Duchenne muscular dystrophy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Duchenne muscular dystrophy (DMD) (also known as muscular dystrophy – Duchenne type) is an eventually fatal disorder that is characterized by rapidly progressive muscle weakness and atrophy of muscle tissue. DMD is the most common form of muscular dystrophy. There is no available cure at this time. DMD affects young males due to its X-linked recessive inheritance pattern. Onset of symptoms usually occurs before the sixth year of life and begins with loss of endurance and strength in the legs and pelvis, eventually progressing to include the musculature within the entire body. Two-thirds of DMD incidences are inherited from the mother, while the remaining one-third are caused by mutations in the genes of the egg or embryo. DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne (1806-1875), who first described the disease in the 1860s. It is caused by mutations in the gene which encodes dystrophin, an essential cell membrane protein in muscle cells.

Duchenne muscular dystroph y was first discovered by Guillaume Benjamin Amand Duchenne, a French neurologist, in 1860s. The association between genetic mutations and Duchenne muscular dystrophy was made in 1986. In 1987, dystrophin gene on X chromosome were first implicated in the pathogenesis of Duchenne muscular dystrophy.

There is no established system for the classification of Duchenne muscular dystrophy but according to the Functional Classification System for DMD (AFCSD), there are 5 stages of Duchenne muscular dystrophy based on the gross motor function.

It is understood that Duchenne muscular dystrophy is the result of genetic mutation of dystrophin gene located on X-chromosome. Duchenne muscular dystrophy arises from muscle cells, which are involved in muscular contraction. Dystrophin protein is a part of the protein complex named dystrophin-associated protein complex (DAPC) which acts as an anchor that connect the intracellular cytoskeleton proteins such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan to the extracellular matrix. On microscopic histopathological analysis, replacement of muscle by fat and connective tissue, muscle degeneration, muscle regeneration, and opaque hypertrophic fibers are characteristic findings of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene which is located on the human X chromosome.

Duchenne muscular dystrophy must be differentiated from other diseases that cause muscle weakness, hypotonia, or paralysis such as adult botulism, infant botulism, Guillain-Barre syndrome, Eaton Lambert syndrome, myasthenia gravis, electrolyte disturbance, organophosphate toxicity, tick paralysis, tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, multiple sclerosis exacerbation, amyotrophic lateral sclerosis, and inflammatory myopathy.

The incidence of Duchenne muscular dystrophy is approximately 20 per 100,00 births worldwide. In 2010, the prevalence of Duchenne/ Becker muscular dystrophy was estimated to be 1.38 per 10,000 male individuals, ages 5 to 24 years. The mortality rate of Duchenne muscular dystrophy is 100%. The symptoms of Duchenne muscular dystrophy commonly presents in children younger than 5 years of age. Duchenne muscular dystrophy usually affects individuals of the Hispanic race. Non-Hispanic white or black individuals are less likely to develop DMD. Since the disease is X-link recessive, almost all of the patients are male but we may have some female carriers with symptoms as well.

The most potent risk factor in the development of Duchenne muscular dystrophy is consanguinity marriage.

There is insufficient evidence to recommend routine screening for Duchenne muscular dystrophy.

If left untreated, 100% of patients with Duchenne muscular dystrophy may progress to develop heart failure, respiratory failure, and death. Common complications of Duchenne muscular dystrophy include cardiomyopathy with heart failure, respiratory failure, cataracts, decreased movement, depression, contractures, mental impairment, scoliosis, and failure to thrive. Prognosis is generally poor, and the mortality rate of patients with Duchenne muscular dystrophy is approximately 100%.

Genetic analysis is the gold standard test for the diagnosis of Duchenne muscular dystrophy.

The hallmark of Duchenne muscular dystrophy is muscle weakness. A positive history of a family member with Duchenne muscular dystrophy and history of consanguinity marriage in their parents is suggestive of Duchenne muscular dystrophy. The most common symptoms of muscle weakness specially in the lower limbs, difficulty rising from a sitting position, balance problems, toe walking, grow retardation, clumsiness, frequent falls, multiple fractures, increase the size of the back of the lower leg, curvature of the spine, and breathing problems. Less common symptoms of Duchenne muscular dystrophy include mild cognitive impairment (OCD, anxiety, autism, ADHD) and developmental delay.

