Exploring Nelson with Vasu : CNS 4
It is a series of blog-post, for asynchronous learning written by Dr Vasu Burli which are actually his handpicked notes he derived from Nelson Textbook of Pediatrics. The notes are divided system-wise. The second in this series is ready to go online!
Series 1: CNS Questions 1. DMD | About Dr Vasu Burli Budding intensivist, currently persuing Pediatric critical care fellowship from Apollo Chennai, did his DNB in Pediatrics from renowned institute Kanchi Kama -Koti CHILD’S trust Hospital, Chennai. His area of interest are pediatric Intensive care and Emergency medicine. |
Definition:
The term dystrophy means abnormal growth, derived from the Greek trophe, meaning “nourishment.”
A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria: It is a primary myopathy, it has a genetic basis, the course is progressive, and degeneration and death of muscle fibers occur at some stage in the disease.
Duchenne muscular dystrophy (DMD) is the most common hereditary neuromuscular disease affecting all races and ethnic groups. This disease is inherited as an X-linked recessive trait.
Its characteristic clinical features are progressive weakness, intellectual impairment, hypertrophy of the calves, and proliferation of connective tissue in muscle.
Clinical Manifestations:
1. Infant boys are only rarely symptomatic at birth or in early infancy.
2. Poor head control in infancy may be the first sign of weakness.
3. Distinctive facies are not an early feature because facial muscle weakness is a late event; in later childhood, a “transverse” or horizontal smile may be seen.
4. Walking is often accomplished at the normal age of about 12 mo, but hip girdle weakness may be seen in subtle form as early as the 2nd year. Toddlers might assume a lordotic posture when standing to compensate for gluteal weakness. Scoliosis often becomes rapidly progressive after confinement to a wheelchair.
5. An early Gowers sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr. A Trendelenburg gait, or hip waddle, appears at this time.
6. Common presentations in toddlers include delayed walking, falling, toe walking and trouble running or walking upstairs, developmental delay, and, less often, malignant hyperthermia after anesthesia.
7. Respiratory muscle involvement is expressed as a weak and ineffective cough, frequent pulmonary infections, and decreasing respiratory reserve. The thoracic deformity further compromises pulmonary capacity and compresses the heart.
8. Pharyngeal weakness can lead to episodes of aspiration, nasal regurgitation of liquids, and an airy or nasal voice quality.
9. The function of the extraocular muscles remains well preserved. Incontinence due to anal and urethral sphincter weakness is an uncommon and very late event.
10. Contractures most often involve the ankles, knees, hips, and elbows.
11. Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles are classic features. After the calves, the next most common site of muscular hypertrophy is the tongue, followed by muscles of the forearm. Fasciculations of the tongue do not occur.
12. Cardiomyopathy, including persistent tachycardia and myocardial failure, is seen in 50-80% of patients with this disease.
13. Intellectual impairment occurs in all patients, although only 20-30% have an IQ less than 70.
14. Epilepsy is slightly more common than in the general pediatric population.
15. Death occurs usually at about 18-20 yr of age. The causes of death are respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction.
Laboratory Findings:
1. The serum CK level is consistently greatly elevated in DMD, even in presymptomatic stages, including at birth.
2. Cardiac assessment by echocardiography, electrocardiography (ECG), and radiography of the chest is essential and should be repeated periodically.
3. Electromyography (EMG) shows characteristic myopathic features but is not specific for DMD. No evidence of denervation is found. Motor and sensory nerve conduction velocities are normal.
Diagnosis:
1. Polymerase chain reaction (PCR) for the dystrophin gene mutation is the primary test, if the clinical features and serum CK are consistent with the diagnosis.
2. If the blood PCR is diagnostic, muscle biopsy may be deferred, but if it is normal and clinical suspicion is high, the more specific dystrophin immunocytochemistry performed on muscle biopsy sections detects the 30% of cases that do not show a PCR abnormality.
