A case of sensory perineuritis with Bowen disease]

A 60-year-old man was admitted because of subacutely progressive sensory disturbance characterized by fluctuating dysesthesia and light pain on the skin of his hands and feet. He exhibited mononeuritis multiplex, and a plaque with sloughing was observed on the left side of his back. Sural nerve biopsy revealed marked thickening of the perineurium with vascularization, and no necrotizing vasculitis. The pathological features of the nerve biopsy were compatible with sensory perineuritis. A biopsy from his skin lesion revealed Bowen's disease. There have been several reported cases of sensory perineuritis accompanied by malignant tumors. In these cases, immune dysfunctions were considered a common underlying cause in both diseases. This is the first reported case of sensory perineuritis associated with Bowen's disease.     

Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar pathology

A 67-year-old woman had frequent subacute ileus, hearing difficulty, muscle atrophy and stroke-like episodes. Computed tomography revealed multiple low-density areas, which did not correlate with the vascular supply, in the cerebral cortex. She had metabolic disturbance comprising lactic acidosis and elevated pyruvate level. Her skeletal muscle biopsy specimen showed ragged-red fibers, and mitochondrial DNA analysis revealed a point mutation at position 3243, findings consistent with MELAS. Examination of her small intestine revealed a necrotic zone and numerous abnormal large mitochondria in the smooth muscle cells, vascular media and endothelium, and intestinal ganglion cells. The cerebral cortex showed multiple microcystic necrotic foci in cerebral cortex. Cactus-like pathology resembling the changes associated with Menkes’ kinky hair disease and torpedoes were observed in the cerebellar Purkinje cells. The intestinal dysmotility due to MELAS and cerebellar changes were presumed to be associated with a disturbance of copper metabolism. Received: 8 October 1999 / Revised, accepted: 18 January 2000     

The importance of liver biopsy in the investigation of possible mitochondrial respiratory chain disease

The diagnosis of mitochondrial respiratory chain deficiency is usually made by analysis of mitochondrial respiratory chain activity in muscle biopsy. We describe 4 patients in whom the diagnosis was based on mitochondrial respiratory chain deficiency in liver alone. In 3 patients, liver complex IV activity was deficient, and the 4th patient had liver complex I deficiency (relative to citrate synthase and complex II activity). The enzyme activities in skeletal muscle biopsies from these patients were normal or equivocal. The age at presentation and the neurological symptoms differed from one patient to another. All 3 patients with complex IV deficiency had non-specific white matter changes on brain MRI. None of the patients had clinical or biochemical evidence of liver disease. These findings illustrate the wide variety of presentations associated with liver mitochondrial respiratory chain deficiency. They also demonstrate the importance of mitochondrial respiratory chain enzyme analysis in liver, in addition to muscle, even in cases where the primary clinical deficit is neurological and there is no liver disease.     

进行性脑灰质萎缩(Alper病)--附一家系4例报告

一家系4兄妹,3人均在6～8岁发生腹泻、抽搐.16～20岁出现亚急性头痛、失明、皮层盲、抽搐发作、智能衰退,进行性加重6～8个月因衰竭而死亡.头颅CT扫描显示,双侧枕、颞叶低密度病变;大脑病理学特点为全脑灰质层状神经细胞变性脱失、星形细胞增生,呈海绵状脑灰质萎缩,但白质受累较轻,不累及基底节、丘脑、脑干和小脑.1例存活者,临床检查身材矮小,弓形足,左侧轮替指鼻试验反应差;肌肉活组织检查可见大量不整红边纤维和异常线粒体.根据临床神经病理学特点该病症属于进行性脑灰质萎缩Alper病;而肌肉病理学特征则归于线粒体脑肌病.推测晚发型Alper病可能是线粒体脑肌病的一种类型.     

