A group of X-linked muscle disorders, with their most recognized pathology being Duchenne muscular dystrophy (DMD), followed by Becker muscular dystrophy (BMD) and the relatively new phenotype DMD associated dilated cardiomyopathy (DCM). The most severe phenotype, DMD, usually presents in childhood with a series of developmental motor problems; while BMD, it's a late onset entity. All pathologies are inherited in an X-linked manner, affecting mainly males; however, females are at risk for DCM.
DMD is 2.2 MB Gene with 79 exons, located on the X chromosome. Deletions of exons, particularly in the exonic regions 2 to 20 and 44 to 53, comprise 60% to 70% of pathogenic variants. Dystrophin is membrane-associated protein in muscle and neurons, part of a protein complex linking cytoskeleton and membrane proteins, who later on bind to extracellular matrix proteins.
The condition is rare.
Dystrophin defect leads to general disorganization of the dystrophin-associated protein complex, making the muscle cell susceptible to membrane damage caused by myocyte contractions. 
Variation in fiber size with foci of necrosis leading to atrophy, inflammatory cell activation, and fibro-fatty infiltration.
Three main phenotypes have been described: DMD, BMD, and DCM, with the first 2 sharing symptoms and history but with an important difference, DMD patients tend to be wheelchair bound by age 13, while BMD after age 16.
Presents in early childhood, delayed motor milestones, most noticeably independent walking and standing from the floor. Consistent with parents' complaints, as well as gait disturbances (toe walking and flat feet). The main affected area is proximal muscles, leading to difficulty climbing stairs, jumping, running. The Gower maneuver is both a major clinical finding and a technique for affected children to stand from seating position on the floor. Calf muscles progressively turned firm due to fat infiltration.
Cardiomyopathy presents in one-third of individuals by adolescence, turning 100% prevalent in all children at age 18.
Some children may present a deficit in executive functioning, leading to decreased visuospatial skills.
Most common cause of death is respiratory failure or cardiomyopathy.
Late-onset muscle weakness, sometimes developing symptoms after age 30.
Heart failure due to cardiomyopathy is the most common cause of lethality. No cognitive impairment evidenced.
Rapidly progressive course, related to ventricular arrhythmias, with no skeletal muscle involvement. Affected females exhibit a mild form around age 40.
Creatine phosphokinase (CK) is the best initial test to perform. Values to consider DMD are above 10-times normal limits, while for BMD are above 5-times the normal limit, and DCM labeled as "elevated" given there's a wide range. The most accurate test is DMD Gene deletion-duplication analysis as 60% to 70% of patients show this abnormality. Should it not be positive on the basis of a strong clinical picture, sequencing would be recommended to cover for the rest (20% to 30%).
Specialties to Involved after Diagnosis
Physical therapy, developmental specialist, cardiology (age 6) and clinical genetics/counselor
When left ventricle section fraction is below 55%, some institutions start angiotensin-converting enzyme (ACE) inhibitors or beta-blockers to improve left ventricular function. Should there be no tolerance to ACE inhibitors, angiotensin II-receptor blockers are similarly effective. When cardiac failure is present, digoxin and diuretics should be added. Cardiac transplant had been recommended for patients with severe cardiomyopathy and mild BMD.
Patients who develop scoliosis may require bracing and surgery (spinal fusion).
Corticosteroids have been proved to improve muscle strength and function. This is, therefore, the main therapy for children younger than 15 years of age, although not recommended for children below age 2. Therapy can start with either prednisone (0.75 mg/kg per day, maximum 40 mg per day) or deflazacort (0.9 mg/kg per day, maximum 36 mg per day), when motor skills begin to decline. To assess efficacy, physicians can perform pulmonary function tests and timed muscle function tests, while also monitoring for side effects Cushing's, short-stature, changes in behavior, gastrointestinal (GI) symptoms, and osteopenia (increased risk for vertebral or long bone fractures). Should a severe side effect present, particularly excessive weight gain, doses can be decreased by 25% until reaching 50% of the original dose. There are conflicting veiws on the use of corticosteroids on BMD patients, as data supporting benefits are quite limited.
