Becker Muscular Dystrophy and Limb-girdle Muscular Dystrophy (LGMD)

00:01 So that's Duchenne's muscular dystrophy.

00:03 Now, let's now shift to Becker's muscular dystrophy.

00:06 We're going to bring a lot of the things that we just learned about Duchenne's and unuse those to understand Becker's.

00:11 It's really a milder form of Duchenne's muscular dystrophy.

00:16 Again, this is an X-linked recessive, inherited muscular dystrophy.

00:20 Here we don't have absent dystrophin protein.

00:23 There is defective or reduced quantity of dystrophin.

00:26 Not enough for the muscle to be normal, but enough for patients to be strong often have delayed onset of symptoms and a better prognosis.

00:34 And the manifestations are similar to Duchenne's muscular dystrophy, but the onset is later and often symptoms are more mild.

00:42 What's the workup? It's similar to Duchenne's muscular dystrophy.

00:46 We look at the CK.

00:47 CK is often elevated and substantially so in that greater than 10,000 times the upper limit of normal.

00:53 Genetic testing is confirmatory of this diagnosis.

00:58 The course it leads to a more benign disease than Duchenne's muscular dystrophy.

01:02 50% of patients will survive to over the age of 50 years.

01:08 And the prognosis as you would expect is similar to slightly improved from Duchenne's muscular dystrophy.

01:14 Men do have a shortened lifespan, often living into the third, fourth, or sometimes fifth decades.

01:20 Again 50% survive to greater than 50 years of age.

01:24 And there are new treatments that are being developed for Becker's just as we've seen for Duchenne's muscular dystrophy.

01:30 Well, the third is Limb-girdle muscular dystrophy.

01:32 This is autosomal recessive in the vast majority of cases, 90% of cases, and some are autosomal dominant.

01:39 Which is different from Duchenne's and Becker's that present as an X-linked disorder, inherited disorder.

01:45 The manifestations here we typically see proximal to some greater than distal muscle weakness without CK elevation, again, different from duchenne's and becker's muscular dystrophy.

01:57 Pediatric onset is more severe, but we see adults who present with this condition.

02:01 Adults and adolescents tend to have proximal weakness that runs in families and so that's different from Duchenne's and Becker's which really presents in young children.

02:12 What's the workup for Limb-girdle muscular dystrophy? And again, that's an adolescent, young adult, or an adult, who presents with proximal muscle weakness without elevation in CK.

02:21 Well, the first, is to check the CK and it should be normal, which is different than what we see with Duchenne's and Becker's muscular dystrophy.

02:28 Genetic testing is required.

02:30 And that really establishes the diagnosis in these patients.

02:33 Biochemical testing can confirm the individual subtype.

02:37 And also help with the inheritance pattern, which we'll talk about on the next slide.

02:42 And again, biochemical testing evaluates the specific abnormality within the dystrophin glycoprotein complex that is defective.

02:51 The course is really supportive treatment.

02:52 There is no disease modifying therapy for limb-girdle muscular dystrophies.

02:57 At this time, though, many are being studied currently.

03:02 So how do we think about and classify the Limb-girdle muscular dystrophy? So this is a group of disorder that presents typically an adolescent, young adults, or adults with proximal muscle weakness that is inherited.

03:14 And they can be grouped by the type of biochemical defect.

03:17 that protein that sits within the protein glycoprotein complex that is defective.

03:23 And we can call them by the name of the protein that's defective.

03:25 So they're calpainopathies sarcoglycanopathies, dystroglycanopathies, and glycosylation defects.

03:34 And wecan group those into two types.

03:36 There's Type 1 and Type II.

03:38 Type 1 or autosomal dominant.

03:39 And we can see that proteins that are involved in type 1.

03:43 Limb-girdle muscular dystrophies, lamin, calveolin, and desmin.

03:46 And then the type II limb-girdle muscular dystrophies are recessively inherited.

03:51 And those are the calpainopathies, the dysferlinopathies, and the sarcoglycanopathies.

03:58 It is important to note that in an adult, or adolescent, young adult, a female with proximal muscle weakness, we must still think excellent first.

04:07 And so those women may have X-linked muscular dystrophy, Duchenne's Muscular Dystrophy, or Becker's Muscular Dystrophy.

04:15 Even though it's x-linked, women can present with those symptoms.

04:19 When the x-link genetic testing is negative, that's when we really look for one of these alternative causes or Limb-girdle muscular dystrophy.

04:27 So, what's going on to cause limb-girdle muscular dystrophies? And again, think back to the lecture on the dystroglycan protein complex, the sarcolemma what's going on at the level of the muscle, we have the extracellular matrix, which is anchored to the sarcoglycan complex with laminin.

04:45 The sarcoglycan complex is made of a number of proteins that we'll learn about in subsequent lectures, and is then anchored into the muscle with dystrophin, the most important protein involved in this complex.

04:57 Dystrophin binds actin, and then actin subsequently binds the muscle.

05:02 The actin, myosin, and Z-band of the muscle.

05:06 And this scaffolding is critical for normal muscle function.

05:10 In Limb-girdle muscular dystrophy, we see a number of proteins that are altered, that are outside of the sarcoglycan complex, but are important support proteins.

05:19 One is myotilin, as you can see here.

05:22 The second is dysferlin, anchored on the sarcolemma.

05:27 Third is calveolin. And then fourth is calpain.

05:30 And again, these are proteins that are important in anchoring that protein complex and resulting in the scaffold that allows the muscle to work, abnormalities in any of those proteins, results in dysfunction, and breaking of the sarcolemma complex.

05:47 And we can see inflammation and degeneration of the muscle in patients present with weakness.

05:53 So in summary, when we think about the proximal predominant muscular dystrophies they are the most common muscular dystrophies.

06:00 They're the ones we have to know as students taking tests and clinical vignettes, as well as seeing patients.

06:05 The most common forms are Duchenne 's and Becker's muscular dystrophy.

06:09 They result from defective or absent dystrophin protein.

06:14 X-linked recessive disorders should make us think of Duchenne's and Becker's.

06:18 In those patients we see young boys presenting with proximal weakness and calf pseudohypertrophy, often with increased CK.

06:26 In adolescence, young adults, or adults, a Limb-girdle muscular dystrophy variant can be present.

06:32 And this occurs typically outside of an X-linked inheritance with normal CK.

06:38 And we also do genetic testing for evaluation of that condition.