A 14-year-old Caucasian boy presented for the evaluation of muscle weakness. He was born full-term to a 27-year-old multipara. The pregnancy was complicated by spotting during the first trimester as well as an episode of abdominal pain accompanied by nausea and vomiting at four months of gestation. The mother recalls active fetal movement. Labor was uncomplicated and the child was delivered vaginally. Birth weight was 9 lb 9 oz. Although early motor milestones were not recalled well, the mother stated that the patient was walking by 14 months of age. Toe-walking was noted early on. Although he played several sports as a child, he did not have the same endurance as other children. By the age of 11, he could not run at all. He became ill at the age of 13 with vomiting, jaundice, and multiple organ failure. Evaluation revealed a dilated cardiomyopathy. This was presumed to be viral in etiology, and he subsequently received a cardiac transplant elsewhere. After the transplant, he was noted to have difficulty climbing stairs as well as arising from the floor without using his arms. He did complain of occasional myalgias in the lower extremities. He denied muscle stiffness.
His medical history was significant only for a history of mild intermittent asthma. He rarely used an inhaler. Medications included tacrolimus, mycophenolate mofetil, citalopram, and montelukast. The immunosuppressives were to prevent rejection of his recent transplant. Family history was notable for parkinsonism in his mother aged 41. There are two siblings, a brother and a sister who are both normal. A maternal uncle, aged 33, is also normal.
On examination the patient was alert and cooperative. Mental status exam was appropriate for age. Cranial nerves II–XII were intact with the exception of a mildly enlarged tongue. Motor examination was notable for markedly enlarged calves. No atrophy was noted. Manual motor testing showed proximal weakness. Neck flexion was 4+. Deltoids, biceps, and triceps were 4/5, while wrist extension and grip were 5/5. Hip abduction was 3/5 and hip flexion was 4/5. Knee flexion was 5/5, while knee extension was 4/5. Foot dorsiflexion was 4/5. Foot plantar flexion was 5/5. The patient arose from the floor with a modified Gower maneuver. Reflexes were 1+ throughout and toes were downgoing to plantar stimulation. Sensation was intact to light touch, vibration, and pinprick. No dysmetria on finger-to-nose or heel-to-shin was noted. His gait was waddling with moderate toe-walking.
Initial laboratory studies from his referring physician were notable for an elevated creatine kinase (CK) of 13,103 units/L (normal, <200 units/L).
What is the Differential Diagnosis for an Adolescent with Proximal Muscle Weakness and Cardiomyopathy?
The patient’s proximal muscle weakness with retained reflexes, normal sensory exam, elevated CK, and possible cardiac involvement point strongly toward a myopathy. Possibilities include the following:
Dystrophinopathies
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
Limb-girdle muscular dystrophy (LGMD)
X-linked Emery–Dreifuss dystrophy
Myotonic dystrophy type 2/proximal myotonic myopathy (PROMM)
Disorders of carbohydrate metabolism
Acid maltase deficiency/glycogenosis type II
Debrancher deficiency/glycogenosis type III
Branching enzyme deficiency/glycogenosis type IV
Carnitine deficiency
Mitochondrial myopathy
Inflammatory myopathies
Hypothyroid myopathy
DMD is an X-linked disorder caused by mutations in the enormous gene DMD on Xp21 which codes for the sarcolemmal protein dystrophin . Most cases of DMD are caused by large deletions or duplications within this gene. The disease is characterized by normal gross motor milestones until the age of 2–3 years when parents may note that the affected child does not run or jump. Calf hypertrophy is common. While periods of stabilization may be noted, the disease is relentlessly progressive: the ability to walk is lost around 10–13 years of age. Dilated cardiomyopathy is common and, given the availability of effective respiratory support, is now the most common cause of death. The posterobasal and lateral aspects of the left ventricle are predominantly affected. In contrast, the right ventricle is relatively preserved. Conduction abnormalities are uncommon until the cardiomyopathy is advanced.
BMD is also caused by mutations within the gene for dystrophin . While the mutations in DMD typically result in a nonfunctioning or absent protein, those in BMD result in a protein that is present in reduced amounts or reduced function. This partial loss of dystrophin correlates with a milder phenotype.
