Limb Girdle Muscular Dystrophy

Limb girdle muscular dystrophy (LGMD) is in fact not one single condition but a number of different inherited muscular dystrophies that are grouped under the label “limb girdle” because they generally affect the pelvic and shoulder girdles, causing weakness in the muscles in the top part of the arms and shoulders and the hips and thighs. These muscles are often called the “proximal” muscles because they are nearest to the body. The weakness usually affects the legs first, followed by the arms. It rarely affects the face. Some types of LGMD may also cause weakness in the “distal” muscles – those in the feet, ankles and calves, and the hands and wrists. A few specific types may cause heart problems or weakness of the breathing muscles.

To date, over 20 different types of LGMD have been identified and an overview is provided in the table at the end of the page. The different types of LGMD are caused by different genetic faults. The genes that may be affected in LGMD are responsible for various aspects of muscle function, and when there is a fault in one of these genes, the muscles cannot work properly and weakness occurs.

The common features all people with any type of LGMD experience include weakness of the large muscles of the legs and/or arms. This may result in frequent falls, difficulty in running, climbing stairs and rising from the floor or from a chair. As the condition progresses, they may start to have problems with walking and may need to use a wheelchair over time. However, each different type has some specific features and characteristics, such as age of onset of symptoms, rate of progression, particular muscles involved, and heart and respiratory involvement.

The types of LGMD are split into two groups: those that are inherited in an autosomal recessive fashion (type 2) and those that are inherited in an autosomal dominant fashion (type 1), which are much rarer. About 90% of the LGMDs are inherited in an autosomal recessive fashion. This means that two copies of the faulty gene need to be inherited, one from each parent, who are both carriers.

LGMDs all progress at different rates, even within the same family. While there is no specific treatment to correct the mutations that cause the LGMDs, there is a lot that can be done to manage the condition. Maintaining good levels of mobility is important and receiving the right physiotherapy to achieve this is paramount. Monitoring heart and respiratory function is also vitally important as the heart and respiratory muscles are known to be affected in particular types of LGMD. Early and prompt treatment and early surveillance is much better than waiting for problems to occur and then trying to deal with them.

The LGMDs are diagnosed using a combination of both the medical history and clinical signs when the patient is seen, and by further testing. These tests include genetic tests which may confirm the diagnosis that was suspected by the clinician. A muscle enzyme blood test (CK), DNA analysis, a muscle biopsy (taking a small sample of an affected muscle) and electrical tests (EMG) may also be performed. Imaging of the muscles as in MRI (Magnetic Resonance Imaging) scans may also be done to look at potential muscles for biopsy as well, to show the clinican the pattern of muscle involvement.

A muscle biopsy looks at the muscle fibres and whether they appear normal or not. Someone with LGMD will demonstrate a loss and change of some of these muscle fibres as well as a substitution of muscle with fat in some cases. In other tests such as (A) immunochemistry and (B) immunoblotting we can look directly at the muscle proteins which are reduced or absent in different types of LGMDs.

Whilst there is not yet a specific treatment other than optimal management, there is ongoing research in the limb girdle muscular dystrophy field, including registries for patients and research studies aiming at developing possible outcome measures for clinical trials.

Registries for specific LGMD types

LGMD2I: The FKRP registry has just been launched for patients with LGMD2I, MDC1C and other FKRP-related conditions across the world. If you would like to find out more about this registry, or if you would like to register as a patient or as a carer/guardian for a patient with a FKRP-related condition, please click on this link: https://www.fkrp-registry.org

LGMD2B: A registry for patients affected with a dysferlinopathy is under development in collaboration with the Jain Foundation and will be launched later in 2011. This International Dysferlinopathy Registry is designed for patients with the most frequent clinical presentations called Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy, but also for patients with all other clinical presentations related to genetic defects in the gene called “dysferlin”.

Registries for Limb Girdle Muscular Dystrophy

Egypt

India

New Zealand newzealand

Serbia

Slovenia

Turkey

World Wide worldwide

Overview of LGMD types

Dominant LGMDs
LGMD form	Protein
LGMD1A	Myotilin
LGMD1B	Lamin A/C
LGMD1C	Caveolin-3
LGMD1D	?
LGMD1E	?
LGMD1F	?
LGMD1G	?

