Nemaline Myopathy
This patient presented with progressive respiratory compromise beginning in his mid-40s, which was initially attributed to a combination of severe scoliosis and asthma. He subsequently developed generalized fatigue followed by mild weakness. A sister was found to have a similar condition. Several neurologic conditions can affect respiratory muscles either early or selectively. These include:
Myopathies: Acid maltase deficiency, amyloid myopathy, centronuclear myopathy, nemaline rod myopathy, cytoplasmic body myopathy, desmin myopathy, congenital diaphragmatic defects, inflammatory myopathy (especially anti-Jo-1 myositis), mitochondrial myopathy, and myotonic dystrophy.
Neuromuscular junction disorders: Myasthenia gravis and the myasthenic syndromes.
Neuropathies: Phrenic nerve lesions, bilateral brachial plexopathy, AIDP and CIDP.
Motor neuron disease: ALS
Spinal cord or lower brainstem syndromes: Arnold-Chiari malformation, cervical spondylotic myelopathy, foramen magnum abnormalities, congenital central hypoventilation syndrome.
Central hypoventilation may also be present in some patients with myotonic dystrophy, and loss of neurons in medullary nuclei has been documented in some of these patients.
This patient's examination revealed atrophy, decreased tone, predominantly proximal weakness, intact or slightly reduced reflexes and normal sensation. The lack of muscle fatigability, sparing of extraocular muscles, and absence of decrementing on repetitive nerve stimulation makes myasthenia gravis unlikely. Nerve conduction velocities were normal and there was no conduction block, arguing against a significant motor neuropathic process. Needle EMG revealed no spontaneous activity and only a mild increase in polyphasic motor units. There was no evidence on clinical examination or imaging to support a brainstem or spinal cord disorder. This clinical presentation is most consistent with an adult-onset myopathic disorder.
The patient's CK level was nearly normal, which would be unusual for inflammatory myopathies, acid maltase deficiency and dystrophinopathies. No irritative features that are frequently present in inflammatory myopathies or acid maltase deficiency were seen on needle EMG. The patient's muscle biopsy revealed findings characteristic of nemaline rod myopathy, but did not show evidence of a glycogen storage disorder. We subsequently found that his sister had also undergone a muscle biopsy in New York, which revealed similar features, suggesting that this patient's disease represented an inherited nemaline myopathy.
Nemaline (rod) myopathy was first described by Shy et al. as one of the nonprogressive congenital myopathies. Most congenital myopathies are characterized by the presence of a specific structural alteration in muscle fibers, such as nemaline myopathy or central core disease. The term nemaline was applied by Shy et al. because of the thread-like appearance of the rod bodies (Greek nema = thread). Nemaline myopathy is an uncommon muscle disease with a wide spectrum of phenotypes, including a congenital form with neonatal onset and fatal outcome, a congenital form with slowly progressive or nonprogressive weakness, and a sporadic adult-onset form.
The severe neonatal form presents at birth with severe hypotonia and muscle weakness, little spontaneous movement, poor sucking and swallowing ability, and respiratory insufficiency. Death due to respiratory insufficiency or recurrent pneumonia is common during the first weeks or months of life.
The mild congenital or "classic" form of nemaline myopathy usually presents at birth or during the first year of life with hypotonia, weakness, and feeding difficulties. However, the severity of muscle weakness is less marked than in the severe neonatal form. Some patients may present later with delay in attainment of motor milestones. Respiratory muscles are always involved. The course of the disease is often static or only very slowly progressive.
The late onset or adult onset form of nemaline myopathy is heterogeneous in terms of clinical presentation and disease progression. In patients with an adult onset form of nemaline myopathy, there is often no family history and no symptoms preceding the onset of proximal and distal weakness in the third to sixth decades. A form of sporadic adult-onset nemaline myopathy has been associated with HIV infection. In some patients, there is minimal skeletal muscle involvement and the patient presents with a cardiomyopathy or is detected during the investigation of other family members. Respiratory and cardiac involvement occurs in a minority of patients, and in these patients the disease often follows a clearly progressive course. It is notable that in several case reports and case series, respiratory insufficiency became evident at a time when limb muscle weakness was mild. This is different from the case in muscular dystrophies, in which respiratory failure typically parallels the progression of limb muscle weakness.