Symptoms of skeletal muscle weakness usually occur between 5 and 15 years of age and the ability to walk is maintained into adulthood. A range of disabilities exists, however, with some patients ambulating beyond the fifth decade. Death occurs from respiratory failure or cardiomyopathy. The pattern of cardiac involvement is similar to DMD. Cardiomyopathy may even be the presenting feature of BMD4. Some patients may only have cardiomyopathy with an elevated CK yet no muscle weakness. These patients can benefit tremendously from cardiac transplantation. Female carriers of DMD/BMD are also increasingly recognized as having dilated cardiomyopathy despite normal muscle strength or only mild weakness. CK levels in DMD/BMD are usually elevated >10 times the upper limit of normal, especially within the first 3 years of illness. Levels may then decline as atrophy dominates. Of note, the degree of CK elevation does not distinguish between the major dystrophinopathies.
LGMD is a clinically and genetically heterogeneous syndrome characterized by proximal weakness that has a variable age of onset and is often less severe than DMD, although some forms can mimic DMD/BMD. Calf hypertrophy is, as a whole, seen less commonly than in the dystrophinopathies. Both autosomal-dominant (AD) and autosomal-recessive (AR) patterns of inheritance have been described; however, the majority of cases are autosomal-recessive. Cardiomyopathy is a feature of some forms of LGMD, especially LGMD1B, 2I, and the sarcoglycanopathies (LGMD2C–F).
CK levels in the LGMDs vary from normal or mildly elevated to markedly abnormal as in the dystrophinopathies.
X-linked Emery – Dreifuss muscular dystrophy is a disorder due to mutation of the gene coding for the nuclear envelope protein emerin . An autosomal-dominant variant is also recognized and is listed under the LGMDs as LGMD1B. This may present with weakness in a limb-girdle or scapuloperoneal pattern. They also have early contractures at the elbow and ankle which are often more problematic than weakness. In addition, they are prone to cardiac conduction abnormalities and rarely dilated cardiomyopathy. The CK is often elevated, up to around 10 times the upper limit of normal, although levels decline with age.
Myotonic dystrophy type 2/PROMM is less common than myotonic dystrophy type 1. It is notable for proximal rather than distal weakness and less muscle atrophy. Other manifestations such as endocrinopathy, balding, and cataracts are present but probably less common than in myotonic dystrophy type 1. Cardiac conduction abnormalities and cardiomyopathy may occur but are often late features and are thought to be less prominent than in myotonic dystrophy 1. The CK is usually elevated but not often more than five times the upper limit of normal.
Disorders of carbohydrate metabolism, or glycogenoses often cause exercise intolerance, cramps, and myoglobinuria with or without affecting other organ systems such as the liver or heart. Some of these disorders, however, can cause fixed weakness. It should be noted that the cardiomyopathy associated with the glycogenoses is usually hypertrophic rather than a primary dilated cardiomyopathy. Acid maltase deficiency (glycogenosis type II) may present as a juvenile form with limb-girdle weakness and calf hypertrophy. A distinguishing feature of this disorder as well as some of the other glycogenoses is the presence of myotonia on electromyography (EMG). In contrast to the infantile form, cardiomyopathy is uncommon. Debrancher deficiency (glycogenosis type III) can also present in a juvenile age group with fixed weakness and cardiomyopathy; however, the weakness is usually distal rather than proximal. Also, additional features such as exercise intolerance or myoglobinuria can occur.
Brancher deficiency (glycogenosis type IV) may also present in childhood with myopathy and cardiomyopathy. CK levels in the glycogenosis are often elevated to variable degree.
Carnitine deficiency , whether primary or secondary to systemic illness, has been reported to cause a myopathy as well as a hypertrophic cardiomyopathy. In systemic primary carnitine deficiency, presentation usually occurs before the age of 10.
Associated features include hepatomegaly, encephalopathy, and hyperammonemia (Reye syndrome–like illness). Serum carnitine levels are low as are muscle carnitine levels in the systemic primary form. Carnitine deficiency causes moderate elevation of the CK.
Mitochondrial myopathies are characterized by proximal weakness and findings of ragged red fibers and/or COX-negative fibers on muscle biopsy. Several clinical syndromes exist, although genotype–phenotype correlations are poor. In addition to the proximal weakness the presence of sensorineural deafness, myoclonic epilepsy, heart block, ophthalmoplegia, or stroke-like episodes should raise the suspicion of a mitochondrial process. Plasma and CSF lactate may be elevated. The CK may be normal or moderately elevated in mitochondrial myopathy.
Inflammatory myopathies are uncommon in the pediatric group. Polymyositis is believed to be particularly rare. Among the inflammatory myopathies, dermatomyositis is probably the most frequent.
Hypothyroid myopathy may present with proximal weakness, myalgias, and muscle hypertrophy as well as cardiomyopathy in severe cases. Additional features suggesting the diagnosis include myoedema and constitutional symptoms. The CK level is often elevated.
