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Flaccid Limb Weakness in Childhood
The majority of children with flaccid limb weakness have a motor unit disorder. Flaccid leg weakness may be the initial feature of disturbances in the lumbosacral region, but other symptoms of spinal cord dysfunction are usually present. Consult Box 12.1 when considering the differential diagnosis of flaccid leg weakness without arm impairment. Cerebral disorders may cause flaccid weakness, but dementia (see Chapter 5 ) or seizures (see Chapter 1 ) are usually concomitant features.
Clinical features of neuromuscular disease
Weakness is decreased strength, as measured by the force of a maximal contraction. Fatigue is an inability to maintain a less than maximal contraction, as measured by exercise tolerance. Weak muscles are always more easily fatigued than normal muscles, but fatigue may occur in the absence of weakness. Chapter 8 discusses conditions in which strength is normal at rest but muscles fatigue or cramp on exercise.
The Initial Complaint
Limb weakness in children is usually noted first in the legs and then in the arms ( Box 7.1 ). The reason for this is because the legs are required to bear weight and are subject to continuous testing while standing or walking. Delayed development of motor skills is often an initial or prominent feature in the history of children with neuromuscular disorders. Marginal motor delay in children with otherwise normal development rarely raises concern, and is often considered part of the spectrum of normal development. Prompts for neurological consultation in older children with neuromuscular disorders are failure to keep up with peers, frequent falls, or easy fatigability.
Box 7.1
Symptoms of Neuromuscular Disease
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Abnormal gait
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Steppage
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Toe walking
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Waddling
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Easy fatigability
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Frequent falls
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Slow motor development
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Specific disability
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Arm elevation
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Climbing stairs
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Hand grip
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Rising from floor
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An abnormal gait can be the initial symptom of either proximal or distal leg weakness. With proximal weakness, the pelvis fails to stabilize and waddles from side to side as the child walks. Running is especially difficult and accentuates the hip waddle. Descending stairs is particularly difficult in children with quadriceps weakness; the knee cannot lock and stiffen. Difficulty with ascending stairs suggests hip extensor weakness. Rising from the floor or a deep chair is difficult, and the hands help to push off.
Stumbling is an early complaint when there is distal leg weakness, especially weakness of the evertors and dorsiflexors of the foot. Falling is first noted when the child walks on uneven surfaces. The child is thought to be clumsy, but after a while parents realize that the child is “tripping on nothing at all.” Repeated ankle spraining occurs because of lateral instability. Children with foot drop tend to lift the knee high in the air so that the foot will clear the ground. The weak foot then comes down with a slapping motion ( steppage gait ).
Toe walking is commonplace in Duchenne muscular dystrophy (DMD) because the pelvis thrusts forward to shift the center of gravity and the gastrocnemius muscle is stronger than the peroneal muscles. Toe walking occurs also in upper motor neuron disorders that cause spasticity and in children who have tight heel cords but no identifiable neurological disease. Toe walking with progressive foot deformity suggests hereditary spastic paraplegia. Compulsive tiptoe walking should be suspected in children with a normal exam and obsessive-compulsive traits. Muscular dystrophy is usually associated with hyporeflexia and spasticity with hyperreflexia. However, the ankle tendon reflex may be difficult to elicit when the tendon is tight for any reason.
Adolescents, but usually not children with weakness, complain of specific disabilities. A young woman with proximal weakness may have difficulty keeping her arms elevated to groom her hair or rotating the shoulder to get into and out of garments that have a zipper or hook in the back. Weakness of hand muscles often comes to attention because of difficulty with handwriting. Adolescents may notice difficulty in unscrewing jar tops or working with tools. Teachers report to parents when children are slower than classmates in climbing stairs, getting up from the floor, and skipping and jumping. Parents may report a specific complaint to the physician, but more often they define the problem as inability to keep up with peers.
A child whose limbs are weak also may have weakness in the muscles of the head and neck. Specific questions should be asked about double vision, drooping eyelids, difficulty chewing and swallowing, change of facial expression and strength (whistling, sucking, chewing, blowing), and the clarity and tone of speech. Weakness of neck muscles is frequently noticed when the child is a passenger in a vehicle that suddenly accelerates or decelerates, as it is normal in the first couple of months of life. The neck muscles are unable to stabilize the head, which snaps backward or forward.
Physical Findings
The examination begins by watching the child sit, stand, and walk. A normal child sitting cross-legged on the floor can rise to a standing position in a single movement without using the hands. This remarkable feat is lost sometime after age 15 years in most children, in which case rising from a low stool is a better test of proximal leg strength. The child with weak pelvic muscles uses the hands for assistance ( Fig. 7.1 ), and with progressive weakness the hands are used to climb up the legs ( Gower sign ).
After normal gait is observed, the child is asked to walk first on the toes and then on the heels ( Box 7.2 ). Inability to walk on the toes indicates gastrocnemius muscle weakness, and inability to walk on the heels indicates weakness of the anterior compartment muscles. Push-ups are a quick test of strength in almost all arm muscles. Most normal children can do at least one push-up. Then ask the child to touch the tip of the shoulder blade with the ipsilateral thumb. This is an impossible task when the rhomboids are weak.