Physical examination of patients with Duchenne muscular dystrophy is usually remarkable for waddling gait, Tachypnea or bradypnea, decreased chest expansion, lordosis, scoliosis, calf muscle hypertrophy, foot drop, tight heel cord, backward bending of the knee, and muscle atrophy in thighs and buttock.

Laboratory findings consistent with the diagnosis of Duchenne muscular dystrophy include increased level of CPK, transaminases, and aldolase.

An ECG may be helpful in the diagnosis of Duchenne muscular dystrophy. Findings on an ECG suggestive of Duchenne muscular dystrophy include tachycardia, shortened PR interval, increased QRS duration, and prolonged QT interval.

An x-ray may be helpful in the diagnosis of Duchenne muscular dystrophy. Findings on an x-ray suggestive of Duchenne muscular dystrophy include enlarged heart on x-ray, scoliosis, gracile bones, hypoinflated lungs, and soft tissue translucency (fat tissue).

Ultrasound may be helpful in the diagnosis of Duchenne muscular dystrophy. Finding on an ultrasound suggestive of Duchenne muscular dystrophy is increased muscle echogenicity as a result of muscle cells replacement by fat and connective tissue and normal muscle thickness.

CT scan may be helpful in the diagnosis of Duchenne muscular dystrophy. Findings on CT scan suggestive of Duchenne muscular dystrophy include fatty infiltration which leads to low attenuation and muscle pseudohypertrophy.

Lower limb MRI may be helpful in the diagnosis of Duchenne muscular dystrophy. Findings on MRI suggestive of Duchenne muscular dystrophy include high T1-weighted signal in affected muscles.

There are no other imaging findings associated with Duchenne muscular dystrophy.

Other diagnostic studies for Duchenne muscular dystrophy include genetic testing, muscle biopsy, Electromyography.

Pharmacologic medical therapies for Duchenne muscular dystrophy include glucocorticoids and disease-modifying treatment.

Medical interventions for Duchenne muscular dystrophy include orthopedic intervention, exercise, and multidisciplinary care.

Surgical intervention is not recommended for the management of Duchenne muscular dystrophy.

There are no established measures for the primary prevention of Duchenne muscular dystrophy.

There are no established measures for the secondary prevention of Duchenne muscular dystrophy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Duchenne muscular dystrophy was first discovered by Guillaume Benjamin Amand Duchenne, a French neurologist, in 1860s. The association between genetic mutations and Duchenne muscular dystrophy was made in 1986. In 1987, dystrophin gene on X chromosome were first implicated in the pathogenesis of Duchenne muscular dystrophy.

• Duchenne muscular dystrophy was first discovered by Guillaume Benjamin Amand Duchenne, a French neurologist, in 1860s.^[1]

• The association between genetic mutations and Duchenne muscular dystrophy was made in 1986.
• In 1987, dystrophin gene on X chromosome were first implicated in the pathogenesis of Duchenne muscular dystrophy.

The following are a few famous cases of Duchenne muscular dystrophy:

• Darwin Ramos
• Bryson Foster
• Hridayeshwar Singh Bhati
• Nawaal Akram

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

There is no established system for the classification of Duchenne muscular dystrophy but according to the Functional Classification System for DMD (AFCSD), there are 5 stages of Duchenne muscular dystrophy based on the gross motor function.

