Muscular Dystrophies
• Duchenne muscular dystrophy (most common)
• Becker muscular dystrophy
• Shoulder-girdle muscular dystrophy (Limb-Girdle Dystrophy)
• Fascio-scapulo-humeral dystrophy
• Congenital muscular dystrophy
• Myotonic dystrophy
Muscle Development Disorders
• Myotubular myopathy
• Congenital muscle fiber type dysfunction
• Nemaline rod myopathy
• Central core disease
• Bening congenital hypotonia
Muscular Dystrophies
Duchenne Muscular Dystrophy
• It is the most common, most severe, and X-linked inherited muscle disease in childhood. Frequency; 1/3600 live male births.
• The disease gene is located at the 2nd locus of the p21 region of the X chromosome. There is a single or multiple exon deletion. Muscle protein called dystrophin is not synthesized. It happens with a new mutation in 30% of patients. The mother is not a carrier. The majority of mutations are caused by deletions in the dystrophin gene.
• The disease is seen in men. It can be seen in girls with Turner syndrome. Apart from this, the Lyon hypothesis can explain the inactivity of the relevant region on the other X chromosome and its occurrence in non-Turner girls.
• Absence of dystrophin leads to a secondary reduction of various dystrophin-related glycoproteins in the sarcolemma, resulting in loss of attachment to the extracellular matrix and further rendering the sarcolemma more susceptible to necrosis.
Clinical Findings
• Early motor activity is usually normal. Since facial muscle weakness occurs in the late period, facial mimic changes are not seen in the early period. Walking usually occurs on time, at 12 months of age. At the age of 3-4, it is seen that the child has difficulty in climbing stairs. They have frequent falls.
• There is proximal muscle weakness.
• Gowers' syndrome: When the child is lying on his back, he cannot get up directly and takes a special position to get up. He turns on the snow, flexes one foot and tries to climb on it with his arms. Gowers' syndrome usually begins at age 3 and becomes fully positive at age 5-6.
• While some patients become wheelchair dependent at the age of 7, most patients can walk by the age of 10. With physiotherapy and some minor surgical procedures (lengthening of the Achilles tendon), some patients can walk up to age 12. Scoliosis develops rapidly in most cases after wheelchair addiction.
• Generally, death occurs at the age of 18-20. Respiratory failure, heart failure, pneumonia, and aspiration during sleep are common causes of death. 80% of cases die from respiratory failure, 20% from heart failure.
• Trendelenburg /ducklike/lordotic gait is seen.
• Delay in walking, falling, walking on tiptoe, difficulty in running or walking properly, growth retardation are common forms of presentation, but they may rarely present with malignant hyperthermia after anesthesia.
• There is pseudohypertrophy in the calf muscles. After the calf, the most common hypertrophy is seen on the tongue and then on the forearm. There is no fasciculation in the tongue.
• Degenerative and fibrotic changes in the muscles are painless, myalgia and muscle spasm are not seen.
• Recurrent lung infections due to respiratory muscles being affected
• Incontinence due to anal and urethral sphincter muscle weakness
• Contractures in the knee, shoulder, ankle
• Deep tendon reflexes in the knee can be taken up to 6 years of age.
• Cardiomyopathy, especially accompanied by dilated cardiomyopathy. It presents with tachycardia and myocardial failure. It does not correlate with skeletal muscle weakness. While some patients die due to severe cardiomyopathy at an early age, cardiomyopathy is well tolerated in most patients until the terminal stage. Fibrosis in the posterobasal region of the left ventricle is characteristic. R wave showing right ventricular dominance on ECG, increase in R/S ratio, deep Q waves in D1, aVL and VS-6.
• Smooth muscle of the gastrointestinal tract may also be minorly affected.
• Mental retardation: Dystrophin is also synthesized in the brain and retina. Intellectual involvement in Duchenne muscular dystrophy can occur in any patient. However, only 20-30% of cases have an IQ below 70. Very rarely, severe mental retardation may occur.
