Clinical and pathological studies on nemaline myopathy in adulthood]

We examined 22 biopsied muscles from adult patients who had the histopathological characteristics of nemaline myopathy. In the first group, 13 patients had muscle weakness and/or skeletal abnormalities, such as high-arched palate, pes cavus and scoliosis which are often accompanied with the congenital nemaline myopathy. Their appropriate diagnosis had never been made until muscle biopsy was done, because of benign clinical course. In the second group, the symptoms of nine patients became manifest in adulthood and failed to show typical skeletal abnormalities. However, six muscle biopsies showed the histopathologic characteristics of congenital nemaline myopathy; abnormal fiber type distribution including type 1 fiber predominancy, type 1 fiber atrophy and type 2B fiber deficiency. Three patients remained in good health until adulthood when they developed muscle weakness with pathologic findings of nemaline myopathy. Accordingly, nemaline myopathy in adulthood can be categorized into three forms; the first two forms have clinical and pathologic evidence of the congenital benign form, whereas the symptoms are too mild to be noticed. The third form is not a hereditary disorder which may result from autoimmune pathophysiology.     

Nemaline myopathy: comparative muscle histochemistry in the severe neonatal, moderate congenital, and adult-onset forms

A histochemical study of biopsied muscle specimens from patients with the 3 forms of nemaline myopathy (i.e., severe neonatal, moderate congenital, and adult-onset), classified on the basis of clinical symptoms, was conducted. A close relationship could not be found between the number of rods and the severity of weakness in any form. Type 1 fiber atrophy and predominance or type 2B fiber deficiency was the usual finding in all forms. In the moderate congenital form, type 1 fiber atrophy and predominance became more apparent in patients with a protracted course, suggesting that the histochemical abnormalities are progressive. The abnormal fiber type distribution is assumed to be related to the pathogenetic mechanism of nemaline myopathy in all forms. Because acid phosphatase activity was increased in muscle fibers of patients with rapid progression, an autodegenerative process inducing lysosomal enzyme activation may be responsible for the acute clinical progression and muscle fiber loss in this disorder.     

Nemaline myopathy of cats

An apparently inherited myopathy, characterized by the presence of large numbers of nemaline rods in skeletal muscle fibers, was investigated in five cats. Onset of signs varied from 6 months to 1.5 years of age and consisted of reluctance to move, jerky gait and muscle twitching, hyporeflexia, and muscle wasting, which was most prominent in the proximal muscles of the forelimbs. All of the cats, three males and two females, were from the same dam. In addition to the presence of rods, the myopathy was characterized by marked fiber size variation, with atrophy of type 1 and type 2a muscle fibers. In addition, there was infolding of the sarcolemma and fiber splitting. Ultrastructurally, the rods closely resembled those described in human nemaline myopathy.     

Focal cytochrome c oxidase deficiency in various neuromuscular diseases

To determine whether focal cytochrome c oxidase (CCO) deficiency characterized by scattered fibers with absent CCO activity among normal fibers was a specific finding for mitochondrial myopathies, we studied 389 muscle biopsies from various neuromuscular diseases other than mitochondrial myopathies. Focal CCO deficiency was found in 14 biopsies: 5 of 26 patients with myotonic dystrophy, 3 of 19 with nemaline myopathy, 1 of 7 with distal myopathy with rimmed vacuole formation, 3 of 22 with limb-girdle muscular dystrophy, 1 of 9 with amyotrophic lateral sclerosis, one of 79 with Duchenne muscular dystrophy. Focal CCO deficiency is known to be a crucial finding for chronic progressive external ophthalmoplegia, but it can also be seen in a variety of other neuromuscular disorders, probably as a secondarily induced phenomenon.     

Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1)

Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.     

Unusual course of nemaline myopathy

A boy with onset features common for a moderate form of congenital nemaline myopathy, after some years developed scapulo-humeral syndrome. Extra- and intrafusal muscle fibers overloaded with rods and indicating focal degenerative changes were seen in the first biopsy. The biopsy was later repeated and revealed an improvement in muscle architecture with a dramatically decreased number of rods. This transformation suggests that rods, as well as Z-line streaming, might be a reversible anomaly of Z-discs.     