There is no established system for the classification of Duchenne muscular dystrophy but according to the Functional Classification System for DMD (AFCSD), there are 5 stages of Duchenne muscular dystrophy based on the gross motor function.^[1]

Stages	Explanation
Stage 1	Walks normally without any help
Stage 2	Impaired posture (lordosis), Impaired gait (tip-toeing or waddling), still doesn’t need any assistive device and walks independently
Stage 3	Can only walk short distances with walker or crutch
Stage 4	Unable to walk but they can use powered mobility devices
Stage5	unable to walk, unable to use powered devices

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

It is understood that Duchenne muscular dystrophy is the result of genetic mutation of dystrophin gene located on X-chromosome. Duchenne muscular dystrophy arises from muscle cells, which are involved in muscular contraction. Dystrophin protein is a part of the protein complex named dystrophin-associated protein complex (DAPC) which acts as an anchor that connect the intracellular cytoskeleton proteins such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan to the extracellular matrix. On microscopic histopathological analysis, replacement of muscle by fat and connective tissue, muscle degeneration, muscle regeneration, and opaque hypertrophic fibers are characteristic findings of Duchenne muscular dystrophy.

The normal physiology of dystrophin protein can be understood as follows:^[1][2]

• Dystrophin protein is a part of the protein complex named dystrophin-associated protein complex (DAPC) which acts as an anchor that connect the intracellular cytoskeleton proteins such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan to the extracellular matrix.
• This protein guaranties muscle strength and integrity.
• The absence of this protein or misfolded protein leads to decreased strength, increased instability, and deformity of sarcolemma.

• It is understood that Duchenne muscular dystrophy is the result of genetic mutation of dystrophin gene located on X-chromosome.
• Duchenne muscular dystrophy arises from muscle cells, which are involved in muscular contraction.
• Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene whose protein product is responsible for the connection of muscle fibres to the extracellular matrix through a protein complex containing many subunits.
• The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane).
• In a complex cascading process involving several pathways, the excess calcium causes the creation of more reactive oxygen species than the cell’s oxide-scavenging enzymes can effectively process.
• This creates oxidative stress within the cell which damages the sarcolemma and allows more entry points for calcium, and ultimately resulting in the death of the cell.
• Muscle fibres undergo necrosis and are ultimately replaced with adipose and connective tissue.

• Duchenne muscular dystrophy is transmitted in X-link recessive pattern.^[3][4][5]

• Gene involved in the pathogenesis of Duchenne muscular dystrophy is Xp21 gene, which encodes the protein dystrophin.

• The development of Duchenne muscular dystrophy is the result of multiple genetic mutations such as:
  • Single gene defect
    • 1/3 New mutation
    • 2/3 X-link recessive inheritance
  • Xp21.2 region
  • Absent dystrophin

• In Duchenne muscular dystrophy, the dystrophin protein is absent.

• Male children, who have an XY chromosome pair, receive one of their mother’s two X chromosomes and their father’s Y chromosome.
• Women DMD carriers who have an abnormal X chromosome have a one-in-two chance of passing that abnormality on to their male children.
• Unlike most female children, a male child with an inherited defective Xp21 gene does not have a second X chromosome to provide correct genetic instructions, and the disease manifests.

• The sons of carrier females each have a 50% chance of having the disease, and the daughters each have a 50% chance of being carriers.
• Daughters of men with Duchenne will always be carriers, since they will inherit an affected X chromosome from their father.
• Some females will also have very mild degrees of muscular dystrophy, and this is known as being a manifesting carrier.^[6]
• In one-third of the cases, the disease is a result of an unspontaneous or new mutation.

• Prenatal testing, such as amniocentesis, for pregnancies at risk is possible if the DMD disease-causing mutation has been identified in a family member or if informative linked markers have been identified.^[7]

• The dystrophin gene contains 24 regions of 109 amino acids that are similar but not exact, making it susceptible to misalignment at the meiotic synapse, which can lead to frameshift mutations and an untranslatable gene.
• This can happen with a frequency of about 1 in 10,000.

• In some female cases, DMD is caused by skewed X inactivation.
• In these cases, two copies of the X chromosome exist, but for reasons currently unknown, the flawed X chromosome manifests instead of the unflawed copy.
• In these cases, a mosaic form of DMD is seen, in which some muscle cells are completely normal while others exhibit classic DMD findings.
• The effects of a mosaic form of DMD on long-term outlook is not known.

There is no charactristic findings on gross pathology for Duchenne muscular dystrophy.