Box 7.2
Signs of Neuromuscular Disease
Finally, face and eye movements are tested. The best test of facial strength is to blow out the cheeks and hold air against compression. Normally the lips are smooth. Wrinkling of the perioral tissues and failure to hold air indicate facial weakness. During this period of observation and again during muscle strength testing, the physician should look for atrophy or hypertrophy. Wasting of muscles in the shoulder causes bony prominences to stand out even further. Wasting of hand muscles flattens the thenar and hypothenar eminences. Wasting of the quadriceps muscles causes a tapering appearance of the thigh that exaggerates when the patient tenses the thigh by straightening the knee. Atrophy of the anterior tibial and peroneal muscles gives the anterior border of the tibia a sharp appearance, and atrophy of the gastrocnemius muscle diminishes the normal contour of the calf.
Loss of tendon reflexes occurs early in denervation, especially when sensory nerves are involved, but parallels the degree of weakness in myopathy. Tendon reflexes are usually normal even during times of weakness in patients with myasthenia gravis, and may be normal between episodes of recurrent weakness in those with metabolic myopathies. The description of myotonia, a disturbance in muscle relaxation following contraction, is in the section on myotonic dystrophy.
Progressive proximal weakness
Progressive proximal weakness in childhood is most often due to myopathy, usually a muscular dystrophy ( Box 7.3 ). Juvenile spinal muscular atrophy (SMA) is the only chronic denervating disease in which weakness is more proximal than distal. Electromyography (EMG) and muscle biopsy readily distinguishes it from myopathic disorders. Limb-girdle myasthenia is rare but is an important consideration because specific treatment is available ( Table 7.1 ).
Box 7.3
Progressive Proximal Weakness
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Spinal cord disorders (see Chapter 12 )
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Juvenile spinal muscular atrophies
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Autosomal dominant
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Autosomal recessive
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GM 2 gangliosidosis (hexosaminidase A deficiency)
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Myasthenic syndromes
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Acquired limb-girdle myasthenia
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Slow-channel syndrome
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Muscular dystrophies
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Bethlem myopathy
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Dystrophinopathies
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Facioscapulohumeral syndrome
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Severe childhood autosomal recessive muscular dystrophy
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Inflammatory myopathies
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Metabolic myopathies
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Endocrine myopathies
Table 7.1
Distinguishing Features in Proximal Weakness
| Neuronopathy | Myopathy | Myasthenia | |
|---|---|---|---|
| Tendon reflexes | Absent | Depressed or absent | Normal |
| Electromyography | Fasciculations; denervation potentials; high-amplitude polyphasic motor potentials | Brief, small-amplitude polyphasic motor units | Normal |
| Nerve conduction | Normal or mildly slow | Normal | Abnormal repetitive stimulation |
| Creatine kinase concentration | Normal or mildly elevated | Elevated | Normal |
| Muscle biopsy | Group atrophy; group typing | Fiber necrosis; fatty replacement; excessive collagen | Normal |
Spinal Muscular Atrophies
Autosomal Recessive Type
Spinal muscular atrophy is the most common inherited disorder of the spinal cord resulting in hypotonia and weakness in infants with an incidence of approximately 1 in 6000 to 1 in 11,000 live births in the United States. It is an autosomal recessive disorder with a molecular defect leading to increased apoptosis in anterior horn cells and in motor nuclei of lower cranial nerves. In approximately 95% of cases the genetic defect is homozygous deletion of the survival motor neuron 1 gene (SMN1) , which is located on the telomeric region of chromosome 5q13. A virtually identical centromeric gene on 5q13, referred to as SMN2 , encodes a similar but less active product. The protein product of SMN2 partially appears to rescue the SMA phenotype such that a larger SMN2 copy number generally results in a milder disease. Although age at onset distinguishes three subtypes of SMA, the subtypes are actually a continuum. The severe type (SMA I) always begins before 6 months of age (see Chapter 6 ), the intermediate type (SMA II) begins between 6 and 18 months, and the juvenile type (SMA III) begins after 18 months.
Clinical features
In SMA II, fetal movements are normal and the child is normal at birth. The initial feature of SMA II is delayed motor development. As a rule, affected children achieve sitting balance, but are unable to stand unsupported and are wheelchair confined. A fine hand tremor is often present. Contractures of the hips and knees and scoliosis eventually develop. Some of those affected die in childhood because of respiratory failure, but most survive into adult life. An unusual form of SMA II is one that begins with head drop, followed by generalized weakness, and respiratory insufficiency. This variant causes death by 3 years of age.
The initial feature of SMA III is gait instability caused by proximal weakness. Similar to SMA II, a fine action tremor is common. Disease progression is very slow, sometimes in a stepwise fashion, and often seems arrested. Weakness may progress either to the distal muscles of the legs or to the proximal muscles of the arms. The hands are the last parts affected. Facial muscles may be weak, but extraocular motility is always normal. Tendon reflexes are hypoactive or absent. The sensory examination is normal. Cases with ophthalmoplegia are probably genetically distinct.
Some children have more profound weakness of the arms than of the legs and are likely to have facial weakness as well. Within a family, some children may have predominant leg weakness, whereas their siblings may have predominant arm weakness.