• Epilepsy is slightly more common than the general population.
Diagnosis
• Definitive diagnosis is made by identification of dystrophin gene mutation by PCR.
• Creatine Kinase (CK) increases 10-20 times of normal. A milder CK elevation is detected in 80% of carriers.
• Muscle biopsy: Endomysial connective tissue proliferation, fragmented degenerative and regenerative myofibrils, mononuclear inflammatory cell infiltration and areas of muscle fibrillar necrosis, structural changes in still functional muscle fibrils, and many dense fibers.
• EMG is not required for diagnosis. Indicates myopathic potentials.
• Due to the development of genetic methods, it is recommended to send a genetic test first to the suspected patients, and if no significant mutation is detected, a muscle biopsy is recommended. Although no abnormality is found in PCR in 30% of patients, specific findings are seen in muscle biopsy.
• The distinction between DMO and BMD can be made mainly by dystrophin analysis. The amino terminal end of the dystrophin protein is attached to actin, and the carboxyl end is attached to the sarcolemma.
It was observed that the clinical course of the disease developed due to the binding problems at the carboxyl terminus was more severe.
• In order to slow down the clinical course, it is recommended to start Prednisolone treatment when patients are able to walk. Drugs that provide protein synthesis with the potential function of dystrophin protein such as drisapersen and eteplirsen have been used.
• If a deletion is detected in the mother, dystrophin gene defect in the fetus can be demonstrated at 12 weeks by chorionic villus biopsy. If positive, therapeutic abortion is performed.
Becker Muscular Dystrophy
• Becker muscular dystrophy is essentially the same disease as Duchenne dystrophy, the genetic defect is at the same locus, but clinically milder, later on, and has a longer lifespan.
• Shows X-linked transition.
• The pathophysiology is the same as Duchenne, but it is distinguished from Duchenne by later onset, slower course, and longer average lifespan.
• Although dystrophin synthesis is present, it is defective.
Shoulder-Girdle Muscular Dystrophy (Limb-Girdle Muscular Dystrophy)
• Muscular dystrophy, which can be seen in boys or girls, usually presents in the second decade of life, comprising a group of progressive hereditary myopathies that mainly involve the hip and shoulder girdle muscles.
• Type I (A-H) is inherited autosomal dominantly while type 2 is inherited autosomal recessively.
• Most cases are inherited autosomal recessively and because of the sarcoglycan mutation it is called sarcoglycanopathy. It usually starts between the ages of 4-5, but each type can start at different times. In autosomal recessive types (type 2A-2Q), Calpalin-3, Dysferlin, sarcoglycan, alpha/beta-sarcoglycan, titin, and fukitin gene mutations are seen. There is a type 2A calpalin-3 gene mutation and it starts between the ages of 8 and shows progression.
• Over time, the distal muscles also become atrophic and weak.
• The first symptoms appear in mid-childhood or later. Patients present with low back pain as a result of lordotic posture caused by weakness of the gluteal muscles. At the age of 30, he progresses to be wheelchair dependent. The feed rate may vary.
• Weakness in neck flexors and extensors is seen in all patients, but face, tongue and other muscles innervated by bulbar-nerves are rarely involved.
• As muscle weakness progresses, deep tendon reflexes also decrease.
• Cardiac involvement is rare.
• Intellectual function is usually normal.
• EMG and muscle biopsy may reveal supportive findings of muscular dystrophy, but without additional clinical criteria, none of the findings are specific enough to make an absolute diagnosis.
In some patients, the diagnosis can be made by demonstrating alpha-sarcoglycan and dystrophin-related glycoprotein defects in immunohistochemical staining in muscle biopsy. The serum CK level is usually increased, but the level of elevation varies between families.
Emery-Dreifus Muscular Dystrophy
• Also called scapuloperoneal or scapohumeral muscular dystrophy.
• Defective gene emerin in X-linked form. In the autosomal dominant form (chromosome Iq, late onset, adolescence or early adulthood, risk of sudden death from ventricular fibrillation) the defective protein lamine is termed A-C.
