Pediatric Annals

The Diagnosis of Muscular Dystrophy

Ashraf A El-Bohy, MD, PhD; Brenda L Wong, MBBS, MRCP

Abstract

Although the precise diagnosis of muscular dystrophy (MD) in a child typically is made in a neuromuscular specialty clinic, it is the pediatrician in the primary care setting who is likely to see a child for initial evaluation for MD. This article provides an updated review of the classification, clinical features, and laboratory workup of MD that can assist pediatricians in recognizing and screening children suspected to have MD.

DEFINITION OF MUSCULAR DYSTROPHY

Muscular dystrophy is a heterogeneous group of inherited muscle disorders characterized by clinical (progressive muscle weakness), pathological (muscle necrosis, fibrosis, fatty replacement), and molecular genetic criteria (defective muscle proteins).1 Duchenne MD is the most common form of childhood MD and was first described clinically in 1852.2 It was not until the 1950s that the availability of histochemistry and electron microscopy for the investigation of muscle biopsies resulted in the classification of the muscular dystrophies by Walton and Nattrass.3

DIAGNOSTICWORKUP FOR MUSCULAR DYSTROPHY

Blood Chemistry

Measuring serum creatine kinase (CK) is a rapid means of screening children suspected to have MD.15 The CK level is a more sensitive and muscle-specific index of MD than aldolases, lactate dehydrogenase (LDH) isoenzymes, and transaminase tests.

It is important to check CK when an incidental unexplained increase in liver enzymes is found on routine testing. Serum levels of CK are very significantly elevated (in the thousands) in Duchenne and Becker MD patients, even in pre-symptomatic patients, including neonates.

Nerve Conduction Studies and Electromyography

Nerve conduction studies and electromyography are not performed routinely to confirm MD, as muscle biopsies or blood mutational analysis are the definitive procedures. However, patients with congenital MD may have associated neuropathies that require electrophys?ological evaluation.

Imaging

Recently, magnetic resonance imaging (MRI) has been found to demonstrate the distribution of muscle pathology in the various muscular dystrophies.16"21 MRI of muscle can be a supplementary tool for assessing the severity or extent of the dystrophic process. MRI also can aid in the selection of the appropriate muscle for biopsy.

Muscle Biopsy

With the recent advances in mutational analysis on blood, muscle biopsy is no longer the definitive means of confirming Duchenne MD. However, for the other forms of childhood MD, a muscle biopsy is essential for establishing a definitive diagnosis.

Routine histological and histochemical studies provide information regarding the pathological changes seen in MD (Figures 3 and 4, see page 529). Newer techniques of immunocytochemistry (Figures 5 and 6, see page 529) and immunoblotting with monoclonal antibodies to specific proteins also are performed to make a specific diagnosis based on the protein defect.

Molecular Genetics

The availability of molecular biology techniques has enabled the specific diagnosis of subtypes of MD to be made based on detecting specific gene mutations (Table). Such precise diagnoses enable accurate prognostication and reliable genetic counseling for families.

Complications

MD may involve associated cardiac, pulmonary, and brain changes. These should be screened with electrocardiogram, 24-hour Holter monitoring, echocardiogram, pulmonary function tests, and brain MRI.

SUMMARY

Pediatricians should be familiar with the common presenting signs and symptoms of MD so that they can make a clinical diagnosis of possible MD based on the patient's medical history, a physical examination, and a CK screen. Appropriate referral to a neuromuscular specialist will then enable the precise diagnosis of MD to be made with definitive histologie, biochemical, and genetic testing.

1. DubowitzV. Muscle Disorders in Childhood. 2nd ed. London, England: Saunders; 1995.

2. Meryon E. On granular and fatty degeneration of the voluntary muscles. Med Chir Trans. 1852;35: 73-84.

3. Walton JN, Nattrass FI. On the classification, natural history and treatment of the myopathies. Brain. 1954;77(2):12-231

4. Huffman EP, Brown…

Although the precise diagnosis of muscular dystrophy (MD) in a child typically is made in a neuromuscular specialty clinic, it is the pediatrician in the primary care setting who is likely to see a child for initial evaluation for MD. This article provides an updated review of the classification, clinical features, and laboratory workup of MD that can assist pediatricians in recognizing and screening children suspected to have MD.

