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Informații şi înregistrări: vezi primul anunț 


Autor: Axinia Corcheş Laura Nussbaum Ghizela Kanalaş Maria Puiu
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Dystrophinopathies are X-linked recessive disorders caused by the deficit in dystrophin, the muscle protein responsible for the disease.
The most important dystrophinopathies are Duchenne progressive muscular dystrophy (DMD) and Becker progressive muscular dystrophy (BMD). Intermediate DMD phenotypes are also described in specialist literature, with mild clinical signs and BMD with severe evolution (the so-called “outliers”).
There are less severe forms, too, without affecting the muscles of the limb girdles: isolated quadriceps myopathy, myopathies affecting the heart muscle, X-linked dilative cardiomyopathy (XLDCM), elevated levels of muscle enzymes without clinical signs, myoglobinuria with muscle cramps, women who are asymptomatic carriers and pass on the genetic mutation / the defective gene.
Material and method
We present the main forms of dystrophinopathies, their clinical and paraclinical aspects with case examples and updates from the literature related to treatment and rehabilitation.
Dystrophinopathies are the most common genetic muscle diseases/disorders with rapidly progressive evolution. It is important to recognize and diagnose them early, while the currently known intervention methods may favourably influence the evolutional pace and the life quality of the affected patients.

Dystrophinopathies are X-linked recessive disorders caused by the deficit in dystrophin, the muscle protein responsible for the disease.
The most important dystrophinopathies are Duchenne progressive muscular dystrophy (DMD) and Becker progressive muscular dystrophy (BMD). Intermediate DMD phenotypes are also described in specialist literature, with mild clinical signs and BMD with severe evolution (the so-called “outliers”).
There are less severe forms, too, without affecting the muscles of the girdles: isolated quadriceps myopathy, myopathies affecting the heart muscle, X-linked dilative cardiomyopathy (XLDCM), elevated levels of muscle enzymes without clinical signs, myoglobinuria with muscle cramps, women who are asymptomatic carriers and pass on the genetic mutation / the defective gene.
The heterogeneity of clinical picture and of the evolution has prompted a wide spectrum of phenotypes. The most severe phenotype is the DMD, BMD, progressive muscular dystrophy with the intermediate phenotype (PDM), with primary damage of the skeletal muscle and the X-linked dilative cardiomyopathy with primary significant impairment of heart muscle[1].

DMD represents the severe phenotype of dystrophin deficiency.
The first description of the disease dates back to 1868. The neurophysiologist Guillaume Benjamin Duchenne described the disease as pseudohypertrophic muscular paralysis associated with deposits of connective tissue and fat. In 1886, Gowers described the sign bearing his name and remarked the transmission of the disease by the mother. In 1891, Erb described the histological changes of the disease. In 1986, several American scientists (Monaco A.P. and Kunkel L.M.) discovered the genetic defect in DMD and in 1987 Hoffman identified the actual damaged protein, namely dystrophin. With the discovery of dystrophin, the classification of progressive muscular dystrophies is based on the protein deficit, provided that it can be determined.
DMD is the most frequent progressive muscular dystrophy in children and it occurs in about 1of 3000 new-born males[2].
The dystrophin gene is one of the longest in the human genome and consists of 79 exons; the transmission of the disease is X-linked recessive.
Genetic locus: The DMD gene is located on band 21of the short (p) arm of the X chromosome at position 21.2. (Xp21.2).
Dystrophin is a large structural protein, respectively 427kDa, which is contained in the muscle membrane, but it is also present in other tissues: brain, retina, and kidneys.


  • deletions, or duplications: the majority located at the level of segment 3 at the end of N-terminal or in the rod area, involving a number of exons. Two mutations may take place in a gene ;
  • punctiform mutations (73% of patients who do not have deletions or duplications) – located across the entire gene, most of them distal of exon 55, many of them at the level of the regulating splice sites or of the gene expression. They are of the following types: nonsense, with a shift in the reading frame, with missense (rare). They may cause DMD or BMD.

In the DMD, 65% of patients have deletions and in the BMD, 55-85% have deletions or duplications. One third of cases occur as new mutations. One third of severe cases come from new mutations
(Haldane’s rule).

Genotype-phenotype correlations:

  • deletions at level E45-47 or E48 affecting the rod, determine the moderate BMD phenotype ;
  • N-terminal deletions cause a more severe Beker phenotype ;
  • C- terminal deletions or those at the level of cysteine-rich region cause severe DMD because it affects the binding of dystrophin to dystroglycan, with the consequent loss of dystroglycan – sarcoglycan complex ;
  • E1 and promoter deletions cause a milder phenotype, with or without severe cardiomyopathy ;
  • deletions of the proximal third of the rod domain (E13-17) cause cramps and myalgia. At the anatomic-pathological examination, the dystrophin appears normal ;
  • the absence of dystrophin causes a severe phenotype and the reduction of the sarcoglycans and of other proteins associated with the dystrophin. Dystrophin is elevated in the cytoplasm ;
  • Mutations at the level of the end of the C-terminal lead to severe clinical pictures.

Women are asymptomatic carriers. Monozygotic female twins with different phenotypes (a symptomatic one and a normal one) represent a particular situation. It is possible that at the time of separation of the two zygotes, one of them might have received more cells in which the normal chromosome had been inactivated, leading to the further development of a more severe phenotype.

The clinical picture:
Onset of the disease
The clinical onset is insidious. It is situated around the age of 3-5 years, although the disease is there since birth. One may note a delay in developing motor skills according to age stages. If they have acquired ambulation, the onset manifestation consists in running difficulties. These children are described by their parents as less active than other children of their age, having difficulty in climbing flights of stairs, in jumping on one leg. In addition, they waddle, are prone to falling and have difficulty in getting up from a seated position. The literature also mentions delayed speech at the onset. Subsequently digitigrade walking appears through the retraction of Achilles tendon.