• It is seen in the q28 region, which is the long arm of the X chromosome. Due to the genetic neighborhood in this region, it can be associated with the following diseases.
- Myotubular myopathy,
- Neonatal adrenoleukodystrophy,
- Bloch-Sulzberg type incontinentia pigment
• Although it occurs between the ages of 5 and 15 years, it is possible to live up to the late stages of adult life due to the slow course of the disease.
• In the early period, scapulohumeroperoneal weakness develops with contractures in the wrists and ankles.
• There is no myotonia.
• Intelligence level is normal.
• There is no pseudohypertrophy.
• Dilated cardiomyopathy is serious and is a common cause of death. At the same time, atrial fibrillation/flutter and sudden ventricular fibrillation are common.
• It differs from other X-linked recessive muscular dystrophies with the amount of increase in CK levels being low to moderate.
• Muscle biopsy: Nonspecific myofiber necrosis and endomysial fibrosis are seen.
Atrophy of centronuclear fibrils and selective histochemical type 1 muscle fibers may confuse myotin with dystrophy.
• The diagnosis can be made by demonstrating emerin deficiency in blood, buccal mucosa or skin fibroblasts in patients with emerin mutation. All types can be diagnosed with specific gene tests. Evaluation of muscles in gluteal and lower extremity MRI is helpful in diagnosis, especially in patients with lamin mutations.
• Its treatment is supportive treatment. Some patients require a pacemaker to prevent sudden death due to VF.
Fascio-Scapulo-Humeral Dystrophy (LANDUZV-DEGERINE Dystrophy)
• Autosomal dominant inheritance is the rule. There is a 4q35 deletion. Genetic antispasm is common.
• It is the 3rd most common muscular dystrophy after Duchenne muscular dystrophy and myotonic dystrophy.
• Clinical severity differs from patient to patient.
• Initial symptoms begin as weakness in the facial and scapular muscles. It then ends with the lower extremity muscles, upper extremity proximal muscles, and finally the hand muscles being affected.
• Unlike other muscular dystrophies, there is asymmetric muscle weakness.
• Trendelenburg gait and gowers positivity are seen. Limb contractures are rare.
Lordosis and kyphoscoliosis are common complications.
• The winged scapula is prominent and can be seen from infancy.
• There is a neonatal form associated with hearing loss.
• Typical clinical onset 2-3. There is also an infantile form that starts in the first few years, although it is in the decade. It moves slowly. Normal life is led. Death from cardiac and respiratory failure may occur in the 4th decade.
• 20% retinal vascular disorders have been identified.
• It may rarely coexist with Mobius syndrome.
• EMG and muscle biopsy findings are the same as in other muscular dystrophies. CK can vary a lot, it can be normal or 1000 values can be seen.
• Muscle biopsy: Widespread proliferation of connective tissue between muscle fibers, presence of very different muscle fibers (some atrophic, some hypertrophic), fragmented degenerative and regenerative muscle fibers. Diffuse lymphocytic infiltration is seen in inflammatory types.
• If mononuclear cell inflammation is seen in the muscle biopsy of a child younger than 2 years old, fascioscapulohumeral dystrophy should come to mind first. It can also be seen less frequently in congenital muscular dystrophy.
Congenital Muscular Dystrophy (CMD)
• This autosomal recessive disease group is characterized by a benign course after severe involvement at birth.
• Although there are many sub-classifications, they can be roughly classified as follows.
• Babies are generalized hypotonic and have contracture or arthrogryposis at birth. Congenital contractures of the wrists are particularly associated with the Ullrich type.
• Head control is poor. Facial muscles may be mildly involved, but ophthalmoplegia, pharyngeal weakness, and poor suction are uncommon. There may be difficulty swallowing, which rarely requires gastrostomy. DTRs are hypoactive or absent.