DEFINITION OF MUSCULAR DYSTROPHY

Muscular dystrophy is a heterogeneous group of inherited muscle disorders characterized by clinical (progressive muscle weakness), pathological (muscle necrosis, fibrosis, fatty replacement), and molecular genetic criteria (defective muscle proteins).1 Duchenne MD is the most common form of childhood MD and was first described clinically in 1852.2 It was not until the 1950s that the availability of histochemistry and electron microscopy for the investigation of muscle biopsies resulted in the classification of the muscular dystrophies by Walton and Nattrass.3

The use of molecular genetic techniques following the discovery of the dystrophin gene for Duchenne MD4 resulted in a revolution for the muscular dystrophies, with the identification of increasing numbers of gene loci and associated protein defects. Hence, muscular dystrophies are now defined not only on clinical grounds but also in terms of their gene mutations and the abnormality in the protein product5'9 (Table).

Broadened Concept of MD

Traditionally, muscular dystrophies were characterized by progressive muscle wasting and weakness, as exemplified by Duchenne MD. It is now evident that the clinical spectrum of muscular dystrophies is broader and more heterogeneous than this typical progressive clinical course. For example, patients with Becker MD, with mutations of the dystrophin gene, can present with only muscle cramps on severe exercise or with isolated cardiomyopathy, without any skeletal muscle weakness.10

Similar gene mutations can present with different clinical phenotypes. For example, mutations of the enzyme Fukutin-related protein are associated with phenotypes ranging from severe congenital MD to mild forms of limb-girdle MD in late adulthood.11'12 Hence, it has been suggested that the nomenclature and classification of muscular dystrophies be changed to one based on the protein defect (eg, dystrophinopathies, sarcoglycanopathies, merosinopathies, dystroglycanopathies). Until the time when the basic questions of nomenclature and classification of muscular dystrophies are resolved, the classification of the categories of muscular dystrophies will continue to be based on clinical phenotype, pathology, and inheritance.

Table

TABLE.Common Genetically Recognized Forms of Muscular Dystrophy

TABLE.

Common Genetically Recognized Forms of Muscular Dystrophy

PRESENTING SYMPTOMS

The clinical evaluation of a patient with suspected MD is the first step in the diagnostic workup leading to a definitive diagnosis. A detailed antenatal and birth history may help early detection of congenital MD, which may be manifested during the perinatal period by decreased fetal movements, malpresentation, contractures, or respiratory or feeding difficulties. In the neonatal period, congenital MD should be considered in babies with hypotonia or joint contractures, including arthrogryposis multiplex congenita.13

The younger toddler presents with delayed walking, and older children may present with gross motor delays. Patients with Duchenne MD and some of the congenital muscular dystrophies with brain involvement also may present to the pediatrician with language or global developmental delays.14

Motor and gait difficulties are common presenting complaints. Parents or caregivers usually describe the child as "walking funny," swinging the upper extremities more, clumsy, walking like a duck, swaying from side to side, or with a waddling gait The child is unable to run, does a fast walk instead, and has difficulty going up steps, arising from the floor, or stepping up onto a sidewalk. Persistent toe walking after the child had started walking independently may be another presenting complaint There also is a tendency to fall frequently, especially in young boys with Duchenne MD.

Some atypical presentations of MD include muscle cramps and myalgias, with severe exercise and congestive cardiac failure associated with a dilated cardiomyopathy. These may be the clinical symptoms of Becker MD even without the presence of any skeletal muscle weakness. Elevated serum transaminases found incidentally often have resulted in liver biopsies for patients with Duchenne MD. When unexplained high serum transaminase levels are noted, serum creatine phosphokinase should be measured to ensure that the elevated transaminases are not of muscle origin and to avoid unnecessary liver biopsies.