Progressive Neuronal Degeneration of Childhood with Liver's Disease (Alpers' Disease) Clinical Features and Neuropathological Studies of 4 Sibling

We report four siblings of a family with Alpers' disease. Three of four siblings occurred diarrhea and myoclonus at the ages of 7 to 8 years old. During the disease evolution, symptoms of subacute encephalopathy such as headache, visual disturbance, cortical blindness, progressive seizures and mental retardation were presented at the ages of 15 to 20 years old. Downhill progression led them to death in multiple organ failure within six to eight months of onset. CT showed hypodensity lesions in the bilateral oc cipital and temporal lobes. Spongiform changes, which characterized by diffuse neuronal degeneration or loss and astrocytosis, were most severe in the gray matter. White matter was slightly involved, while basal ganglia, pons, brain stem and cerebellum were not involved. Physical examination of the only live brother of the four siblings showed short status (165 cm), arched feet and improper nose-pointed test of the left side. Muscle biopsy of him showed a large amount of Red-Ragged (RR) fibers and abnormal mitochondria. Clinical features and pathological findings of autopsy in all the four siblings were consistent with progressive neuronal degeneration of childhood with liver disease (PNDC) - Alpers' disease. The muscle biopsy showed the characteristic findings of mitochondrial myopathy. Our report confirmed the classification of late onset Alpers' disease as a mitochondrial disorders.     

Apoptosis and ROS detoxification enzymes correlate with cytochrome c oxidase deficiency in mitochondrial encephalomyopathies

The aim of this work was to investigate in muscle the role of apoptosis and of oxidative stress in mitochondrial disorders with dysfunction of respiratory chain. In patients with cytochrome c oxidase deficiency (COX) we found a variable number of myofibers with apoptotic nuclei that matched with the level of enzymatic reduction and roughly correlated with muscle weakness. In parallel, a positive immunostaining for apoptosis-related proteins and Mn and Cu/Zn superoxide dismutase (SOD) were mostly localized in COX-negative fibers. Moreover, glutathione peroxidase activity was increased in muscles with high number of SOD-positive myofibers and prominent apoptotic features. No signs of apoptosis were observed in patients with deficiencies of complexes I and II and without muscle weakness. These data suggest that apoptosis along with increased ROS production, revealed by anti-oxidant enzymes overexpression, may play an important role in the pathophysiology of mitochondrial diseases associated with COX deficiency.     

The Kearns-Shy syndrome. A multisystem disease with mitochondrial abnormality demonstrated in skeletal muscle and skin

An 11-year-old girl presented with external ophthalmoplegia and lid ptosis, pigmentary degeneration of the retina, complete heart block, skeletal muscle weakness, cerebellar deficit, stunted physical growth, fatigue and some mental subnormality. Total protein and IgM, IgA and IgG immunoglobulins were increased in the cerebrospinal fluid. Histochemical studies on the gastrocnemius and quadriceps muscle biopsies revealed many abnormal histochemical type I fibres in which excessive amounts of granular material having strong oxidative enzyme activity were prominent. On electron microscopy these muscle cells contained clusters of many abnormally large mitochondria in which the normal arrangement of the cristae was disturbed, the matrix was increased and sometimes contained dense deposits, and crystalloids were present in the intracristal space. Analogous mitochondrial abnormalities were present in many secretory cells of eccrine sweat glands in a skin biopsy. In skeletal muscle excessive lipid droplets (presumably glycerides) were present close to the abnormal mitochondria. Many patients exhibiting the main clinical and laboratory features of our patient have been recognized and reported in the literature. A clinically identifiable entity emerges which we propose to designate the Kearns-Shy syndrome. While the described mitochondrial abnormalities in muscle cells are not found only in this syndrome, their demonstration is useful in confirmation of the diagnosis, since they have been observed in all cases of the syndrome where muscle biopsies were studied by histochemistry and electron microscopy. Mitochondrial alterations have also been reported in liver cells, cerebellar cortical cells and extraocular muscle fibres. The relationship between the mitochondrial abnormalities and the disturbed tissue function remains obscure. The aetiology of this disorder is unknown; there has been no documented familial occurrence to suggest a genetically determined process.     

Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review

Thirty-two autopsied cases of progressive neuronal degeneration of childhood with liver disease are reviewed. The typical clinical course is intractable seizures and liver failure following a period of developmental delay and failure to thrive in early infancy, but some children first present with seizures. Characteristic changes on the electroencephalogram, loss of visual-evoked potentials, occipital atrophy on computed tomographic scan, and particular changes on liver biopsy may assist diagnosis. Most patients succumb in less than 3 years, but some have a protracted survival into their teens, and very rarely they may present in early adulthood. Liver pathology comprises fatty change, hepatocyte loss, bile duct proliferation, fibrosis, and often cirrhosis. Gradual progression can be followed in sequential biopsies. Macroscopically, the cerebral cortex is variably involved, but usually there is patchy thinning and discoloration, with a striking predilection for the striate cortex. Microscopic changes include spongiosis, neuronal loss, and astrocytosis, which progresses down through the cortical layers. All areas may be affected but the calcarine cortex is usually most affected. Etiology is still obscure, though mitochondrial and slow viral disorders have been postulated.     

糖原累积病的临床电生理、骨骼肌和肝脏病理及基因研究

目的探讨和总结糖原累积病(GSD)的临床病理和基因突变特点。方法回顾性分析18例GSD患者EMG、骨骼肌病理、肝脏病理及二代测序结果。结果GSD慢性起病、波动性,主要表现为四肢近端肌无力,累及膈肌可发生呼吸困难。EMG多为肌源性损害,偶可正常或神经源性损害。骨骼肌活检可见肌纤维胞浆内出现空泡(糖原流失)及嗜碱性颗粒物(糖原蓄积);PAS染色示空泡内异常糖原颗粒沉积。电镜示肌原纤维间糖原贮积伴溶酶体或髓样小体形成。4例患者行肝脏活检示肝细胞肿胀,呈植物细胞壁样镶嵌状排列;胞质内见红色粉尘样物,PAS强阳性证实为糖原。6例患者行二代测序,5例发现GAA杂合突变。7例患者病情迅速进展,5年内死亡;7例缓慢进展,存活5~9年;4例失访。结论(1)GSD早期仅有单纯肌无力症状或低血糖、EMG缺少特异性,多系统受累伴有呼吸困难、肝肿大等提示本病。(2)肌肉和肝脏病理出现大量PAS染色阳性的糖原颗粒对确诊GSD有重要作用。肌活检空泡肌纤维抗线粒体抗体增高提示GSD伴发线粒体代谢紊乱。Dysferlin蛋白免疫组化呈斑片状肌膜和肌质染色,提示钙介导的肌膜融合修复受损可引起继发性肌膜受损。(3)GAA复合杂合突变导致Pompe病(GSDⅡ型)。     

Cytoplasmic body myopathy masquerading as motor neuron disease

Cytoplasmic body myopathy (CBM) is characterized by proteinaceous inclusion bodies in muscle tissue. A 43-year-old woman presented with rapidly progressive weakness and dysphagia. Electromyography (EMG) elsewhere demonstrated lower-limb chronic partial denervation. Muscle biopsy showed fiber size variation without diagnostic features. A diagnosis of possible motor neuron disease was made and the patient was commenced on riluzole. Subsequently, the patient's condition stabilized, prompting reassessment. Repeat EMG demonstrated no features of denervation and was more suggestive of a myopathic process. Review of the original muscle biopsy showed cytoplasmic bodies. The case highlights a further diagnostic possibility in the assessment of patients with "possible" motor neuron disease. The clinical features of CBM are briefly reviewed.     

An “inflammatory” mitochondrial myopathy. A case report

We describe a case of an adult male patient with progressive external ophthalmoplegia and upper limb weakness, who presented with an episode of sudden respiratory failure. Muscle biopsy showed ragged-red and COX-negative fibers associated with discrete inflammatory infiltrates and necrotizing features. Apart from artificial ventilator support, he was treated with intravenous immunoglobulins and carnitine, with excellent clinical outcome. Mitochondrial DNA analysis revealed the 3251A > G mutation, previously reported in association with rapidly progressive mitochondrial myopathy and respiratory failure. Our case expands the spectrum of this mutation and suggests a therapeutic attempt with immunoglobulins in mitochondrial patients with acute respiratory failure, at least when this mutation and/or muscle inflammation is present. Moreover, this case supports the idea of a pathologic inflammatory response induced by mitochondrial disease; such an abnormal response may be a contributory factor in disease progression or acute exacerbation typical of some mitochondrial diseases, but further studies are needed.     

