Multineuropathy in a patient with HBV infection, polyarteritis nodosa and celiac disease

A 53‐year‐old man came to our observation for impaired gait and painful paresthesia in his hands and feet. Three years before he suddenly presented tingling in his hands, followed, after a few months, by paresthesia in his feet, weakness of the right hand and foot and cutaneous erythema. Nearly one year after the onset, he presented left abducens nerve palsy that completely resolved in three months with steroid therapy. The patient's conditions progressively worsened and when he was admitted to our clinic the neurological examination revealed a stepping gait and severe muscular atrophy. Sensory abnormalities involved pin, light touch and vibration perception. In three years he had severe weight loss. Blood test revealed HBV infection and high levels of antibodies to transglutaminase, endomysium, and gliadin. EMG showed sensorimotor asymmetric axonal neuropathy. Nerve biopsy showed fiber loss, axonal degeneration with asymmetrical distribution and focal ischaemia. A duodenal biopsy was consistent with celiac disease. The patient was treated with high dose steroids, plasma exchange, immunoglobulin and lamivudine and began a gluten‐free diet. At discharge he could walk unassisted; sensory abnormalities were greatly reduced. One year later a new duodenal biopsy showed a complete resolution of the pathological abnormalities. Celiac disease, a chronic inflammatory intestinal disease whose pathogenesis involves a HLA DQ2‐DQ8 restricted T‐cell immune‐reaction, can be related to a higher risk of autoimmune disorders, such as insulin‐dependent diabetes or thyroid disease. We report the association of celiac disease, polyarteritis nodosa and HBV infection in a patient who developed a neuropathy and discuss the pathogenetic implications.     

14‐3‐3 protein in the CSF of inflammatory peripheral neuropathies

We describe a 65‐year‐old smoker male followed for five years for a pure motor demyelinating peripheral neuropathy. The patient had a monthly motor relapse with severe weakness restricting him to a wheelchair, so he needed monthly high dose IVIg. On EMG the MCV were very slowed (30 m/sec) without evidence of conduction blocks while SCV were in the normal range. CSF disclosed a high protein level. Laboratory findings did not reveal any other abnormality except for the presence of monoclonal gammopathy IgMk and high titer anti GD1a serum IgM antibodies (1:5000). In March 2003 he had the most severe relapse with flaccid tetraplegia and respiratory failure so severe that he required ventilatory support. A total body CT scan revealed a nodular lung lesion with diffuse lymphangiitis. Biopsy disclosed a lung adenocarcinoma with a severe infiltration of CD8 cells. Surgical eradication of the tumor caused the last severe relapse. At the moment the patient is relapse‐free and no more treatment was administered. The clinical course of the motor demyelinating relapsing neuropathy suggests a possible paraneoplastic pathogenesis of the neurological illness also supported by the severe inflammatory infiltration of the tumor.     

Coexistence of Charcot‐Marie‐Tooth disease type 1A and anti‐MAG neuropathy

At age 35, a man with a genetic diagnosis of Charcot‐Marie‐Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM‐kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti‐myelin associated glycoprotein (anti‐MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a “double hit”. Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate.     

Molecular analysis of the litaf/simple and prx genes in patients with demyelinating charcot‐marie‐tooth (CMT) disease

Mutations in the GJB1/Cx32 gene (Xq13.1) cause the most common X‐linked form of CMT (CMTX1) and are the most frequent cause of CMT disease after the CMT1A duplication. The disorder is characterized by a moderate‐to‐severe neuropathy in affected males and mild‐to‐no symptoms in carrier females. We report here a CMT1A‐negative family in which 4 females and 2 males were affected, exhibiting different disease severity. Molecular analysis of the GJB1/Cx32 gene uncovered a nonsense mutation (Arg22stop) in exon 2. The mutation, which had been previously described by others and observed by us in numerous other families, occurred in heterozygous form in the 4 females. However, while one of the two male patients was severely affected and shown to be hemizygous, as expected, the other was mildly affected and found to carry the mutation in heterozygous form. Genotyping at the SRY (Yp11.3) and DMD (Xp21) loci suggested the occurrence of the XXY genotype associated with Klinefelter syndrome. Microsatellite analysis indicated that the nondysjunctional error was of paternal origin, as it is usually observed in about half the cases. The patient had no children. At clinical examination, he exhibited a very mild neurologic phenotype and showed signs of hypogonadism (mild gynecomastia and small testes) as well as moderate cognitive impairment. Electrophysiologic, cytogenetic and endocrinologic investigations are in progress in order to define the unusual phenotype in this patient.     