Figure 1. Gowers' maneuver, as described by Gowers in 1879 and illustrated in his book The child with proximal muscle weakness will use his arms for support on the floor to push his pelvis up, then place his hands on his knees to gradually ascend his thighs to reach a standing position.

Figure 1. Gowers' maneuver, as described by Gowers in 1879 and illustrated in his book The child with proximal muscle weakness will use his arms for support on the floor to push his pelvis up, then place his hands on his knees to gradually ascend his thighs to reach a standing position.

Physical Signs

The clinical signs of MD should be evaluated carefully in a patient with suspected muscular disease. Examination of muscle bulk may reveal muscle atrophy or hypertrophy. Pseudohypertrophy, especially in calf muscles, is a feature in patients with dystrophin, sarcoglycan, or Fukutin-related protein mutations. On the other hand, prominent muscle atrophy and wasting are seen in congenital MD and limb-girdle MD with calpainopathy.

Weakness is a cardinal feature of most muscular dystrophies. As a general rule, weakness of proximal muscles is seen in muscular diseases in contrast to involvement of distal muscles in neuropathies. The exceptions include the distal muscular dystrophies seen in adult patients. Proximal pelvic girdle weakness can be evaluated by having the patient arise from the sitting position on the floor. A normal child can get up from a sitting position on the floor in less than 1 second; a child with Duchenne or limb girdle MD will take more than 2 seconds (Figure 1). To rise from the floor, the patient normally uses a Gowers' maneuver - using his arms for support on the floor to push his pelvis up, then placing his hands on his knees to gradually ascend the thighs ("climbing up himself) to get to the standing position. A boy with Duchenne MD with proximal muscle weakness is not able to jump or hop and has difficulty flexing his neck against gravity and moving to a sitting position when lying supine.

The distribution of predominant muscle weakness, whether mainly proximal or distal and whether facial muscles are affected, was used in the original classification scheme of muscular dystrophies by Walton and Nattrass (Figure 2). The progression of muscle weakness helps in differentiating between subtypes of MD; that is, Bucherine is highly progressive, whereas Becker and limb-girdle MD phenotypes tend to be slowly progressive. Many of the congenital MD cases are static or nonprogressive.

Figure 2. Distribution of predominant muscle weakness indifferenttypesofdystrophy:(a)Duchenne/Becker type; (b) Emery-Dreifuss; (c) limb girdle; (d) fascioscapuloh limerai; (e) distal; and (f) oculopharyngeal. (From: BMJ. 1998;317:991-995. Reproduced with permission.)

Figure 2. Distribution of predominant muscle weakness indifferenttypesofdystrophy:(a)Duchenne/Becker type; (b) Emery-Dreifuss; (c) limb girdle; (d) fascioscapuloh limerai; (e) distal; and (f) oculopharyngeal. (From: BMJ. 1998;317:991-995. Reproduced with permission.)

Gait examination yields the valuable sign of a waddling gait due to weakness of the gluteal muscles, leading to difficulty in supporting weight on one leg while raising the other leg off the ground. A very mild waddling gait on walking can be accentuated with an increased pace of walking or running. This can be missed easily if the patient is examined in the limited confines of the examination room, rather than walking along a hallway.

Other neurological findings include decreased or absent deep tendon reflexes and hypotonia. In Duchenne MD, deep tendon reflexes often are absent in the upper extremities and knees even in the early stages, while ankle reflexes are preserved up to the terminal stages. Hypotonia is a prominent finding in infants with congenital MD. Contractures and skeletal deformities can be seen at presentation or occur at late stages of the disease process. Heel cord tightness can lead to ankle contractures and toe walking.