Adult polyglucosan body disease (APBD)

Three patients aged 63, 63 and 74 years had various combinations of progressive lower and upper motor neuron dysfunction, sensory loss, urinary incontinence and dementia. Postmortem examinations in two cases showed moderate cerebral and spinal atrophy, ill-defined areas of incomplete myelin loss in white matter and small necrotic foci in the white matter of gyri, around the basal ganglia and near the dentate nuclei. The main microscopic abnormality was a massive accumulation of PAS-positive polyglucosan bodies (PB) of various sizes and shapes in the cerebral hemispheres, brainstem, cerebellum, spinal cord, nerve roots and nerves. These PB were found in the processes of nerve cells and astrocytes, but not in their perikarya. Similar PB were present in peripheral nerves and in the lungs, heart, liver and kidneys. In the third case, a nerve biopsy revealed several, unusually large, PB in the axons of myelinated fibers. These clinicopathologic features are consistent with adult polyglucosan body disease (APBD) and are distinctive from other conditions in which PB may accumulate. Twelve similar cases have been reported previously. The diagnosis can be made by nerve biopsy. The pathogenesis of APBD is not known, but it may be a polysaccharide storage disease.     

A fatal congenital myopathy with severe type I fibre atrophy,central nuclei and multicores

An unusual fatal congenital myopathy in a Chinese female infant is described. Muscle biopsy showed type I fibre smallness with central nuclei and focal decrease in oxidative enzyme activities affecting mainly larger type II fibres. Longitudinal sections from glutaldehyde-fixed araldite-embedded material stained with toluidine blue revealed multiple small foci of myofibrillar degeneration (multicores) along the muscle fibres. Electron-microscopic examination confirmed the presence of multicore lesions affecting mainly the larger fibres. In addition, there were definite degenerative changes involving the smaller fibres with central nuclei. The degenerative process started around the pericentronuclear zones with diffuse extension along the whole length of the muscle fibres resulting in severe atrophy. These degenerative changes were similar to those described in pericentronuclear myopathy. It is therefore suggested that the patient might have either had 2 co-existing myopathies viz. multicore disease and pericentronuclear myopathy or a single entity with combinations of features which had not hitherto been described.     

Vascular dementia clinically resembling Creutzfeldt-Jakob disease

An autopsy case of vascular dementia, clinically resembling Creutzfeldt-Jakob disease, is reported. A 74-year-old woman showed progressive dementia, transient myoclonus of the right upper arm, diffuse periodic synchronous discharges on electroencephalography, and brain atrophy on computed tomography. The duration of the illness was 17 months. Neuropathologic findings were numerous small necrotic foci in the middle and lower layers of the cerebral cortex, myelin pallor of the cerebral white matter, and fibrous thickening of the arterial and arteriolar walls in the cerebrum and cerebellum (both cortex and white matter). Vascular dementia was diagnosed. On the basis of these features, it is considered that such neuropathologic changes caused Creutzfeldt-Jakob-like symptoms, such as dementia and periodic synchronous discharges.     

Leigh disease with mitochondrial DNA A8344G mutation: case report and brief review

Leigh disease, subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder often seen in infancy or childhood but rarely reported in adults. Genetic heterogeneity is well recognized, and the associated etiologies include both mitochondrial and nuclear DNA defects. We describe an infant presenting with developmental delay and then progressive multisystem disorder and neuroradiologic features of Leigh disease. He and his maternal relatives all have the A8344G mitochondrial DNA mutation. However, only minor clinical features are seen in his maternal relatives, with migraine being the most common problem. Additionally the A8344G mitochondrial DNA mutation is associated with spinocerebellar degeneration, other nonspecific mitochondrial encephalomyopathies, atypical Charcot-Marie-Tooth disease, and progressive external ophthalmoplegia. The A8344G mitochondrial DNA mutation may present with Leigh disease or other different atypical clinical features without myoclonic epilepsy and ragged red fibers.     