DNA‐fragmentation and expression of apoptosis‐related proteins in muscular dystrophies

Although numerous sarcolemmal protein defects in muscular dystrophies have been identified, the mechanisms linking these defects and muscle fibre degeneration are not fully characterized. As there is evidence that apoptosis is part of muscle fibre loss in dystrophin‐deficient mdx‐mice, apoptotic muscle fibre death may also play a role in humans with muscular dystrophies. We investigated in‐situ DNA‐fragmentation by the TUNEL‐method and expression of apoptosis‐related proteins immunohistochemically in 14 children suffering from deficiencies of dystrophin, adhalin, and merosin, and found TUNEL‐positive chromatin‐cleavage of muscle fibre nuclei in about 10% of non‐necrotic muscle fibres. DNA‐fragmentation also occurred in groups of 'necrotic and regenerating' muscle fibres with labelling of nuclei in myogenic cells and phagocytizing macrophages. These lesions also revealed expression of apoptosis‐promoting factors, such as bax and ICE, inducing cleavage of myofilaments, and of the apoptosis‐inhibiting proteins bcl‐xL and bcl‐2 which neutralized high bax levels. Mimicking embryonal myogenesis, chromatin‐fragmentation in 'necrotic and regenerating' areas seems to be part of the regulating events in muscle regeneration to eliminate excessive proliferating satellite cells. Nevertheless, macrophages are also affected by apoptosis after successful removal of necrotic fibres. In humans, DNA‐fragmentation and expression of apoptosis‐related proteins indicate that apoptosis plays a role in muscle degeneration and regeneration in muscular dystrophies.     

Toxic myopathy with multiple deletions in mitochondrial DNA associated with long‐term use of oral anti‐viral drugs for hepatitis B: A case study

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long‐term use of NAs for hepatitis B. A 68‐year‐old woman, who underwent long‐term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged‐red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress‐induced mtDNA damage. This case study indicates that long‐term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.     

Non‐HTLV‐I associated pleomorphic T‐cell lymphoma of the brain mimicking post‐vaccinal acute inflammatory demyelination

Two weeks after vaccination against tick‐borne encephalitis (TBE), a 57‐year‐old female suddenly developed mental confusion and hemiparesis of the left side. Cranial MRI demonstrated extensive bilateral lesions in the fronto‐parietal white matter of both hemispheres, suggesting an acute inflammatory demyelinating disease following vaccination. Despite administration of high‐dose corticosteroids, the patient died 3 weeks after onset of neurological symptoms. Autopsy revealed diffuse infiltrates of a primary cerebral pleomorphic T‐cell lymphoma of medium and large cell type. PCR on brain tissue for HTLV‐I and serology for anti‐HTLV‐I antibodies in CSF and serum were negative; immunocytochemistry on brain tissue did not detect EBV‐related antigen. This is the first recorded observation of a diffusely infiltrating primary central nervous system T‐cell lymphoma, clinically and radiologically mimicking a fatal acute inflammatory demyelinating complication after vaccination.     

Peripheral neuropathy as initial sign of mitochondrial disorder

Charcot‐Marie‐Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into demyelinating (type 1) and axonal (type 2) neuropathies. The form of Charcot‐Marie‐Tooth neuropathy that maps to Xq13 may present mild electrophysiological changes (NCV > 40 M/s), mixed neuropathy (NCV: Intermediate (30–40 M/s), or demyelinating neuropathy (NCV: Slow (<37 M/s). On molecular grounds, CMTX is caused by mutations in GJB1 gene, coding for Connexin 32 protein. A 42‐year‐old man, with no other affected family members, was clinically evaluated for CMT. Three years ago he noticed thumb abductor atrophy and then leg muscle atrophy. He presented with hand and leg muscle atrophy, bilateral pes cavus, areflexia, and apallesthesia. The median and ulnar motor NVC were 35–38 m/s, and the median sensory NVC was 35 m/s. Both motor and sensory nerve action potentials were markedly reduced. After exclusion of CMT1A and 1B, analysis for CMTX was performed. The mutation screening of GJB1 gene showed a 9bp insertion upstream the 194ATG codon (Met194) with preservation of the downstream sequence. The three new amino acids (Thr‐Val‐Phe) inserted are localized between the end of the second extracellular domain and the beginning of the fourth transmembrane domain. This is the first 9bp insertion found in GJB1 gene; a genotype‐phenotype correlation may be deduced.     

