DMD and BMD are X-linked recessive muscular dystrophies caused by mutations in the dystrophin gene resulting in deficiency of dystrophin, a muscle membrane protein. Prior to the discovery of the dystrophin gene in 1987, the distinction between DMD and BMD was based on the onset of symptoms and clinical features including the age at which ambulation is lost.
DMD: age of onset <5 years and loss of ambulation <12 years.
BMD: age of onset >5 (mean: 11 years) and ability to ambulate beyond 15 years and well into adulthood.
Intermediate cases of DMD and BMD
Mutation that result in complete absence of dystrophin result in the more severe phenotype of DMD, while mutations that result in a truncated but partially functioning dystrophin result in milder phenotype of BMD.
DMD is the most common form of muscular dystrophy in children. The worldwide birth prevalence of DMD is 1.3 – 2.6 per 10,000 population. In the U.S the incidence is 1:3.500 male births and prevalence is 1.8 per 18,000 (males 5-24 years).
New born screening is proposed to add DMD to the panel of diseases for which newborns are routinely screened. A 2 tier analysis is proposed involving checking CK levels on dried blood spot in a new born and if elevated further testing using genetic testing is advised.
The dystrophinopathies are X-linked recessive mutations in dystrophin gene at locus Xp21.2. Approximately 30% of cases are de novo mutations. Dystrophin is the largest known gene, spanning 2.4 million base pairs and constitutes 1.5% of X chromosome. It has 70 exons. The full 14,000 base pairs (bp) mRNA transcribed from dystrophin gene is expressed mostly in skeletal and cardiac muscles, with small amounts also expressed in the brain. Full length of dystrophin which is 427 kilodalton (kDa) is localized in the inner muscle membrane and is a part of a protein complex that links muscle membrane to the cytoskeleton and extracellular matrix. The dystrophin-glycoprotein complex offers stability to the sarcolemma and prevents contraction induced damage and necrosis. Shorter forms of dystrophin are expressed in brain, retina, kidney, liver, heart, lung, and peripheral nerves.
>3000 mutation are present in DMD patients.
60-70% are exon deletions, 25-35% are point mutations, and 5% and duplications.
There is no correlation between the size of mutation and resulting phenotypic severity. For example, deletion of a single exon such as exon 44 frequently result in classic DMD, while mutations encompassing as much as 50% of the gene have been described in a mild BMD. Frameshift that caused a complete lack of dystrophin expression are responsible for the severe phenotype of DMD, while in-frame mutations that result in an abnormal but partially functional dystrophin account for the milder phenotype of BMD.
An out of frame mutation, means it is DMD and it must be put back 'in frame' to make the body 'read' it. For example:
Regular DNA: The fat cat ate the rat
Mutated (deletion DNA) in frame: The cat ate the rat (still makes sense even though fat is missing)
Mutated (deletion DNA) out of frame: Tha eth era t (8 letters missing, the sentence no longer makes sense, so the body can't read it)
Exon skipping puts the sentence back in a readable '3 count' form. Dystrophin will be produced, but more like the in frame option rather than the regular DNA producing a Becker rather than a Duchenne.
Disease penetrance is complete in males. Carrier females have a 50% chance to transmit the pathogenic mutation in each pregnancy; their daughters have 50% chance of being carriers and theirs sons will have 50% chance of having DMD. Female carriers are usually asymptomatic but can rarely manifest a moderate-severe DMD phenotype due to a skewed X chromosome inactivation defined by >75% of nuclei harboring the mutant DMD gene on the active X chromosome (manifesting carrier). DMD or BMD phenotype is also seen in females with an XO genotype (Turner’s syndrome), with a structurally abnormal X chromosome or with an X-autosome translocation.
When the proband’s disease causing mutation is known, carrier testing can be performed in at-risk females in the family. Prenatal testing is possible in pregnant carriers if their specific mutation is known. Fetal sex is determined by chromosomal analysis from cells obtained from chorionic villus sampling at 10-12 weeks gestation or by amniocentesis at approximately 15-18 weeks gestation; if the phenotype is XY, the known disease-causing mutation can be analyzed in DNA extracted from fetal cells to establish disease status. Mom, if carrier will need cardiac screening.
Although DMD is diagnosed at birth based on family history and elevated CK, clinical abnormalities at birth are uncommon. Parents and school teachers recognize the signs and symptoms first when the child is between ages of 2 and 5 years.
Delayed motor milestones.
At birth some boys may present with hypotonia and weakness which may be subtle if neck flexors are carefully examined, otherwise in most cases patient appear normal and have normal motor milestones (sitting and standing).