经皮肤活体组织检查确诊的Lafora病五例

目的 探讨Lafora病的临床、病理特点及诊断方法.方法 总结分析5例经腋窝皮肤活体组织检查确诊的Lafora病患者的临床和组织病理学特点.5例患者都进行了腋窝皮肤活体组织检查,常规行HE、糖原(PAS)和阿辛蓝-糖原(AB-PAS)染色.结果 5例患者中4例青少年发病,1例成年起病.所有患者均表现为进行性加重的强直阵挛发作、肌阵挛和智能损害,可早期出现性格改变,构音障碍和行走不稳.腋窝皮肤活体组织检查发现Lafora包涵体存在于大、小汗腺的肌上皮细胞和导管细胞内.结论 经皮肤活体组织检查发现PAS阳性圆形或卵圆形包涵体,结合Lafora病典型的临床表现可以确诊该病;皮肤活体组织检查的部位可选择腋窝或腋窝以外的部位.     

A case of progressive myoclonus epilepsy with the first and second branchial syndrome]

A 22-year-old woman with progressive myoclonus epilepsy associated with the first and second branchial syndrome is described. Clinical features included generalized convulsive seizure, myoclonus, cerebellar ataxia and intellectual deterioration with micrognathia and malformation of auricles. She was initially suspected of mitochondrial encephalomyopathy, but the analysis of muscle biopsy and mitochondrial enzyme activities was negative. Her micrognathia and malformation of auricles were diagnosed as the first and second branchial syndrome. The case of progressive myoclonus epilepsy associated with this syndrome has never been reported, and the relationship between them remains unknown.     

Alzheimer's disease with widespread presence of Lewy bodies

Progressive mental deterioration associated with parkinsonism was observed in a 68-year-old patient in the senile period. Pathologically, evidence of senile changes was obtained consisting of degeneration of the neurons and numerous senile plaques with classical and perivascular types. Further, neuronal degeneration in the form of Lewy bodies was evidently observed in the hypothalamus, substantia nigra et innominata, locus caeruleus of the vagus nerve, some nuclei in the reticular formation of the brainstem and neurons in the cerebral cortex. The clinical and pathological manifestations were those of Alzheimer's disease and Parkinson's disease. It is suggested that some common etiological factors may cause those lesions as Alzheimer's disease and Parkinson's disease.     

Ophthalmoplegia due to mitochondrial DNA disease: the need for genetic diagnosis

We describe a patient with chronic progressive external ophthalmoplegia (CPEO) who underwent muscle biopsy for suspected mitochondrial disease. In spite of normal histocytochemical cytochrome c oxidase (COX) activity and respiratory chain enzyme measurements in muscle, subsequent molecular genetic analysis revealed the presence of a single, large-scale deletion of mitochondrial DNA (mtDNA). The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings.     

Autosomal dominant sensory ataxia: a neuroaxonal dystrophy

Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with ADSA who died of congestive heart failure. Autopsy specimens of brain, thoracolumbar spinal cord, peripheral nerve and skeletal muscle were examined. There was no abnormality on gross examination. Microscopically, there were occasional swollen axons within the cerebral cortex and deep nuclei, particularly the subthalamic nucleus, with no neuronal loss, gliosis or microglial activation. There were many axonal spheroids within the medulla, particularly in the dorsal column nuclei. Axonal spheroids were also seen in the dorsal columns and ventral horns in the thoracolumbar spinal cord, but there was no Wallerian degeneration or demyelination. Amyloid precursor protein (APP) immunostaining of some of the spheroids suggested continuing dysfunction of axoplasmic flow in some regions. There was mild inflammation of peripheral nerve roots but no spheroid, and patchy chronic inflammation of skeletal muscle. In summary, the major pathological process in ADSA is a neuroaxonal dystrophy most prominent in the dorsal columns and dorsal column nuclei, consistent with the clinical pattern of central sensory pathway degeneration.