Mitochondrial abnormalities of late motor neuron degeneration following poliomyelitis and other neurogenic muscular atrophies

Summary A case of late motor neuron degeneration following poliomyelitis with abnormal mitochondria in muscle fibers is presented with two additional cases of systemic neurogenic muscular atrophy (Charcot-Marie-Tooth disease). Muscle biopsy revealed a neurogenic pattern of variable severity in all cases. Subsarcolemmal zones of hyperactivity and hyperpositive intermyofibrillar collections of granular material present in a variable proportion of type I fibers were demonstrated by oxidative enzymes. Ultrastructurally they corresponded to abnormal mitochondria, with paracrystalline inclusions in one case. The finding is discussed in the light of the previous literature on mitochondrial myopathies. Mitochondrial alterations are not specific and their significance in neurogenic conditions is debated.Presented at the 23. Jahrestagung der deutschen Gesellschaft für Neuropathologie und Neuroanatomie, Bonn, 23.–25. November 1978     

Oculopharyngeal muscular dystrophy: clinical and morphological follow-up study reveals mitochondrial alterations and unique nuclear inclusions in a severe autosomal recessive type

Oculopharyngeal muscular dystrophy (OPMD) is usually a late onset, autosomal dominant dystrophy that affects extraocular eye muscles, pharyngeal muscles, and the trunk and limb musculature. In the present presumably recessively inherited case, with a clinical history of oculopharyngeal myopathy and distal weakness, paracrystalline mitochondrial inclusions and unique nuclear inclusions were found. In a biopsy obtained from the erector spinae muscle, marked muscle fibre atrophy and hypertrophy, occasional muscle fibre necrosis, and considerable fibrosis of the endomysium were noted. Similar signs of a chronic myopathy could already be detected in a biopsy from the anterior tibial muscle that had been obtained 10 years before. In both muscles, nuclear inclusions were seen in numerous severely affected, atrophic muscle fibres. These inclusions consisted of straight or helically wound 2–4 nm filaments. The outer diameter of the double helix was 12–1 5 nm and the periodicity of its repeats was about 15 rim, The filaments were often accumulated in clusters with a paracrystalline arrangement. No nuclear inclusions consisting of 8.5 nm tubular filaments, typically found in cases of OPMD, were detected. In addition, paracrystalline inclusions were present in a large number of mitochondria in several muscle fibres of the erector spinae muscle indicating that mitochondria could be primarily involved in the disease.     

Pleomorphic mitochondrial and different filamentous inclusions in inflammatory myopathies associated with mtDNA deletions

Mitochondrial changes are frequently observed in muscle fibers of patients with inclusion body myositis (IBM) and polymyositis (PM), suggesting that mitochondrial function may be especially impaired in these forms of inflammatory myopathies. Intranuclear and cytoplasmic tubulofilamentous inclusions are characteristic, although not totally specific for IBM. In the present cases, the inclusions were strikingly pleomorphic when chloroquine had been given for long periods. The nuclear inclusions were always tubular, whereas the cytoplasmic filaments had either a tubular, a helical, or a cross-striated structure with different diameters and arrangements in association with myelin-like figures, and vacuoles. Abnormal mitochondria containing paracrystalline, globoid, and other inclusions, noted in IBM, were occasionally also seen in PM or vasculitis. By contrast, in the latter, no intranuclear or cytoplasmic tubulofilamentous inclusions were apparent in muscle fibers. This study reports for the first time the presence of membrane-bound crystalloid inclusions in a muscle fiber with numerous abnormal mitochondria; similar structures have thus far only been observed in macrophages. The identity and function of these inclusions remains unknown. Using PCR analysis we detected different mtDNA deletions not only in IBM, but also in PM and vasculitis, indicating at least some degree of association between the structural mitochondrial abnormalities and the mtDNA mutations. There was no topographical correlation between the presence of tubular or helical filaments and the mitochondrial abnormalities. As already noted by others, the mitochondrial changes in IBM were more frequent than expected in this age group. It is suggested that the presence of the mtDNA deletions in IBM and PM are not primary, but rather the result of the underlying, presumably immunological disorder causing nuclear and secondary or simultaneous mitochondrial changes. Received: 12 May 1997 / Revised, accepted: 17 February 1998     

Pathological Findings of the Sural Nerve in Mitochondrial Encephalomyopathy

Abstract: We examined the muscle and peripheral nerve of a 55–year-old woman with familial mitochondrial encephalomyopathy. In the gastrocnemius muscle, many ragged red fibers and mitochondria containing paracrystalline inclusions in those fibers were observed by light and electron microscopy, respectively. Histopathological studies of the sural nerve revealed a marked decrease in the number of large myelinated fibers. Electron microscopic studies showed an accumulation of glycogen particles and mitochondria containing abnormal, structurally obscure cristae in the Schwann cell cytoplasm. These results suggest that the cause of loss of the large myelinated fibers may be some disturbance of metabolism in the Schwann cells due to mitochondrial dysfunction.     