Description of symptoms by apparatuses and systems:

1. Muscle damage
Ambulation is pendular (waddling gait), with lumbar hyperlordosis and forwardly extended abdomen.

Muscular deficit

  • Represents the onset symptom with proximal and symmetrical distribution, the lower limbs being affected before upper limbs ;
  • The firstly affected muscles in the legs are: iliopsoas, gluteal muscles, followed by those of the anterior tibial joint, the great adductor and, more rarely, gracilis and Sartorius muscles ;
  • The damage of the paravertebral and lumbosacral muscles leads to a characteristic, lordotic posture in standing position with the abdomen stretched out ;
  • Bilateral deficit of knee and thighs extensor muscles causes balance impaired and difficulty in climbing stairs, standing up from the chair, or from a leaning position ;
  • Bilateral deficit of medium gluteal muscle determines waddling gait.

Gower’s sign is pathognomonic in progressive muscular dystrophies and consists of pulling up in orthostatic posture by climbing on one’s own body, with support on the knee. The child sets one foot in the rear position, leans forward to support himself on both hands, extends his arms to push his trunk upward and then continues the lifting motion while rocking his body and climbing on oneself with the support of hands on his own thighs. Gowers sign appears when a pronounced weakness of the pelvic girdle has been installed, especially that of the great gluteal muscle. The peak incidence is around the age of 5-6 years and the sign is present before 8 years of age[1]. (Fig. 1).

  • Muscles of the shoulder girdle and of the upper limbs are affected after those of the pelvic girdle: the lower part of the pectoral muscles, latissimus dorsi, biceps and the brachioradialis ;
  • The deficit of neck flexor muscles is present in all phases of the disease, though it usually goes unnoticed. In the early stages, patients with DMD are unable to raise their head anti-gravitationally in supine position. This mark distinguishes the patients with DMD from those with mild phenotypes and the BMD patients, who, at least in the early stages, have not changed muscular strength of the neck flexors ;
  • The ocular, bulbar, neck extensor muscles, and the small muscles of the hand are unaffected ;
  • The facial muscles are impaired in advanced stages of the disease.

The osteotendinous reflexes or deep tendon reflexes ( DTRs):
DTRs are present at disease onset, with slow decline to extinction as the muscle fibres deteriorate. Achilles tendon reflex and styloradial (or brachioradial) reflex are abolished last. Patellar reflex diminishes or disappears early in the evolution.

Changes in muscle volume:
Muscle hypertrophy is particularly evident in the calf muscles, with firmness on palpation, more frequent in the sural triceps muscle. In a smaller proportion, it may also be present in the deltoid muscle and in vastus lateralis[3]. It may be noticed from the age of 8 months, and becomes clinically apparent after the age of 3-4 years. Muscle hypertrophy is actually a pseudohypertrophy, a consequence of muscle fibrosis (Fig. 2). Sometimes, the hypertrophy of the tongue may be observed[1].

Muscular atrophies are proximally apparent at the onset and tend to generalize with loss of ambulation.

Associated signs:
Muscle twitching

  • Muscle twitching arises from maintaining the limbs in a specific position and from lack of balance between the agonist and antagonist muscles ;
  • Muscle contractures lead to musculotendinous retractions with the emergence of vicious attitudes ;
  • The foot is in varus equine and ambulation becomes digitigrade early, in the ambulatory stage, due to the shortening of the gastrocnemii ;
  • The weakness of the pelvic girdle occurs early, with the anterior rotation of the hips, placement of the shoulder to the rear in order to maintain the centre of gravity perpendicular to the line of the shoulders, hips and ankles; due to the force acting on the gastrocnemius muscle, the retraction of Achilles tendon occurs ;
  • Retraction of the tensor fasciae latae with hyperlordosis and, in parallel, ankle contractures with onset around the age of 5-6 years, followed by retractions of the hips and knees ;
  • Muscular contractions cause the characteristic posture of child with DMD with lumbar hyperlordosis, flexion of the thighs on the abdomen, flexion of the calves on the thighs, flexion of the knees and plantar flexion.

Between 6-10 years of age, 70% of patients with DMD display contractures at the level of Achilles tendon, the iliotibial bands and hip joints, causing toe walking and limiting the flexion of the thighs. (Brooke MH, Fenichel GM, Griggs RC, Mendell JR et al,1981) .

At the age of 8, contractures occur in knees, ankle and hip extensors which correlate with deterioration in gait. Contractures in the shoulders appear later in evolution.

It occurs in 80-90% of patients after loss of locomotion due to deficiency in paraspinal muscles; it can be improved if walking and sitting on the breech are extended until the age of 17-18 years old.
Scoliosis and deficit of respiratory muscles result in the damage of the respiratory function. The age when respiratory failure occurs is correlated with the degree of scolios[5].

2. Other clinical manifestations
They are due to lack of dystrophin expression in other organs.
Cardiac damage
It is very common and it ought to be investigated systematically. Because muscle fibre degeneration, especially in the left ventricle, EKG modifications occur in 90% of cases – larger R waves in the right precordials and deep Q waves on the left. Cardiac ultrasound will show hypokinesia and decrease of ejection fraction of the left ventricle. Often, the only clinical sign is tachycardia (heart rate over 100 beats per minute). Conduction disturbances may occur, too.
Heart damage is slowly evolving with good clinical tolerance. In rare cases, phenomena of congestive heart failure with dilated cardiomyopathy may occur.
The incidence of this disorder increases with age. Age of onset is usually after 15 years. In 50% of cases, the onset is at 18 years.
Initially ECG modifications occur, then clinical decompensation.
A regular monitoring of cardiac function allows the choice of the moment for major surgery (especially for the column), severe heart damage being absolute contraindication.
In cases where surgery is performed, it requires clinical supervision, EKG and ultrasound pre and post operatively.

Damage of the central nervous system
Intellectual disability (Mental retardation)
The literature indicates association with light mental retardation with IQ under 70 and slurred speech. Mental retardation is correlated with deletion in exons 44-45 of the gene, while better IQ is linked to the deletion of exons 8-44[6].
Several authors have noted that patients with DMD may also have increased intelligence but difficulty with recent memory[7]. Nonverbal cortical functions are more affected than the verbal function[6].
EEG is not specific. Anatomopathologic study in deceased patients has described pachygyria, abnormal cortical neuronal response and low weight of the brain.

Behavioural and emotional disorders
They appear in the evolution of the disease.
Reactive depression associated with borderline intellect has been diagnosed in some cases[8].
Low frustration tolerance, emotional immaturity are added to the progressive pathological dependence on parents, nurtured by parental hyper protection. The inevitable evolution leads to social isolation. Early psychotherapeutic intervention with family counselling, maintaining possible current social activities help to improve the psychological tension and to accept the disease more easily.

