“Axial myopathy” is a nonspecific term for the primary disorders of skeletal muscle that cause isolated or predominant weakness of axial muscles. Patients with axial myopathy of paraspinal extensor muscles may develop contracture of the vertebral column (rigid spine syndrome) or an anterior curvature of the spine without contractures, including head ptosis (dropped head syndrome) and camptocormia (bent spine syndrome).1,2 Camptocormia is a rare but debilitating gait disorder characterized by hyperflexion of the thoracolumbar spine in the erect position, which increases during walking and abates in the supine position. Stooped posture can be corrected with passive extension of the spine.3 Back pain is not uncommon among these patients.4,5 Camptocormia was initially described as a psychiatric condition, but over the past few decades, several organic disorders have been linked to camptocormia.3,6
The 2 most common disorders associated with camptocormia are idiopathic Parkinson disease, especially in the advanced stage, and a broad range of neuromuscular disorders, including motor neuron diseases, peripheral nerve disorders, disorders of neuromuscular transmission, and myopathies.3 Camptocormia is now increasingly recognized as an atypical presentation of various well-characterized myopathies or muscular dystrophies that typically involves appendicular muscles.7–14 Isolated paraspinal extensor myopathy was reported in a number of patients with late-onset, non-parkinsonian camptocormia or head ptosis and was thought to be a unique, separate, and underrecognized subtype of axial myopathy by some authors.2,4,15 Genetic analysis was limited in these studies.
Calpainopathy refers to a clinically heterogenous, autosomal recessive muscular dystrophy due to the mutations of calpain-3 gene (CAPN3). Calpain-3 is a muscle-specific protease that is involved in sarcomere remodeling. An early-onset, symmetrical limb girdle weakness is the most common phenotype associated with calpainopathy (limb girdle muscular dystrophy type 2A or LGMD2A), but scapulohumeral or distal predominant weakness, exercise-induced myalgia, rigid spine syndrome, eosinophilic myositis, and asymptomatic hyperCKemia have also been reported.16–19 The age at onset of muscle weakness ranges from 2 to 40 years.20 Myopathological findings in an early stage of calpainopathy are indistinguishable from other muscular dystrophies, but the presence of lobulated fibers in an advanced stage serves as a diagnostic clue.21 Herein, we report a late-onset axial myopathy with lobulated fibers and non-parkinsonian camptocormia in a patient with a single CAPN3 mutation. Symptomatic carriers of calpainopathy have never been reported.20
A 70-year-old man presented with a 10-year history of low back pain. The patient described the back pain as a burning sensation and sometimes dull aching pain in the lumbosacral and occasionally in the buttock area but not in the distal leg muscles. The pain was present only with standing and intensified with further ambulation. He did not have pain while sitting or lying. The patient learned to lean forward while walking to alleviate the pain. He often found himself walking with stooped posture. The degree of the spine flexion increased proportionally to the distance he walked. The patient denied weakness, cramps, numbness, bulbar symptoms, fatigue, urinary incontinence, or changes of bowel movement. His medical history included cancer of urinary bladder treated surgically 10 years ago, atrial fibrillation, and dyslipidemia. His father also developed progressive stooped posture while walking since age 60. The cause for this problem was never elucidated.
Neurological examination was only remarkable for a mild weakness of neck flexors and a moderate weakness of iliopsoas, gluteus medius, and gluteus maximus muscles. Left side was weaker than right side. Weakness was nonfatigable. The patient was able to sit upright and lie in bed without pain or abnormal spine curvature. He stood up with a mild forward flexion of the spine and low back pain (Fig. 1A). Both vertebral flexion and pain increased proportionally to the walking distance. Passive extension of the spine corrected the stooped posture (Fig. 1B). There was no contracture of the vertebral column or other joints. Serum creatine kinase (CK) was 160 U/L (normal value, 52–336 U/L). Nerve conduction study was normal. Needle examination revealed mildly small motor unit potentials in proximal upper and lower limb muscles and thoracic paraspinal muscles without fibrillation potentials. Magnetic resonance imaging of thoracic and lumbosacral spine showed a moderate to severe atrophy and fatty replacement of paraspinal (Fig. 1C) and iliopsoas muscles; left was more affected than right. Diffuse epidural lipomatosis was observed in the thoracic region. There was no significant narrowing of neural foramen or cord compression. Magnetic resonance imaging of the lower extremities revealed a mild to moderate atrophy and fatty infiltration of glutei and anterior thigh muscles (Fig. 1E). The adductor and semimembranosus muscles were relatively spared (Fig. 1G).