DNA‐fragmentation and expression of apoptosis‐related proteins in experimentally denervated and reinnervated rat facial muscle

Muscle fibres may undergo apoptotic cell death in several neuromuscular disorders such as denervated muscle fibres in spinal muscular atrophies. We investigated DNA‐fragmentation ( in situ by the TUNEL‐method) and expression of apoptosis‐associated proteins in experimentally denervated and reinnervated rat facial muscle up to 24 weeks after surgery to evaluate the rate and time lapse of apoptotic muscle fibre loss. While denervated muscle displayed constantly high rates of DNA‐fragmentation, denervated and immediately reinnervated muscle showed a distinct decrease of primarily elevated DNA‐cleavage, finally resembling rates of normal controls. Denervated muscle fibres revealed strong immunoreactivity of the anti‐apoptotic proteins bcl‐2 and bcl‐xL, and the pro‐apoptotic factor bax. In reinnervated muscle fibres, only bcl‐2 was constantly up‐regulated while bcl‐xL and bax diminished after the 7th week. The present findings indicate that denervation may prompt muscle fibres to activate an intrinsic 'suicide' programme to undergo apoptosis. High levels of bcl‐2 after denervation may sustain cell survival until reinnervation, e.g. after accidental nerve damage or in neurodegenerative disorders. Furthermore, increasing levels of bcl‐2 are able to neutralize high apoptosis‐promoting bax levels. Interventions modifying DNA‐fragmentation and the expression of apoptosis‐related proteins may lead to new therapeutic concepts in denervating disorders of muscle in the absence of other primary therapies.     

Neuromuscular complications of jejunoileal shunt for morbid obesity: case report and literature review

Intestinal malabsorption by jejunoileal bypass has been used to treat morbid obesity. Although the procedure is considered safe, several long‐term neurological complications have been described. A 47‐year‐old man was evaluated because of increasing gait difficulties five years after jejunoileal bypass at age 42. Neurological examination showed upper, lower extremities proximal weakness, distal sensory loss for touch, pin‐prick, vibration and position. Deep jerks were absent. Electrophysiology was consistent with axonal neuropathy. Blood tests revealed microcitic anemia (Hb 9 g/dl), normal thyroid function, tumor marker titer, and viral screenings. Vitamin A was 1.12 umol/l (n.v. 0.56–4.25) and vitamin E was 10.7 umol/l (n.v. 11.5–31). B12, folate levels were within normal range. A 42‐year‐old obese man had a similar surgery. Two years later he developed an acute episode of confusion and unsteadiness due to lactic acidosis, from which he recovered. He was first evaluated neurologically fifteen years after jejunoileostomy because of muscle cramps, paraesthesias, and progressive imbalance. On examination there were trunk, extremity ataxia, proximal and distal muscle weakness, distal atrophy, loss of reflexes, and severe loss of all sensory modalities. Electrophysiology confirmed a sensorimotor neuropathy. Blood tests showed macrocitic anemia, low free calcium (3.7 mEq/l, n.v. 4–5), increased PTH (75 pg/ml, n.v. 10–65), and low serum level of vitamins A and E. Brachial biceps biopsy showed neurogenic changes. General conditions progressively deteriorated because of repeated episodes of dehydration leading to terminal uremia within 27 years.     

A case of mitochondrial DNA depletion syndrome type 11 – expanding the genotype and phenotype

Mitochondrial DNA depletion syndrome type 11 (MTDPS11) is caused by pathogenic variants in MGME1 gene. We report a woman, 40-year-old, who presented slow progressive drop eyelid at 11-year-old with, learning difficulty and frequent falls. Phisical examination revealed: mild scoliosis, elbow hyperextensibility, flat feet, chronic progressive external ophthalmoplegia with upper eyelid ptosis, diffuse hypotonia, and weakness of arm abduction and neck flexion. Investigation evidenced mild serum creatine kinase increase and glucose intolerance; second-degree atrioventricular block; mild mixed-type respiratory disorder and atrophy and granular appearance of the retinal pigment epithelium. Brain magnetic resonance showed cerebellar atrophy. Muscle biopsy was compatible with mitochondrial myopathy. Genetic panel revealed a homozygous pathogenic variant in the MGME1 gene, consistent with MTDPS11 (c.862C>T; p.Gln288*). This case of MTDPS11 can contribute to the phenotypic characterization of this ultra-rare mitochondrial disorder, presenting milder respiratory and nutritional involvement than the previously reported cases, with possible additional features.     

