Muscular dystrophies are inheritable disorders of voluntary muscle or skeletal muscle that predominantly affect young children and adolescents, and range in severity from mild to fatal. Like many neurogenetic disorders, the muscular dystrophies have overlapping symptoms and signs that often make them difficult to diagnose clinically. Presentations can vary and inheritance patterns can be difficult to predict for all affected families. The diagnosis of the muscular dystrophies is often even more difficult for the sporadic cases than for the familial cases.

The following table compares four common forms of muscular dystrophy: Duchenne (DMD), Becker (BMD), Fascioscapulohumeral dystrophy (FSHD), and Myotonic Dystrophy.

	DMD	BMD	FSHD	Myotonic Dystrophy
Inheritance	X-linked recessive2, sporadic	X-linked recessive2, sproadic	Autosomal dominant3, sporadic	Autosomal dominant1, sporadic
Affected Gene And its Abnormal Protein	Mutation of the dystrophin gene2 Dystrophin: <3% of normal8	Mutation of the dystrophin gene2 Dystrophin: Severe, 3-10% of normal8 Mild, 20% of normal8	Deletion of the EcoRI fragment*4 Unknown	CTG trinucleotide repeat in the DMPK gene1 Abnormally expressed myotonin-protein kinase1
Incidence	1/3,500 male births10	1/18,450 male births10	1/20,000 births6	1/20,000 births1
Typical Onset	Childhood8	Variable, childhood through adulthood2	Variable, childhood through adolescence3	Variable, birth through adulthood1
Common Clinical Course	A more severe8 form of muscular dystrophy	A more mild/moderate8 form of muscular dystrophy	A more mild/moderate3 form of muscular dystrophy	A more mild/severe1 form of muscular dystrophy
Typical Rate of Progression	Rapid, usually wheelchair-bound by age 122	Slower than DMD; severe cases may be wheelchair-bound by age 168	Slow to very slow; wheelchair usually necessary in 15-20% of cases4,6	Variable, slow and rarely requires need of a wheelchair in noncongenital cases1
Major Clinical Features	Severe muscle weakness; mental retardation8; cardiomyopathy2	Mild muscle weakness; cardiomyopathy2	Asymmetric weakness; muscle atrophy of face, shoulder girdle, upper arms; hearing loss; retinal vasculopathy7	Generalized weakness; muscle atrophy of face, neck, hands, and/or distal legs; myotonia; cataracts; frontal balding; cardiac abnormalities1
Creatine Kinase (CK) Levels	Markedly elevated2	Markedly elevated2	Usually modest elevation in 75% of affected individuals3	Normal or mildly elevated1
Mortality	Usually late teens to early 20s8	Usually beyond age 308	Usually normal lifespan3	Variable1, usually normal lifespan
* The deletion associated with FSHD does not disturb any known transcribed gene, but it is hypothesized that the deletion interferes with the expression of neighboring genes.6

Reaching a More Definitive Diagnosis

DNA deletion/duplication tests using blood can identify 60-70% of patients with DMD/BMD.² To diagnose the DMD/BMD patients with negative DNA deletion/duplication studies, the phenotype can be differentiated by evaluating the quality and quantity of dystrophin protein obtained from muscle biopsy.²

Due to sporadic mutations and variation of phenotype expression, a family history is not always sufficient to reach a definitive diagnosis of a muscular dystrophy.⁴ When evaluating individuals with neuromuscular disorders where the diagnosis is not clear, genetic tests can now confirm certain clinical diagnoses to allow appropriate medical management, including genetic counseling for these patients and their at-risk or other affected family members.

The following case studies provide compelling examples of the utility of genetic testing in muscular dystrophies.

• Muscle Tells All
• Dystrophy in Disguise
• Misdiagnosis of Duchenne Muscular Dystrophy
• The Face of Myotonic Dystrophy

A five-year-old boy who began to show signs of progressive muscle weakness in his legs (exhibited by increasing difficulty in climbing stairs and standing up after sitting on the floor) was referred by his pediatrician to a neurologist for a neuromuscular evaluation. The neurologist and the boy’s parents decided to have a DMD/BMD genetic test performed to determine if the child had Duchenne/Becker muscular dystrophy. No deletion or duplication was detected. However, since only about 65% of cases of Duchenne/Becker muscular dystrophy are due to a deletion/duplication of the dystrophin gene, the disorder could not be ruled out by the blood test for the genetic mutation in this patient.

Muscle tissue was then obtained for a Dystrophin test. The test did detect a very low amount of dystrophin and a diagnosis of Duchenne muscular dystrophy was made. The child and his family were referred to a neuromuscular clinic for further medical management and genetic counseling.