• The Fukuyama type of congenital muscular dystrophy is the second most common muscular dystrophy in Japan after Duchenne muscular dystrophy. This type is accompanied by severe cardiomyopathy/ heart failure and brain malformations (mental retardation, seizures, microcephaly, growth retardation).
• Neurological findings may also be observed in other types. These findings range from severe dysplasia (holoprosencephaly, lissencephaly) to mild findings (corpus callosum agenesis, focal heterotopia, cerebellar hypoplasia).
• Serum CPK levels are found to be moderately increased. Nonspecific myopathic features are observed in EMG. Cardiac and cerebral circulation should be investigated in all patients.
• Muscle biopsy is the most valuable method in diagnosis. Muscle biopsy: There is widespread proliferation in endomysial collagen tissue, increase in adipose tissue and fibrosis. In tissue cultures, an increase in collagen synthesis of fibroblasts is detected, collagen structure is normal. Muscle fibers are of different lengths, there is a central nucleus, fragmented-degenerate-regenerated fibrils can be seen.
No inflammation or abnormal inclusions are seen.
• In the immunohistochemical staining, 40% of the cases are negative for merosin (laminin alpha 2 chain) in the sarcolemmal region. Adhalen (α-dystroglycan) may be decreased secondary to some cases. Collagen VI is selectively reduced or absent in Ullrich patients.
• There is no effective treatment. In collagen 6 myopathies, cyclosporine can correct muscular apoptosis.
Myotonic Muscular Dystrophy
• Autosomal dominant inheritance, multisystemic disorder, myotonia, muscle weakness, cataracts (may be congenital), mental retardation endocrinopathy (hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus, early and late puberty, testicular atrophy and testosterone deficiency), cardiac disease, gastrointestinal disease is characterized by dementia and an increased risk of malignancy.
• Myotonic dystrophy usually has an antisipation pattern. That is, the involvement in each generation tends to be more severe than the previous one.
• The head is flat from the sides. Because weak temporal and pyterigoid muscles cause the head to take this shape during head shaping.
• There is a typical inverted V-shaped mouth structure on the face.
• Muscle involvement;
- Prolonged relaxation of the muscle following the contracture is the most typical feature. In the first year, weakness is mild.
- Thenar hypothenar atrophy is observed, the grooves between the fingers deepen. Weakness of the sternocleidomastoid muscle draws attention in the long, thin cylindrical neck. The tongue is thin and atrophic. Scapular winging is seen.
- Myotonia is not painful muscle spasm. Myalgia is not seen.
- Has difficulty in climbing stairs, gowers is positive.
- Constipation may occur due to gastrointestinal involvement.
- Cardiomyopathy is rare in cardiac involvement, heart blocks and arrhythmias can cause sudden death.
- Immunoglobulin G level is usually low.
- In particular, the incidence of autism has increased.
- Deep tendon reflexes are preserved.
• There are three types;
- Type 1 is the classical type and is a gene disease with an increase in the trinucleotide (CTG) repeat formed in the q13 region of the 19th chromosome. Since this gene encodes serine-threonine protein kinase, it leads to the current clinical picture. It can start at any age. Except for severe neonatal forms, patients are usually normal at birth.
- Type 2 is a tetra-nucleotide repeat gene disease and the responsible gene is in the 3q21 region. It is rare in infancy or early childhood.
- Type 3 is the late-onset form, the responsible gene is in the 15q21-q24 region.
- Severe congenital form is seen in babies of symptomatic sick mothers. Severe hypotonia and contractures are present at birth. Its mortality is 25%. Mortality and morbidity rates are lower in those who need a mechanical ventilator for less than 1 month.
• CK may be normal or slightly elevated.
• In muscle biopsy: muscle fibers with central nuclei, selective atrophy of type 1 fibers, degenerative and somewhat fragmented muscle fibers, little or no fibrosis. Muscle biopsy findings may be normal in younger children, while they may be this way in older children. Unlike Duchenne muscular dystrophy, there is little or no myofibrillary necrosis.