Recessive LGMDs
LGMD form	Protein
LGMD2A	Calpain-3
LGMD2B	Dysferlin
LGMD2C	γ-Sarcoglycan
LGMD2D	α-Sarcoglycan
LGMD2E	β-Sarcoglycan
LGMD2F	δ-Sarcoglycan
LGMD2G	Telethonin
LGMD2H	TRIM32
LGMD2I	FKRP
LGMD2J	Titin
LGMD2K	POMT1
LGMD2L	TMEM16E
LGMD2M	Fukutin
LGMD2N	POMT2
LGMD2O	POMGnT1

Care standards for LGMD

Limb girdle muscular dystrophy was first described as a clinical entity in 1954. It wasn’t until the 1990s, however, as understanding of the disease developed further, that the number of different genes associated with LGMD began to be understood and the links between the affected gene and the clinical picture could begin to be established. Further advances have now established more than 20 different types of LGMD, classified according to the gene affected. Even so, there are still some patients showing typical LGMD symptoms in whom a known mutation is not found, so this number may still increase in future.

There are still no drug treatments affecting the course of LGMD or correcting the underlying genetic defect, but optimal management of the condition can make an enormous difference to the quality of life of affected individuals. Particularly in those types of LGMD where the heart or respiratory muscles may be involved, careful monitoring and timely intervention is crucial.

However, the history of difficult disease diagnosis coupled with the rarity of the condition has resulted in a great deal of variation in the care that people with LGMD receive. Medical professionals who diagnose and care for people with neuromuscular diseases do not always have the required expertise to recognise LGMD or to ensure its optimal management.

Several useful articles provide a good overview of best practice in diagnosis and management of LGMD.

The ‘EFNS guideline on diagnosis and management of limb girdle muscular dystrophies’ was published in 2007. Available for download below, the document provides an overview of the following areas: clinical assessment, specific clinical pointers/indicators, investigation, respiratory management, cardiac management, good practice points, physical management, genetic counselling and also drug treatment.

EFNS guideline on diagnosis and management of limb girdle muscular dystrophies.

Norwood F, de Visser M, Eymard B, Lochmüller H, Bushby K; EFNS Guideline Task Force.

Eur J Neurol. 2007 Dec;14(12):1305-12.

http://dx.doi.org/10.1111/j.1468-1331.2007.01979.x

An overview from Practical Neurology aimed at clinicians provides details of the LGMD types and information on diagnosis and management.

Diagnosis and management of the limb girdle muscular dystrophies

Bushby K

Pract Neurol. 2009 Dec;9(6):314-23

LGMD clinical research and trials

While there is still no cure for the genetic faults that cause the LGMDs, doctors and researchers across the world are working to understand how these diseases progress and to find potential future treatments. A lot of the current clinical research in the LGMDs aims to gain a better understanding of the different LGMD types and the precise clinical picture of each.

In this section on clinical research and trials you will find information about research that has reached the “clinical” stage – i.e. drugs that are being tested on humans, not just in the lab.

About clinical research

Clinical research is medical research that is carried out on humans. Individuals volunteer to participate in studies that aim to uncover better ways to treat, prevent, diagnose and understand human disease.

Clinical research includes both clinical trials that test new treatments and natural history studies, which provide valuable information about how diseases progress.

If you are considering taking part in a clinical trial, the doctor in charge of the trial will give you a lot of information about the treatment being tested, the possible results and the possible side-effects. It is always worth finding out as much as you can before you agree to take part.

Even before you get to the stage of talking to a doctor about a specific trial, you can read a lot about the general principles of clinical trials online.

Two useful resources providing general information about clinical research created by the US National Institutes of Health (NIH) are provided below.

How does clinical research work?

Children and clinical studies

Finding out information about clinical trials

The most comprehensive online listing of trials is at www.clinicaltrials.gov: you can search for trials for a particular condition. We have also collected the listings of trials for specific diseases and you can find this in the “current trials” section in the menu on the left.

The UK Muscular Dystrophy Campaign also has a listing of neuromuscular-related clinical trials in the UK and across the world available from the following link:

UK MDC clinical trials listing

Current trials in LGMD

TREAT-NMD is working closely with the pharmaceutical companies planning trials in neuromuscular diseases. The resources and expertise available through the network can make it much easier for companies to do trials, and many of the doctors involved in the network are principal investigators for the trials that are currently ongoing.

Nevertheless, we cannot ourselves keep an up-to-date overview of all the trials that are currently happening across the world. The most comprehensive online listing of trials is at clinicaltrials.gov – companies are obliged to provide details of their trials there.

The table below lists all LGMD trials registered or updated on clinicaltrials.gov in the last 1000 days. Because it links directly to clinicaltrials.gov it is automatically updated whenever the information on clinicaltrials.gov changes.

Please note that TREAT-NMD can take no responsibility for the accuracy of the information below, which is pulled directly from clinicaltrials.gov.

The Global FKRP Patient Registry
Published on 28-06-2019
Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)
Published on 10-06-2019

Start Date: August 30, 2019

Location: Hyatt Regency Chicago, Chicago, IL, USA