Myopathies series - Part 7

Hello :)

In previous post, We discussed about myopathy caused due to structural changes.
Today, I will explain it in detail. (SOURCE :- Harrison's Principle of internal medicine )

Two complex are important here :-
1. DYSTROPHIN COMPLEX
2. SARCOGLYCAN COMPLEX

- Dystrophin-glycoprotein complex confer stability to the sarcolemma
- deficiency of dystrophin (Duchennes dystrophy) may lead to secondary loss of the sarcoglycans and dystroglycan
-Loss of a single sarcoglycan (LGMD) results in secondary loss of other sarcoglycans in the membrane without affecting dystrophin
-Disruption of the dystrophin-glycoprotein complexes weakens the sarcolemma, causing membrane tears and a cascade of events leading to muscle fiber necrosis.

Let us discuss dystrophinopathies first .

1.Duchene’s muscular dystrophy 
-Most common muscular dystrophy
- X-linked recessive disorder
- Onset before age 5

-Age : Present at birth ,Usually becomes apparent between ages 3 and 5
-Sex : Male

Etiology
-XR (Deletion mutation of the gene that encodes dystrophin)


Laboratory Tests
• Serum CK
 – Elevated to between 20 and 100 times normal
 – Abnormal at birth but declines late in the disease because of inactivity and loss of muscle mass.

 Mutation analysis on peripheral blood leukocytes
• Identification of a specific mutation in dystrophin gene
– Allows for unequivocal diagnosis
– Makes possible accurate testing of potential carriers
 – Is useful for prenatal diagnosis

Diagnostic Procedures
• EMG -> Myopathic

Muscle biopsy
• Muscle fibers of varying size
• Small groups of necrotic and regenerating fibers
• Connective tissue and fat replace lost muscle fibers.
• Definitive diagnosis is established on the basis of dystrophin deficiency.
• Diagnosis can also be made by Western blot analysis of muscle biopsy specimens.
– Abnormalities on the quantity and molecular weight of dystrophin protein

• Immunocytochemical staining of muscle with dystrophin antibodies
– Can be used to demonstrate absence or deficiency of dystrophin
 – localizing to the sarcolemmal membrane
– Possible mosaic pattern in carriers of the disease
 – Dystrophin analysis of muscle biopsy specimens for carrier detection not reliable

Treatments
Prednisone 0.75 mg/kg per d
– Significantly slows progression for up to 3 years
– Some patients cannot tolerate glucocorticoid therapy
• Weight gain is significant
– Complications of long-term use often outweigh the benefits.

Exon skipping therapy
• Duchenne's disease may benefit from novel therapies that either replace the defective gene or missing protein or implement downstream corrections (e.g., skipping mutated exons or reading through mutations that introduce stop codons)

2. Becker’s Muscular dystrophy
-Less-severe form of XR muscular dystrophy
-allelic defects of same gene of Duchenne ( ~10 times less frequent than Duchenne)

 -Age : – Most between ages 5 and 15
– Onset in the third or fourth decade or even later can occur 
- Sex : Male

Symptoms & Signs
• Onset of symptoms occurs between ages 5 and 15.

I.Muscular manifestations – Pattern of muscle wasting closely resembles Duchenne.
– Progressive weakness of girdle muscles, especially of lower extremities
 – Weakness becomes generalized as disease progresses.
 – Hypertrophy, particularly in calves, is an early and prominent finding.
– By definition, patients walk beyond age 15 (whereas patients with Duchenne dystrophy are typically in a wheelchair by the age of 12). 
– Significant facial muscle weakness is not a feature.
– Respiratory failure may develop by fourth decade.

II. Extramuscular manifestations
– Cardiac, may result in heart failure
– Mental retardation may occur, not as common as in Duchenne
• Other less common presentations
 – Asymptomatic hyper-CK-emia
– Myalgias without weakness 
– Myoglobinuria

Laboratory Tests
• Serum CK – Closely resembles findings in Duchenne dystrophy
• Mutation analysis on peripheral blood leukocytes
– Deletions or duplications of the dystrophin gene in 65% of patients (same as in Duchennes dystrophy)
– 95% of patients, the DNA deletion does not alter the translational reading frame of mRNA.
 These "in-frame" mutations allow for production of some dystrophin, which accounts for the presence of altered rather than absent dystrophin on Western blot analysis 
• EMG – Myopathic
• Muscle biopsy – Results closely resemble those in Duchenne dystrophy.
 – Diagnosis requires Western blot analysis of muscle biopsy samples demonstrating a reduced amount or abnormal size of dystrophin.

Treatments 
• Use of glucocorticoids has not been adequately studied
• Endurance training may be helpful

That's all for today.
-Upasana Y. :)