Diagnosis
Showing the gene abnormality on chromosome 5 establishes the diagnosis. EMG and muscle biopsy are unnecessary if genetic analysis shows the appropriate mutation. The findings on both tests are similar to those described for SMA I in Chapter 6 . The serum concentration of creatine kinase (CK) may be two to four times the upper limit of normal, and the increase in concentration correlates directly with the duration of illness.
Management
Nusinersen (Spinraza) was approved by the FDA in 2017 for the treatment of children and adults with SMA. This is a survival motor neuron 2-directed antisense oligonucleotide given intrathecally with the goal to promote SMN protein production. The recommended dose is 12 mg per injection three times at 14 day intervals, then 30 days later, and then every 4 months thereafter. The evidence for approval of this drug was class IV and based on improvement or stabilization in motor function on a phase 1 clinical trial for up to 14 months. Proper management of SMA in children increases longevity and decreases disability. The goals are to maintain function and prevent contractures. Children who quickly take to a wheelchair develop disuse atrophy. Dietary counseling prevents obesity, which only increases the strain on weak muscles. The prevention of contractures usually requires range of motion exercises and the early use of splints, especially at night. Families need genetic counseling for this autosomal recessive illness with a 25% risk for future children from the same parents.
Autosomal Dominant Type
Several childhood autosomal dominant types of SMA exist, but account for less than 2% of cases. A BICD2 genetic variant was identified in three families with autosomal dominant SMA. BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Other heterozygous mutations in DYNC1H1 and MAPT have recently been identified. The onset of weakness begins in childhood and extends into adult life. A new dominant mutation would be difficult to distinguish from the autosomal recessive form.
Clinical features
A more generalized pattern of weakness is more prominent in the autosomal dominant type than in the autosomal recessive type, but proximal muscles are weaker than distal muscles. The weakness is slowly progressive and may stabilize after adolescence. Most patients walk and function well into middle and late adult life. Bulbar weakness is unusual and mild when present. Extraocular muscles are not affected. Tendon reflexes are depressed or absent in weak muscles. Joint contractures are uncommon.
Diagnosis
The serum concentration of CK is normal or only mildly elevated. The EMG is the basis for diagnosis and confirmatory genetic testing is available.
Management
Treatment for the dominant type is the same supportive therapy as for the recessive type, but the use of intrathecal Nusinersen is not applicable. Antenatal diagnosis is not available. When the family has no history of SMA, genetic counseling is difficult, but autosomal dominant inheritance is a consideration if the onset is after 3 years of age.
Non-SMN1 related SMA
The differential diagnosis includes X-linked infantile SMA with arthrogryposis, SMA due to mitochondrial dysfunction, SMA with pontocerebellar hypoplasia, and SMA with respiratory distress (SMARD), which is the most common form in this category and is associated with mutations in IGHMBP . The X-linked form may present with polyhydramnios secondary to impaired fetal swallowing and arthrogryposis. The diagnosis should be considered in any case of a male infant with an SMA phenotype and normal SMN1 genetic test. Another causative gene encodes the ubiquitin-activating enzyme 1 ( UBE1 ), for which testing is available on a research basis only. This condition is also discussed in Chapter 6 .
GM 2 Gangliosidosis
The typical clinical expression of hexosaminidase A deficiency is Tay-Sachs disease (see Chapter 5 ). Several phenotypic variants of the enzyme deficiency exist, with onset throughout childhood and adult life. Transmission of all variants is by autosomal recessive inheritance. The initial features of the juvenile-onset type mimic those of juvenile SMA.
Clinical features
Weakness, wasting, and cramps of the proximal leg muscles begin after infancy and frequently not until adolescence. Distal leg weakness, proximal and distal arm weakness, and tremor follow. Symptoms of cerebral degeneration (personality change, intermittent psychosis, and dementia) become evident after motor neuron dysfunction is established.
Examination shows a mixture of upper and lower motor neuron signs. The macula is usually normal and the cranial nerves are intact, with the exception of atrophy and fasciculations in the tongue. Fasciculations also may be present in the limbs. Tendon reflexes are absent or exaggerated, depending on the relative severity of upper and lower motor neuron dysfunction. Plantar responses are sometimes extensor and sometimes flexor. Tremor, but not dysmetria, is present in the outstretched arms, and sensation is intact.
Some children never develop cerebral symptoms and have only motor neuron disease; some adults have only dementia and psychosis. The course is variable and compatible with prolonged survival.
Diagnosis
The serum concentration of CK is normal or only mildly elevated. Motor and sensory nerve conduction velocities are normal, but needle EMG shows neuropathic motor units. Showing a severe deficiency or absence of hexosaminidase A activity in leukocytes or cultured fibroblasts establishes the diagnosis.
Management
No treatment is available. Heterozygote detection is possible because enzyme activity is partially deficient. Prenatal diagnosis is available. Gene therapy or enzyme replacement therapy research may eventually lead to a treatment to slow progression or cure Tay-Sachs.
Myasthenic Syndromes
Proximal weakness and sometimes wasting may occur in acquired immune-mediated myasthenia and in a genetic myasthenic syndrome.
Limb-Girdle Myasthenia
Limb-girdle myasthenia is immune-mediated myasthenia gravis that begins as progressive proximal weakness of the limbs and affects ocular motility later. This entity is very uncommon.