3. The muscle biopsy is diagnostic and shows endomysial connective tissue proliferation, scattered degenerating and regenerating myofibers.
Genetic Etiology and Pathogenesis:
Despite the X-linked recessive inheritance in DMD, about 30% of cases are new mutations, and the mother is not a carrier. Symptomatic girls are explained by the Lyon hypothesis in which the normal X chromosome becomes inactivated and the one with the gene deletion is active.
The asymptomatic carrier state of DMD is associated with elevated serum CK values in 80% of cases. The level of increase is usually in the magnitude of hundreds or a few thousand but does not have the extreme values noted in affected males.
A 427-kd cytoskeletal protein known as dystrophin is encoded by the gene at the Xp21.2 locus.
The molecular defects in the dystrophinopathies vary and include intragenic deletions, duplications, or point mutations of nucleotides.
Analysis of the dystrophin protein requires a muscle biopsy and is demonstrated by Western blot analysis or in tissue sections by immunohistochemical methods using either fluorescence or light microscopy of antidystrophin antisera. In classic DMD levels of less than 3% of normal are found
Prenatal diagnosis is possible as early as the 12th wk of gestation by sampling chorionic villi for DNA analysis by Southern blot or PCR and is confirmed in aborted fetuses with DMD by immunohistochemistry for dystrophin in muscle.
Treatment:
1. There is neither a medical cure for this disease nor a method of slowing its progression. Much can be done to treat complications and to improve the quality of life of affected children.
2. Cardiac decompensation often responds initially well to digoxin.
3. Pulmonary infections should be promptly treated. Patients should avoid contact with children who have obvious respiratory or other contagious illnesses. Immunizations for influenza virus and other routine vaccinations are indicated.
4. Preservation of a good nutritional state is important. Adequate calcium intake is important to minimize osteoporosis in boys confined to a wheelchair.
5. Physiotherapy delays but does not always prevent contractures. Excessive exercise can actually accelerate the process of muscle fiber degeneration.
6. Other treatment of patients with DMD involves the use of prednisone, prednisolone, deflazacort, or other steroids.
7. Research areas: Another potential treatment still under investigation is the intramuscular injection of antisense oligonucleotide drugs that induce exon skipping during mRNA splicing to restore the open reading frame in the DMD gene.
8. Stem cell implantation or activation in muscle was theoretically plausible but has not proved practical.
The term dystrophy means abnormal growth, derived from the Greek trophe, meaning “nourishment.”
A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria: It is a primary myopathy, it has a genetic basis, the course is progressive, and degeneration and death of muscle fibers occur at some stage in the disease.
Duchenne muscular dystrophy (DMD) is the most common hereditary neuromuscular disease affecting all races and ethnic groups. This disease is inherited as an X-linked recessive trait.
Its characteristic clinical features are progressive weakness, intellectual impairment, hypertrophy of the calves, and proliferation of connective tissue in muscle.
Clinical Manifestations:
1. Infant boys are only rarely symptomatic at birth or in early infancy.
2. Poor head control in infancy may be the first sign of weakness.
3. Distinctive facies are not an early feature because facial muscle weakness is a late event; in later childhood, a “transverse” or horizontal smile may be seen.
4. Walking is often accomplished at the normal age of about 12 mo, but hip girdle weakness may be seen in subtle form as early as the 2nd year. Toddlers might assume a lordotic posture when standing to compensate for gluteal weakness. Scoliosis often becomes rapidly progressive after confinement to a wheelchair.
5. An early Gowers sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr. A Trendelenburg gait, or hip waddle, appears at this time.
6. Common presentations in toddlers include delayed walking, falling, toe walking and trouble running or walking upstairs, developmental delay, and, less often, malignant hyperthermia after anesthesia.
7. Respiratory muscle involvement is expressed as a weak and ineffective cough, frequent pulmonary infections, and decreasing respiratory reserve. The thoracic deformity further compromises pulmonary capacity and compresses the heart.
8. Pharyngeal weakness can lead to episodes of aspiration, nasal regurgitation of liquids, and an airy or nasal voice quality.