CK screening is advised for all boys who show delay in their motor milestones (especially walking)
At ~2-6 years of age the gait is wide-based, waddling, compensating for hip abductor weakness.
Difficulty walking, running, climbing or going upstairs and keeping up with peers by age 8 yaers.
Inability to jump
Frequent falls by 2-6 years
Walking on toes occurs as center of gravity/balance is shifted anteriorly secondary to axial and hip-girdle weakness and also from heel cord tightness. Lumbar hyperlordosis while standing; compensatory measure for hip extensor weakness.
By age 6 - 12 years, weakness progresses in upper limbs and torso muscles are affected.
Neck flexion weakness and inability to lift head against gravity is common at all stages, but when seen <5 years of age, it indicates a more severe phenotype of DMD rather than BMD.
Proximal lower extremity weakness always precedes upper extremity weakness.
Gower's maneuver - difficulty arising from floor, and walks up to his knees with hands in order to rise.
Strength worsens over time in a stereotypical manner:
Progressive loss of functions such as running, getting up from the floor, climbing stairs, and eventually walking.
Cranial nerve innervated muscles are unaffected except for the tongue, which often is enlarged.
Pseudohypetrophy of calves is common.
Joint contractures are seen by age 6, when most patients develop contractures at the iliotibial bands, hip joints, and heel cords. Heel cord contractures produce “toe walking.” Knee, elbow, and wrist contractures develop later, usually after loss of ability to ambulate, and become progressive thereon once patients are confined to a wheelchair, typically by 12 years of age. However, it may be delayed if patient is on corticosteroids.
MSR: Biceps, triceps, and knee reflexes are diminished or absent in 50% by age 10 years. Ankle reflex may be seen in 1/3rd of patients.
Delayed speech may be seen.
By early 20 years of age, ventilatory function gradually declines, secondary to combination of ventilatory muscle weakness, altered thoracic anatomy secondary to kyphoscoliosis and superimposed cardiac involvement. Arrhythmias and CHF can occur later in disease. 90% of ECG abnormalities: sinus tachycardia, tall right precordial R waves, deep and narrow Q waves in left precordial leads. TTE shows dilatation and/or hypokinesis of ventricular walls.
Death secondary to ventilatory or cardiac failure.
Smooth muscle is affected and patients can develop gastroparesis and intestinal pseudo-obstruction.
Neuropsychology
Global developmental delay is not uncommon.
CNS involvement; average IQ is 1 SD below normal range. Dystrophin is expressed at some synpases in the brain.
Most patents demonstrating a pure “motor DMD” phenotype with normal intelligence.
Intellectual deficits, unlike motor deficits do not worsen over time.
There is clear evidence of overall cognitive, psychosocial, and behavioral deficits in DMD. Intellectual disability is described but has great heterogeneity. Only 30% of boys demonstrate such deficits.
Full-length dystrophic is normally expressed in the cerebral cortex, hippocampus, and cerebellum. The shorter isoforms of dystrophin, Dp71, Dp116, Dp140, and Dp260 are also located in the brain. A correlation between mutation affecting the Dp140 isoform and intellectual impairment has been reported.
Verbal intelligence is seen to more affected than non-verbal performance-based skills in DMD.
Increased comorbidity between DMD and autism spectrum disorders (3.1%), ADHD (11.7%), and OCD (4.8%) has been described.
Social relations may worsen over time as shown in a study investigating psychosocial functioning in a large group of boys with DMD ages 5 to 17 years compared with a control group with chronic condition by using the Personal Adjustment and Role Skills Scale-III (PARS-III study). DMD patients had poor social relations with their peers and this worsened over time. No difference was found in boys who did or did not take corticosteroids.
Orthopedic
Long bone and vertebral fractures are common in all patients with DMD and full-time use of wheelchair and use of corticosteroids increases the risk for fractures.
Low –impact fractures in ambulatory and non-ambulatory patients may lead to the difficult-to-recognize fat emboli syndrome, with presentation of acute respiratory distress and altered mental status. This syndrome should be promptly recognized. It is commonly reported after falls from wheelchairs, which are not uncommon and frequently due to inconsistent use of seat belts.
Scoliosis is very common, occurring rarely before age 11 years, and most frequently seen after the patient has loss the ability to ambulate. Curvatures increase over time with wheelchair use.
Increasing scoliosis, together with progressive diaphragmatic weakness compromises respiratory function over time.