A case of congenital neuromuscular disease with uniform type I fibers, abnormal mitochondrial network and jagged Z-line

Histological, histochemical and ultrastructural studies of muscle biopsy in a case of congenital neuromuscular disease revealed unusual findings consisting of muscle fibers uniformity which were all type I and of small diameter, jagged Z-line and abnormally developed transverse network of mitochondria. E.M.G. examination demonstrated a myopathic pattern, but mitochondrial changes are quite different from those reported in mitochondrial myopathies and jagged Z-line seems poorly correlated with Z-line streaming present in denervation atrophy, target fibers, core-like lesions or other Z-line abnormalities of the nemaline myopathy. On the other hand type I histochemical uniformity seems more likely related to some dysfunction of the neuronal mechanisms that control both the fiber type differentiation and other trophic influences. It also suggests that myogenic E.M.G. pattern might actually be pseudo-myopathic and due to a reduction of the cross sectional area of the individual muscle fibers composing the motor unit.     

A case of adult-onset nemaline myopathy (adult-onset rod disease) with distal muscular hypertrophy]

We reported a 40-year-old male with adult-onset nemaline myopathy (adult-onset rod disease) showing muscular hypertrophy of distal limbs. At the age of 25, he noticed thinness of his thighs. Difficulty in climbing stairs slowly progressed from the age of 35. On admission neurological examination revealed muscular weakness and atrophy of proximal limbs and hypertrophy of distal flexors. Normal laboratory tests included serum creatine kinase, myoglobin, aldolase and pyruvate. Electromyography revealed severe neurogenic changes in the right biceps brachial muscle and the right quadriceps muscle, and moderate changes in the right gastrocnemius. Biopsy specimen of the deltoid muscle demonstrated type 1 fiber predominance and type 1 fiber atrophy, and there was small group atrophy and type grouping. Abundant nemaline rods were found mainly in type 1 fibers (81.5%). In order to evaluate hypertrophy of calf muscles, T1-weighted MRI of lower extremity was performed. While transaxial images through mid thigh showed moderate fatty replacement, increased volume and little fatty replacement were found in the mid calf. Therefore, hypertrophy of the calf muscle seemed to be compensative hypertrophy. But in this case neurogenic factors were indicated electromyographically and histologically. These findings may advocate the notion that neurogenic factors involved not only congenital but adult-onset rod disease.     

Muscle Phenotypic Variability in Limb Girdle Muscular Dystrophy 2 G

Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy.     

Nemaline myopathy: two autopsy reports

Nemaline myopathy belongs to the group of congenital non-progressive myopathies; however, in rare cases death occurs in early infancy. We report two cases of rapidly fatal nemaline myopathy. The first patient, who died at the age of 26 months, showed atrophy of type 1 fibers containing numerous rods in biopsy sections. Biopsy of the second patient, who had died at the age of 5 months, revealed severe maturational arrest and myopathy, but rods were so rare that diagnosis could only be made at the ultrastructural level. Autopsy of both patients showed that atrophy of type 1 fibers and maturational arrest had disappeared in the very same muscles; rods had moved to a central position in the first and significantly increased in number in the second case. Diaphragma muscles contained abundant amounts of rods in both cases. The cardiac musculature showed a few rods only in the first patient, who had developed heart insufficiency 11 months prior to death. Immunohistochemical analysis showed that rods did not contain desmin or ubiquitin.     

A case of severe infantile form of congenital nemaline myopathy with extensive fatty replacement of the skeletal muscles

A case of severe infantile form of congenital nemaline myopathy who developed extensive fatty replacement of the skeletal muscles was described. A girl was born with severe hypotonia and flaccidity of the extremities. She was put on a ventilator because of the severe respiratory insufficiency. Muscle biopsy performed at 3 months of age revealed numerous nemaline rods in myofibers. She had an anoxic episode at 2 years of age and fell into a vegetative state after that. Serum creatine kinase and aldolase levels were normal. At 8 years of age, X-ray CT scan of the skeletal muscles revealed diffuse and severe fatty replacement of the skeletal muscles of the trunk and extremities; this was far more extensive than in the case of Duchenne muscular dystrophy of similar age. Second muscle biopsy performed in the anterior tibialis muscle at the age of 8 years revealed atrophic muscle fibers and extensive proliferation of connective and fatty tissues. Electron microscopy revealed, numerous rod-containing muscles fibers with severe disorganization and loss of myofilaments. Sural nerve biopsy performed at the same time showed decreased number of large myelinated fibers. Although a possibility could not be excluded completely that the episode of anoxia and chronic debilitation may have contributed to these pathological neuromuscular findings, it was presumed that severe degeneration and fatty replacement of the skeletal muscles progress rapidly after birth in some cases of severe infantile form of congenital nemaline myopathy.     

