Desminopathy

Synonyms

1

Overview

Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations.

Symptoms

Progressive Skeletal Myopathy

Initial symptoms were bilateral distal muscle weakness in the lower extremities that later spread to proximal leg muscles, upper extremities and neck flexors.

Respiratory Dysfunction

Respiratory insufficiency can be a major cause of disability and death. Respiratory dysfunction causes nocturnal hypoventilation with oxygen desaturation and, eventually, daytime respiratory failure. The diaphragm, unlike other skeletal muscles, is functioning in an environment in which forces can be transmitted both in longitudinal and transverse directions during each respiratory cycle; desmin is the only known molecule having dual orientation and therefore serving as a viscoelastic element that dissipates mechanical energy in both planes. Reflecting on this critical significance of desmin in respiratory function, its content in the diaphragm is 38% higher than in the biceps femoris muscle.

Cardiomyopathy

Primary cardiomyopathies are classified pathophysiologically as dilated cardiomyopathy(DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM) andarrhythmogenic right ventricular cardiomyopathy (ARVC). DCM is characterized by an increased ventricular chamber size and reduced systolic output.57 RCM results from processes that stiffen the myocardium by infiltration or fibrosis leading to impaired ventricular filling and reduced diastolic volume of either or both ventricles with the cavity size, wall thickness of the ventricles and ejection remaining near normal. Desminopathy patients with cardiomyopathy in which EchoCG was performed, DCM was diagnosed in 18, RCM in 10 and HCM in 6.

Causes

Desminpothy is associated with mutations in desmin, alphaB-crystallin and possibly other proteins that interact with desmin.

Diagnosis

Diagnostic Criteria

The diagnosis of desminopathy should be consistent with the following basic criteria , History of slowly progressive muscle weakness, dyspnea, dysphonia, dysphagia and cardiac symptoms. Physical examination reveals distal and proximal weakness; trunk, neckflexor and facial muscles are involved in some patients. Tendon reflexes are diminished or normally active. Joint retractions at ankles may be present. A restrictive ventilatory defect may result from respiratory muscle weakness. ECG shows conduction blocks in a high proportion of cases. EMG reveals abnormal electrical irritability (fibrillation potentials, positive sharp waves, complex repetitive discharges and occasional myotonic discharges) in most patients. The motor unit potentials show myopathic features or a combination of myopathic and neurogenic changes. Serum creatine kinase concentration can be normal or elevated to no greater than seven-fold above the upper normal limit.

Muscle histology reveals:

  1. characteristic alterations in trichromatically stained frozen sections consisting of amorphous, or granular material in a variable proportion of the muscle fibers,
  2. sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions,
  3. small vacuoles in a variable number of fibers;
  4. abnormal ectopic expression of desmin, alphaB-crystallin and dystrophin in immunocytochemical studies. Electron microscopy shows granulofilamentous material under the sarcolemma or within the myofibrils. Autophagic vacuoles are observed in some cases                   

Recommended Investigations

  • Electrophysiological investigations including nerve conduction studies and EMG examination to exclude neurogenic causes of weakness, motor neuron disease and peripheral neuropathy.
  • ECG used routinely to identify arrhythmias and cardiac conduction defects. Holter monitoring is indicated if symptoms suggest an intermittent arrhythmia.
  • EchoCG to detect and diagnose the type of cardiomyopathy, it should be performed even in patients with no cardiac symptoms.
  • Respiratory function tests even if respiratory symptoms are not present.
  • Muscle imaging to differentiate desminopathies from other MFMs.

Molecular Testing

Genetic testing has become essential to establish an accurate diagnosis of desminopathy. Clinical and myopathological diagnosis must precede genetic testing. It is expected that more patients with the clinical diagnosis of desminopathy will in fact show mutations in other interacting genes, or a combination of genes. Routine genetic testing is necessary for providing appropriate genetic counseling. The true prevalence of desminopathy may be established only when most or all patients clinically and pathologically resembling desminopathy are tested genetically. The era of gene-specific and mutation-specific treatments for inherited diseases is quickly approaching.

 

 

Treatment

There is no specific treatment for desminopathy, but some of the complications and premature death can be prevented. Early detection and treatment of cardiac arrhythmias and conduction defects is essential since implantation of a pacemaker can be lifesaving. Pacemaker and implantable cardioverter defibrillator (ICD) should be considered in individuals with arrhythmia and/or cardiac conduction defects. Individuals with progressive or life-threatening cardiomyopathy are candidates for cardiac transplantation. Respiratory support, consisting of continuous or bilevel positive airway pressure (CPAP and BIPAP), initially at night and later at daytime, are indicated in patients with hypercapnea and other signs of incipient ventilatory failure. Risk of chest infection should be considered in these patients. Assistive devices should be used in individuals with advanced muscle weakness. Gene and stem-cell therapy is an active area of research that promises effective treatments in the future.