On microscopic histopathological analysis, these findings are characteristic of Duchenne muscular dystrophy:^[8][9]

• Replacement of muscle by fat and connective tissue
• Muscle degeneration
• Muscle regeneration
• Opaque hypertrophic fibers

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene which is located on the human X chromosome.

• Duchenne muscular dystrophy is caused by different mutations in the dystrophin gene which is located on the human X chromosome including:^[1][2]

• Single gene defect
  • 1/3 New mutation
  • 2/3 X-link recessive inheritance

• Xp21.2 region
• Absent dystrophin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2] Fahimeh Shojaei, M.D.

Duchenne muscular dystrophy must be differentiated from other diseases that cause muscle weakness, hypotonia, or paralysis such as adult botulism, infant botulism, Guillain-Barre syndrome, Eaton Lambert syndrome, myasthenia gravis, electrolyte disturbance, organophosphate toxicity, tick paralysis, tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, multiple sclerosis exacerbation, amyotrophic lateral sclerosis, and inflammatory myopathy.

Duchenne muscular dystrophy must be differentiated from other diseases that cause muscle weakness, hypotonia, or paralysis such as adult botulism, infant botulism, Guillain-Barre syndrome, Eaton Lambert syndrome, myasthenia gravis, electrolyte disturbance, organophosphate toxicity, tick paralysis, tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, multiple sclerosis exacerbation, amyotrophic lateral sclerosis, and inflammatory myopathy.

Duchenne muscular dystrophy must be differentiated from other diseases that cause muscle weakness, hypotonia, or paralysis:^{[1][1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]}

Diseases	History and Physical								Diagnostic tests		Other Findings
	Motor Deficit	Sensory deficit	Cranial nerve Involvement	Autonomic dysfunction	Proximal/Distal/Generalized	Ascending/Descending/Systemic	Unilateral (UL) or Bilateral (BL) or No Lateralization (NL)	Onset	Lab or Imaging Findings	Specific test
Adult Botulism	+	–	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis
Infant Botulism	+	–	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis
Guillian-Barre syndrome[17]	+	–	–	–	Generalized	Ascending	BL	Insidious	CSF: ↑Protein ↓Cells	Clinical & Lumbar Puncture	Progressive ascending paralysis following infection, possible respiratory paralysis
Eaton Lambert syndrome[18]	+	–	+	+	Generalized	Systemic	BL	Intermittent	EMG, repetitive nerve stimulation test (RNS)	Voltage gated calcium channel (VGCC) antibody	Diplopia, ptosis, improves with movement (as the day progresses)
Myasthenia gravis[19]	+	–	+	+	Generalized	Systemic	BL	Intermittent	EMG, Edrophonium test	Ach receptor antibody	Diplopia, ptosis, worsening with movement (as the day progresses)
Electrolyte disturbance[20]	+	+	–	–	Generalized	Systemic	BL	Insidious	Electrolyte panel	↓Ca++, ↓Mg++, ↓K+	Possible arrhythmia
Organophosphate toxicity[21]	+	+	–	+	Generalized	Ascending	BL	Sudden	Clinical diagnosis: physical exam & history	Clinical suspicion confirmed with RBC AchE activity	History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating
Tick paralysis (Dermacentor tick)[22]	+	–	–	–	Generalized	Ascending	BL	Insidious	Clinical diagnosis: physical exam & history	–	History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)
Tetrodotoxin poisoning[23]	+	–	+	+	Generalized	Systemic	BL	Sudden	Clinical diagnosis: physical exam & dietary history	–	History of consumption of puffer fish species.
Stroke[24]	+/-	+/-	+/-	+/-	Generalized	Systemic	UL	Sudden	MRI +ve for ischemia or hemorrhage	MRI	Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.
Poliomyelitis[25]	+	+	+	+/-	Proximal > Distal	Systemic	BL or UL	Sudden		PCR of CSF	Asymmetric paralysis following a flu-like syndrome.
Transverse myelitis[26]	+	+	+	+	Proximal > Distal	Systemic	BL or UL	Sudden	MRI & Lumbar puncture	MRI	History of chronic viral or autoimmune disease (e.g. HIV)
Neurosyphilis[27][16]	+	+	–	+/-	Generalized	Systemic	BL	Insidious	MRI & Lumbar puncture	CSF VDRL-specifc CSF FTA-Ab -sensitive[28]	History of unprotected sex or multiple sexual partners. History of genital ulcer (chancre), diffuse maculopapular rash.
Muscular dystrophy[29]	+	–	–	–	Proximal > Distal	Systemic	BL	Insidious	Genetic testing	Muscle biopsy	Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.
Multiple sclerosis exacerbation[30]	+	+	+	+	Generalized	Systemic	NL	Sudden	↑CSF IgG levels (monoclonal)	Clinical assessment and MRI [31]	Blurry vision, urinary incontinence, fatigue
Amyotrophic lateral sclerosis[32]	+	–	–	–	Generalized	Systemic	BL	Insidious	Normal LP (to rule out DDx)	MRI & LP	Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).
Inflammatory myopathy[33]	+	–	–	–	Proximal > Distal	Systemic	UL or BL	Insidious	Elevated CK & Aldolase	Muscle biopsy	Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The incidence of Duchenne muscular dystrophy is approximately 20 per 100,00 births worldwide. In 2010, the prevalence of Duchenne/ Becker muscular dystrophy was estimated to be 1.38 per 10,000 male individuals, ages 5 to 24 years. The mortality rate of Duchenne muscular dystrophy is 100%. The symptoms of Duchenne muscular dystrophy commonly presents in children younger than 5 years of age. Duchenne muscular dystrophy usually affects individuals of the Hispanic race. Non-Hispanic white or black individuals are less likely to develop DMD. Since the disease is X-link recessive, almost all of the patients are male but we may have some female carriers with symptoms as well.