Gyure et al. recently reported a case of nemaline myopathy presenting in a 65-year old man. These authors reviewed 22 additional cases of adult-onset nemaline myopathy reported in the literature. The mean age of cases was 45 years. Most patients presented with slowly progressive proximal muscle weakness unresponsive to steroids. Respiratory failure was the most common cause of death in the patients. Creatine kinase levels were normal or mildly elevated. Electromyography is usually abnormal (but sometimes only mildly so), suggesting a myopathy, and occasionally exhibiting mild neurogenic features. Pathology showed muscle fiber atrophy and intracytoplasmic nemaline rods. The authors are quick to point out that the presence of nemaline rods alone is insufficient for a diagnosis of nemaline myopathy. These structures rarely may be seen in a number of other neuromuscular disorders, including mitochondrial myopathies, polymyositis, spinal progressive muscular atrophy, and acute alcoholic myopathy. An accurate diagnosis requires the presence of large numbers of nemaline rods in a symptomatic patient, as well as the absence of findings typically seen in other myopathies.
The pathologic features of nemaline myopathy are difficult to detect on routine H&E staining. Staining of cryostat sections by the modified Gomori trichrome technique is the best method for detecting the rods, which appear purple or red against the blue-green myofiber background. Rods show a tendency to cluster under the sarcolemma and around nuclei. The proportion of fibers containing rods varies from case to case and from muscle to muscle. There is often marked type 1 fiber predominance, but a disproportion in fiber size, with type 1 fibers being small and type 2 fibers being large or normal. Electron microscopy reveals accumulation of the rods with localized enlargement and streaming of the Z lines. The rods appear to arise from the Z disks. Also, like the Z disks, the rods are contiguous with thin filaments. Immunocytochemical techniques have shown that alpha-actinin, actin, and desmin are components of the nemaline rods.
Nemaline myopathy is genetically heterogeneous, with both autosomal dominant and autosomal recessive forms now identified. It remains to be determined whether adult-onset cases represent a uniform disease entity, and whether they are genetic in origin. To date, two genetic loci for nemaline myopathy have been identified. NEM1 at chromosome 1q22-23 has been linked to a childhood onset autosomal dominant form. Liang et al have recently identified alpha-tropomysin (TPM3) as the disease gene at this locus. They described a point mutation close to the N-terminal end of the protein. Alpha-tropomysin is a component of thin filaments of the sarcomere. Two muscle-specific isoforms form an alpha-helical dimer, bind head to tail, and lie in the major groove of filamentous actin with each tropomysin molecule binding to seven actin molecules. It is not yet known how the mutation in TPM3 results in rod formation or muscle weakness.
An autosomal recessive form of nemaline myopathy has been linked to the NEM2 locus at chromosome 2q22. Pelin et al have recently demonstrated mutations in the nebulin gene (NEB) associated with autosomal recessive nemaline myopathy. Nebulin is a large protein asociated with thin filaments, which contributes to the formation of the Z disk. The autosomal recessive form of the disease is heterogeneous and other loci for this disorder may yet be found.
The pathogenesis of nemaline myopathy is not well understood. The effect of nemaline rod bodies on loss of muscle force production is unclear. There is no correlation between the number of rods seen on muscle biopsy studies and the degree of clinical weakness. A neurogenic component has been suspected in some patients with this disorder, due to the findings of fiber type grouping and occasional evidence of denervation in some biopsies.
No curative therapy is currently available for nemaline myopathy. The effects of anabolic agents in this disorder are unknown. The main factors influencing prognosis seem to be the respiratory capacity and the development of scoliosis. Monitoring of respiratory capacity is an essential element in the care of these patients. The need for intermittent or permanent use of a mechanical ventilator should be evaluated at an early stage because of the risk of nocturnal hypoxia and sudden respiratory failure.
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