Other common contractures involve the hip flexors, knee flexors, elbows and forearm pronators. Lumbar lordosis resulting from weakness of hip extensors produces a forward pelvic tilt. Spinal scoliosis is a prominent feature of MD that progresses rapidly with pubertal growth spurts and after the loss of independent ambulation with consequent full time wheel chair use. Ocular abnormalities are seen in patients with Fukuyama congenital MD, muscle-eye-brain disease, and Walker-Warburg syndrome, described in detail elsewhere in this issue (Mercuri et al., see page 560).

Figure 3. Cross-section of normal muscle (hematoxylin and eosin [H&E] stain) showing thin, delicate, endomysial connective tissue, uniform fiber size, and peripherally placed nuclei. (Courtesy Dr. Lili Miles)

Figure 3. Cross-section of normal muscle (hematoxylin and eosin [H&E] stain) showing thin, delicate, endomysial connective tissue, uniform fiber size, and peripherally placed nuclei. (Courtesy Dr. Lili Miles)

Figure 4. Cross-section of dystrophic muscle (H & E stain) showing dystrophic features, marked endomysial and perimysial f?brosis, and increased variability of fiber size due to the presence of atrophied and hyperatrophied fibers. (Courtesy Dr. Lili Miles)

Figure 4. Cross-section of dystrophic muscle (H & E stain) showing dystrophic features, marked endomysial and perimysial f?brosis, and increased variability of fiber size due to the presence of atrophied and hyperatrophied fibers. (Courtesy Dr. Lili Miles)

Figure 5. lmmunocytochemical staining using an antibody to dystroph in. Normal muscle shows locilization to sarcolemma. (Courtesy Dr. LJIi Miles)

Figure 5. lmmunocytochemical staining using an antibody to dystroph in. Normal muscle shows locilization to sarcolemma. (Courtesy Dr. LJIi Miles)

Figure 6. lmmunocytochemical staining in a dystrophic muscle. The fibers of this muscle fail to stain with antibodies to the dystrophin molecule. (Courtesy Dr. Lili Miles)

Figure 6. lmmunocytochemical staining in a dystrophic muscle. The fibers of this muscle fail to stain with antibodies to the dystrophin molecule. (Courtesy Dr. Lili Miles)

DIAGNOSTICWORKUP FOR MUSCULAR DYSTROPHY

Blood Chemistry

Measuring serum creatine kinase (CK) is a rapid means of screening children suspected to have MD.15 The CK level is a more sensitive and muscle-specific index of MD than aldolases, lactate dehydrogenase (LDH) isoenzymes, and transaminase tests.

It is important to check CK when an incidental unexplained increase in liver enzymes is found on routine testing. Serum levels of CK are very significantly elevated (in the thousands) in Duchenne and Becker MD patients, even in pre-symptomatic patients, including neonates.

Nerve Conduction Studies and Electromyography

Nerve conduction studies and electromyography are not performed routinely to confirm MD, as muscle biopsies or blood mutational analysis are the definitive procedures. However, patients with congenital MD may have associated neuropathies that require electrophys?ological evaluation.

Imaging

Recently, magnetic resonance imaging (MRI) has been found to demonstrate the distribution of muscle pathology in the various muscular dystrophies.16"21 MRI of muscle can be a supplementary tool for assessing the severity or extent of the dystrophic process. MRI also can aid in the selection of the appropriate muscle for biopsy.

Muscle Biopsy

With the recent advances in mutational analysis on blood, muscle biopsy is no longer the definitive means of confirming Duchenne MD. However, for the other forms of childhood MD, a muscle biopsy is essential for establishing a definitive diagnosis.

Routine histological and histochemical studies provide information regarding the pathological changes seen in MD (Figures 3 and 4, see page 529). Newer techniques of immunocytochemistry (Figures 5 and 6, see page 529) and immunoblotting with monoclonal antibodies to specific proteins also are performed to make a specific diagnosis based on the protein defect.

Molecular Genetics

The availability of molecular biology techniques has enabled the specific diagnosis of subtypes of MD to be made based on detecting specific gene mutations (Table). Such precise diagnoses enable accurate prognostication and reliable genetic counseling for families.

