|Year : 2007 | Volume
| Issue : 3 | Page : 175-177
Nemaline myopathy: A report of four cases
AN Deepti1, N Gayathri1, M Veerendra Kumar2, Susarla K Shankar1
1 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Nemaline myopathies are a group of genetically determined (autosomal dominant/recessive) congenital myopathies characterized by the formation of nemaline rods within muscle fibers. Congenital, childhood, and adult forms with hypotonia, proximal muscle and facial weakness, and skeletal deformities have been described. The diagnostic hallmark is the presence of nemaline rods on modified Gomori's trichrome staining. We report the clinical and morphological features of four patients with nemaline rod myopathy: congenital classic (2), childhood (1), and adult (1), and speculate on the disease's evolution.
Keywords: Nemaline rods, myopathy, Z disc
|How to cite this article:|
Deepti A N, Gayathri N, Veerendra Kumar M, Shankar SK. Nemaline myopathy: A report of four cases. Ann Indian Acad Neurol 2007;10:175-7
| Introduction|| |
Congenital myopathies (CM) are a heterogeneous group of disorders that are frequently hereditary, manifesting at birth or in early infancy as floppy infants. These diseases are generally nonprogressive or slowly evolving, phenomenologically involving the structural proteins of the muscle and thus, leading to floppiness. Among this group of disorders, nemaline rod myopathy (NM) represents a genetically determined (autosomal dominant/recessive) congenital myopathy characterized by the formation of thread-like ( nema being Greek for 'thread') or rod-like protein aggregates within the muscle that stain dark red with modified trichrome stain. These patients have weakness, hypotonia, elongated facies, and skeletal deformities and, at times, may be associated with cardiomyopathy in view of the close structural resemblance of cardiac muscle to striated skeletal muscle. The disease manifests at different ages, depending on the penetrance of the genetic mutations. Clinically, neonatal, childhood, and adult forms are distinguished on the basis of the age of onset and the clinical features. The neonatal form is the most severe, while childhood and adult forms have slower progression. Ultrastructurally, the nemaline rods resemble the dense Z lines of skeletal muscle and are closely associated with Z disc material.  The causative genetic mutations in at least five genes, µ-actinin, µ-tropomyosin 3, b-tropomyosin, nebulin, actin, and troponin, have been identified. ,, Among these the µ-actinin and µ-tropomyosin mutations have been localized to the long arm of chromosome 1(1q21-23 and 1q 24.1); both these mutations manifest as autosomal dominant forms with low penetrance, while the mutation in nebulin is localized to 2q21.2-q22 and is an autosomal recessive form that presents at a very young age with severe manifestations (the congenital form). We report four cases of NM, one presenting in childhood and three in adults, and speculate on the pathogenesis of the disease. There is only one other such report from North India,  reflecting the relative rarity of this congenital myopathy.
| Case Reports|| |
The clinical features are summarized in [Table - 1].
A 2 ½-year-old boy presented with wasting of the limbs from 6 months of age. Following his birth, the immediate postnatal period had been uneventful, with no discernable floppiness, respiratory distress, or difficulty in swallowing. He had had difficulty in getting up from a sitting position and there was a history of frequent falls. Bilateral distal symmetric hypotonia and neck flexor weakness was noted. There was mild elevation of serum creatine phosphokinase (CPK). Echocardiography was normal.
A 25-year-old man presented with difficulty in climbing stairs and getting up from a squatting position since childhood; the disability was nonprogressive in nature. On clinical examination, he had mild neck flexor and facial weakness, a high arched palate, and a pes cavus deformity; there were no cardiac symptoms.
A 26-year-old lady presented with slowly progressive proximal and distal muscle weakness of both upper and lower limbs since the age of 12 years. She had no hypotonia of the limbs or of the neck muscles; no ocular, facial, or bulbar weakness; and there were no contractures or cardiac symptoms. Serum was nonreactive for human immunodeficiency virus (HIV) 1 and 2.