Congenital neuromuscular disease with uniform type 1 fibers : a case report

A 3-year-old boy was seen because of delayed developmental milestones, waddling gait, nonprogressive proximal muscle weakness and hyporeflexia. Serum creatine kinase levels were normal and EMG was non-diagnostic. Muscle biopsy revealed complete absence of type 2 A and 2 B fibers in addition to a moderate variation in fiber size. Diagnostic findings for congenital nonprogressive myopathies were not present such as nemaline bodies, cores, targetoid structure, central nuclei or selective type 1 fiber atrophy. This was the first case of a distinct form of non-progressive congenital myopathy, "congenital neuromuscular disease (myopathy) with uniform type 1 fibers", accompanied with mental retardation in Japan.     

Respiratory muscle involvement in nemaline myopathy

A boy who had experienced generalized muscle weakness and hypotonia since early infancy was diagnosed as having nemaline myopathy on the basis of muscle biopsy at 3 years of age. At 8 years of age, he developed severe respiratory failure and required respiratory support during sleep. Because of recurrent pneumothorax, he underwent thoracic surgery, at which time biopsy specimens were obtained from the respiratory and truncal muscles. The histologic findings of the respiratory muscles included marked variation in fiber size with a notable increase in fibrous tissue, type 2 fiber deficiency, elevated acid phosphatase activity, and a disorganized intermyofibrillar network. The findings from the truncal muscles were similar to those of the biceps brachii muscle: little variation in fiber size, numerous nemaline bodies in all fibers, and type 1 fiber predominance. The preferential damage to the respiratory muscles was probably responsible for the sudden onset of severe respiratory failure.     

Two adult cases of nemaline myopathy presenting different clinical symptoms and CT findings]

We report herein two cases of nemaline myopathy which showed peculiar muscle involvement and clinical symptoms. Case 1: A 44-year-old woman had developed gradual woresening of muscle weakness. Neurologically, only flexion of her neck was found to be weak. Her muscular CT revealed mild atrophy of four extremities and the sternocleidomastoid muscles. Histological examinations with Gomori-trichrome staining revealed tiny structures whose form was compatible with nemaline rods. Moreover, electronmicroscopic examination demonstrated the lattice pattern of electron-dense structures, and they also appeared to possess structural continuity with the Z-band. Case 2: A 56-year-old woman visited our department because of neck pulsations. Neurological examinations revealed bilateral hearing disturbance, marked atrophy of neck muscles, muscle weakness in four extremities and hypoactive deep tendon reflexes. She also exhibited steppage and waddling gaits. Her muscular CT demonstrated degenerative processes in the neck muscles(splenius muscles and semispinal muscles), trapezius muscles, para-spinal muscles, deltoid muscles and gluteal muscles. Among them, the para-spinal muscles and extensor muscles of the lower limbs showed marked degeneration and had been partly replaced by fatty tissues. A muscle biopsy was performed, and the presence of nemaline rods was confirmed by Gomori-trichrome staining. Although these two cases could be diagnosed as nemaline myopathy, the clinical symptoms and muscular CT findings were not quite the same. Whether these differences might simply indicate different clinical phases during the disease progression or be of further pathogenic significance still remains unclear. Additionally, since long-term follow-up studies of nemaline myopathy are quite rare, further follow-up examinations of these cases are necessary in order to understand the clinical and pathological alterations of nemaline myopathy.     

A novel de novo ACTA1 variant in a patient with nemaline myopathy and mitochondrial Complex I deficiency

We describe the presentation and follow-up of a three-year-old girl with nemaline myopathy due to a de-novo variant in ACTA1 (encoding skeletal alpha actin) and moderately low enzyme level of Complex I of the mitochondrial respiratory chain. She presented in the neonatal period with hypotonia, followed by weakness in the facial, bulbar, respiratory and neck flexors muscles. A biopsy of her quadriceps muscle at the age of one year showed nemaline rods. Based on her clinical presentation of a congenital myopathy and histopathological features on a muscle biopsy, ACTA1 was sequenced, and this revealed a novel sequence variant, c.760 A>C p. (Asn254His). In addition, mitochondrial respiratory chain enzymatic activity of skeletal muscle biopsy showed a moderately low activity of complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase). Disturbances of Complex I of the respiratory chain have been reported in patients with nemaline myopathy, although the mechanism remains unclear.     