Respiratory impairment
It is the consequence of intercostal muscles and diaphragm damage.
The damage of neck flexors – sternocleidomastoid and paraspinals – causes severe kyphoscoliosis, aggravating the respiratory deficit. As the disease evolves, anoxemia and CO2 retention develop, even in the absence of infection. Nocturnal CO2 retention is manifested by headaches upon awakening.
Respiratory and cardiac deficiencies are responsible for the evolution of the disease to death.

Smooth muscle damage
Impairment of the digestive muscles with peristaltic disorders, gastric dilation, volvulus, cramps, malabsorption and megacolon are possible in evolution[9].

Visual Impairment
Hemeralopia consists in disorders of adaptation to darkness, with altered responses intermittent light stimuli. Molecular biology studies have revealed the presence in the retina of Dp260 protein, which is an isomer of dystrophin[10].

Changes in the bone tissue
They are a result of osteoporosis and are evidenced in early onset cases. It has been found that osteoporosis is more severe in the legs, which leads to frequent fractures.

Laboratory exams:
Muscle enzymes
Creatine kinase (CK) proved to be the most effective for diagnosis. It is normally located in the striated and smooth muscles, in thyroid and brain.
In 1987, it was demonstrated that CK is composed of two dimers and comes in three types: muscle, brain and intermediary that may be distinguished by qualitative immunological techniques[11]. In DMD, the three types have elevated values as a whole.
Serum CK in DMD reaches very high values: over 5000 I.U. even from birth, in the absence of clinical signs, peaking at the age of 3, with lower values ​​later, under 1000 IU, due to lower muscle mass.
The increase of other blood enzymes in DMD has been shown: serum aldolase, serum lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), phosphoglucose isomerase (PGI) phosphoglucomutase (PGM). Being present in muscles, the elevated values of GOT and GPT hepatic enzymes are high both in DMD and in BMD. Thus, their unexplained increase leads to suspicion of DMP, even in asymptomatic female carriers and in other forms of muscular dystrophies, too.

Other serum and urine anomalies:
Myoglobinaemia is common in patients with DMD. The highest values have been found in patients with very high serum CK and in those performing intense physical activity. In patients who did not have lost ambulation, values ​​correlate with the degree of physical activity.

Electrophysiological exams:
Electromyogram (EMG) shows the myogenic track with short potentials: 3-7 msec, low amplitude: 0.4-1.8 Mv, the multiphase ones with early recruitment, especially in the muscles with muscle deficiency.
Increased insertion activity with fibrillation potential and repetitive discharges can also be detected, probably due to segmentation necrosis separating muscle fibres from nerve fibres or to the fibres that regenerate[12].
As the disease progresses, the amplitude of action potential decreases, insertional activity diminishes, motor unit potentials become very small with low recruitment and fibrillation potentials decrease gradually.
Towards the final stages of the disease, some muscle regions become electrically silent.
Nerve conduction velocities (NCV) in both sensory and motor fibre types are normal.

Imaging exams:
Muscle computed tomography (muscle-CT) is used for intramuscular changes and allows the study of deep muscle masses.
Diffuse areas of muscle signal attenuation are described.
Routine muscle-CT scan consists of five axial sections performed in the neck, trunk, pelvis, thighs and calf muscles. Magnetic resonance imaging (muscle MRI) has been limited mainly to assess adults; in children, the impediment consists in the extended examination time, about 90 minutes. The disadvantage of this method is in the high cost of the investigation.

In 90% of cases, there are changes in the R-wave that is larger in the right precordials and deep left Q waves in asymptomatic patients, too.

Pulmonary function tests:
Routine spirometry, pneumogram, oximetry, capnography, capillary blood gases allow early detection of the deterioration of respiratory function and the appropriate initiation of assisted mechanical ventilation to (AMV).

Muscle biopsy:
Puncture muscle biopsy reveals primitive muscle degeneration in association with degeneration and loss of consecutive fibre with sizes ranging from atrophy to abnormal hypertrophy, proliferation of connective tissue of endomysium and perimisium, replacement of fibres with connective and fat tissue, increase of organelles with occasional internalisation of the nuclei of sarcolemma and variable cellular response.

The differentiation of the type of fibre is affected. Origin of adipocytes is uncertain. Intramuscular nerves and vessels are evolving within the limits of normal structure.
In perimisium, endomysium and perivascular spaces, inflammatory cell infiltration has been noted, in particular from cytotoxic T cells and macrophages.
Electron microscopy is not performed routinely, while immunohistochemistry techniques and Western Blot analysis are considered useful and specific[1].
The study of dystrophin may be qualitative by immunohistochemistry on frozen muscle cups and quantitative by Western Blot analysis.

Immunohistochemistry tests:
In DMD patients, using anti-dystrophin antibodies, sarcolemma does not stain, or stains very little. The ratio of detectable dystrophin immunoreactivity depends on the amount of dystrophin present in the sarcolemma and the anti-dystrophin antibody levels used in the immunohistochemistry test.
In 80% of DMD patients, dystrophin expression is found in less than 1% of the fibres.
Immunostaining techniques are useful for identifying sporadic cases of symptomatic or asymptomatic female carriers who have elevated levels of CK in families with no sick boys or in families where genetic tests do not detect deletion or duplication.
In patients with other muscular diseases, plasma membrane becomes stained homogeneously [1].

Western Blot analysis:
Western Blot analysis can be used for the determination and quantitative assessment of the size (molecular weight) of residual dystrophin. In DMD, there is a significant decrease in the amount of the dystrophin or its absence[13].

Genetic tests:
About 65% of boys with DMD have deletions, or duplications involving one or more exons in the DMD gene and these are identified using the chain-polymerisation reaction (CPR).
Other mutations including small deletions or insertions are involved in the rest of the patients with DMD, which can be identified by sequencing techniques in special laboratories[14].