• The incidence of Duchenne muscular dystrophy is approximately 20 per 100,00 births worldwide.^[1][2]

• In 2010, the prevalence of Duchenne/ Becker muscular dystrophy was estimated to be 1.38 per 10,000 male individuals, ages 5 to 24 years.^[3]

• The mortality rate of Duchenne muscular dystrophy is 100%.

• The symptoms of Duchenne muscular dystrophy commonly presents in children younger than 5 years of age.^[4]

• Duchenne muscular dystrophy usually affects individuals of the Hispanic race. Non-Hispanic white or black individuals are less likely to develop DMD.

• Since the disease is X-link recessive, almost all of the patients are male but we may have some female carriers with symptoms as well ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The most potent risk factor in the development of Duchenne muscular dystrophy is consanguinity marriage.

The most potent risk factor in the development of Duchenne muscular dystrophy is consanguinity marriage.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

There is insufficient evidence to recommend routine screening for Duchenne muscular dystrophy.

There is insufficient evidence to recommend routine screening for Duchenne muscular dystrophy.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

If left untreated, 100% of patients with Duchenne muscular dystrophy may progress to develop heart failure, respiratory failure, and death. Common complications of Duchenne muscular dystrophy include cardiomyopathy with heart failure, respiratory failure, cataracts, decreased movement, depression, contractures, mental impairment, scoliosis, and failure to thrive. Prognosis is generally poor, and the mortality rate of patients with Duchenne muscular dystrophy is approximately 100%.

• The symptoms of Duchenne muscular dystrophy usually develop in the first decade of life, and start with symptoms such as muscle weakness and gait abnormalities.^[1]
• If left untreated, 100% of patients with Duchenne muscular dystrophy may progress to develop heart failure, respiratory failure, and death.

• Common complications of Duchenne muscular dystrophy include:^[2][3][4][5]
  • Cardiomyopathy with heart failure
  • Respiratory failure
  • Cataracts
  • Decreased movement
  • Depression
  • Contractures
  • Mental impairment
  • Scoliosis
  • Failure to thrive

• Prognosis is generally poor, and the mortality rate of patients with Duchenne muscular dystrophy is approximately 100%.^[6]
• The presence of low vital capacity or a sharp decline of vital capacity is associated with a particularly poor prognosis among patients with Duchenne muscular dystrophy.

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