Complications

MD may involve associated cardiac, pulmonary, and brain changes. These should be screened with electrocardiogram, 24-hour Holter monitoring, echocardiogram, pulmonary function tests, and brain MRI.

SUMMARY

Pediatricians should be familiar with the common presenting signs and symptoms of MD so that they can make a clinical diagnosis of possible MD based on the patient's medical history, a physical examination, and a CK screen. Appropriate referral to a neuromuscular specialist will then enable the precise diagnosis of MD to be made with definitive histologie, biochemical, and genetic testing.

REFERENCES

1. DubowitzV. Muscle Disorders in Childhood. 2nd ed. London, England: Saunders; 1995.

2. Meryon E. On granular and fatty degeneration of the voluntary muscles. Med Chir Trans. 1852;35: 73-84.

3. Walton JN, Nattrass FI. On the classification, natural history and treatment of the myopathies. Brain. 1954;77(2):12-231

4. Huffman EP, Brown RH, Kunkel LM. Dystro[hin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919-928.

5. Bushby KMD, Beckmann JS. The limbgirdle muscular dystrophies - proposal for a new nomenclature. Neuromusc Disord. 1995;5(4): 337-343.

6. Tsao C, Mendell JR. The childhood muscular dystrophies: making order out of chaos. Semin Neural. 1999;19(l):9-23.

7. Emery AE. Muscular dystrophy into the new millennium. Neuromuscul Disord. 2002; 12(4): 343-349.

8. Kirschner J, Bonnemann C. The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries. Arch Neural. 2004;61(2):189-199.

9. Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. Neuromuscul Disord. 2005;15(3):207-217.

10. Cox GF, Kunkel LM Dystrophies and heart disease. CurrOpin Cardiol 1997; 12(3): 329-343.

11. Zatz M, Vainzof M, Passos-Bueno MR. Limbgirdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes. Curr Opin Neuml. 2000;13(5):51 1-517.

12. Mercuri E, Brockington M, Sträub V, et al. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neuml. 2003;53(4):537-542.

13. Philpot J, Counsell S, Bydder G, et al. Neonatal arthrogryposis and absent limb muscles: a muscle developmental gene defect? Neuromuscul Disord. 2001; 1 1(5):489-493.

14. Essex C, Roper H. Lesson of the week: late diagnosis of Duchenne's muscular dystrophy presenting as global developmental delay. BMJ. 200 1;323(7303): 37-38.

15. Swaiman KF, Sandier B. The use of serum creatine phosphokìnase and other serum enzyemes in the diagnosis of progressive muscular dystrophy. JPediatr. 1963 Dec;63: 1 1 16-1 1 19.

16. Semnic R, Vucurevic G, Kozic D, et al. Emery-Dreiffus muscular dystrophy: MR imaging and spectroscopy in the brain and skeletal muscle. A JNR Am J Neuroradiol. 2004;25(2). 1840-1842.

17. Garg A, Gulati S, GuptaV, Kalra V. Congenital muscular dystrophy with characteristic radiological findings similar to those with Fukuyama congenital muscular dystrophy. Neural India. 2004;52(4):496498.

18. Mercuri E, Bushby K, Rìcci E, et al. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromuscul Disord. 2005; 15(2): 164- 171.

19. Fischer D, Walter MC, Kesper K, et al. Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs. J Neural. 2005;252(5):5 38-547.

20. Leite CC, Lucato LT, Martin MG, et al. Merosin-deficient congenital muscular dystrophy (CMD): a study of 25 Brazilian patients using MRI. Pedialr Radial. 2005;35(6):57 2-579.

21. Mercuri E, Lampe A, Allsop J, et al. Muscle MRI in Ullrìch congenital muscular dystrophy and Bethlem myopathy. Neuromuscul Disord. 2005;15(4):303-310.

TABLE.

Common Genetically Recognized Forms of Muscular Dystrophy

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