Positive diagnosis:
It is based on the clinical picture
It is confirmed by the very high levels of blood CK, EMG and muscle biopsy. Correct diagnosis is based on the absence or marked reduction of dystrophin in muscle biopsy by immunohistochemistry tests, or genetic tests that reveal specific mutations. To avoid a delay in the diagnosis of Duchenne muscular dystrophy, the dosage of CK is recommended[15] in the following patients:
All boys who:

  • do not have the ability to climb four successive steps at the age of 18 months,
  • do not have a vocabulary of at least 10 words at the age of 2 years,
  • have unexplained delay in global development acquisitions,
  • have neuro-motor retardation of 4-6 months at 2 years of age,
  • have clumsy gait under the age of 4,
  • cannot jump on both feet or run at 4 years of age,
  • have pains in their hips or legs under 4 years of age.

Prenatal diagnosis:

  • Molecular genetic studies are possible after the age of 7-10 weeks gestation. DNA deletion test can be performed from chorionic villi as early as the first trimester of pregnancy, when chromosomal deletions are highlighted[10].
  • Neonatal screening
  • This can be achieved by dosing neonatal serum CK in new-borns, its values being ​​very high in blood on the 15th day of life in male patients with DMD.
  • Carrier diagnosis can be performed since an early age revealing anomalies in the dystrophin gene or chromosome abnormalities, especially X autosomal translocation. Carriers are usually without symptoms, but may have moderately elevated CK values, mild hypertrophy of calf muscles, myalgia or cardiac symptoms.

Differential diagnosis:
After topographic impairment:

1. Chronic disorders of the spinal motoneuron

  • spinal muscular atrophy types II and III;
  • have similar clinical picture;
  • muscle enzymes are normal;
  • EMG has a neurogenic type aspect with fibrillation potential.

2. Peripheral nerve disorders

  • polyneuropathies – muscular deficit is predominantly distal,
  • DTRs are absent early,
  • atrophies are predominantly distal,
  • they are associated with sensitivity disorders,
  • muscle enzymes are normal,
  • EMG has a neurogenic route,
  • NCV may be low or normal, depending on axonal or demyelinating pathology.

3. Diseases of the neuromuscular junction

  • Congenital myasthenic syndromes,
  • Myasthenia gravis:
  1. Late onset,
  2. Extraocular and bulbar muscular weakness at the root of the limbs, with diurnal variability and increased at effort,
  3. DTRs are normal,
  4. Muscular atrophy is not present,
  5. Muscle enzymes are normal,
  6. EMG is normal, with repetitive stimulation over 10% decrement is noted.

4. Muscle disorders
Congenital myopathies :

  • Neonatal onset or in infancy,
  • Hypotonia and proximal motor deficit,
  • Breathing muscles are affected by flattening the anteroposterior chest,
  • Diffuse atrophies, symmetrical predominant axially and at the roots of the limbs,
  • Secondary dysmorphic features,
  • Normal CK,
  • Muscle biopsy allows diagnosis: predominance of type 1 fibres with their hypotrophy.

Congenital muscular dystrophies:

  • Early onset in the first year of life,
  • Hypotonia and proximal muscle deficiency,
  • Moderate increase in CK,
  • Dystrophin is present in muscle biopsy


  • Is accompanied by rash,
  • Onset is acute or sub-acute,
  • Dystrophin is present

Other muscular dystrophies
1. Limb-girdle muscular dystrophies

  • Dystrophin is present,
  • Other protein deficits in immunohistochemistry tests.

2. Emery – Dreifuss muscular dystrophy

  • Pseudohypertrophy of calf is missing,
  • Slightly elevated CK values,
  • Biceps and triceps muscles are interested,
  • Contractures are early at the elbow and the knee,
  • Genetic tests highlight anomalies for genes encoding emerine and lamina.

Table I. Muscular dystrophies
(differential clinical genetic forms)

AD 2q -31 TITIN
Subunit a1 and a2
Subunit a3
17q 12 – q 21.33 ADALINE = a sarcoglycan
4q 12 ADALINE = b sarcoglycan
With CAPLAIN deficit AR 15q 15.1- q 21.1 CAPLAIN 3
AD 5q 22 – q 34 1A
1q 11 – 21 1B
With CAVEOLIN deficit AD 3p 25 CAVEOLIN 3 1C
AD 6 q 23 1D
AD 7q 1E
AD 5q 31

3. Facioscapulohumeral dystrophy

  • It is autosomal dominant,
  • It has later onset,
  • Initially and predominantly it affects facial muscles, then the scapular girdle and the muscles of the anterior joint of the calf,
  • The disorder of the pelvic girdle occurs late,
  • Heart muscle is not affected,
  • CK values are normal or slightly elevated,
  • Dystrophin is present.

4. Becker Muscular Dystrophy

  • With similar phenotype,
  • Later onset,
  • Slower disease progression,
  • Life expectancy is higher,
  • Quantitative study of the dystrophin shows values ​​above 20% and represents the element of diagnostic certainty (Table I).


Becker muscular dystrophy (BMD) is a muscular dystrophy similar to Duchenne muscular dystrophy, with lighter clinical manifestations.

The disease was presented by Becker and Kiener in 1955 as a disease distinct from DMD through different degrees of clinical manifestations.

It is considered 3 times less frequent than DMD. It reports an incidence of 3-6 per million newborns[16].

It is with X-linked recessive transmission, on the short arm p of band 21 (XP21.). Duchenne and Becker are allelic diseases, as demonstrated by the damage of the gene for dystrophin. Dystrophin is different qualitatively (with smaller molecular weight) and quantitatively. DNA studies in Becker disease have revealed the deletion of different exons from those in DMD, located toward the end of the gene for dystrophin.

The clinical picture:
The disease begins after the age of 7 years (between 5 and 15 years of age), sometimes in decade 3 or 4 of life. At approximately 10 years, 50% of patients are symptomatic and at 20 years, 90% have clinical signs of disease.

Muscle injury:
Clinically speaking, there is predominantly proximal muscle deficit, lower limbs being more affected than the upper ones.
Pelvic girdle muscles and those of the thigh are affected predominantly.
Evolution is slowly progressive.
Scapular girdle deficit develops later.
Facial and neck flexor muscles are not affected.
The severity and age of onset are correlated with the values of muscle dystrophin.
Pseudohypertrophy of the calf muscles occurs early in most patients.
Onset symptoms may be pain in the calves.
Osteotendinous reflexes are preserved and contractures are uncommon.

Damage of the CNS:
Intellect is normal. There are reported cases with lower IQ. They are associated with deletion of exons 48 and 49 of the dystrophin gene or of the transcriptional unit Dp140.