The use of botulinum toxin is contraindicated. Non-depolarizing anesthetics or succinylcholine are also contraindicated despite no increased risk for malignant hyperthermia; a small subset has been reported to show severe malignant hyperthermia-like reactions.
Emery-Dreifuss muscular dystrophy: Triad of childhood joint contractures, slowly progressive muscle weakness and initial wasting in humeroperoneal distribution extending to scapular and pelvic girdle muscles; Cardiac involvement after the second decade of life; Limb-Girdle muscular dystrophy; Autosomal recessive or dominant; Defect on genes encoding sarcoglycans
Spinal muscular atrophy: Reduced muscle tone, weakness (sparing facial muscles), anterior horn cell involvement manifesting as tongue fasciculations and absent deep tendon reflexes; Onset from birth to adolescence
Barth syndrome: X-linked, TAZ gene; Cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay
To date, there are several therapies under investigation, from gene repair and therapy to drugs affecting the expression of dystrophin. Eteplirsen is one of the latter. Approved by the FDA for infusion on 2016, it works by skipping exon 51 during pre-mRNA splicing correcting dystrophin expression. Ataluren is another drug on trials, with the goal of bypassing pathogenic variants through promoting ribosomal read-through, therefore continuing dystrophin expression.
The difference between phenotypes (DMD and BMD), relies on a Reading frame rule, stating that if the pathogenic variant does not alter the reading frame, then the expression will be milder, i.e., BMD; while, on the contrary, should express as DMD (severe phenotype). Prediction is about 92% accurate.
DMD-associated DCM involve pathogenic variants affecting the muscle promoter and first exon.
There are several genetically inherited muscular dystrophy disorders, which are progressive and have no cure. Because of the high morbidity and mortality, these disorders are best managed by a multidisciplinary team that includes a neurologist, physical therapist, internist, pediatrician and a geneticist. Many of these patients develop severe motor problems and either become bed ridden or confined to a wheelchair. It is important to get social work involved early in their treatment to help improve the home environment and the quality of life.
|||Takeshima Y,Yagi M,Okizuka Y,Awano H,Zhang Z,Yamauchi Y,Nishio H,Matsuo M, Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. Journal of human genetics. 2010 Jun [PubMed PMID: 20485447]|
|||D'Amario D,Gowran A,Canonico F,Castiglioni E,Rovina D,Santoro R,Spinelli P,Adorisio R,Amodeo A,Perrucci GL,Borovac JA,Pompilio G,Crea F, Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine. Journal of clinical medicine. 2018 Sep 19 [PubMed PMID: 30235804]|
|||Hoffman EP,Fischbeck KH,Brown RH,Johnson M,Medori R,Loike JD,Harris JB,Waterston R,Brooke M,Specht L, Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. The New England journal of medicine. 1988 May 26 [PubMed PMID: 3285207]|
|||Muntoni F,Torelli S,Ferlini A, Dystrophin and mutations: one gene, several proteins, multiple phenotypes. The Lancet. Neurology. 2003 Dec [PubMed PMID: 14636778]|
|||Li QX,Yang H,Zhang N,Xiao B,Bi FF,Li J, [Clinical and pathological features of 50 children with Duchenne's muscular dystrophy]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2012 Oct [PubMed PMID: 23092565]|