The biopsy of mid-thoracic paraspinal muscles showed predominantly fibrous and fatty connective tissue reflecting end-stage muscle (Fig. 1D). Biopsy of gluteus maximus (Fig. 1F) and gluteus medius muscles revealed a mild variation in fiber size and a moderate increase of perimysial fibrous and fatty connective tissue. Extremely rare fibers contained cytoplasmic bodies. Necrotic or regenerating fibers were absent. Inflammatory changes were not observed. In NADH dehydrogenase–reacted section, nearly 75% of muscle fibers displayed a lobulated appearance of the enzyme activity. The atrophic fibers were of either histochemical fiber type. Type 1 fibers were more abundant than type 2 fibers, and rare atrophic fibers overreacted for nonspecific esterase. There were no congophilic deposits. Calpain-3 and dysferlin were immunolocalized with monoclonal antibody as previously described22,23 and revealed normal sarcoplasmic immunoreactivity. Sequencing of calpain-3 gene (CAPN3) identified a known heterozygous c.759-761delGAA (p.DelLys254) in exon 5.24,25 The reported similar symptoms in the patient's father raise the possibility of his camptocormia being hereditary in origin. Recently, autosomal dominant camptocormia was shown to be allelic to facioscapulohumeral dystrophy10,11; however, analysis of the D4Z4 repeat units in the current patient demonstrated no contraction. The genetic studies of other limb girdle muscular dystrophy-related genes were deferred because patient does not have limb girdle weakness.
The patient returned a year after the initial visit. His axial myopathy, camptocormia, and mild proximal limb weakness remained stable. The camptocormia is relieved while wearing a backpack.26
The current patient presented with classical symptoms and signs of camptocormia. The absence of parkinsonian features and the electrophysiological evidence of myopathic changes in the axial and proximal limb muscles indicate a primary skeletal muscle disorder. Biopsy of the glutei muscles depicted lobulated fibers in addition to nonspecific myopathic changes. The lobulated fibers are characterized by a lobular pattern of misaligned myofibrils best visualized on oxidative enzyme-reacted sections. They are almost always atrophic and more common in type 1 fibers. Lobulated fibers are considered as the pathological hallmark of calpainopathy especially in the advanced stage of the disease,21 but they are also less commonly present in neurogenic disorders and other muscular dystrophies (eg, collagen-6 related muscular dystrophies, dystrophinopathy, sarcoglycanopathy, dysferlinopathy, and facioscapulohumeral dystrophy).27,28
Calpainopathy or LGMD2A is one of the most common LGMD worldwide.25,29,30 Its phenotypic variability, low sensitivity of protein analysis in muscle biopsies, and the absence of mutational hot spots in the CAPN3 make the diagnosis of calpainopathy challenging. Despite its autosomal recessive inheritance, nearly one-fourth of patients were found to carry only one mutation.16 Such findings are commonly attributed to incomplete mutation screening; the second unidentified mutation may lie in the promoter or deep intronic region or is a result of chromosomal rearrangement. This conflict creates the challenge in differentiating patients in whom only a single mutation was identified from the carriers of calpainopathy. The carriers are generally asymptomatic and have normal CK level, whereas patients with a single identified mutation have muscle weakness, elevated CK level, decreased protein expression, and/or impaired autolytic activity of calpain 3.30,31 Calpain 3-2C4 antibody used in the current study was shown to be equally sensitive and more specific compared with the immunoblot study.22 In our patient, the normal CK level and unremarkable calpain 3 expression favor the carrier status of calpainopathy, whereas the abundance of lobulated fibers is indistinguishable from calpainopathy patients in their advanced stage of disease. The late-onset myopathic camptocormia in the current patient may or may not be related to the carrier status of calpainopathy. The presence of a single heterozygous c.759-761delGAA mutation in our patient could be just a coincidental finding because of the high frequency of the calpainopathy carrier in the general population, but it certainly raises and favors the possibility of axial myopathy and camptocormia being the manifestations of this single mutation, given the similar symptoms in his father. The clinical evaluation and CAPN3 sequencing of the patient's father could shed the light on this issue, but his medical record and DNA sample were not available.
Interestingly, Vissing et al32 recently reported the autosomal dominant variant of calpainopathy in 4 unrelated families. In comparison with the classical autosomal recessive calpainopathy, these patients developed a milder degree of weakness with asymmetrical involvement of pelvic girdle muscles and hyperCKemia at the later age of onset. The question remains whether a late-onset axial myopathy and camptocormia in this patient represent the manifesting carrier or the autosomal dominant variant of calpainopathy or is in fact a result of other unidentified muscle disorders. The future study of calpain-3 expression and CAPN3 sequencing in camptocormia patients due to axial myopathy may help deciphering this perplexing finding. Calpainopathy should be considered in patients with axial myopathy, particularly in those with a positive family history or lobulated fibers on muscle biopsy.
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