Heart damage:
Heart damage is much rarer and less severe.
Rare cases have been described with heart disorder and early-onset, preceding the motor deficit[17].

Effect on smooth muscles:
Smooth muscles are unaffected.
Adult patients present hypo-fertility or infertility due to testicular atrophy.

Laboratory exams:
CK has elevated levels, between 5000-20000 IU / l, similar to those in DMD. The values ​​decrease with age and degree of mobilization.
The EMG show a myogenic route.
Muscle biopsy reveals primitive myogenic degeneration with lower severity than in DMD, with basophilia, inflammation and fibrosis.
Immunohistochemistry tests revealed a partial staining of sarcolemma.
Western Blot analysis indicates a decrease of the dystrophin quantity, with normal molecular weight or lower in 80% of cases – in mutations of the deletion type, with increased molecular weight (in duplications) in about 5% of cases and with normal molecular weight but quantitatively reduced in about 15% of patients with DMD[18].

Treatment is common in DMD and BMD.
There is no effective cure but only supportive medication and the treatment of complications.
Prophylactic measures:

  • The avoidance of weight gain and of supramaximal physical efforts,
  • Early corrective interventions to prevent deformities in limbs and spine and early orthotics,
  • Early mobilization after corrective orthopaedic surgery,
  • Use of assisted mechanical ventilation at the first sign of respiratory failure, initially nocturine and diurnal, too, in the late stages of the disease.
  • Avoidance of general anaesthesia with halothane and succinylcholine, to avoid malignant hyperthermia and dilated cardiomyopathy.

Drug treatment:
1. Cortisone treatment
Corticotherapy extends ambulation by around 2-3 years, improves muscle strength and function.
Glucocorticoids are the only drugs that have proven their efficacy, having a stabilizing effect on membranes and possibly an anti-inflammatory effect. They are used for more than 30 years as a palliative treatment.
Various schemes have been used:

  • In the beginning prednisone 1.5-5 mg / kg of body / day, every other day; important side effects have been recorded: weight gain, hypertension, hyperactivity, cataracts, osteoporosis.
  • Daily administration of prednisone at a dose of 0.75 mg / kg of body / day resulted in increased muscular strength after 3 months of therapy and slowing down to stopping the deterioration after 18 months of dosing. It was found that adverse effects appear and that it is a less effective scheme[19, 20].
  • The most advantageous scheme in terms of adverse effects, consists in the administration of 0.75 mg / kg / day prednisolone in a single dose in the morning for 10 days per month, with a break of 20 days, for a longer period. The therapeutic effects consist in the extension of ambulation, sometimes by 5 years, in the increase of muscle strength, the reduction of falls. The effect is especially beneficial as it is administered early in patients who lost ambulation at the age of 3-5 years. This protocol has been used regularly since 2000 in the Dubowitz Neuromuscular Disease Centre, Hammersmith Hospital, London.
  • Prednisone in the scheme presented above, leads to improved muscle strength in 10 days and peaks in 3 months[21].
  • Currently, the best treatment is 0.75 mg / kg / day for 10 days per month, the maximum dose of 40 mg/day in patients with DMP, patients aged 5 to 15 years[1].
  • For patients immobilized in a wheelchair, treatment with the same dose of prednisone has been shown to prolong the muscle function and strength in the upper limbs and maintain the vital capacity[22].
  • To monitor treatment with prednisone, patients must be evaluated every 3-6 months. Blood pressure, height, weight, vital capacity are checked and assesses clinically. Clinical assessment will include the time required to achieve various tests: time needed to perform the 40 steps, to climb up six 5 stairs, to get up from the floor to a standing position. These assessments are performed both for the hips and legs, and for the arms and shoulders. (see Table II – Functional Assessment Scale of patients with DMD)

Table II. Functional Assessment Scale of patients with DMD
(after Moxlev RTII, 2003)[23].

Shoulders and upper limbs Thighs and lower limbs
1 From orthostatic posture with arms along the body, the patient can perform the abduction of the arms in the shape of a circle, so that they touch above the head. 1. Walks and climbs stairs without help.
2. Patient may raise arms above the head only with flexed elbows, or using accessor muscles. 2. Walks and climbs stairs helped by arms.
3. Patient cannot raise hands above the head but can take a glass of 250 ml of water to his mouth using both hands if necessary. 3. Walks and climbs stairs slowly, with the help of arms. Climbs 4 stairs in more than 4 seconds.
4. Patient can take his hands to the mouth but cannot take a glass of 250 ml with water to his mouth. 4. Walks without help and can stand up from the chair but cannot climb the stairs.
5. Patient cannot raise hands to the level of the mouth but he can use them to hold a pen or to lift it. 5. Walks without help but cannot stand up from the chair and cannot climb the stairs.
6 Patient cannot take his hands to the mouth and cannot use them for functional purposes. 6. Walk only with help.
Patient is in the wheelchair

To monitor treatment further, routine laboratory tests are performed: -summary Urinalysis at 3 months, blood count, serum electrolytes, liver and kidney tests at 6 months. The testing of muscle enzymes does not matter because the values ​​fluctuate depending on physical activity and they are influenced by the treatment with prednisone.
Prednisone is generally well absorbed and metabolised in the liver to prednisolone.
About 80% of prednisolone is located to plasma proteine. Free prednisolone (20%) is the active fraction exercising cellular metabolic effects.

Cortisone side effects:

  1. 1.prednisone and deflazocort The most common are: weight gain, cushingoid facies, mood disorders, insomnia, facial erythema. Serious adverse reactions like fractures of the vertebrae, diabetes, hypertension and gastrointestinal bleeding are rare if the presented protocol is observed. It is recommended to associate calcium and D3 products, 1 cps / day, to prevent osteoporosis and maintain bone mass. Doses are adjusted depending on body weight. If severe adverse reactions appear, the doses will be decreased by 25%. Discontinuation of the treatment is recommended after 6 months if there is no improvement or stabilization of the motor performance or if side effects are intolerable. No abrupt discontinuation is recommended. Side effects diminish at lower doses of 0.75 mg / kg / day. The doses of 0.3-0.5 mg / kg / day produce a beneficial response but not so important one. Deflazocort, which is a synthetic derivative of prednisolone, seems to produce similar effects of the corticotherapy. The doses are 0.9-1.2 mg / kg / day, with fewer side effects, except cataract, which is common. Deflazocort is used in Europe. It is not used in the United States.
  2. Hormonal treatment was not proved to be effective.
  3. Treatment with supplements – Creatine – is considered to improve muscle performance. The studies involved a small number of patients and therefore they have no statistical value to support its effectiveness. Q10 Coenzyme – recent studies have shown an improvement in physical activity in patients with PDM.
  4. Other treatments

The cyclosporine may be useful in the dose range of 5-10 mg / kg / day[24].