Clinical features
Onset occurs after 10 years of age, and girls are more often affected than are boys. Weakness does not fluctuate greatly with exercise. Muscles of facial expression may be affected, but other bulbar function is not. Tendon reflexes are usually present, but may be hypoactive. The clinical features suggest limb-girdle dystrophy or polymyositis.
Diagnosis
The diagnosis of limb-girdle myasthenia is possible in every child with proximal weakness and preserved tendon reflexes. Repetitive nerve stimulation shows a decremental response, and the serum concentration of antibodies that bind the acetylcholine receptor is increased. Some reports of families with limb-girdle myasthenia affecting two or more siblings have appeared recently. Some of these families may have had the slow-channel syndrome or another genetic myasthenia.
Management
The treatment is the same as for other forms of antibody-positive myasthenia (see Chapter 15 ).
Slow-Channel Syndrome
The slow-channel syndrome is a genetic disorder of the skeletal muscle acetylcholine receptor. Genetic transmission is by autosomal dominant inheritance and may involve a variety of genes.
Clinical features
No symptoms are present at birth. Onset is usually during infancy, but delay until adult life occurs. Weakness of the cervical and scapular muscles is often the initial feature. Other common features are exercise intolerance, ophthalmoparesis, and muscle atrophy. Ptosis, bulbar dysfunction, and leg weakness are unusual. The syndrome progresses slowly, and many patients do not come to medical attention until after the first decade.
Diagnosis
Weakness does not respond either to injection or to oral administration of anticholinesterase medication. Two patients were hypersensitive to edrophonium (Tensilon) and responded with muscarinic side effects. Repetitive nerve stimulation at a rate of three stimuli per second causes an abnormal decremental response, and single-nerve stimulation causes a repetitive muscle potential. Muscle biopsy shows type I fiber predominance. Group atrophy, tubular aggregates, and an abnormal endplate configuration are present in some specimens.
Management
Cholinesterase inhibitors, thymectomy, and immunosuppression are not effective. Quinidine sulfate improves strength and fluoxetine is equally beneficial in patients who do not tolerate quinidine. Salbutamol has been reported to be beneficial in some patients.
Muscular Dystrophies
No agreed upon definition of muscular dystrophy exists. We prefer to use the term to embrace all genetic myopathies caused by a defect in a structural protein of the muscle ( Fig. 7.2 ). Enzyme deficiencies, such as acid maltase deficiency, are not dystrophies but rather metabolic myopathies . For most dystrophies the abnormal gene and gene product is established.
The term limb-girdle muscular dystrophy (LGMD) encompasses several muscular dystrophies characterized by progressive proximal muscle weakness. The discussion of LGMD transmitted by X-linked inheritance is in the section on Duchenne and Becker Muscular Dystrophy . Not discussed is Danon disease , an X-linked cardiomyopathy and skeletal myopathy, with onset in late adolescence.
The more common forms of LGMD transmitted by autosomal dominant inheritance are facioscapulohumeral dystrophy (FSHD; see Chapter 17 ), the dominant form of Emery-Dreifuss dystrophy, Bethlem myopathy, and the myopathies associated with caveolinopathies. The caveolinopathies are uncommon and not discussed.
Autosomal recessive types may begin in childhood or adult life. These are distinguishable by the location of the abnormal gene and in some cases by the abnormal gene product ( Table 7.2 ). Deficiencies in the dystrophin-associated glycoprotein complex called the sarcoglycan cause many muscular dystrophies. Some of the phenotypes are similar to DMD and explain most cases of affected females with a DMD phenotype (see the later section on Severe Childhood Autosomal Recessive Muscular Dystrophy).
Table 7.2
Autosomal Recessive Limb-Girdle Muscular Dystrophies (LGMDs)
| LGMD type | Location | Gene product | Clinical features |
|---|---|---|---|
| LGMD-2A | 15q | Calpain 3 | Onset at 8–15 years, progression variable |
| LGMD-2B | 2p13-16 | Dysferlin | Onset at adolescence, mild weakness; gene site is the same as for Miyoshi myopathy |
| LGMD-2C | 13q12 | Sarcoglycan | Duchenne-like, severe childhood autosomal recessive muscular dystrophy (SCARMD1) |
| LGMD-2D | 17q21 | A-Sarcoglycan (adhalin) | Duchenne-like, severe childhood autosomal recessive muscular dystrophy (SCARMD2) |
| LGMD-2E | 4q12 | B-Sarcoglycan | Phenotype between Duchenne and Becker muscular dystrophies |
| LGMD-2F | 5q33-34 | Sarcoglycan | Slowly progressive, growth retardation |
Bethlem Myopathy
Bethlem myopathy is a slowly progressive limb-girdle muscular dystrophy transmitted by autosomal dominant inheritance. The causative mutation is on the collagen type VI gene located on chromosome 21 encoding the COL6A1 , COL6A2 , or COL6A3 genes.
Clinical features
The onset of contractures or weakness always occurs in the first 2 years. Diminished fetal movements and congenital hypotonia may be present. The usual initial features are congenital flexion contractures of the elbows, ankles, and interphalangeal joints of the last four fingers, but sparing the spine. The contractures are at first mild and unrecognized by parents. Mild proximal weakness and delayed motor development are common. Both the contractures and the weakness progress slowly and produce disability in middle life, but do not shorten the life span. Tendon reflexes are normal or depressed. Cardiomyopathy does not occur.