9. The function of the extraocular muscles remains well preserved. Incontinence due to anal and urethral sphincter weakness is an uncommon and very late event.
10. Contractures most often involve the ankles, knees, hips, and elbows.
11. Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles are classic features. After the calves, the next most common site of muscular hypertrophy is the tongue, followed by muscles of the forearm. Fasciculations of the tongue do not occur.
12. Cardiomyopathy, including persistent tachycardia and myocardial failure, is seen in 50-80% of patients with this disease.
13. Intellectual impairment occurs in all patients, although only 20-30% have an IQ less than 70.
14. Epilepsy is slightly more common than in the general pediatric population.
15. Death occurs usually at about 18-20 yr of age. The causes of death are respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction.
Laboratory Findings:
1. The serum CK level is consistently greatly elevated in DMD, even in presymptomatic stages, including at birth.
2. Cardiac assessment by echocardiography, electrocardiography (ECG), and radiography of the chest is essential and should be repeated periodically.
3. Electromyography (EMG) shows characteristic myopathic features but is not specific for DMD. No evidence of denervation is found. Motor and sensory nerve conduction velocities are normal.
Diagnosis:
1. Polymerase chain reaction (PCR) for the dystrophin gene mutation is the primary test, if the clinical features and serum CK are consistent with the diagnosis.
2. If the blood PCR is diagnostic, muscle biopsy may be deferred, but if it is normal and clinical suspicion is high, the more specific dystrophin immunocytochemistry performed on muscle biopsy sections detects the 30% of cases that do not show a PCR abnormality.
3. The muscle biopsy is diagnostic and shows endomysial connective tissue proliferation, scattered degenerating and regenerating myofibers.
Genetic Etiology and Pathogenesis:
Despite the X-linked recessive inheritance in DMD, about 30% of cases are new mutations, and the mother is not a carrier. Symptomatic girls are explained by the Lyon hypothesis in which the normal X chromosome becomes inactivated and the one with the gene deletion is active.
The asymptomatic carrier state of DMD is associated with elevated serum CK values in 80% of cases. The level of increase is usually in the magnitude of hundreds or a few thousand but does not have the extreme values noted in affected males.
A 427-kd cytoskeletal protein known as dystrophin is encoded by the gene at the Xp21.2 locus.
The molecular defects in the dystrophinopathies vary and include intragenic deletions, duplications, or point mutations of nucleotides.
Analysis of the dystrophin protein requires a muscle biopsy and is demonstrated by Western blot analysis or in tissue sections by immunohistochemical methods using either fluorescence or light microscopy of antidystrophin antisera. In classic DMD levels of less than 3% of normal are found
Prenatal diagnosis is possible as early as the 12th wk of gestation by sampling chorionic villi for DNA analysis by Southern blot or PCR and is confirmed in aborted fetuses with DMD by immunohistochemistry for dystrophin in muscle.
Treatment:
1. There is neither a medical cure for this disease nor a method of slowing its progression. Much can be done to treat complications and to improve the quality of life of affected children.
2. Cardiac decompensation often responds initially well to digoxin.
3. Pulmonary infections should be promptly treated. Patients should avoid contact with children who have obvious respiratory or other contagious illnesses. Immunizations for influenza virus and other routine vaccinations are indicated.
4. Preservation of a good nutritional state is important. Adequate calcium intake is important to minimize osteoporosis in boys confined to a wheelchair.
5. Physiotherapy delays but does not always prevent contractures. Excessive exercise can actually accelerate the process of muscle fiber degeneration.
6. Other treatment of patients with DMD involves the use of prednisone, prednisolone, deflazacort, or other steroids.
7. Research areas: Another potential treatment still under investigation is the intramuscular injection of antisense oligonucleotide drugs that induce exon skipping during mRNA splicing to restore the open reading frame in the DMD gene.
8. Stem cell implantation or activation in muscle was theoretically plausible but has not proved practical.
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