Pathological findings of the sural nerve in mitochondrial encephalomyopathy

We examined the muscle and peripheral nerve of a 55-year-old woman with familial mitochondrial encephalomyopathy. In the gastrocnemius muscle, many ragged red fibers and mitochondria containing paracrystalline inclusions in those fibers were observed by light and electron microscopy, respectively. Histopathological studies of the sural nerve revealed a marked decrease in the number of large myelinated fibers. Electron microscopic studies showed an accumulation of glycogen particles and mitochondria containing abnormal, structurally obscure cristae in the Schwann cell cytoplasm. These results suggest that the cause of loss of the large myelinated fibers may be some disturbance of metabolism in the Schwann cells due to mitochondrial dysfunction.     

Mitochondrial DNA deletions in inherited recurrent myoglobinuria

We describe two brothers with inherited recurrent exertional myoglobinuria and alcohol intolerance associated with distinct morphological abnormalities of muscle mitochondria and multiple deletions of muscle mitochondrial DNA. Patient 1 (26 years old) and Patient 2 (21 years old) had recurrent episodes of myoglobinuria provoked by strenuous exercise or alcohol intake, from the age of 18 years. Although their serum lactate and pyruvate levels were normal at rest, they were significantly elevated by aerobic exercise. Histochemistry of their biopsied limb muscles showed ragged-red fibers and cytochrome c oxidase-negative fibers as well as degenerating and regenerating fibers. Electron microscopy showed pronounced accumulation of abnormal mitochondria containing paracrystalline inclusions and moderate increases of glycogen particles. The enzyme activities of the electron-transfer complexes in the isolated muscle mitochondria of Patient 2 were within normal ranges. Southern blot analysis revealed multiple deletions of mitochondrial DNA, some of which were common between the patients. Polymerase chain reaction of their muscle mitochondrial DNA detected multiple abnormal fragments indicating mitochondrial DNA deletions. We propose that a defect of the mitochondrial energy-transducing system due to multiple mitochondrial DNA deletions is a novel genetic cause of inherited recurrent myoglobinuria.     

Mitochondrial encephalomyopathy. Report of a case

A typical case of mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes (MELAS) was reported. The main clinical manifestations consisted of short stature, psychomotor deterioration, sensorineural deafness, and hemiparesis. The laboratory findings disclosed abnormal lactic acid tolerance abnormal EEG, VEP, AEP, SEP, and MCV. The CT scan showed multiple intracerebral infarcts, basal ganglia calcifications, and cerebral atrophy. A muscle biopsy was performed. The frozen sections with modified gomori trichrome stain revealed ragged-red-fiber which reacted strongly positive in NADH-TR stain. The electron microscopy revealed subsarcolemmal aggregation of mitochondria of various sizes with paracrystalline inclusions, abnormally arranged cristae, and osmiophilic dense-bodies in their matrices.     

16例线粒体肌病和线粒体脑肌病电镜观察分析

目的探讨线粒体肌病与脑肌病患者肌肉的超微结构特征,分析该病的病因和可能的发病机制。方法对16例线粒体肌病与脑肌病患者的肌活检组织进行光镜和电镜超微病理观察。结果电镜观察16例,在肌原纤维间和肌膜下可见弥漫的线粒体数目增多,13例表现为形态异常,可见巨大线粒体,嵴结构不清,排列紊乱,呈同心圆样,均可见线粒体内类结晶状包涵体,有的同时伴有糖原颗粒的异常增多、脂滴沉积及溶酶体异常,有的线粒体只能靠双层膜结构及残存的嵴被识别。3例仅线粒体数量增多,未见其他异常。结论电镜观察肌膜下和肌原纤维间线粒体异常增多且形态异常,特别是线粒体内类结晶状包涵体,对本病的诊断有重要价值。     

Kearns-Sayre syndrome with a novel mitochondrial DNA deletion

We describe a 17-year-old boy with a clinical neurologic picture consistent with Kearns-Sayre syndrome. His manifestations included progressive external ophthalmoplegia, bilateral ptosis, retinitis pigmentosa, and muscle weakness. He was found to harbor an abundant novel deletion in skeletal muscle mitochondrial DNA. Biochemical analysis of the patient's biopsied skeletal muscle showed that the specific activities of all four respiratory complexes with mitochondrial DNA-encoded subunits were markedly reduced in contrast to normal activity levels of entirely nuclear DNA-encoded enzyme activities (eg, complex II and citrate synthase). Ultrastructural analysis also indicated the presence of strikingly abnormal mitochondria with both unusual cristae and frequent paracrystalline inclusions. The great amount of the deleted mitochondrial DNA in this patient's muscle, as well as the concomitant reduction in specific respiratory complex activity, suggests that the mitochondrial DNA deletion plays a role in the pathogenesis of this neurologic disease.     

The occurrence of paracrystalline mitochondrial inclusions in normal human skeletal muscle

Summary Two different types of paracrystalline mitochondrial inclusions identical with or very similar to those already described in the literature for a variety of muscle diseases were found in human skeletal muscle biopsies obtained under general anesthesia before ischemia and after various periods of anoxia up to 150 min. As these crystalloids could be observed in seven of 14 healthy subjects and occurred in five of these seven cases either before or only 10 min after onset of ischemia, it is suggested that such mitochondrial inclusions develop not only under the influence of variant noxious stimuli, but may also represent a normal constituent of human skeletal muscle mitochondria.