Kembara Xtra - Medicine - Muscular Dystrophy

Kembara Xtra - Medicine - Muscular Dystrophy 
The distribution of weakness, other accompanying symptoms, and disease prognosis depend on the exact gene damaged and the severity of the mutation. Primary hereditary myopathies are diseases caused by malfunctioning proteins of muscle fibers and extracellular matrix.
Duchenne muscular dystrophy (DMD) is the most common kind of progressive, early-onset, X-linked muscular dystrophy. By the age of 13, patients are dependent on a wheelchair.
Becker muscular dystrophy (BMD) has a less severe phenotype than Duchenne muscular dystrophy (DMD); it is similarly brought on by a mutation in the DMD gene.
- Clinical distinction from DMD At the age of 16, patients are typically wheelchair-dependent.
The second most prevalent inherited muscle illness is myotonic muscular dystrophy (MMD), which causes myotonia (slow relaxation following muscle contraction), distal weakness, and facial weakness.
Facioscapulohumeral muscular dystrophy (FSHMD), the third most prevalent hereditary muscle disease, most commonly affects the facial and shoulder muscles.
The prognosis for Limb-Girdle Muscular Dystrophy (LGMD), which has proximal weakness and atrophy and a wide range of known mutations, is varied.
Oculopharyngeal muscular dystrophy (OPMD), which typically manifests as ptosis and dysphagia in adults, damages the extraocular and pharyngeal muscles.
Emery-Dreifuss muscular dystrophy (EDMD) can manifest as unexpected mortality in young, seemingly healthy people and is characterized by the early onset of joint contractures, progressively progressing muscle wastage, and cardiomyopathy.
Congenital muscular dystrophies (CMD) are a heterogeneous collection of myopathic autosomal recessive illnesses that often manifest in infancy and have a dismal prognosis.


Epidemiology 
Incidence CMD: 0.99 per 100,000 Myotonic dystrophy: 1/10,000 births Duchenne: 1/3,600 male births Other muscular dystrophies vary greatly by population but are often uncommon.

Pathophysiology and Etiology 

Muscle fibers become brittle and easily injured as a result of mutations that alter the proteins that connect the cytoskeleton to cell membrane and extracellular matrix. This leads to muscle weakening and atrophy.
Dystrophin, the protein involved in calcium transport in muscle cells and stabilizing fibers during contraction, is the defective protein that results from the largest human gene, DMD. Duchenne phenotype is caused by mutations that result in profound loss of dystrophin, while Becker phenotype is caused by less severe mutations in the DMD gene; patients have low but detectable levels of functional dystrophin.
Myotonin-protein kinase is encoded by the gene DMPK, which has a trinucleotide repeat expansion in its untranslated region on chromosome 19.
Genes for the dystrophin-related proteins calpain, dysferlin, and fukutin are most frequently impacted by LGMD mutations.
 EDMD: Dysfunctional proteins, including lamin A/C in autosomal variants and emerin in its X-linked version, are located near the nuclear membrane in muscle fibers.
OPMD: Trinucleotide repeat expansion in PABPN1 impairs the normal transit of mRNA from the nucleus, causing nuclear inclusions in muscle cells.
The most widely recognized theory on the function of the deleted genes is that they most likely have an impact on the expression of numerous genes through epigenetic changes. FSHMD: loss in the untranslated region of chromosome 4.

Duchenne and Becker muscular dystrophies are X-linked genetic diseases that are caused by the Xp21 gene.
A de novo mutation (mother is not a carrier) affects 30% of the affected boys.
20% of female carriers of the mutation have some symptoms, most often mild cardiomyopathy or muscle weakness.
Autosomal dominant disorders, such as FSHMD, OPMD, some kinds of LGMD, and EDMD, typically have a delayed start and less severe symptoms than diseases with recessive or X-linked heredity. Muscular dystrophy
Trinucleotide repeat expansion with a worse phenotype in succeeding generations as a result of repeat accumulation
Autosomal recessive: Most CMD types

Prevention 

counseling on genetics for carriers and early pregnancy detection


Accompanying Conditions 

Speech and language delay; decreased IQ; dilated cardiomyopathy and conduction problems, which can be severe in EDMD; the ability to impact otherwise asymptomatic female DMD carriers; and progressive scoliosis

DMD is characterized by normal achievement of early motor milestones followed by abnormal gait and slowing gross motor development, including clumsiness, waddling gait, frequent falls, difficulty running, or difficulty climbing stairs. BMD is characterized by progressive difficulty with ambulation and frequent falls in later childhood. MMD is characterized by slurred speech, muscle wasting, and difficulty with ambulation; this condition is frequently inherited.
 EDMD: contractures of the elbows and ankles, problems with ambulation in adolescence OPMD: ptosis and dysphagia; frequently with family history LGMD: back pain, lordosis/inability to stand from a chair, climb stairs, and utilize arms overhead FSHMD: facial weakness, inability to totally close eyes EDMD: contractures of the elbows and ankles, difficulty with 

Clinical examination: Proximal muscular weakness; Gower sign (usage of arms to lift the upper body from a prone position into a standing one); Trendelenburg gait (asymmetric hip waddling); DMD/BMD
- Hypo- and areflexia
- Lordosis and scapulae with wings
- Calf pseudohypertrophy brought on collagen fibroadipose tissue replacing muscle.
- Elbow and lower extremities joint contractures
MMD - Narrow face, open triangular mouth, high-arched palate, concave temples, drooping eyelids, and frontal baldness in males are characteristic facial features.
Distal muscle weakness and wasting are symptoms of myotonia, which is the inability to relax muscles after contraction.
Infants with widespread hypotonia, arthrogryposis (many joint contractures), and muscle atrophy.