Treatments under investigation:

1. The transfer of myoblasts
In Mdx mice it does not have the expected effects[25]. The principle consists in implanting myoblasts – stem-cells – from unaffected individuals into the atrophied muscles of patients that would be followed by the alleged recovery of muscle mass with post-mitotic, structurally normal myocytes. Initial studies in humans have shown positive clinical effects and mild side effects[26]. Subsequent studies performed on humans during 1993-2000 were similarly unsuccessful because the host immune system has eliminated donor myoblasts which survived the transplant procedure[27].
Although the number of donor myoblasts remained in the host was higher than expected, about 50% were merged into myofibres at the host level and out of the merging ones, only 50% have produced dystrophin. In DMD, the entire muscle mass is affected, accounting for 40% of body weight, therefore isolated but repeated implant proves insufficient. The method requires multiple intramuscular injections, while access to certain muscles is restricted, consequently, this method almost inaccessible.

2. Gene Therapy
It has been in the research stage in Paris clinics since 2000, alongside with other centres. The method consists in correcting the dystrophin gene by action on human DNA. Gene therapy uses two techniques: ex vivo and in vivo.
Ex vivo technique is more secure, it occurs in two-stages and consists of collecting abnormal myocytes, external processing of their DNA and subsequent reimplantation.
In vivo technique requires a vector to introduce the correcting gene into the body. The vector used may be a non-pathogenic virus with purified DNA, to deliver into myocytes the corrective genes or a non-virus vector: plasmid DNA, liposomes.
The viruses used in gene therapy are of the retrovirus, lentivirus, adenovirus types.
It has been demonstrated that utrophin, autosomal homologue of dystrophin, may substitute dystrophin functionally, so that increased gene expression can prevent the Duchenne phenotype in mutant mice[28].
Enabling it can solve problems of conventional gene therapy in the case of dystrophin.
3. The treatment by inducing the stop-codon mutation
By administering ​​aminoglycosides in animal models, it has been shown the slowdown in the dystrophic process in mice affected by this disease[29]. In May 2002, several authors [30] published the preliminary results of the study on the effectiveness of treatment with Gentamycin in four human subjects with DMD, who were still able to walk or who were confined to the wheelchair for at most 4 months, with punctiform mutations in the gene for dystrophin.
Gentamycin was administered in the following dose: iv 7.5 mg / kg in two six-day cycles, with an interval of 7 weeks, in compliance with the protocol supervised by the University of Naples, with the collection of the muscle biopsy after the second cycle and the monitoring of muscle enzymes. The results were favourable for the forms with punctiform mutations.
During the last years, researchers have tried to answer the question: Is gene therapy able to “heal” or to prevent muscle weakness? There are on-going clinical studies that involve gene therapy based on a technique called “exon skipping”. The first results seem promising, although the research is only at the beginning. The drug that achieves this target is supposed to be released on the market. At the end of July 2014, the pharmaceutical company Sarepta Therapeutics announced the results obtained following a study on 12 cases of Duchenne muscular dystrophy, using the product Eteplirsen (based on the ‘exon skipping” mechanism).
The results obtained have been promising. For the treatment of Duchenne muscular dystrophy there is also the possibility of a cell therapy, using cells to produce normal dystrophin. A protein variant is available as pharmaceutical product that is very similar with dystrophin. This synthetic alternative is called utrophin.
Approximately 13% of the patients with muscular dystrophy have nonsense mutations at the level of the gene that encodes for the dystrophin and this is the reason why incomplete, non-functional proteins are synthesised[31,32,34].
Translarna (Ataluren) is the first treatment approved which addresses the basic aetiology of DMD with nonsense mutation in patients aged 5 and over who have not lost autonomous ambulation. It was authorised to be released on the market on 31st July, 2014 and it is available in Romania, too[32].
A molecule (named RTC13) has been discovered, which acts at the level of mRNA of the gene of mutant dystrophin, allowing the synthesis of an integral and functional protein.

Treatment of complications
Treatment of heart failure with digoxin and diuretics in patients with early cardiac decompensation.
Treatment of respiratory disorderr.
This is done by assisted mechanical ventilation (AMV).
Assisted mechanical ventilation proved to be the only therapeutic method with which the average lifespan of patients with hereditary neuromuscular diseases may be extended[35].
In case of severe ventilatory defects, the restrictive syndrome may remain compensated for a long time. At this stage, clinical symptomatology is absent and vital capacity (VC) is normal.
In the initial stages of the disease, the arterial pressure of blood gases (O2, CO2) has normal values, both in waking and in REM and non REM sleep.
In evolution, hypoxemia and hypercapnia are present in both phases of sleep. Clinical sleep disorders occur with frequent awakenings due to disordered breathing, with shortness of breath. In advanced disease, breathing failure is clinically apparent both during sleep and during wakefulness: dyspnea, cyanosis, daytime sleepiness. AMV maintains normal levels of blood gas concentration and puts the respiratory muscles to rest because they have muscular deficit. Nocturnal ventilation assistance improves the daytime respiratory activity and reduces the annual rate of decline in vital capacity. Because continuous mechanical ventilation can cause atrophy of disuse, AMV with intermittent positive pressure is considered the method of choice to prevent the onset early respiratory failure. Treatment of respiratory failure by AMV was introduced in 1990 (25). AMV is indicated in cases of nocturnal hypercapnia (AP of CO2 of less than 60 mm Hg) caused by hyperventilation and AC values ​​below 100 ml.
For preventive purposes, it is indicated during the compensated phase when arterial pressure of breathing gases is normal and the curve of the vital capacity is downward (annual drop of 200 ml).
Early respiratory rehabilitation is achieved by intermittent assisted mechanical ventilation, through the nose, which slows down the restrictive respiratory syndrome.
Tardy respiratory rehabilitation consists in applying AMV in case of respiratory failure with decreased blood gases.
The specific rehabilitation treatment should be started early: active physical exercises may slow down the progression of the disease[10], great physical efforts that lead to muscle fatigue and faster development of the disease should be avoided, regular walks daily, 2 hours per day, will be encouraged to maintain muscle strength and delay retractions[36]. Surgery for the release of contractures is necessary to extend ambulation and early mobilization after surgery is a priority.
It is recommended: prevention and early treatment of intercurrent respiratory diseases, constant climate of thermal comfort and humidity, avoid crowded spaces to reduce exposure to infections, for respiratory tract infections, encourage deep breathing and coughing and antitussives with high intake of fluids to ensure good sputum and avoid sedatives, prevention of obesity, immunizations must be updated annually.
Family counselling is absolutely necessary to help maintain the emotional integrity of the family and encourage the child to comply with the rehabilitation program and the special life style imposed by the disease.

