Progressive Muscle Disease Research Articles

Autosomal dominant congenital fibre type disproportion: a clinicopathological and imaging study of a large family

Congenital fibre type disproportion (CFTD) is considered a non-progressive or slowly progressive muscle disease with relative smallness of type 1 fibres on pathological examination. Although generally benign, CFTD has a variable natural course and severe progression has been observed in some patients. The pathogenesis of the disorder is unknown and many authors consider CFTD a syndrome with multiple aetiologies rather than a separate clinical entity. A positive family history has been reported in about 40% of cases, but the inheritance pattern is not clear. Both autosomal recessive and dominant modes of inheritance have been suggested. The present paper describes a large, multigenerational kindred that has an inherited myopathy fulfilling the histological criteria of CFTD, with autosomal dominant transmission and high penetrance. The clinical picture, remarkably similar in all affected family members, started in early infancy with mild limb muscle weakness. There was slow progression of symptoms into adulthood, with moderate to severe, mainly proximal, muscle weakness without loss of ambulation. Muscle biopsy from two affected individuals demonstrated predominance of small type 1 muscle fibres without other significant findings. Nerve conduction studies were normal and needle electromyography showed a myopathic pattern. MRI examination performed on three patients from successive generations showed involvement of proximal limb and paraspinal muscles. The clinical and pathological homogeneity in the present family, together with the lack of additional histological abnormalities after decades of disease progression in two affected individuals, supports this being a distinct myopathy with fibre type disproportion. Whether the disease in this family can be regarded as a form of the congenital myopathy known as CFTD or rather a unique condition sharing histological features with CFTD needs further investigation. This is, to our knowledge, the largest kindred with muscle fibre type disproportion reported to date. Our data confirm autosomal dominant inheritance, and this is the first MRI document of this disorder.

Treatment for swallowing difficulties (dysphagia) in chronic muscle disease.

The management of dysphagia (difficulty in swallowing), a common complication of long-term progressive muscle disease in children and adults, is currently unclear. Our objective was to determine the most appropriate intervention for dysphagia in people with chronic, untreatable, non-inflammatory muscle disease. We searched the Cochrane Neuromuscular Disease Group trials register, Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2003), MEDLINE (from January 1966 to Week 2 June 2003), EMBASE (from January 1980 to Week 2 June 2003), AMED (from January 1985 to Week 2 June 2003), LILACS (from January 1982 to June 21 2003) and CINAHL (from January 1982 to Week 2 June 2003) and contacted authors of published studies and other experts. We included randomised and quasi-randomised controlled trials of adults and children with chronic untreatable non-inflammatory muscle disease. The interventions under review included dietary modification, swallowing manoeuvres, a range of surgical interventions and enteral feeding. Our primary outcome was stabilisation of previously documented progressive weight loss not attributable to any other cause or weight gain of at least 5 kg in adults or increase in weight to at least the 10th centile in children, maintained for at least six months following the intervention. Secondary outcomes were: reduction in laryngeal penetration of bolus and/or aspiration observed on videofluoroscopy (modified barium swallow), reduction in chest infections attributable to aspiration over a six-month period, improvement in quality of life using a validated rating scale, the proportion of subjects who refused the intervention, the proportion of carers who refused the intervention, and serious adverse events related to the intervention within the first twelve months after intervention. We identified no randomised controlled trials. We identified seven case series reporting the results of surgical intervention for moderate to severe dysphagia, and one reporting on the outcome of feeding advice and enteral feeding in children with a congenital myopathy. No studies were found that fulfilled the inclusion criteria. Therefore it was not possible to determine the benefit or otherwise of surgical intervention (cricopharyngeal myotomy or upper oesophageal dilatation) for oculopharyngeal muscular dystrophy or other chronic progressive muscle diseases, and dietary advice or enteral feeding for children with congenital myopathy, compared with no intervention or an alternative intervention. There are no trials that have adequately evaluated treatments in the management of dysphagia for chronic muscle disease. It is therefore not possible to decide on the most appropriate treatment for a given individual based on current evidence.