Down‐regulation of receptors for semaphorins and VEGF in a transgenic model of CMT1A

Oxcarbazepine (OXC) is a keto‐10‐analogue of carbamazepine (CBZ) with linear pharmacokinetics and a better tolerability profile compared to CBZ. For this reason, OXC has been used in some studies in the treatment of neuropathic pain of various genesis, with administration doses ranging from 300 to 2400 mg/day. In this study we have assessed the efficacy and tolerability of OXC 600 mg/day, a dose considered, based on previous data, the minimal therapeutic dose in the treatment of neuropathic pain in some neuropathies, such as diabetic neuropathy. We have studied 11 patients affected by predominant sensitive painful neuropathy, of metabolic, compressive, inflammatory or dysimmune genesis, clinically characterized by paresthesias, dysesthesias and neuralgic pain not responding to other pharmacologic therapies. At the follow‐up analysis, 7 patients have referred an improvement of painful symptoms, as evidenced by Visual Analogue Scale score, the reduction of which ranged from 20 to 60% compared to baseline values. One patient interrupted the trial for incompliance, two patients for collateral events (excessive sleepiness) and another one for a worsening of clinical picture. In conclusion, our study suggests that OXC can be considered as a valid alternative in the treatment of painful neuropathies owing to its characteristics of tolerability and efficacy in such conditions.     

Acute demyelinating sensorimotor polyneuropathy in B‐cell lymphoma with IGM autoantibodies against glycolipid GD1B

A 20‐year‐old man developed weakness without sensory complaints ten days after rubella. Examination showed limb weakness and brisk tendon reflexes but no sensory abnormalities. Laboratory investigations revealed IgG and IgM anti‐Rubella and increased CSF protein content (0,8 g/L). Electrophysiological examination showed partial motor conduction blocks in eight nerves and normal sensory conductions even across the sites of CB. Brain and spinal cord MRI and SEPs were normal. The patient was treated with four plasmaphereses and fully recovered in six months. Conduction blocks gradually improved with increasing duration and abnormal temporal dispersion in proximal CMAPs. GBS has been rarely reported after rubella. Anti‐myelin basic protein antibodies have been found in a patient with a relapsing motor neuropathy following rubella vaccination. As antibodies cross‐reacted with a viral protein, molecular mimicry has been proposed as a pathophysiological mechanism. In our patient we did not find anti‐MBP antibodies and antibodies to‐glycolipids (GM1, GM2, GA1, GD1a, GD1b, GQ1b, sulfatides, galactocerebroside) were also negative. Indirect immunofluorescence after incubation of patient's serum on rabbit sciatic nerve and human sural nerve and roots was negative. Our patient confirms the occurrence of GBS following Rubella and shows some uncommon features: 1) hyperactive deep tendon reflexes; 2) demyelination selectively involving motor fibres; and 3) widespread early conduction blocks in intermediate nerve segments.     

Interleukin‐1 expression in inflammatory myopathies: evidence of marked immunoreactivity in sarcoid granulomas and muscle fibres showing ischaemic and regenerative changes