Cardiac abnormalities
Dystrophin is important for the structural integrity of cardiac and skeletal muscles. Sarcolemmal proteins also have a regulatory role with NO and TGF-B superfamily in stabilizing the muscle membrane.
As many as 90% of patients with DMD have ECG abnormalities. Tall right precordial R waves with an increased R/S amplitude ratio in V1 and deep narrow Q waves in left precordial leads are the most common and distinctive changes.
Labile or persistent sinus tachycardia or other sinus arrhythmias.
Ectopic rhythms, including atrial and ventricular premature beats are seen less frequently; ectopic tachyarrhythmias occur rarely. Intra-atrial conduction system defects are more common than atrioventricular and infranodal disturbances. AV block seldom occurs.
Progressive cardiomyopathy is an important cause of morbidity and mortality in DMD, especially now that patients survive longer with the disease.
Respiratory problems
Without respiratory support, death is usually due to respiratory failure and pneumonia around age 18 to 20.
Restrictive pattern of progressive weakness of respiratory muscles is a cardinal feature of DMD.
FVC increases until the age of 10 years and after a plateau phase, it progressively decreases. When the FVC reaches the value of 1 L, 5-years survival is less than 10%.
The first sign of respiratory muscle weakness is a weak cough as measure by peak cough flow (PCF), followed by nocturnal hypoventilation and disturbed sleep and finally diurnal ventilation. A weak cough contributes to prolonged upper respiratory infection due to inability to clear secretions.
GI
Constipation is common throughout the disease due to involvement of smooth muscle of GIT
Pseudo-obstruction is a syndrome of acute gastric dilatation and consists of sudden episodes of vomiting, associated abdominal pain and distention, and may lead to death. It results from gastric hypomotility and can be demonstrated from delayed gastric emptying using a standard radiolabelled meal of oatmeal. Autopsy of GIT shows degeneration of outer, longitudinal smooth-muscle layer of stomach, likely due to dystrophin deficiency.
Incidence: 5: 100,000; ~10% spontaneous mutation.
Family history: X-linked recessive inheritance.
Onset of proximal lower extremity weakness after age 5 years, ability to ambulate past the age of 15 years and frequently into adulthood even in the absence of corticosteroids. Limb girdle pattern weakness, calf pseudohypertrophy, preferential involvement of quadriceps. Proximal upper extremity weakness develops after the onset of leg weakness. Sparing of neck flexors is a differentiating feature from DMD. By age 40, most are unable to ambulate.
Scoliosis, joint contractures, and cognitive abnormalities are less common in DMD.
Patients present with isolated myalgias, myoglobinuria, CM, asymptomatic hyper-CKemia have been demonstrated to have mild forms of dystrophinopathy.
Some patients have subclinical muscle weakness, calf hypertrophy, myalgias, and muscle cramps; some patients maintain their ability to walk into their 40s.
Heart failure from dilated CM is a common cause of morbidity and mortality in BMD.
Mildly impaired IQ.
Life expectancy is reduced, although many patients live well into adulthood.
Labs: CK of 20 - 200 x normal.
MRI demonstrate fatty replacement of affected muscles (thighs) which on T1W images appear as bright and feathery appearance of fat and connective tissue replacing muscle in the thighs.
EDMD
X-linked due to mutations in EMD gene (encoding emerin) or the FHL1 gene, or in an AD or AR manner when mutations are in the LMNA gene encoding lamin A and C (laminopathy).
Early childhood contractures of elbow flexors, neck extensors, and Achilles tendons, followed by slowly progressive muscle weakness and wasting, and CM and arrhythmias.
Unlike DMD, elbow contractures are an early feature of the disease and precede loss of ambulation.
Cardiac transplantation is frequently necessary well before patients lose their ability to walk.
LGMD2L, caused by mutations in the FKRP gene encoding fukutin-related protein and sarcoglycanopthies (LGMD2C, 2D, 2E, and 2F) most resemble DMD.
Juvenile spinal muscular atrophy (SMA)
CK is not as much elevated as seen in DMD
EMG can distinguish SMA from a muscular dystrophy.
X-linked myopathy with recessive autophagy is a vary rare disease of childhood characterized by progressive weakness predominantly in the legs. It is caused by mutations in the VMA21 gene. It is clinically similar to DMD. Muscle biopsy distinguished it from DMD due to absence of necrotic fibers and presence of prominent membrane-bound vacuoles which are dystrophin and lysosome-associated membrane protein-2- positive. Deposition of the C5b-9 complement attack complex, subsarcolemma deposition of calcium, and expression of MHC1 complex is also typical.