Diagnosis
Molecular genetic testing is available. The serum concentration of CK is normal or slightly elevated, EMG usually shows myopathy, and muscle biopsy shows a nonspecific myopathy.
Management
Physical therapy for contractures is the main treatment.
Dystrophinopathies: Duchenne and Becker Muscular Dystrophy
DMD and Becker muscular dystrophy (BMD) are variable phenotypic expressions of a gene defect at the Xp21 site. Several different phenotypes are associated with abnormalities at the Xp21 site ( Box 7.4 ). The abnormal gene product in both DMD and BMD is a reduced muscle content of the structural protein dystrophin. In DMD, the dystrophin content is 0%–5% of normal, and in BMD the dystrophin content is 5%–20% of normal. DMD has a worldwide distribution with a mean incidence of 1 per 3500 male births. The traditional phenotypic difference between the two dystrophies is that BMD has a later age of onset (after age 5 years), unassisted ambulation after age 15 years, and survival into adult life. However, a spectrum of intermediate phenotypes exists depending on dystrophin content. Survival into the 30s and beyond is not uncommon for DMD.
Box 7.4
Phenotypes Associated With the Xp21 Gene Site
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Becker muscular dystrophy
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Dilated cardiomyopathy without skeletal muscle weakness
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Duchenne muscular dystrophy
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Familial X-linked myalgia and cramps (see Chapter 8 )
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McLeod syndrome (elevated serum creatine kinase concentration, acanthocytosis, and absence of Kell antigen)
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Mental retardation and elevated serum creatine kinase
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Quadriceps myopathy
Among the spectrum of dystrophinopathy phenotypes are quadriceps myopathy and cramps on exercise . The characteristic features of quadriceps myopathy are slowly progressive weakness of the quadriceps muscle, calf enlargement, and an elevated serum concentration of CK.
Clinical features
The initial feature in most boys with DMD is a gait disturbance; onset is always before age 5 years and is often before age 3 years. Toe walking and frequent falling are typical complaints. Often one obtains a retrospective history of delayed achievement of motor milestones. Early symptoms are insidious and likely dismissed by both parents and physicians. Only when proximal weakness causes difficulty in rising from the floor with an obvious waddling gait is medical attention sought. At this stage, mild proximal weakness is present in the pelvic muscles and the Gower sign is present (see Fig. 7.1 ). The calf muscles are often large ( Fig. 7.3 ). The ankle tendon is tight, and the heels do not quite touch the floor. Tendon reflexes may still be present at the ankle and knee, but are difficult to obtain.
The decline in motor strength is linear throughout childhood. Motor function usually appears static between the ages of 3 and 6 years because of cerebral maturation. Most children maintain their ability to walk and climb stairs until 8 years of age. Between ages 3 and 8, the child shows progressive contractures of the ankle tendons and the iliotibial bands, increased lordosis, a more pronounced waddling gait, and increased toe walking. Gait is more precarious, and the child falls more often. Tendon reflexes at the knees and ankles are lost, and proximal weakness develops in the arms. Considerable variability of expression occurs even within the DMD phenotype. On average, functional ability declines rapidly after 8 years of age because of increasing muscle weakness and contractures. By 9 years of age, some children require a wheelchair, but most can remain ambulatory until age 12 and may continue to stand in braces until age 16.
The range of intelligence scores in boys with DMD shifts downward. While most of these boys function in the normal range, the percentage of those with learning disabilities and cognitive impairment is increased.
Scoliosis occurs in some boys and early use of a wheelchair is not the cause. Deterioration of vital capacity to less than 20% of normal leads to symptoms of nocturnal hypoventilation. The child awakens frequently and is afraid to sleep. The immediate cause of death is usually a combination of respiratory insufficiency and cardiomyopathy. In some patients with chronic hypoxia, intercurrent infection or aspiration causes respiratory arrest.
Diagnosis
Before 5 years of age, the serum concentration of CK is 10 times the upper limit of normal. The concentration then declines with age at an approximate rate of 20% per year.
Mutation analysis is the standard for diagnosis, carrier detection, and fetal diagnosis. Intragenic deletions occur in 60% of affected boys, and duplications in another 6%. The use of multiple polymerase chain reaction covering 18 exons at the deletion hotspots is able to detect 90%–98% of deletions. The use of multiplex ligation-dependent probe amplification has a higher sensitivity. Dystrophin analysis of muscle is useful to distinguish DMD from BMD. However, muscle biopsy is not essential when molecular diagnosis is positive.
Management
Although DMD is not curable, it is treatable. Prednisone 0.75 mg/kg/day increases strength and function. The mechanism of action is not clearly understood. Treatment goals are to maintain function, prevent contractures, and provide psychological support, not only for the child, but also for the family. The child must be kept standing and walking as long as possible. Passive stretching exercises prevent contractures, lightweight plastic ankle-foot orthoses maintain the foot in a neutral position during sleep, and long-leg braces maintain walking. Scoliosis is neither preventable nor reversible by external appliances; only surgery is effective to straighten the spine.