|||Beggs AH, Dystrophinopathy, the expanding phenotype. Dystrophin abnormalities in X-linked dilated cardiomyopathy. Circulation. 1997 May 20 [PubMed PMID: 9170393]|
|||Battini R,Chieffo D,Bulgheroni S,Piccini G,Pecini C,Lucibello S,Lenzi S,Moriconi F,Pane M,Astrea G,Baranello G,Alfieri P,Vicari S,Riva D,Cioni G,Mercuri E, Cognitive profile in Duchenne muscular dystrophy boys without intellectual disability: The role of executive functions. Neuromuscular disorders : NMD. 2018 Feb [PubMed PMID: 29305139]|
|||Hermans MC,Pinto YM,Merkies IS,de Die-Smulders CE,Crijns HJ,Faber CG, Hereditary muscular dystrophies and the heart. Neuromuscular disorders : NMD. 2010 Aug [PubMed PMID: 20627570]|
|||Yazaki M,Yoshida K,Nakamura A,Koyama J,Nanba T,Ohori N,Ikeda S, Clinical characteristics of aged Becker muscular dystrophy patients with onset after 30 years. European neurology. 1999 [PubMed PMID: 10529540]|
|||Cox GF,Kunkel LM, Dystrophies and heart disease. Current opinion in cardiology. 1997 May [PubMed PMID: 9243091]|
|||Jefferies JL,Eidem BW,Belmont JW,Craigen WJ,Ware SM,Fernbach SD,Neish SR,Smith EO,Towbin JA, Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation. 2005 Nov 1 [PubMed PMID: 16246949]|
|||Allen HD,Flanigan KM,Thrush PT,Dvorchik I,Yin H,Canter C,Connolly AM,Parrish M,McDonald CM,Braunlin E,Colan SD,Day J,Darras B,Mendell JR, A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy. PLoS currents. 2013 Dec 12 [PubMed PMID: 24459612]|
|||Moxley RT 3rd,Ashwal S,Pandya S,Connolly A,Florence J,Mathews K,Baumbach L,McDonald C,Sussman M,Wade C, Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2005 Jan 11 [PubMed PMID: 15642897]|
|||King WM,Ruttencutter R,Nagaraja HN,Matkovic V,Landoll J,Hoyle C,Mendell JR,Kissel JT, Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology. 2007 May 8 [PubMed PMID: 17485648]|
|||Finder JD,Birnkrant D,Carl J,Farber HJ,Gozal D,Iannaccone ST,Kovesi T,Kravitz RM,Panitch H,Schramm C,Schroth M,Sharma G,Sievers L,Silvestri JM,Sterni L, Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. American journal of respiratory and critical care medicine. 2004 Aug 15 [PubMed PMID: 15302625]|
|||Bushby K,Finkel R,Birnkrant DJ,Case LE,Clemens PR,Cripe L,Kaul A,Kinnett K,McDonald C,Pandya S,Poysky J,Shapiro F,Tomezsko J,Constantin C, Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. The Lancet. Neurology. 2010 Feb [PubMed PMID: 19945914]|
|||Towbin JA, A noninvasive means of detecting preclinical cardiomyopathy in Duchenne muscular dystrophy? Journal of the American College of Cardiology. 2003 Jul 16 [PubMed PMID: 12875770]|
|||Bamaga AK,Riazi S,Amburgey K,Ong S,Halliday W,Diamandis P,Guerguerian AM,Dowling JJ,Yoon G, Neuromuscular conditions associated with malignant hyperthermia in paediatric patients: A 25-year retrospective study. Neuromuscular disorders : NMD. 2016 Mar [PubMed PMID: 26951757]|
|||Jacobson RD,Feldman EL, Antisense Oligonucleotides for Duchenne Muscular Dystrophy: Why No Neurologist Should Skip This. JAMA neurology. 2016 Mar [PubMed PMID: 26746046]|
|||Finkel RS, Read-through strategies for suppression of nonsense mutations in Duchenne/ Becker muscular dystrophy: aminoglycosides and ataluren (PTC124). Journal of child neurology. 2010 Sep [PubMed PMID: 20519671]|
|||Monaco AP,Bertelson CJ,Liechti-Gallati S,Moser H,Kunkel LM, An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988 Jan [PubMed PMID: 3384440]|