Serum CK is the most useful screening test for the diagnosis of DMD. Whole-blood DNA analysis for dystrophin gene mutations has largely replaced the clinical need for muscle biopsy to confirm the diagnosis.
Creatinine Kinase (CK)
Highly elevated (50-100 times normal) in all patients with DMD even at birth and in the first years of life and before symptoms become apparent. CK peaks ~ at 3 years of age. Serum CK declines by ~20% per year with advancing age and in the late stages of disease due to progressive loss of muscle and replacement by fibrofatty tissue; but usually does not normalize. CK can be used to screen boys with a known family history of DMD. Serum CK levels less than 10 times normal, except in the very advanced stage of the disease, is strong evidence against the diagnosis of DMD.
Increase CK (2-10 times normal) can be found in 30% to 50% of DMD female carriers with higher mean concentration in carriers younger than 20 years of age.
Once CK is found to be elevated, DNA testing can confirm the diagnosis.
DNA Analysis
95% sensitive in detecting mutations in the dystrophin gene.
Southern blot and PCR identify deletion in about 65% of DMD and upto 85% of BMD cases.
Deletions are more common in two hot spots, one in the distal portion of the gene between exons 44 and 53 (70%) and one more proximal between exons 2 and 20.
25% to 35% have smaller rearrangements such as point mutations, nonsense mutations, and microdeletions.
5% to 10% have duplication.
Mutations that disrupt the mRNA reading frame lead to complete lack of dystrophin and result in the severe DMD phenotype, while inframe mutations that allow for translation of some shorter but partially functional dystrophin with intact N and C termini cause the milder BMD phenotype. This reading frame rule is accurate in about 92% of cases in predicting phenotype severity. Exceptions may exist and are likely due to exon-skipping and differences in intronic deletion breakpoints.
Genetic diagnosis is very important for genetic counseling in the family members and because new treatments that are presently being developed are mutation specific (e.g., splicing correction, exon skipping).
Muscle Biopsy and Histology
Increased fiber size variability with both small and hypertrophied fibers.
Altered fiber-type distribution consisting of type 1 fiber predominance and type 2B fiber deficiency. Type 2 C fibers frequently appear.
Mononuclear cells, commonly seen in the endomysial connective tissue and occasionally in the invading necrotic fibers, consist of 80% cytotoxic T cells and 20% macrophages.
Small groups of basophilic regenerating and necrotic fibers are a distinctive common feature.
Large, opaque, darkly stained fibers are very frequent and most likely result from segmental hypercontraction. These fibers often show small tears in the plasma membrane.
Proliferation of endoymysial connective tissue (fibrosis) is a consistent feature that progresses over time.
Fat gradually replaces degenerating muscle fibers.
Internal nuclei and split fibers occur less often than in the other muscular dystrophies.
Dystrophin Analysis
Dystrophin is a cytoskeletal protein localized in the inner surface of the sarcolemma and is demonstrable by immune staining of fresh frozen sections using dystrophic antibodies.
Immune staining by using dystrophin antibodies shows complete or almost complete absence of dystrophin in DMD cases and reduce or patchy dystrophin stain in BMD. A mosaic pattern in seen in female carriers.
Approximately 1% of the muscle fibers in DMD biopsies will demonstrate sarcolemmal staining. These dystrophin positive fibers are called revertants. They arise from spontaneous mutations superimposed on the underlying disease-causing mutation. This new mutation restores the reading frame and allows for dystrophin expression in some muscle fibers.
Western blot analysis, a technique by which electrophoresis of muscle components measures proteins with specific molecular weights, is the best method to detect reduced amounts or variants of dystrophin with lower molecular weights.
EMG/NCS
It can differentiate a myopathic process from a neurogenic disorder.
It is no longer a diagnostic tool for DMD or BMD due to its low specificity and the improved sensitivity and availability of DNA testing.
It shows abnormal spontaneous activity (fibrillation potentials and positive sharp waves) and short-duration, low-amplitude, polyphasic, and early recruited motor unit potentials consistent with a myopathy with muscle fiber irritability. Decreased insertional activity and reduced number of motor units are seen in advance disease and end-stage muscle which is replaced by fibrofatty connective tissue. These findings occur late in many of the muscular dystrophies and do not differentiate DMD or BMD from other forms of muscular dystrophies or inflammatory myopathies.
Sensory and motor nerve conduction studies are usually normal.
Goal is to prolong ambulation for as long as possible and preventing and managing the secondary complications, especially respiratory failure, cardiomyopathy, and scoliosis.
