buccal, Inst, Ins, GeneDx Sequencing tube; Oral rinse: 30-40 ml; 4 wks GAA, GMPPB, LMNA, MYOT, POMGNT1, POMK, POMT1, POMT2, SGCA, Yes E: [email protected] Oral Self-pay Panel Buccal swabs SGCB, SGCD, SGCG, TCAP, TNPO3, TOR1AIP1, TRAPPC11, TRIM32, TTN, VCP W: www.genedx.com rinse ANO5, CAPN3, CAV3, DAG1, DES, DMD, DNAJB6, DYSF, FKRP, FKTN, GAA, LGMD WB: 3 ml EDTA (lavender) Blood, P: 800-436-3037 GMPPB, ISPD, LMNA, MYOT, PLEC, PNPLA2, POMGNT1, POMK, POMT1, Inst, Ins, Invitae Sequencing tube; Saliva/assisted saliva 10-21 d DBS, Yes E: [email protected] POMT2, SGCA, SGCB, SGCD, SGCG, TCAP, TNPO3, TOR1AIP1, TRAPPC11, Self-pay Panel (per Oragene kit) Saliva W: www.invitae.com TRIM32, TTN ACTA1, ADSSL1, AK2, AMPD1, ANO5, ATP2A1, BAG3, BIN1, BVES, CAPN3, CAV3, CFL2, CHAT, CHRNA1, CNRNB1, CHRND, CHRNE, CLCN1, CNBP, COL12A1, COL6A1, COL6A2, COL6A3, COLQ, CRYAB, DAB2, DAG1, DES, The Lantern DMD, DMPK, DNAJB6, DNM2, DOK7, DPM3, DYSF, EMD, FHL1, FKRP, FKTN, LGMD WB: 3-5 ml EDTA (lavender) FLNC, GAA, GMPPB, GNE, HNRNPA1, HNRNPDL, HSPG2, IGHMBP2, ISPD, Blood, P: 866-354-2910 Project (performed No Sequencing tube, DBS card: 5 circles, 3 wks ITGA7, KLHL9, LAMA2, LARGE, LDB3, LIMS2, LMNA, LYST, MATR3, MRE11, DBS, Yes E: [email protected] charge* at PerkinElmer Panel Saliva: Oragene MTM1, MTMR14, MUSK, MYH2, MYH7, MYOT, NBN, NEB, PABPN1, PLEC1, Saliva W: www.lanternprojectdx.com Genomics) PNPLA2, POMGNT1, POMK, POMT1, POMT2, PRF1, PRKDC, PTRF, PYGM, RAPSN, RNF123, RYR1, SCN4A, SELENON, SEPN1, SGCA, SGCB, SGCD, SGCE, SGCG, SIL1, SMCHD1, STK19, SYNE1, SYNE2, TCAP, TIA1, TNNT1, TNPO3, TOR1AIP1, TPM2, TPM3, TRAPPC11, TRIM32, TTN, TYK2,VCP The MDA Limb- ANO5, APN3, CAV3, COL6A1, COL6A2, COL6A3, DAG1, DES, DMD, DNAJB6, LGMD WB: 2-10 ml EDTA (lavender) Girdle Muscular 2-3 DYSF, EMD, FHL1, FKRP, FKTN, GAA, GNE, ISPD, LMNA, MYOT, PLEC, Blood, No Sequencing tube, volume varies with age; No E: [email protected] wks POMGNT1, POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, SMCHD1, SYNE1, Saliva charge* Dystrophy Testing Panel Saliva Program TCAP, TNPO3, TRIM32, TTN, VCP WB: 3-5 ml EDTA (lavender) ANO5, CAPN3, CAV3, DES, DNAJB6, DYSF, FKRP, FKTN, GAA, GMPPB, Blood, LGMD P: 715-387-0484 Prevention or ACD (yellow) tube; Saliva HNRNPDL, ISPD, LIMS2, LMNA, MYOT, PLEC, PNPLA2, POMGNT1, POMK, Saliva, Inst, Ins, Sequencing 28 d No E: [email protected] (per Oragene kit); Buccal POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, SMCHD1, TCAP, TNPO3, Buccal Self-pay Genetics Panel W: www.preventiongenetics.com swab (per ORAcollect kit) TOR1AIP1, TRAPPC11, TRIM32, TTN, VCP swab ANO5, CAPN3, CAV3, DAG1, DES, DNAJB6, DYSF, FKTN, FLNC, FKRP, GAA, University of LGMD P: 888-UC-GENES (824-3637) WB: 3-10 ml EDTA (lavender) GMPPB, HNRNPDL, ISPD, LIMS2, LMNA, MYOT, PLEC, POMGNT1, POMK, Inst, Chicago, Genetic Sequencing 8 wks No No E: [email protected] tube; saliva (Oragene) POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, TCAP, TNPO3, TRAPPC11, Self-pay Panel W: www.dnatesting.uchicago.edu Services Laboratory TRIM32, TTN

*Testing is performed at no charge; local charges may apply for sample collection, processing, or shipping. avg TAT = average turnaround time; d = days; DBS = dried blood spot; Ins = insurance; Inst = institution; WB = whole blood; wks = weeks.

References: 1. Barba-Romero MA, et al. Rev Neurol. 2012;54:497-507 2. Narayanaswami P, et al. Neurology. 2014;83:1453-1463. 3. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). 2014. American Academy of Neurology. https://www.aan.com/Guidelines/home/ GetGuidelineContent/672. Accessed July 28, 2018. 4. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).Muscle Nerve. 2009;40:149-160. 5. Martiniuk F et al.Am J Med Genet. 1998;79:69-72. 6. Murphy AP, et al. J Neuromusc Dis. 2015;2:S7-S19. 7. Pegoraro E, et al. NCBI Bookshelf. 2012;1-31. SGUSMA.PD.18.09.0536 Exp: 9/25/19