Facioscapulohumeral Dystrophy
Although the classification of progressive facioscapulohumeral (FSH) weakness is as a muscular dystrophy, patients with genetic FSH weakness may have histological evidence of myopathy, neuropathy, and inflammation. The FSH syndrome is associated with a deletion within a repeat motif named D4Z4 at chromosome 4q35. The size of the deletion correlates with the severity of disease. Considerable interfamily and intrafamily heterogeneity exists. A negative family history may result because affected family members are unaware that they have a problem.
Clinical features
Weakness usually begins in the second decade. Initial involvement is often in the shoulder girdle ( Fig. 7.4 ), with subsequent spread to the humeral muscles. The deltoid is never affected. Facial weakness is present but often overlooked until late in the course. The progression of weakness is insidious and delays the diagnosis. Late in the course, leg muscles may be involved. Anterior tibial weakness is most prominent, but proximal weakness may occur as well.
The course of FSH syndrome is variable. Many patients do not become disabled, and their life expectancy is normal. About 20% of patients eventually become wheelchair dependent. In the infantile form, progression is always rapid and disability is always severe (see Chapter 17 ). Deafness and retinal vascular abnormalities are part of the phenotype. The most severe manifestations are retinal telangiectasia, exudation, and detachment ( Coats disease ).
Diagnosis
Molecular genetic testing is the standard for diagnosis. The serum concentration of CK can be normal or increased to five times normal. The EMG may show denervation potentials, myopathic motor units, or both. Histological changes are minimal in many limb muscles and are never diagnostic. Occasional fibers are myopathic, some appear denervated, and inflammatory cells may be present.
Management
No treatment for the weakness is available. Low intensity aerobic exercise, management of chronic pain by physical therapy and medications, ventilatory support for hypoventilation, lubricants or eyelid taping for incomplete eye closure to decrease conjunctival dryness and keratitis, and ankle/foot orthotics to prevent falls, may be helpful. Retinal examination for Coats disease is required. Coagulation of retinal telangiectasia prevents blindness.
Proximal Myotonic Dystrophy
Myotonic dystrophy 2 (DM2) or proximal myotonic dystrophy is genetically distinct from the more common distal form (DM1). A CCTG repeat expansion is present at locus 3q21. Unlike DM1, a congenital form does not exist. Onset of symptoms is usually between the third and fourth decade of life, although myotonia may be present in childhood. Therefore discussion of the disorder is outside the spectrum of this book, except that molecular genetic testing is available for children at risk, and may provide an answer for the cases of early onset myotonia.
Severe Childhood Autosomal Recessive Muscular Dystrophy
A deficiency of any of the subunits of the sarcoglycan complex of proteins associated with dystrophin causes severe childhood autosomal recessive muscular dystrophy (SCARMD) (see Table 7.2 ). Sarcoglycan complex defects account for 11% of children with Duchenne phenotypes.
Clinical features
SCARMD affects both genders equally. The clinical features are identical to those described for the dystrophinopathies.
Diagnosis
SCARMD is a likely diagnosis in all girls with a Duchenne phenotype and in boys who appear to have DMD, but show normal dystrophin content in muscle. Immunohistochemical reagents applied to muscle sections show the absence or presence of the sarcoglycan components. Mutation analysis is available for diagnosis.
Management
Management is similar as for DMD including the use of steroids, which has been reported to be beneficial for some patients, although the mechanism of action remains unclear.
Inflammatory Myopathies
The inflammatory myopathies are a heterogeneous group of disorders whose causes are infectious, immune-mediated, or both. A progressive proximal myopathy occurs in adults, but not in children, with acquired immunodeficiency syndrome (AIDS). However, the concentration of serum CK is elevated in children with AIDS treated with zidovudine. The description of acute infectious myositis is in the section on acute generalized weakness. The conditions discussed in this section are immune-mediated.
Dermatomyositis
Dermatomyositis is a systemic angiopathy in which vascular occlusion and infarction account for all pathological changes observed in muscle, connective tissue, skin, gastrointestinal tract, and small nerves. More than 30% of adults with dermatomyositis have an underlying malignancy, but cancer is not a factor before the age of 16. The childhood form of dermatomyositis is a relatively homogeneous disease. The female to male ratio is about 2:1 with a reported incidence between 1.2 and 17 per 1,000,000 and prevalence between 5 and 11 per 100,000. An increase in both incidence and prevalence during the last century is likely due to awareness and better diagnostic tools.
Clinical features
Peak incidence is generally between the ages of 5 and 10 years, but onset may be as early as 4 months. The initial features may be insidious or fulminating. Characteristic of the insidious onset is fever, fatigue, and anorexia in the absence of rash or weakness. These symptoms may persist for weeks or months and suggest an underlying infection. Dermatitis precedes myositis in most children. An erythematous discoloration and edema of the upper eyelids that spread to involve the entire periorbital and malar regions is characteristic. Erythema and edema of the extensor surfaces overlying the joints of the knuckles, elbows, and knees develop later. With time, the skin appears atrophic and scaly. In chronic, long-standing dermatomyositis of childhood, the skin changes may be more disabling than the muscle weakness.
Proximal weakness, stiffness, and pain characterize the myopathy. Weakness generalizes, and flexion contractures develop rapidly and cause joint deformities. Tendon reflexes become increasingly difficult to obtain and finally disappear.