Corticosteroids
The use of corticosteroids in DMD patients allow them to live longer and frequently into the third decade.
Corticosteroids are the only treatment option currently available.
Corticosteroids and NIV support have changed the natural history of and significantly improved life expectancy in DMD and the majority of patients now survive into adulthood.
Prednisone improves muscle strength, improves motor performance and pulmonary function, and slows progression of disease in boys between 5 and 15 years.
Prednisone at a dose of 0.75 mg/kg/day should be offered as treatment to all patients with DMD. Daily regimen is superior than alternate day dosing and intermittent dosing and pulse dosing.
Deflazacort at a dose of 0.9 mg/kg/day produces similar effects in muscle strength and function in DMD but is not currently FDA approved in the US.
Limited data suggest that starting corticosteroids before age 5 years is more effective.
Corticosteroid therapy is recommended to be initiated between the age of 5 and 15 years, although many experts in the field have started using steroids before age 5 years when symptoms and signs first become evident..
There is insufficient evidence regarding the optimal duration of treatment and whether treatment should be continued after ambulation is lost, however, in recent years, many recommend continuing corticosteroid treatment in nonambulatory patients due to some evidence for beneficial effects on upper extremities and cardiopulmonary function, and for delay in scoliosis development.
Side-effects: weight gain, Cushingoid facial appearance and slowed growth. Side-effects should be fully discussed with the patient and his or her family, and strategies to prevent weight gain, optimize bone health should be implemented prior to initiation of corticosteroid treatment. If side-effects develop from daily dose of prednisone, the dose is often decreased to 0.3 mg/kg/day. If side-effects are still unmanageable at this lower dose, discontinuation or switching to deflazacort or an intermittent schedule of prednisone (10 days on/10 days off).
Gene Replacement Therapy
Suppression of Stop Codons
Exon Skipping
Other drugs and supplements
Creatine supplementation in mouse models of DMD reduced muscle necrosis and stress induced elevation of calcium, increased myogenesis and improved mitochondrial respiration.
No consensus recommendations about the use of creatine in DMD.
If used, ensure good hydration and monitor kidney function. Creatine should be stopped in case of kidney dysfunction.
Coenzyme Q10 (CoQ10) is a potent antioxidant that is shown to preserve muscle strength in mice.
There is no consensus on the use of CoQ10 for treatment of DMD.
Losartan and angiotensin II type I receptor blocker improved muscle regeneration, decreased fibrosis, and significantly slowed disease progression in the diaphragm, cardiac, and gastrocnemius muscles of mice.
Respiratory Care
Perioperative management
Cardiac care
Bone Health and Orthopedic Management
Nutrition
Physical therapy
Speech, Cognitive, and Behavioral management
Palliative care
Differential diagnosis of toe walking:
Idiopathic toe walking: Uneventful history. Normal neurologic examination.
Diplegic cerebral palsy: History of perinatal brain injury, static symptoms, upper motor neuron signs in the lower extremities.
Neurodevelopmental disorders (ASD and ADHD): Presence of symptoms of these conditions. Neurological examination essentially normal.
Dystonia including dopa responsive dystonia (DRD): Progressive symptoms. Diurnal variation. Positive family history. Dystonic posture of the limbs.
Hereditary spastic paraparesis: Progressive symptoms. Positive family history. Upper motor neuron signs in lower extremities.
Tethered cord, spinal cord tumors: Progressive symptoms. Back pain and bowel or bladder symptoms. Upper motor neuron signs in the lower extremities.
CMT: Progressive symptoms. Positive family history. Feet deformities. Decreased sensation. LMN signs and lower extremities.
Duchenne muscular dystrophy: Progressive symptoms. Positive family history. Muscle weakness and pseudohypertrophy. Elevated CK.
Glycogen storage disorders McArdle disease: Muscle cramps. Second window phenomena. Elevated CK.
Musculoskeletal disorders: Short Achilles tendon, hip dislocation: Skeletal deformities. Contractures, neurological examination essentially normal.
Ataluren (Translarna). Enabling the ribosome to read through a premature stop codon (nonsense mutations) is the mechanism of ataluren, another treatment for Duchenne muscular dystrophy. “Nonsense mutations” in the dystrophin gene prematurely stops the production of a normal dystrophin protein and lead to a shortened and nonfunctional dystrophin protein. Ataluren works in these patients by enabling the protein-making apparatus in cells to move past the nonsense mutation, allowing the cells to produce a functional dystrophin protein.
ELEVIDYS (delandistrogene moxeparvovec-rokl) suspension, for intravenous infusion
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