The most frequent autoimmune adult inflammatory myopathies are dermatomyositis, polymyositis, inclusion body myositis, and sarcoid myopathy. Interleukin‐1 (IL‐1) is a pleiotropic molecule, implicated in the inflammatory process, but also in tissue protection and remodelling. We evaluated the immunocytochemical expression of IL‐1α and β in frozen muscle biopsy specimens from patients with dermatomyositis (15 cases), polymyositis (five cases), inclusion body myositis (five cases) and sarcoid myopathy (five cases). Positive immunoreactivities, were observed in both inflammatory cells and muscle fibres. Specificity of the immunostaining was assessed by Western blot experiments. IL‐1 positive inflammatory cells were rare in polymyositis and inclusion body myositis, moderately abundant in dermatomyositis, and prominent in sarcoid myopathy granulomas. In sarcoid myopathy, 24.6±4.1% inflammatory cells were IL‐1α‐positive and 45.2±2.6% were IL‐1β‐positive. IL‐1 positive muscle fibres were mainly observed in dermatomyositis, usually remote from inflammatory infiltrates. Positive immunostaining for IL‐1 was observed in fibres showing ischaemic punched‐out vacuoles, that correspond to areas of myosinolysis, in atrophic perifascicular fibres, and in fibres located within healing microinfarcts. All NCAM‐positive regenerating fibres were IL‐1 positive. We conclude that: (i) IL‐1 is expressed in granulomas of sarcoid myopathy, which is in keeping with the role ascribed to IL‐1 in the formation of granulomas; (ii) IL‐1 is expressed by muscle fibres undergoing ischaemic damage; and (iii) IL‐1 expression by muscle fibres is associated with myofibrillar protein breakdown and regeneration.     

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.     

线粒体肌病合并周围神经病的临床病理研究

目的:分析线粒体肌病合并周围神经病的临床特点、电生理和病理特征。方法:对10例肌肉活检确诊为线粒体肌病同时又合并周围神经病的患者从临床症状与体征、电生理检查和腓肠神经活检等几方面予以分析,并探讨周围神经病的病理基础。结果:本组10例患者中1例仅有临床下受累,另外9例表现为轻中度感觉运动性周围神经病,以感觉症状为重。结论:对线粒体肌病患者应将详细的神经系统查体与神经电生理检查相结合,提高周围神经病的检出率。电生理检查和腓肠神经活检有助于诊断。周围神经病的发病机制可能与线粒体功能异常有关。     

Immune-mediated neuropathy and myopathy in post-streptococcal disease: electron-microscopical, morphometrical and immunohistochemical studies.

A 22-year-old man suffered from a complete flaccid tetraparesis and an immune complex-mediated rapid progressive glomerulonephritis after group A streptococcal infection. Serum creatine kinase was excessively elevated and myoglobinuria occurred. Nerve conduction studies revealed evidence of axonal neuropathy. Recovery was satisfactory within 18 months. Sural nerve and peroneus muscle biopsies were performed in the 4th and 14th week of the disease. Light microscopy of the sural nerve showed an incipient axonal type of neuropathy in the first biopsy. Ultrastructurally, Wallerian degeneration and endoneurial inflammatory cells were present. In the muscle biopsy, few atrophic fibers and altered blood vessels without further anomalies were found. In the second sural nerve biopsy, macrophages were numerous, some of which were immunoreactive for HLA-DR, and only a few myelinated and some unmyelinated nerve fibers remained. Muscle fibers in the second biopsy showed high-grade atrophy and myofibrillar abnormalities. Immunohistochemistry revealed diffuse endoneurial immunoglobulin deposition in the first sample, while in the later biopsy specimen, deposits of IgG, and kappa and lambda light chains were visible in circumscribed endoneurial areas. Immune-mediated neuropathy and myopathy are not well-known complications of streptococcal disease. This is, to our knowledge, the first detailed report on morphological findings in muscle and nerve in such a disorder.     

A patient with mitochondrial encephalomyopathy presenting gynecomastia with elevation of serum estriol level]

