Despite the word “muscular” in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), the pathological effects of these diseases go far beyond skeletal muscle wasting. In reality, these dystrophinopathies affect multiple organs in the body, and patients are best managed through a multidisciplinary approach.
Ohlendieck and Swandulla wrote about the organ crosstalk observable in dystrophinopathies. They elucidated why muscular dysfunction should be viewed as a multi-organ disease: “Many of the functional and structural specializations of the muscular system play body-wide roles in health and disease, affecting especially locomotion, posture, heat homeostasis, and metabolic networks and their integration.”
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Suthar and Sankhyan, in their study on DMD, wrote, “DMD is a multi-systemic disease and depending on the type and amount of expression of dystrophin protein, other organ system involvement can be seen. Heart, brain, and smooth muscles are commonly involved, because of the expression of dystrophin in these organs.”
The domino effect that muscular dysfunction triggers in the body should not be underestimated.
“In addition to neurological, metabolic, and autoimmune diseases that indirectly affect the motor system, intrinsic disorders of skeletal muscles manifest as inflammatory myopathies, myotonias, congenital myopathies, pharmacogenetic myopathies, and muscular dystrophies,” Ohlendieck and Swandulla wrote.
Currently, over 1000 individual pathologies are included in the list of neuromuscular disorders. In this article, we will take a closer look at the effect of dystrophinopathies on the cardiorespiratory and neurological systems.
Cardiorespiratory Involvement
A staggering 90% of boys with DMD/BMD are known to have subclinical or clinical cardiac involvement. “Progressive cardiomyopathy manifests with electrocardiography changes, conduction abnormalities, arrhythmias; and in late stages, signs of congestive cardiac failure can be seen,” according to Suthar and Sukhyan.
The impairment of the cardiorespiratory system in patients with X-linked muscular dystrophies triggers a chain reaction of complications that can eventually lead to death. An impaired cardiorespiratory system makes patients susceptible to respiratory insufficiency and progressive cardiomyopathy. As Ohlendieck and Swandulla noted, “interstitial fibrosis and myofiber necrosis cause cardiac weakness, which in turn negatively affects efficient circulation.” This eventually leads to a decreased supply of oxygen, nutrients, and hormones to the whole body, which later causes multi-organ dysfunction.
To complicate matters, “cardiomyocytes, which only exhibit limited regenerative capacity, do not undergo extensive degeneration-regeneration cycles in muscular dystrophy,” Ohlendieck and Swandulla wrote. This makes DMD/BMD patients extremely susceptible to cardiorespiratory deterioration, eventually reaching a point of no return, resulting in a swift deterioration in the clinical condition of the patient.
Neurological Involvement
The signs of neurological involvement of patients with X-linked dystrophinopathies can be observed from an early age. Suthar and Sankhyan wrote, “In early life, development quotient, cognitive and language skills are shifted to one standard deviation below the normal. Some children may also have intellectual disabilities.”
However, some children with DMD/BMD demonstrate normal intellectual abilities. Scientists have discovered that intellectual abilities do not show signs of progressive worsening in the same way that skeletal muscles do. There appears to be little association between intellectual abilities and muscle condition; for example, patients with severe intellectual abilities have been documented in both benign and severe forms of dystrophinopathies.
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Much information regarding the association between dystrophinopathies and neurological involvement comes from studies on X-linked muscular dystrophy (mdx) mice models. These mice models have provided scientists with a wealth of information on the neurological pathologies that occur in patients with DMD/BMD.
“Important findings include the establishment of disturbed interactions between glial and endothelial cells at the blood-brain barrier, abnormal neuronal receptor density in Purkinje cells, and the central role of impaired cerebellar function as highlighted by disrupted circuit signals between Purkinje cells and the cerebellar nuclei in the dystrophin-deficient brain,” Ohlendieck and Swandulla said.
In human participants, brain studies have shown abnormalities in the white matter in children with dystrophinopathies. These brain studies were conducted using diffusion tensor imaging, an MRI technique that is particularly useful in observing the axonal organization within the brain. Scientists have connected this finding to altered developmental pathways in the cerebellum.
Clinical Implications
Suthar and Sankhyan brilliantly summed up the problem of viewing dystrophinopathies through a narrow lens of inevitable progressive muscle wasting. They wrote: “The belief that DMD is incurable has led to a certain neglect in the comprehensive management of this disorder. A lot can be done to comfort affected children and their caregivers even in resource-limited settings.”
No matter how poor the prognosis of a disease, clinicians must not fall into the trap of becoming fatalists. Most of the time, the improvement of the quality of life of patients under our care is possible, especially when they are treated in a multidisciplinary setting.
“In order to decisively increase the long-term survival of Duchenne patients, new combinations of pharmacological therapy, cellular interventions, and gene substitution approaches should be designed that can be employed together with physiotherapy and optimum nutritional support to address the complex and body-wide pathology of dystrophinopathy,” Ohlendieck and Swandulla concluded.
References
Ohlendieck K, Swandulla D. Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy. Pflugers Arch. Published online September 22, 2021. doi:10.1007/s00424-021-02623-1
Suthar R, Sankhyan N. Duchenne muscular dystrophy: A practice update. Indian J Pediatr. 2018;85(4): 276-281. doi:10.1007/s12098-017-2397-y