Several family members who were at-risk for carrying the abnormal dystrophin gene were interested in testing. However, because the disorder was caused by a mutation in the dystrophin gene other than by a deletion/duplication, they were referred to genetic counseling for linkage analysis. Blood was obtained from the necessary family members and a linkage analysis was performed. Results of the analysis were used to determine who in the family carried the mutated gene and who did not, allowing them to make family planning decisions. (back to list)

A ten-year-old boy was referred to a pediatric neurology clinic for evaluation of an elevated CPK (3,000 units/L), found incidenttally following laboratory tests for recurrent complaints of abdominal pain. The patient denied any muscle weakness and had no problem keeping up with other children while playing. He was quite athletic, participating in basketball, baseball, and swimming. Upon questioning, however, he admitted to muscle aches involving his calves and thighs and also to easy fatigability when engaging in athletic activities.

His physical examination was remarkable for mild calf hypertrophy and mild weakness in the proximal muscles of both upper and lower extremities. Strength was normal distally. A muscle biopsy showed modest variation in fiber size, but no significant muscle fiber degenerative or regenerative changes. Dystrophin testing of a muscle biopsy specimen showed reduced levels of dystrophin protein with a slightly reduced molecular weight, which is a pattern typical of Becker muscular dystrophy. Thus, a confirmed diagnosis of mild/moderate Becker muscular dystrophy was made. Subsequent DNA analysis of the dystrophin locus by PCR showed a deletion of exons 48-51. Using this deletion as a molecular marker, the diagnosis of Becker muscular dystrophy was made in a mildly symptomatic brother; also, the carrier status was established in several at-risk female family members. The diagnosis of BMD was excluded in an asymptomatic first male cousin of the proband. Many other male and female members of this family are currently being tested with DNA analysis. (back to list)

PW presented to a neurologist at the age of 16 years with the diagnosis of Duchenne muscular dystrophy, which was made earlier at three years of age. Thirteen years earlier, he had presented with a waddling gait, raised muscle enzymes, a dystrophin-deficient muscle biopsy, and an abnormal EMG purportedly confirming the diagnosis. His present complaint was muscle cramps in the lower limbs during exercise, which were relieved by rest. He stated that he felt that he had gradually become stronger over the years, had stopped toe walking, and had an improved gait. The family history was negative for any musculoskeletal disorders. On examination, the general physical examination was normal and on neurological examination there was only very mild proximal muscle weakness. The creatine kinase (CK) level was more than 20 times the upper limits of normal. A muscle biopsy from the quadriceps showed an increase in the variation of muscle fiber diameter with internalization of the nuclei. There were many large round fibers as well as round atrophic fibers and muscle fiber splitting, whorled fibers, and fibers undergoing phagocytosis with occasional basophilic fibers. Histochemistry was normal. However, analysis of dystrophin in the muscle by immunofluorescence, using both amino- and carboxy- terminus antibodies, revealed a variable and faint pattern around all muscle fibers. A follow-up Western blot detected a band at about 427 kD. DNA analysis by multiplex PCR detected a deletion spanning exons 13-48.

Conclusion: This is a case of mild Becker muscular dystrophy presenting in early childhood with a large central deletion in the dystrophin gene. The earlier failure to detect any dystrophin protein on muscle biopsy represents an example of a case where Becker muscular dystrophy was misdiagnosed as Duchenne muscular dystrophy in a patient presenting at an early age. Using a combination of Western blotting with amino- and carboxy-terminus antibodies or immunofluorescence, with DNA deletion/duplication testing provides a highly accurate and prognostically informative diagnosis. (back to list)

A 39-year-old male was evaluated by a neurologist for muscular dystrophy of unknown etiology. The patient reportedly had mildly progressive muscle weakness beginning at age 25. A physical exam showed mild myotonia with marginal muscle weakness. Facial features were unremarkable for myotonic dystrophy. CK levels were moderately elevated and EMG results showed myotonia. A myotonic dystrophy DNA test was performed to confirm a suspected case of myotonic dystrophy. The PCR test showed only a single band corresponding to 5 CTG trinucleotide repeats, while the Bam H1 Southern blot assay showed a band in the optimal range, accounting for the normal gene, and a band of 171 CTG trinucleotide repeats in the affected range. The patient was diagnosed with myotonic dystrophy based on the test results and clinical findings. He and his family were counseled on the genetic implications of the diagnosis. Several family members were found to be at-risk for having the disorder and they also decided to be tested. (back to list)

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