Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 16 peer-reviewed journal articles Updated
Neurology

The Path to a Diagnosis: Tests and Reports

At a Glance

LGMDR1 is primarily diagnosed through genetic testing that identifies mutations in the CAPN3 gene. If genetic results are unclear, doctors may also use muscle MRIs to look for specific patterns, evaluate blood biomarkers, or perform a muscle biopsy to confirm the diagnosis.

The journey to a diagnosis of LGMDR1 (calpainopathy) has changed significantly in recent years. While doctors once relied heavily on invasive procedures like muscle biopsies, the modern “gold standard” focuses on genetic precision and advanced imaging.

Genetic Testing: The Definitive Answer

Today, Next-Generation Sequencing (NGS) is the primary tool used to diagnose LGMDR1 [1]. This technology allows doctors to scan the entire CAPN3 gene quickly and accurately to look for mutations [2].

  • Why Genetic Testing First?: Unlike a biopsy, which looks at the damage, genetic testing looks at the cause. It can distinguish LGMDR1 from dozens of other similar-looking muscular dystrophies [1][3].
  • The “Second Mutation” Challenge: Since LGMDR1 is usually recessive, a patient must have two mutations in the CAPN3 gene. Sometimes, standard tests only find one. In these cases, doctors may need to look for “hidden” mutations, such as copy number variants (missing or extra chunks of DNA) or deep intronic mutations (errors in the parts of the gene that are usually ignored) [4][2].

The Role of Muscle MRI

Skeletal muscle MRI has become a powerful “second opinion” for doctors. It creates a map of which muscles are being replaced by fat, a process called fatty infiltration [5][6].

  • The Pattern: In LGMDR1, the MRI typically shows significant fat replacement in the hip adductors (inner thigh) and hamstrings (back of the thigh) [5][7].
  • The Pseudocollagen Sign: This is a unique pattern found in about 72% of LGMDR1 patients [5]. It looks like a “stripe” or a central area of healthy muscle left behind inside a muscle that is otherwise severely affected [5][6].
  • Tracking Progress: MRI is not just for diagnosis; it is also used to monitor how the disease is progressing over time, as the amount of fat in the muscles correlates with physical function [8][7].

Blood and Urine Biomarkers

Biomarkers are substances in the body that can be measured to show the presence or progress of a disease.

  1. Creatine Kinase (CK): When muscles are damaged, they leak an enzyme called CK into the blood [9]. While LGMDR1 patients often have high CK levels initially, these levels can be unpredictable and decrease over time. This decrease does not mean the disease is getting better. Instead, as the disease progresses and active muscle tissue is gradually replaced by fat, there is simply less muscle left to break down and release the CK enzyme into the blood [10][11].
  2. Urinary N-terminal Titin Fragments: This is an exciting new “liquid biopsy.” Because calpain-3 is so closely linked to the protein titin, researchers have found that fragments of broken-down titin show up in the urine of LGMDR1 patients [12]. This test may eventually be a more sensitive and non-invasive way to track muscle damage than standard blood tests [13][14].

Is Muscle Biopsy Still Necessary?

While less common today, a muscle biopsy (removing a small piece of muscle tissue) is still used if genetic testing is inconclusive [15]. Specialists use a technique called immunoblotting to see if the calpain-3 protein is actually present in the muscle. If the protein is missing, it confirms the diagnosis even if the genetic mutations are hard to find [16].

Common questions in this guide

Why is genetic testing the primary way to diagnose LGMDR1?
Genetic testing uses Next-Generation Sequencing to scan the CAPN3 gene for mutations. This test identifies the exact genetic cause of the disease, allowing doctors to distinguish LGMDR1 from other similar muscular dystrophies without needing an invasive muscle biopsy.
What does it mean if my genetic test only finds one CAPN3 mutation?
Because LGMDR1 is a recessive condition, you must have two mutations in the CAPN3 gene to have the disease. If a standard genetic test only finds one, your doctor may order advanced testing to look for hidden changes like copy number variants or deep intronic mutations.
What does a muscle MRI show for LGMDR1, and what is the pseudocollagen sign?
A muscle MRI maps out which muscles are being replaced by fat. In LGMDR1, doctors often look for a unique pattern called the pseudocollagen sign, which looks like a stripe of healthy muscle inside an otherwise affected muscle in the thigh.
Why might my creatine kinase (CK) levels drop over time?
High CK levels indicate active muscle damage. As LGMDR1 progresses and muscle tissue is gradually replaced by fat, there is less muscle left to break down, which causes CK levels in the blood to decrease. This drop does not mean the disease is improving.
Is a muscle biopsy still needed to diagnose LGMDR1?
A muscle biopsy is usually only necessary if genetic testing results are unclear. If performed, specialists check the tissue to see if the calpain-3 protein is missing, which can confirm the diagnosis even when genetic mutations are hard to find.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.My genetic report only shows one mutation in the CAPN3 gene; should we perform further testing for 'copy number variants' or deep intronic mutations to find a second one?
  2. 2.Does my muscle MRI show the 'pseudocollagen sign,' and how does that help confirm my diagnosis?
  3. 3.Given that my CK levels vary, how often should we check them to monitor my muscle health?
  4. 4.Is the urinary titin test available to help track my disease progression, or is that still only for research?
  5. 5.If my genetic results are unclear, should we reconsider a muscle biopsy or immunoblotting to check for calpain-3 protein levels?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India.