Alpha-actinin and myosin light chains in congenital nemaline myopathy

The muscle fibers of patients with congenital nemaline myopathy contain nemaline bodies, of which alpha-actinin is a major constituent. In some cases, deficiencies of fast myosin light chains have been reported. We performed 1-dimensional polyacrylamide sodium dodecyl sulfate gradient gel electrophoresis of muscle proteins from 13 patients with congenital nemaline myopathy and 10 controls to examine the alpha-actinin and the distribution of myosin light chains in congenital nemaline myopathy. At 95 kd (corresponding to alpha-actinin), 4 patients and all controls had 1 band, 2 patients did not have any bands, and 7 had bands that were clearly weaker than those of the controls. Because alpha-actinin is present in the nemaline bodies of congenital nemaline myopathy muscle, only the deficiency of this protein must be apparent. No apparent differences in fast myosin light-chain distribution could be documented between patients and controls; no correlation was observed between muscle fiber type and light-chain distribution. The results suggest that alpha-actinin is abnormal in congenital nemaline myopathy.     

Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency

Thirteen of 15 patients with complex I deficiency had the multisystemic form, with strokelike episodes and other symptoms that fulfilled the diagnostic requirements for MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), and 2 had only muscle fatigability and weakness, having the purely myopathic form. In the multisystemic form, 12 patients had ragged-red fibers. All multisystemic patients had myopathic histochemical abnormalities that consisted of mild to moderate variation in fiber size, disorganized intermyofibrillar networks, type 2 fiber atrophy, and an increased number of type 2C fibers. Five of 13 multisystemic patients had decreased cytochrome c oxidase (CCO) activity in extrafusal fibers, with sparing of intrafusal muscle fibers. In the myopathic form, pathological findings were similar to those in the multisystemic form. In addition to complex I and NADH dehydrogenase activities being decreased, the CCO activity was significantly decreased (less than 50% of control value) in 8 patients, especially when the disease was in its advanced stages, suggesting that CCO enzyme might be secondarily affected as the disease progresses.     

Clinical and pathological studies on two patients with adult-onset nemaline myopathy

Clinical and pathological findings of two patients, a 44-year-old male and a 54-year-old female, with adult-onset nemaline myopathy were described. Both patients showed normal motor development through their childhood; Patient 1 ran fast and was involved in powerful heavy labor until the age of 40, and Patient 2 was in good health until 49, when they began to have progressive muscle weakness. They had no family history of neuromuscular diseases. On neurological examination, they had moderate muscle weakness and atrophy in their limb-girdle and paravertebral muscles. Because paravertebral and neck muscles were preferentially involved, they had difficulty in holding the head straight up. They stood in a lordotic posture. They had neither high-arched palate nor facio-skeletal abnormalities which were common findings in congenital nemaline myopathy. Serum enzymes derived from muscle were normal and needle electromyography showed myogenic and neurogenic changes in both patients. On CT scan of the skeletal muscles, the paravertebral muscles were markedly decreased in density suggesting advanced fat tissue replacement in large areas. In patient 2 who was in more advanced stage, the quadriceps femoris, hamstrings and soleus muscles also showed the similar CT findings. Light microscopic examination of biopsied biceps brachii (Patient 1) and quadriceps femoris (Patient 2) demonstrated abundant rod-like structures in the majority of type 1 fibers. In both patients, there was a marked variation in fiber size. Type 1 fibers were atrophic and type 2C fibers increased in number.(ABSTRACT TRUNCATED AT 250 WORDS)     

The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders

To determine the incidence of selective type 1 fiber atrophy (hypotrophy) and its possible significance in various muscle diseases of childhood, we reviewed 2212 muscle biopsies from children which we had examined in the past 20 years histochemically with ATPase staining. Type 1 fiber atrophy was seen in a variety of neuromuscular disorders, but predominantly in congenital myopathies, including all patients with congenital fiber type disproportion myopathy (20 patients), central core disease (12 patients) and multicore disease (four patients). Although type 1 fiber atrophy was not a constant feature in nemaline myopathy and myotubular myopathy, all patients with these diseases had abnormal fiber type distribution which included type 1 fiber predominance both with and without type 2B fiber deficiency. Together with abnormal fiber type distribution, type 1 fiber atrophy was a common finding in childhood neuromuscular disorders, especially congenital myopathies.     

Histopathologic progression and a novel mutation in a child with nemaline myopathy

Nemaline myopathy is a clinically heterogeneous congenital myopathy caused by mutations in at least 6 genes related to thin filaments. Histologically, they show a characteristic if not homogeneous picture of nemaline rods, essential for the diagnosis. However, little is known regarding the development and progression of muscle histopathologic changes in nemaline myopathy. Results of muscle biopsies at 7 weeks of age and at 15 months of age from a child with nemaline myopathy due to a novel mutation in the ACTA1 gene are presented. The findings of the biopsies, separated by 13 months, demonstrate progression from vague cytoplasmic bodies in the first biopsy to typical nemaline rods in the second biopsy.