We report a 23-year-old man with mitochondrial encephalomyopathy. At 21 years of age, he noted speech distubance. Since his dysarthria did not improve thereafter, he was admitted to our hospital. On admission, he showed mild gynecomastia. Neurological examination revealed mild decrease in performance IQ in WAIS-R, mild scanning speech, mild left hearing disturbance, mild to moderate muscle weakness in proximal four extremities, mild bilateral limb ataxia, and mild to moderate truncal ataxia. While, no brisk deep tendon reflex, pathological reflex, aberrant muscle tonus, sensory disturbance, retinopathy, myoclonus or autonomic disorder was found. Serum levels of lactate (23.2 mg/dl, normal<18.7) and pyruvate (1.23 mg/dl, normal<0.94) were elevated, and serum lactate levels were markedly elevated (118.1 mg/dl) after 15-minute exercise (15 Watts/minute). CSF levels of lactate (31.2 mg/dl, normal<12.5) and pyruvate (1.48 mg/dl, normal<0.75) were also elevated. Head MRI showed mild cerebral and cerebellar atrophy, but 1H-MRS showed no lactate peak. Moreover, muscle biopsy from left biceps muscle showed lots of ragged-red fibers, and he was thus diagnosed as having mitochondrial encephalomyopathy. However, nt3243 mutation of mitochondria DNA was not present. Next, we confirmed gynecomastia by mammography, and checked serum levels of estrogens. Mildly decreased estradiol (19.9 pg/ml, normal, 20-59), normal estrone (24.0 pg/ml, normal<30.0) and mildly increased estriol (6.03 pg/ml, normal<5.0) were found. While, the serum levels of cortisol, dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were all within normal limits. Since the steroid hormone synthesis system and hypothalamus-pituitary system seem to be normal, 16alpha-hydroxylase that converts estradiol to estriol may be upregulated. While, aromatase (P-450arom) is well known to convert androgens to estrogens. In addition, 16alpha-hydroxylase and P-450arom convert DHEA-S to estriol. Since it is recently reported that P-450arom is considerably expressed in muscle tissues as well as fat tissues and that muscle tissue may be a major organ to produce estrogens in men and postmenopausal women, estriol production may be increased in the present patient's muscle. Although hypogonadism due to hypothalamus-pituitary disorders was sometimes reported, there have been no reports that suggest an increased estrogen production in skeletal muscles in mitochondrial encephalomyopathies. Recently, estrogen has been known to protect muscle fibers from oxidative damages due to exercise. Thus, it is of potential that estrogens increased locally in muscle tissues of the patients with mitochondrial encephalomyopathies protect muscle fibers from oxidative damage due to mitochondrial dysfunction.     

Experimental axonopathy induced by immunization with campylobacter jejuni lipopolysaccharide from a patient with guillain‐barré syndrome

Campylobacter jejuni (C. jejunj) infection is the most common antecedent in the axonal variant of Guillain‐Barré syndrome (GBS). Antibodies against nerve gangliosides found in GBS patients recognize cross‐reactive epitopes in the lipopolysaccharide (LPS) of C. jejuni. This led to the molecular mimicry hypothesis of GBS. We immunized eleven rabbits with a LPS extracted from HS:19 C. jejuni strain isolated from a patient with GBS and complete Freund's adjuvant (CFA)(group I). In a second experiment we immunized seven rabbits with LPS, CFA and keyhole limpet hemocyanin (KLH)(group II). All group I rabbits developed high titers of anti‐LPS, anti‐GM1, anti‐GD1b antibodies and lower titers of anti‐GD1a. One rabbit, 50 days after initial inoculation, showed tremor and weakness. All rabbits of group II developed high titres of antiganglioside antibodies and six animals showed weakness 59–113 days after initial inoculation. Two rabbits died. Pathology showed mild to moderate, tendentially grouped, axonal degeneration in sciatic nerves of four out of five animals. Control rabbits of group I (immunized with CFA only) did not develop antibodies, controls of group II (immunized with CFA + KLH) developed low titers of IgG anti‐GM1. None developed neurological signs or showed axonal degeneration. C. jejuni LPS is a potent B‐cell stimulator capable to induce a strong antiganglioside response in rabbits. However, to induce the neuropathy is crucial to employ KLH, a glycoprotein known to stimulate both humoral and cellular responses. This animal model reproduces the pathogenetic process hypothesized in axonal GBS with antiganglioside antibodies post C. jejuni infection.     

An adult case of congenital fiber type disproportion (CFTD) with cardiomyopathy]

A 30 year-old man with CFTD was reported. He had normal motor milestone during infancy but had been poor at sports. At 28, he experienced exertional and nocturnal dyspnea and had been diagnosed as having dilated cardiomyopathy. At 29, a cardiac pace-maker was implanted because of the complete atrio-ventricular block. Around that time, he began to notice limb muscle weakness. Examination at 30 showed mild diffuse muscle atrophy and weakness at the torso and limbs. No dysmorphic features or joint contractures were noted. His serum CK was normal. A histochemical study of his muscle biopsy showed type 1 fiber predominancy (64.6%) and that the mean diameter of type 1 fibers was smaller than that of type 2 by 14.6% (36.9 microm vs. 42.3 microm). Results of immunostaining of dystrophin, emerin, laminA/C, alpha, beta, gamma, delta-sarcoglycan or dysferlin were normal. He was diagnosed as having CFTD because there were no histochemical abnormalities which characterize other congenital myopathies except for the type 1 predominancy and atrophy.