Evolution and prognosis
Gait disturbance progresses to confinement to bed after age 6.
The duration of the disease is variable and in cases with slow evolution, ambulation can be preserved up to 12-13 years.
Failure to walk starts after the age of 9-13 years or later if steroid treatment was performed.
From 6 to 11 years there is a decrease in muscle strength with the deterioration of functions such as: climbing stairs, getting up from lying to standing position, climbing stairs with his hands and walking on a short distance.
Respiratory disorders are restrictive with lung volume reduction due to the damage of the intercostal muscles and the diaphragm.
It is necessary to assess respiratory function regularly, 1-4 times a year as needed.
In evolution, severe kyphoscoliosis occurs due to damage of the neck muscles, sternocleidomastoid and paravertebral muscles, which worsens respiratory impairment. It appears after the age of 10 and it is progressive and irreversible.
Pulmonary complications that can occur are pneumonia and atelectasis. They require emergency hospitalization treatment with intermittent positive pressure, AMV, tracheostomy if needed.
Sleep disorders are due to hypoxia and consist in sleep insomnia, nightmares, Pavor nocturnus, nocturnal ambulatory automatism – require AMV.
Death occurs between 15 and 25 years of age by respiratory failure associated with respiratory infections in underweight patients or with cardiomyopathy in obese patients.
Life expectancy can be increased with the help of AMV, and following a lifestyle adapted to the needs imposed by the progression of the disease.

Table III shows schematically the clinical evolution and the therapeutic methods
(After Lupu C. and Corches Axinia, 2002,[37] News in genetic neuro-muscular pathology).

Genetic counselling:
It is the most effective intervention in carrier families because of the X-linked mechanism, and tracking the status of carrier mother .
In families with DMD and BMD patients, the carrier mother has 50% probability of transmitting the mutation to each pregnancy .
The boy who inherits the mutation will be affected and the motherwill be the carrier.

Table III. Developmental stages in DMD.

DMD stages Clinical signs Treatment
Stage 1
– Discrete or absent clinical signs
– Delay in the acquisition of ambulation
– Gowers’s sign is positive
– Difficulties in climbing stairs
– CPK – high levels
– EMG myogenic
– Muscle biopsy- immunohistochemistry tests –dystrophin in absent
– Avoiding prolonged immobilisations and bed rest
Stage 2
3-6 years
– Progressive motor deficit
– Muscle fatigue
– Emergence of movement restrictions
-Emergence of tendinous retractions
– Specific rehabilitation treatment – stretching
– Surgery for retractions
Stage 3
– Contractions (retractions) and severe muscle deficit – Ankle-foot orthoses
– Symptomatic treatment
Stage 4
10-14 years
-Progressive loss of independent ambulation through accentuated retractions, and severe, evolving motor deficit – Measures to limit and prevent the accentuation of the tendinous retractions and the correction of kyphoscoliosis
-Corrective surgery for retractions with precocious orthosis
Stage 5
14-18 years
– Loss of autonomous ambulation with immobilisation to bed of wheelchair
-Phenomena of respiratory failure
– Ambulation and orthostatic posture are maintained as much as possible with the help of orthoses and corticotherapy
-Nocturnal Assisted Ventilation is initiated
Stage 6
over 18 years
– Stage of immobilised adult
– Generalised muscle atrophies
– Nocturne and diurnal respiratory failure
– Permanent mechanical ventilation
– Technical devices for mobilization

Differential diagnosis between DMD and BMD:

In most cases, BMD is distinguished from DMD by age of onset, severity and development. If in DMD the onset is around the age of 3 years, in the BMD is situated between the ages of 5-10 years, confinement to the wheelchair occurs after 13 years and the dystrophin level is over 20%, compared to DMD in which it has lower values or it is absent.
There is also a group of patients with intermediate phenotype (Outliers) with moderate DMD and severe BMD.
They – preserve ambulation over the age of 12,

  • are immobilized in a wheelchair before the age of 16 years,
  • do not have their flexor muscles of the neck affected. Table IV presents genetic, clinical and anatomopathological data in dystrophinopathies that are important to differentiate the presented phenotypes.

Table IV. Genetic data in clinical and pathological dystrophinopathies. (After Darras B.T., Menachem C.C., Kunkel L.M., 2003)[1]

Phenotype Genetic locus Protein Hereditary transmission Clinical exam Anatomopathological exam
DMD Xp21 Dystrophin XR* Onset at 2-5 years
Pseudo hypertrophy
Low IQ
Heart impairment
Rapid evolution
Immobilization at
10-12 years
Death at the age of 15-30 years
Severe dystrophic changes
Immunohistochemically – Dystrophin is totally or almost totally absent Western blot: Dystrophin 0-5% of normal values
Intermediary form Xp21 Dystrophin XR* Intermediate severity
Immobilisation at
12-16 years
Western blot: Dystrophin values are 5-20% of the normal ones
BMD Xp21 Dystrophin XR* Variable onset
Slower evolution
Immobilisation after the age of 16
Moderate dystrophic changes
Immunohistochemically – Dystrophin staining is normal or slightly reduced
Western blot: Dystrophin over 20% of normal values

Case report:
Patient aged 12 years, came to hospital for: abnormal gait, difficulty in climbing stairs, myalgia in minor physical efforts. Onset at the age of 5 years.
From the history we retain that the phased motor development was slightly delayed: he held the head at 5 months, stood in upright posture without support from 8 months, walked independently at 1 year and 6 months. Personal and family history was not significant.