    Ganaraja VH, Polavarapu K, Bardhan M, et al.

    Global medical genetics 2022; (9(1)):34-41 doi:10.1055/s-0041-1736567.

    PMID: 35169782
  2. 2

    A retrospective study on the clinical and molecular outcomes of calpainopathy in a Turkish patient cohort.

    Şahin İO, Karataş E, Demir M, et al.

    Turkish journal of medical sciences 2024; (54(1)):86-98 doi:10.55730/1300-0144.5769.

    PMID: 38812636
  3. 3

    Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report.

    Strafella C, Campoli G, Galota RM, et al.

    Frontiers in neurology 2019; (10()):619 doi:10.3389/fneur.2019.00619.

    PMID: 31263448
  4. 4

    Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

    Mohan S, McNulty S, Thaxton C, et al.

    Annals of clinical and translational neurology 2024; (11(9)):2268-2276 doi:10.1002/acn3.52127.

    PMID: 39215466
  5. 5

    European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A).

    Barp A, Laforet P, Bello L, et al.

    Journal of neurology 2020; (267(1)):45-56 doi:10.1007/s00415-019-09539-y.

    PMID: 31555977
  6. 6

    Whole-Body MRI in Limb Girdle Muscular Dystrophy Type R1/2A: Correlation With Clinical Scores.

    Aivazoglou LU, Guimarães JB, Costa MAF, et al.

    Muscle & nerve 2022; (66(4)):471-478 doi:10.1002/mus.27686.

    PMID: 35894554
  7. 7

    Fatty infiltration evaluation and selective pattern characterization of lower limbs in limb-girdle muscular dystrophy type 2A by muscle magnetic resonance imaging.

    Feng X, Luo S, Li J, et al.

    Muscle & nerve 2018; (58(4)):536-541 doi:10.1002/mus.26169.

    PMID: 29797799
  8. 8

    Quantitative muscle magnetic resonance imaging in limb-girdle muscular dystrophy type R1 (LGMDR1): A prospective longitudinal cohort study.

    Forsting J, Wächter M, Froeling M, et al.

    NMR in biomedicine 2024; (37(10)):e5172 doi:10.1002/nbm.5172.

    PMID: 38794994
  9. 9

    Serum creatine kinase: requesting and interpreting results.

    Walters J, Gailani G

    Practical neurology 2025; (25(4)):323-329 doi:10.1136/pn-2024-004422.

    PMID: 39961685
  10. 10

    Eosinophilic myositis: could it be an adult-onset dystrophy?

    Reardon K, McKelvie P

    Practical neurology 2022; doi:10.1136/pn-2022-003448.

    PMID: 35863881
  11. 11

    Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1).

    Gangfuß A, Hentschel A, Heil L, et al.

    Molecular genetics and metabolism 2022; (136(3)):226-237 doi:10.1016/j.ymgme.2022.05.005.

    PMID: 35660068
  12. 12

    Titin fragment is a sensitive biomarker in Duchenne muscular dystrophy model mice carrying full-length human dystrophin gene on human artificial chromosome.

    Hiramuki Y, Hosokawa M, Osawa K, et al.

    Scientific reports 2025; (15(1)):1778 doi:10.1038/s41598-025-85369-5.

    PMID: 39805937
  13. 13

    Diagnostic and clinical significance of the titin fragment in urine of Duchenne muscular dystrophy patients.

    Awano H, Matsumoto M, Nagai M, et al.

    Clinica chimica acta; international journal of clinical chemistry 2018; (476()):111-116 doi:10.1016/j.cca.2017.11.024.

    PMID: 29175173
  14. 14

    Urinary N-terminal fragment of titin: A surrogate marker of serum creatine kinase activity after exercise-induced severe muscle damage.

    Tanabe Y, Shimizu K, Sagayama H, et al.

    Journal of sports sciences 2021; (39(13)):1437-1444 doi:10.1080/02640414.2021.1876329.

    PMID: 33722155
  15. 15

    Novel Missense CAPN3 Mutation Responsible for Adult-Onset Limb Girdle Muscular Dystrophy with Calves Hypertrophy.

    Rekik S, Sakka S, Ben Romdhan S, et al.

    Journal of molecular neuroscience : MN 2019; (69(4)):563-569 doi:10.1007/s12031-019-01383-z.

    PMID: 31410652
  16. 16

    Divergent Features of Mitochondrial Deficiencies in LGMD2A Associated With Novel Calpain-3 Mutations.

    El-Khoury R, Traboulsi S, Hamad T, et al.

    Journal of neuropathology and experimental neurology 2019; (78(1)):88-98 doi:10.1093/jnen/nly113.

    PMID: 30500922

This page explains LGMDR1 diagnostic testing for educational purposes. Your neurologist and genetic counselor are the best sources for interpreting your specific test results.

Get notified when new evidence is published on Calpain-3-related limb-girdle muscular dystrophy R1.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.