A 42-year-old lady presented with a history of insidious onset of progressive weakness of the flexors and extensors of the upper and lower limbs for the past 5 years. She had neck flexor weakness and bilateral flexion contractures of the ankles and knees. She did not have any endocrinopathies and serum for HIV 1and 2 was nonreactive
In all the patients the quadriceps muscle was biopsied. Flash-frozen and formalin-fixed muscle biopsy was processed for histological evaluation. Routine hematoxylin and eosin (HE)-stained cryosection showed normal polygonal fibers with peripherally placed nuclei and subsarcolemmal aggregation of eosinophilic material. Modified Gomori's trichrome (MGT) stain and toluidine blue-stained resin sections revealed subsarcolemmal linear rods forming palisading clusters [Figure - 1]a and b in a variable proportions of fibers (5-100%). These nemaline rods occupied a major portion of the cross-sectional area of the muscle in some, and the center of the fiber in a few, fibers. The rods were not stained by succinic dehydrogenase (SDH), nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), adenosine triphosphatase (ATPase) pH 4.6 and 9.4, and periodic Schiff's (PAS). Type 1 predominance was noted in patients 2 and 4. The muscle spindle noted in patient 1 (the 2 1/2-year-old child) did not reveal rods in the intrafusal fibers. Ultrastructurally (studied under JEOL 100CX TEM at 60 KV), the rods were of varying size and peripherally placed among the myofibrils. They were square to rectangular, with the density of the Z band, and had no specific orientation to the sarcomere or other organelles [Figure - 1]c. Thin filaments were attached to the rods [Figure - 1]d. The other intracellular organelles were normal. No intranuclear rods were observed in any of our four patients. The histological and ultrastructural features are characteristic of NM. Genetic analysis was not performed in our cases.
| Discussion|| |
Nemaline myopathies are reported to be the most frequently occurring of the congenital myopathies.  However, at the neuropathology department of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, South India, among the 100 cases of congenital myopathies diagnosed over a period of 20 years (with a total of 6 241 muscle biopsies examined), only 4 cases of NM were recorded (0.064% of the 6241 muscle biopsies) in contrast to a report from North India, which identified 4 NM cases (26.6%) out of 15 CM cases (0.53% of the 750 muscle biopsies performed over a 18-month period).  This high prevalence of NM among the CM described from North India could be fortuitous. The spectrum of CM diagnosed at NIMHANS during 20 years following systematic study were centronuclear myopathy (CNM) ( n = 39), myotubular myopathy (5), congenital fiber type disproportion (CFTD) ( n = 35), central core disease ( n = 9), multicore disease ( n = 7), and one case of congenital myopathy with tubular aggregates. Ryan et al.  classified the NM as congenital, childhood, and adult forms, on the basis of age of onset and clinical features. The congenital type is subclassified into severe, intermediate, and classic/typical categories. Patients 1 and 2 who had onset of disease in infancy and childhood, respectively fit into the category of congenital classic NM, while patient 3 can be classified as the childhood form and patient 4 as the adult form. The cases reported from North India are of the congenital form. More coordinated, multicentric recording of these cases would give a realistic estimate of the prevalence. Rod formation within myofibers is the hallmark of NM.  There is poor correlation between the number of rods and the age of onset or the severity of the disease.  In the present series, patients who had a longer duration of symptoms (cases 2 and 3) showed more number of rods, reflecting the dynamic nature of their formation. Similar rods have been seen after tenotomy and in thyroid myopathy, schizophrenia, and HIV myositis, suggesting a generalized phenomenon affecting the assembly of filamentous proteins.
In the structural organization of the sarcomere in the skeletal muscle the I (isotropic)-band is made up of the thin filaments actin, tropinin, and tropomysin and the A band (anisotropic) is constituted of thick filaments that are anchored to the Z disc by the elastic filaments nebulin and titin, interacting with telethonin. Genetic mutations involving actin, tropmyosin, troponin, and nebulin will probably result in defective anchoring to the Z disc and fragmentation and streaming of Z material to form protein aggregates and rod-like structures. The presence of Z band-like material in the rods could be a degenerative epiphenomenon associated with abnormal µ-actinin. The cardiomyopathy associated with NM could be related to involvement of the Z band-like 'intercalated disc' and the anchoring proteins in cardiac muscle. Although none of these cytoskeletal elements have any role in the nucleus, the nemaline rod formation that occurs infrequently in the nucleus could be related to altered transcription and translation of mRNA and the immature assembly of the filamentous protein involved in the formation of the nemaline rods inside the nucleus. Proteomic studies of the nemaline rods and the affected skeletal muscle, and in situ hybridization-PCR evaluation for the altered expression of these cytoskeletal filamentous proteins, would be better than just genetic analysis in providing insights into the pathobiology of this genetic disorder. Though the views expressed are speculative, they do provide useful leads for future studies.
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[Figure - 1]
[Table - 1]
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