Neurological examination revealed abnormal gait: ambulation with broad-based support, waddling with hyperlordosis. The patient climbed the stairs only with support on the rail and helped by a caregiver. Gowers’sign: rises with difficulty in seated position, climbing on his own body with help, segmental strength is reduced proximally, with marked atrophies worsened by the girdles and by pseudohipertrophy, tendon retractions, joint deformations, kyphoscoliosis, club foot, talus valgus.
Biochemical laboratory tests: blood count, glycemia, calcemia – normal values; transaminases – elevated levels, CPK and LDH muscle enzymes highly elevated levels (10 times higher than the normal level) CPK in mother – slightly elevated;
EMG: highlights myogenic lesion;
Normal cardiac ultrasound, EKG normal.

The clinical and laboratory aspects orient us to BMD, considering the age and the evolution with the preservation of ambulation at 12 years of age.

Genetic tests on the other hand detect a deletion that is specific for the the DMD.

We chose this case for presentation as slow, evolutionary clinical aspect has oriented us towards BMD, but genetic analysis has shown that we are facing a case of DMD or it could have been an intermediate phenotype. Therefore, the immunohistochemistry test is important to highlight the presence or absence of dystrophin and its percentage if it is present.

The peculiarity of the case: the child was found out at the age of 5 years, he followed a corticosteroid treatment and specific rehabilitation according to protocols, which may explain the slow progress of the disease, preserving ambulation at 12.(Fig.3)

It is important to know the clinical and laboratory diagnostic elements in dystrophinopathies to detect these diseases as early as possible .
Tracking and applying the presented therapeutic protocols increase the life expectancy of these patients, improves the quality of their lives and of their families .
An important goal is to keep the patient as much as possible in the stage of independent ambulation, the stage where, in the near future, they could benefit from genetic therapy .
Since 2014, patients diagnosed with Duchenne muscular dystrophy caused by a nonsense mutation at the level of the dystrophin gene, have benefited from treatment with Ataluren (Translarna ) from the age of 5 and over this age, before losing the autonomous gait.


  1. Darras BT, Menache CC, Kunkel LM- Dystrophinopaties(cap 37) in Neuromuscular disorders of infancy, childhood and adolescence.A clinicians Approach, 2003, HR Jones Jr, DC De Vivo, Basil T Darras, Elsevier Science, Inc.
  2. Emery AEH,1993, Duchenne Muscular Distrophy, 2nd dition, New York, Oxford University Press.
  3. Aicardi J., 1998- Cap. Primary muscle disease Diseases of the Nervous Sistem in Childhood, 2nd edition, Mac Keith Press.
  4. Brooke MH, Fenichel GM, Griggs RC, Mendell JR et al,1981, The natural history of Duchenne muscular dystrophy : A caveat for therapeutic trials. Trans Am Neurol Assoc, 106:195-199.
  5. Fukunaga H, Sonoda Y, Atusuchi H, Osame M, 1991- Respiratory failure and its care in Duchenne muscular dystrophy. Rinsho Shhinkeigaku, 31:154-158.
  6. Smith CL, ShapiroEG, Best K et al – 1991, Corelation of Duchenne muscular dystrophy X chromosome deletion site with cognitive impairment. Ann Neurol, 30:449.
  7. Solle ND, Latham EE, Kindlon DJ et al, 1985, WelanTB,- 1987, Neurophysiological imparemant in Duchenne muscular dystrophy, J Clin Exp neuropsychol, 486.
  8. Fitzpatrick C, Barry C, Garvevy C, 1986- Psychiatric disorder among boys with Duchenne muscular dystrophy. Dev Med Child Neurol 28:589.
  9. Simpson AJ, Khilnani MT- 1975, Gastrointestinal manifestation of the muscular dystrophyes. Am J Roentgenol Radium Ther Nucl med, 125:948.
  10. Smith S.A., Swalmann KF- Muscular dystrophies in 91 K, F Ashwal S, Pediatric Neurology, Principles andpractice, 1999, ed.aIII-a, Mosby.
  11. Dawson DM, Fine IH, 1967- Creatinekinase in human tissues. Arch neurol, 16:175.
  12. Desmedt JE, Borenstein S, 1976- Regeneration in Duchenne muscular dystrophy: Electromyographic evidence. Arch Neurol, 33:642-650.
  13. Manole E, 1995- Imunohistochemistry in diagnosis of dystrophinopathies Rom J Neurol Psychiatry, 33:51-55.
  14. Malhotra SB, Hart KA, Klamut HJ, et al, 1998- Frameship deletion in patients with Duchenn and Becker muscular dystrophy. Science, 242:755.
  15. Mohamed K, Applelton R, Nicolaides P, 2000- Delayed diagnosis of Duchenne muscular dystrophy, Ped Neurol, 4:219-223.
  16. Gardner- Medwin D- 1970, Mutation rate in Duchenne type of muscular dystrophy. J. Med Genet:7:334, conform 10.
  17. Kuhn E, Fiehn W, Schroder J M, et al, 1979- Early myocardial Disease and cramping
  18. myalgial in Becker-type muscular dystrophy: Akindred. Neurology, 29:1144-1149.
  19. Hoffman EP, Kunkel LM, 1989- Dystrophin abnormalities in Duchenne/Becker muscular dystrophy. Neuron, 2:1019.
  20. Dubowitz V, Kanale M, Mercuri E, Muntoni F, – 2002, Remission of clinical signes in early Duchenne muscular dystrophy on intermitent low dose prednisolon therapy. European J of Pedriatic Neurology, 6,1.
  21. Dubowitz V, 1991- Prednisone in Duchenne Distrophy. Neuromuscular disord.1:161-163.
  22. Brooke MH, Fenichel GM, Griggs RC et al, 1987- Clinical investigation of Duchenn musculadystrophy. Intersting results in a trial of prednisone, Arch Neurol,, 44(89):812-817.
  23. Pandya S, Myers G, Moxley RT, 2002- Long tarm daily Prednisone Theraphy delays loss of ambulation and decline in Pulmonari function in patients with Duchenne Dystrophy in Xth International Congress on Neuromuscular Diseases Vancouver Canada, 8-12 July.