• Physiotherapy can prevent the development of contractures, but care should be taken as myotonia may occur with exercise.
• Mexiletine, phenytoin, carbamazepine, procainamide and quinidine sulfate can be used in treatment because they increase the depolarization threshold of the muscle and decrease myotonia.
Muscle development disorders
Congenital myopathies are a heterogeneous group of congenital neuromuscular disorders. The common features of these diseases are;
• Often hereditary
• They are mostly non-progressive
• Definitive diagnosis is made by muscle biopsy.
• CK levels are normal
• There is no specific treatment, supportive treatment is given.
• Nerve conduction velocity is normal in EMG
• Cardiomyopathy is rare.
• There is usually a decrease in fetal movements.
Myotubular myopathy ( Centronuclear myopathy)
• 8-15th of pregnancy. cessation of fetal muscle maturation during the myotubular developmental stage
• It shows X-linked recessive inheritance most frequently.
• Fetal vimentin and desmin persist in muscle fibers
• Decreased fetal movements, polyhydromnios, generalized hypotonia and weakness from birth. Ptosis may be seen.
• Muscle biopsy: It is diagnostic at birth, even in premature babies. Muscle fibers show strong immunoreactivity for vimentin and desmin. There is no vimentin and desmin activity in healthy full-term newborn muscles.
• About 75% of affected newborns die within the first few weeks or months.
Congenital muscle fiber type disproportion
• Patients often have hypotonia and weakness, but the weakness is usually not severe. Respiratory distress and dysphagia are rare.
• Poor head control and gross motor retardation are common in infancy. Walking is usually 18-24. Even if it takes up to a month, this skill is gained at the end.
• The head is dolichocephalic and there is facial weakness (the appearance may not be distinguishable from nemaline rod myopathy).
• The high palate can be seen. Myalgia is not seen. The clinical course is benign and not progressive.
• It may be associated with cerebellar hypoplasia. It may accompany other muscle development diseases and metabolic diseases.
• Muscle biopsy: There is an impairment in the proportions of both size and histochemical fiber types; type 1 fibers are small, type 2 fibers are hypertrophic, type 1 is more than type 2.
Nemaline rod myopathy
• Inheritable to OR/0D/X.
• There are neonatal, infantile and juvenile forms. The neonatal form is fatal.
• The faces of neonatal and infantile forms may be indistinguishable similar to myotonic dystrophy.
• Characteristically, there is generalized hypotonia and very thin muscle mass, including the respiratory muscles.
• The head is dolichocephalic and the palate is highly arched, cleft palate may be present. The jaw muscles may be too weak to keep the jaw closed. Gastrostomy may be required for chronic dysphagia.
• Babies may be severely weak at birth and may be lost in the neonatal period. There may be a decrease in fetal movements.
• Muscle biopsy: Intranuclear Nemaline rods/rods (actin+alpha actin+tropomyosin 3+nebulin) are seen within the muscle fibers, indicating type 1 fiber dominance. Sometimes no type 2 fibers are seen.
Central Core Disease
• It is inherited as an autosomal dominant. There is a ryanodine receptor mutation.
• It is characterized by structures consisting of amorphous, granular cytoplasm (central core) within the muscle fibers, which do not contain myofibrils and organelles.
• Typical features are infantile hypotonia, proximal weakness, muscle wasting, and involvement of the facial and neck flexor muscles.
• The going is not progressive. Congenital dislocated hip and skeletal deformities are common. Scoliosis, too far! occurs without weakness.
• Central core disease is associated with malignant hyperthermia and premedication with dantrolene should be considered before administering anesthetic to all patients.
Bening congenital hypotonia
• Benign congenital hypotonia is a term used for an unknown, non-progressive and hypotonic infant or child, rather than a disease.
• Although some children acquire gross motor skills more slowly than normal, hypotonia is not usually associated with weakness or developmental delay. Intelligence is normal.
• The prognosis is generally good.
• Recurrent dislocations in joints, especially in the shoulder joint, are common.