Differential Diagnosis Mitochondrial Myopathies MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes), MERRF (Myoclonus with Epilepsy and Ragged- Red Fibers), and other metabolic myopathies
Motor neuron illnesses include amyotrophic lateral sclerosis and spinal muscular atrophy. Inflammatory myopathies include polymyositis, dermatomyositis, and inclusion-body myositis. Neuromuscular junction diseases include myasthenia gravis and Lambert-Eaton syndrome.
Friedreich ataxia, Charcot-Marie-Tooth disease, etc.

Initial test results from the laboratory and imaging
Elevated aspartate transaminase/alanine transaminase (AST/ALT) from muscle Elevated creatine kinase (CK): initial screening test if MD is suspected Elevated in DMD (10 to 100 times); elevated at birth, peaks at time of presentation, and falls during illness Genetic testing/molecular diagnosis: For definitive diagnosis in patient with characteristic presentation and elevated CK
- Deletion and duplication analysis (MLPA or CGH) will identify the majority of patients (70–80%), and genomic sequencing of the DMD gene for point mutations will identify the remaining patients (20–30% of patients).- Clinical genetic testing is accessible for the majority of other muscular dystrophies.

Other/Diagnostic Procedures

Muscle biopsy: if genetic testing is ineffective in identifying a mutation, it can be utilized for dystrophin analysis in DMD (dystrophin protein missing) cases.
Unless alternative diagnoses are being considered, nerve conduction tests and electromyography are not required.
 ECG: abnormalities detected in up to 10% of female and >90% of male DMD carriers, respectively, Test Interpretation
Heterogenic muscle fibers experience both atrophy and hypertrophy along with an increase in connective tissue in the muscle
 Dystrophin protein immunohistochemistry: DMD: no detectable dystrophin in the majority of fibers; occasionally revertant fibers with normal dystrophin; BMD: extremely variable dystrophin staining throughout muscle

Management 
The only treatment now in use that slows the course of illness is glucocorticoid therapy. There are now novel medications that influence gene expression, but their clinical utility is unknown.


General Actions 
Orthoses for the knee, ankle, and foot can extend ambulation. Contractures can be treated with serial casting.
Polysomnography can be used to diagnose sleep apnea and noninvasive ventilation can be used to treat it. Adaptive devices can be used to improve function.

Prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day), synthetic oral corticosteroids that have been reported to cause less weight gain than prednisone, are examples of glucocorticoids.
 Prolongs effective ambulation, extends lifespan, slows the loss of muscle function, the development of scoliosis, and the degradation of pulmonary function. Enhances cardiac outcomes.
When there is no longer any improvement in motor abilities but before there is a decrease, therapy should be started.
Watch out for side effects. supplementing with dietary calcium and vitamin D.
Annual eye exams for cataracts, yearly DEXA scans, consideration of bisphosphonates, monitoring of hypertension, avoidance of NSAIDs due to the risk of peptic ulcer disease (PUD), and stress-dose steroid use during procedures and sickness are all recommended.
- Patients who experience immune suppression should let emergency personnel know.
Treatment of cardiomyopathy with ACE inhibitors, which may also be used with beta-blockers


Referral 
To receive a conclusive diagnosis and coordinated multidisciplinary care, contact a center for neuromuscular illnesses.
Physical medicine and rehabilitation for managing adaptive devices, cardiology for managing cardiomyopathy, and pulmonary medicine for monitoring lung function and clearing regimen.
 Nutrition/swallowing: Pay attention to dysphagia for regular weight gain.
Orthopedics: scoliosis surgery and psychosocial assessments of learning, behavior, and coping, as well as social development

Further Therapies 

Possible advantage of dissociative steroids like vamorlone.
The FDA granted Golodirsen approval in 2019 to boost dystrophin production.
SURGERY/OTHER PROCEDURES Scoliosis spinal surgery slows the rate at which the deformity progresses.
Scapular fixation for scapular winging may be helpful, although there are no clinical trials for it.
Consider undergoing surgery to alleviate ankle or knee contractures.


Healthcare Alternatives 

Exercises using full-body vibration


Patient Follow-Up Monitoring
 An electrocardiogram (ECG), an echocardiography, and a cardiologist consultation at diagnosis and every year beyond age 10 - Every five years, female DMD mutation carriers should be observed.
 Pulmonary function testing twice yearly if no longer ambulatory; Annual spinal radiography for scoliosis; Dual-energy X-ray absorptiometry (DEXA) scanning and serum marker tests for osteoporosis
Psychosocial issues include coping, emotional growth, and depression.

Diet 
Diet may be restricted by dysphagia; a swallow evaluation can help decide the right things to eat; a gastrostomy may be necessary.

DMD/BMD prognosis includes kyphoscoliosis, a progressive loss in respiratory vital capacity, and recurrent lung infections. It also includes progressive weakening, contractures, and immobility.
 Considerably shorter life expectancy (DMD: 16 4 years; BMD: 42 16 years). 90% of deaths are caused by respiratory failure; the remaining 5% are cardiac in nature (heart failure and dysrhythmia).

Scoliosis, joint contractures, dysphagia, gastroesophageal reflux disease (GERD), constipation, obstructive sleep apnea, malignant hyperthermia-like reaction to anesthesia, cardiomyopathy, respiratory failure, and early mortality are complications.

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