Which of these Disorders is More Likely to Affect the Patient?
Although one cannot be certain just from the history that the cardiac disease is related to the patient’s muscle weakness, it is assumed that this is the case. While a number of the above conditions could account for our patient’s findings, the most likely diagnosis is BMD. The next most plausible diagnosis would be an LGMD with a BMD-like phenotype. X-linked Emery–Dreifuss is less likely since the patient had only mild contractures at the ankle after significant weakness developed. Additionally, presentation with a primary dilated cardiomyopathy would be unusual for X-linked Emery–Dreifuss. Myotonic dystrophy type 2/PROMM appears unlikely, as there was neither clinical myotonia nor any systemic manifestation of the disease. Although hypertrophic cardiomyopathy may progress to a dilated cardiomyopathy, the severity and early appearance of systolic failure in this patient make carnitine deficiency and the glycogenoses less likely. Also, with the exception of acid maltase deficiency, a myopathy of the severity seen in this case is uncommon in the disorders of carbohydrate metabolism.
A mitochondrial myopathy is a consideration, although this is less common than BMD or LGMD. Additionally, no mitochondrial “red flags” as discussed above were noted in our patient. The low incidence of inflammatory myopathies in this age group along with the absence of dermatologic abnormalities in this case makes dermatomyositis and systemic sclerosis/overlap syndrome unlikely. Hypothyroidism in males of this age group is uncommon, and no additional findings support this diagnosis.
What Diagnostic Testing would be Helpful in Establishing the Diagnosis?
Definitive diagnosis of DMD/BMD can often be accomplished noninvasively with the use of multiplex PCR or Southern blotting analysis of the DMD gene.
Approximately 30%–35% of cases will have false-negative results with this test. These patients have point mutations, small insertions/deletions, or splicing errors. Sequencing of the gene may be useful for these cases; this was not available at the time of the initial evaluation.
When genetic testing fails to identify a mutation, muscle biopsy is recommended. Immunostaining for dystrophin is then performed. Staining is nearly or completely absent in DMD, while it is often reduced or patchy in BMD. Unfortunately, immunostaining in BMD can occasionally be normal. Western blotting in these instances often shows a dystrophin molecule with an abnormal molecular weight, confirming the diagnosis. Muscle biopsy may also be diagnostic for the glycogenoses, mitochondrial myopathy, dermatomyositis, and certain forms of LGMD.
In the glycogenoses causing fixed weakness the muscle shows vacuoles containing periodic acid–Shiff positive material. Mitochondrial myopathies often have ragged red fibers and/or COX-negative fibers. In childhood dermatomyositis, perifascicular atrophy is the most specific histologic feature. Histochemical studies are routinely available for only a few LGMDs such as LGMD2A, 2B, and 2C–F.
EMG is unnecessary for diagnosing DMD/BMD except in the rare instances where one needs to rule out spinal muscular atrophy. EMG can be helpful, however, in finding subclinical myotonia in PROMM or the glycogenoses.
Additional laboratory testing such as TSH and carnitine levels could be done. Serum or CSF lactate/pyruvate is also prudent when a mitochondrial disorder is suspected. Serologic tests such as ANA, ENA, and other autoantibodies may be done if the suspicion for dermatomyositis/overlap syndrome is high.
Finally, genetic testing is available for a number of the other myopathies listed above including PROMM.
Results of Initial Diagnostic Testing
Genetic testing for DMD/BMD by multiplex PCR was negative. An EMG was not performed. The patient underwent biopsy of the deltoid muscle (see Fig. 83-1 ). On H&E and trichrome stains, there is fiber size variability with small round fibers. There were necrotic fibers and an increase in connective tissue. There was no inflammation seen. Notably, dystrophin staining by immunoperoxidase was entirely normal. Western blotting for dystrophin was not performed in this case. Staining for α-sarcoglycan was diminished in a patchy distribution. Staining for the remaining sarcoglycans was normal. Dysferlin staining (for LGMD2B) was also unremarkable.
What Is the Differential Diagnosis Now?
At this point, an LGMD is the most likely diagnosis. To date, 9 AD forms (LGMD1A–L) and 26 AR forms (LGMD2) have been described. This information is according to the classification of LGMD proposed by the European Neuromuscular Center of Classification in 2018, and this modifies the previous classification of 1995 which included disorders such as dystrophinopathies, and Pompe disease, for example (see Table 83-1 ). Gene products for most of these are known. While some LGMDs are due to mutations in structural proteins related to the dystrophin–glycoprotein complex, others alter nonstructural proteins and may have unique pathogenic mechanisms.
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