Calcinosis of subcutaneous tissue, especially under discolored areas of skin, occurs in 60% of children. When severe, it produces an armor-like appearance, termed calcinosis universalis , on radiographs. In some children, stiffness is the main initial feature, and skin and muscle symptoms are only minor. In the past, gastrointestinal tract infarction was a leading cause of death. The mortality rate is less than 5% with modern treatment.
Diagnosis
The combination of fever, rash, myalgia, and weakness is compelling evidence for the diagnosis of dermatomyositis. The serum concentration of CK is usually elevated early in the course. During the time of active myositis, the resting EMG shows increased insertional activity, fibrillations, and positive sharp waves; muscle contraction produces brief, small-amplitude polyphasic potentials. The diagnostic feature on muscle biopsy is perifascicular atrophy ( Fig. 7.5 ). Capillary necrosis usually starts at the periphery of the muscle fascicle and causes ischemia in the adjacent muscle fibers. The most profound atrophy occurs in fascicular borders that face large connective tissue septae.
Management
The inflammatory process is active for approximately 2 years. Corticosteroids may suppress the inflammatory response and provide symptomatic relief but do not cure the underlying disease. The best results are obtained when corticosteroids are started early in high doses and are maintained for long periods.
Initiate prednisone at 2 mg/kg/day, not to exceed 100 mg/day. The response follows a predictable pattern. Temperature returns to normal within 48 hours. The serum CK concentration returns to normal by the second week, and muscle strength increases simultaneously. When these events occur, reduce the prednisone dosage to alternate day therapy to reduce the frequency and severity of corticosteroid-induced side effects. Alternate-day or every-day therapy is equally effective if the doses are large and the treatment maintained. As muscle strength increases, taper the original dosage of alternate-day prednisone by 10% per month for 5 months. Further reductions are at a rate of 5% per month. For most children the alternate-day maintenance dosage needed for normal muscle strength and a normal serum CK concentration is 25% of the starting dosage. When the response is inadequate, add methotrexate. The response of the skin rash to prednisone is variable; in some children, the rash heals completely, but most will have some permanent scarring from the disease.
Although most children show a dramatic improvement and seem normal within 3 months, continue prednisone for a full 2 years. Relapse invariably follows premature discontinuation of treatment. Calcinosis and contractures are more likely to develop in children treated intermittently. Corticosteroids also are useful in the treatment of calcinosis universalis. In addition to prednisone, a well-structured program of physical therapy prevents contractures.
Eighty percent of children with dermatomyositis have a favorable outcome after initiating high-dose prednisone within 4 months of the onset of symptoms. Start oral methotrexate, 10–20 mg/m 2 , twice weekly to children who do not respond to high-dose prednisone. Regular monitoring of liver function and the white blood cell count is required. Other immunotherapies such as cyclosporine, tacrolimus, cyclophosphamide, and rituximab have been reported as alternative therapies for cases resistant to treatment.
Plasmapheresis or courses of intravenous immunoglobulin (2 g/kg per month for 3 months) are a valuable adjunct in children whose condition is refractory to corticosteroids. Once the disease becomes inactive, reactivation is unlikely. However, late progression or recurrence may occur and require treatment with an additional 1-year course of corticosteroids.
Polymyositis
Polymyositis without evidence of other target organ involvement is uncommon before puberty. Children with systemic lupus erythematosus may have myalgia and arthralgia as early symptoms, but rarely have muscle weakness at onset. Skin, joint, and systemic manifestations usually precede the onset of myopathy. Polymyositis in children is similar to the disorder in adult life except that malignancy is not a causative factor.
Clinical features
Polymyositis begins as a symmetric proximal weakness that develops insidiously and progresses to a moderate handicap within weeks to months. The patient may have prolonged periods of stability or even remission that suggest the diagnosis of LGMD because of the slow progress. Tendon reflexes are present early in the course, but are less active as muscle bulk is lost. Cardiorespiratory complications are less common in childhood than in adult polymyositis.
Diagnosis
The serum CK concentration is not always increased, but EMG usually shows both myopathic and neuropathic features. Muscle biopsy may show several different patterns of abnormality, and perivascular inflammation may not be present. Instead, one observes features of myopathy, denervation, or both.
Management
The same treatment schedule suggested for childhood dermatomyositis is useful for children with polymyositis. Unfortunately, the response to corticosteroids is far less predictable in polymyositis than in dermatomyositis. Treat those who fail to respond to corticosteroids with methotrexate. Plasmapheresis and intravenous immunoglobulins (IVIgs) are reasonable alternatives when other therapies fail.
Metabolic Myopathies
Acid Maltase Deficiency (Pompe Disease)
Acid maltase deficiency is an autosomal recessive deficiency of the lysosomal enzyme acid α-1, 4-glucosidase (acid maltase) characterized by skeletal and cardiac myopathy and sometimes encephalopathy. The initial features of acid maltase deficiency may occur in infancy, childhood, or adult life depending on the percentage of residual enzyme deficiency. The enzyme defect is the same regardless of the age of onset, and different ages of onset may occur within the same family. The speed of progression is variable, but the severity of cardiorespiratory involvement correlates with the amount of residual enzyme activity.
Clinical features
Infants with acid maltase deficiency have glycogen storage in both skeletal and cardiac muscles. Death occurs from cardiac failure during infancy (see Chapter 6 ). In the childhood form, only skeletal muscle is involved and the main clinical feature is slowly progressive proximal limb weakness. Tendon reflexes are hypoactive or unobtainable. Some children have mild hypertrophy of the calves simulating DMD. The weakness is steadily progressive and leads to disability and respiratory insufficiency by 20 years of age. Onset at a later age predicts a more benign course.
Diagnosis
Routine histochemical stains show accumulation of glycogen in lysosomal vacuoles and within the sarcoplasm. The diagnosis is confirmed with biochemical assay of enzyme (acid maltase) activity in muscle or in cultured skin fibroblasts. Complete deficiency is associated with classic infantile onset, whereas residual activity produces later-onset disease. Genetic testing is available.
Management
Recombinant human enzyme is approved by the United States FDA for replacement therapy, which can prolong survival. The most recent information indicates that α-glucosidase is safe and effective in treating infant onset Pompe disease and is more effective when given early. Begin enzyme replacement therapy with Myozyme (alglucosidase alfa) as soon as the diagnosis is established. Myozyme initiated before age 6 months and before the need for ventilatory assistance, improves ventilator-independent survival and acquisition of motor skills. Genetic counseling is needed for the families of affected children.
Other Carbohydrate Myopathies
Slowly progressive proximal weakness is sometimes the initial feature of McArdle disease and debrancher enzyme deficiency. Both disorders are considerations in the differential diagnosis. The initial symptom of these disorders is usually exercise intolerance and is discussed in Chapter 8 .
Carnitine Deficiency
Carnitine is an essential cofactor in the transfer of long-chain fatty acids across the inner mitochondrial membrane and modulates the ratio of acyl to acyl-coenzyme A. For this reason, carnitine is one of the supplements often given in cases of suspected mitochondrial disease. Its deficiency causes a failure in the production of energy for metabolism and the storage of triglycerides. It occurs as follows: (1) in newborns receiving total parenteral alimentation; (2) in several systemic disorders; (3) as the result of several genetic disorders of organic acid metabolism; (4) in children treated with valproate; (5) as primary genetic defects that cause deficiency of the cellular carnitine transporter; and (6) may occur if not supplemented while receiving ketogenic diet therapy. The myopathic and systemic forms are caused by different genetic loci.
Transmission of the primary genetic defect on chromosome 5q33.1 is by autosomal recessive inheritance. Primary carnitine deficiency is rare (1:40,000–1:140,000 newborns) except in the Faroe Islands (1:300). The clinical features include hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy, and arrhythmia.
Clinical features
The main clinical feature of muscle carnitine deficiency is the childhood onset of slowly progressive proximal weakness, affecting the legs before, and more severely, than the arms. Sudden exacerbations or fluctuations are superimposed. Occasionally patients have recurrent attacks of myoglobinuria and cardiomyopathy. The cardiomyopathy is usually asymptomatic, but is demonstrable on electrocardiography (ECG) and echocardiography.
Diagnosis
The serum concentration of CK is elevated. EMG findings are nonspecific. Muscle biopsy specimens show a vacuolar myopathy with lipid storage mainly in type I fibers. The biochemical measurement of carnitine, both free and total, establishes the diagnosis.
Management
Dietary therapy with l -carnitine is usually effective. Diarrhea and a fishy odor are the most common side effects. The usual dosage is 100 mg/kg/day in three or four divided doses.
Other Lipid Myopathies
Children with progressive proximal weakness associated with lipid storage in muscle and normal carnitine content usually have a disturbance of mitochondrial fatty acid oxidation. These disorders are genetically heterogeneous and difficult to distinguish from other mitochondrial myopathies.
Clinical features
Progressive proximal weakness begins any time from early childhood to adolescence. The legs are affected first and then the arms. Exercise intolerance is noted, and in some cases, the ingestion of fatty foods leads to nausea and vomiting. The pattern and progression of weakness may simulate those of DMD even to the presence of calf hypertrophy. Limb weakness is steadily progressive, and cardiomyopathy may develop.
Diagnosis
The serum concentration of CK is markedly elevated. EMG findings are abnormal and are consistent with a myopathic process. Muscle biopsy is critical to diagnosis. Type I muscle fibers contain fatty droplets. Carnitine and carnitine palmitoyl transferase concentrations are normal.
Management
Patients with fat intolerance may show improvement on a diet free of long-chain fatty acids.
Endocrine Myopathies
Progressive proximal limb weakness may occur in children with hyperthyroidism, hypothyroidism, hyperparathyroidism, hypoparathyroidism, hyperadrenalism, and hypoadrenalism.
Clinical features
Systemic features of endocrine disease usually predate the onset of weakness. However, weakness may be the initial feature in primary or secondary hypoparathyroidism and in thyroid disorders. Weakness is much more prominent in the legs than in the arms. Tendon reflexes, even in weak muscles, are normal or diminished, but generally are not absent.
Diagnosis
The serum concentration of CK is typically normal. EMG is not useful for diagnosis. Many endocrinopathies produce both neuropathy and myopathy. In Cushing disease and in hyperparathyroidism, muscle histological studies show type II fiber atrophy. Other endocrinopathies show nonspecific myopathic changes that vary with the severity of disease.
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