Drug treatment for facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy is a progressive muscle disease which has no agreed treatment. Early suggestions that corticosteroids might be helpful were not supported by a subsequent open label study. The beta 2 adrenergic agonist albuterol, also known as salbutamol, is known to have anabolic effects which might be beneficial for facioscapulohumeral muscular dystrophy. Creatine has been used as a muscle performance enhancer by athletes and it might be helpful in muscular dystrophies including facioscapulohumeral muscular dystrophy. The objective of the review was to determine whether there is any drug treatment which alters the progression of facioscapulohumeral muscular dystrophy. We searched the Cochrane Neuromuscular Disease Group specialised register (searched August 2003), MEDLINE (January 1966 to August 2003) and EMBASE (January 1980 to August 2003) for any references to facioscapulohumeral muscular dystrophy. Abstracts from the major neurological meetings and trial bibliographies were also searched for further references to trials. Experts were contacted for information regarding unpublished trials or trials in progress. We included all randomised or quasi-randomised trials of any drug treatment for facioscapulohumeral muscular dystrophy, in adults with a recognised diagnosis of facioscapulohumeral muscular dystrophy. Trials had to include an assessment of muscle strength at one year. All identified trials were independently assessed by both reviewers to ensure that they fulfilled the selection criteria and were then rated for their quality. Trial data were extracted and entered by one reviewer and checked by the other. If appropriate data existed a weighted treatment effect was to be calculated across trials using the Cochrane statistical package, Review Manager. The results were to have been expressed as relative risks and 95% confidence intervals and risk differences and 95% confidence intervals for dichotomous outcomes, and weighted mean differences and 95% confidence intervals for continuous outcomes. Two published high quality randomised controlled trials fulfilled the selection criteria. One compared creatine supplementation with placebo and the other compared high and low-dose albuterol with placebo. A further unpublished randomised controlled trial of albuterol in facioscapulohumeral muscular dystrophy was identified. The creatine trial showed a non-significant difference in favour of creatine. The albuterol trial showed no significant difference in muscle strength at one year but some secondary measures such as lean body mass and handgrip strength did improve. There is no evidence from randomised controlled trials to support any drug treatment for facioscapulohumeral muscular dystrophy but only two randomised controlled trials have been published.

Unfolding story of inclusion-body myositis and myopathies: role of misfolded proteins, amyloid-beta, cholesterol, and aging.

Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are progressive muscle diseases leading to severe disability. We briefly summarize their clinical pictures and pathologic diagnostic criteria and discuss the latest advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis, including (a) increased transcription and accumulation of amyloid-beta precursor protein and accumulation of its proteolytic fragment amyloid-beta; (b) abnormal accumulation of components related to lipid metabolism, for example, cholesterol, accumulation of which is possibly owing to its abnormal trafficking; (c) oxidative stress; (d) accumulations of other Alzheimer's disease-related proteins; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss a potentially very important role of unfolded and/or misfolded proteins as a possible mechanism in the formations of the inclusion bodies and other abnormalities.

BACE1 and BACE2 in pathologic and normal human muscle

BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid β precursor protein (AβPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-β generation, and hence the pathogenesis of Alzheimer’s disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of AβPP and accumulation of its presumably toxic proteolytic product amyloid-β (Aβ) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle AβPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought.

Workshop: Management of adults and children with feeding difficulties secondary to chronic muscle disease, 22nd March 2002, Sheffield, UK

Workshop: Management of adults and children with feeding difficulties secondary to chronic muscle disease, 22nd March 2002, Sheffield, UK

Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms.

Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion body myopathies are progressive muscle diseases that lead to severe disability. We discuss recent advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. Our basic hypothesis is that over-expression of amyloid-beta precursor protein within aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis: (a) increased transcription and accumulation of amyloid-beta precursor protein, and accumulation of its proteolytic fragment Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol accumulation possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss unfolded and/or misfolded proteins as a possible mechanism in formation of the inclusion bodies and their consequences. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease brain are discussed. Unfolding knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion body myopathies may lead to new therapeutic avenues.

Impaired performance of skeletal muscle in alpha-glucosidase knockout mice.

Glycogen storage disease type II (GSD II) is an inherited progressive muscle disease in which lack of functional acid alpha-glucosidase (AGLU) results in lysosomal accumulation of glycogen. We report on the impact of a null mutation of the acid alpha-glucosidase gene (AGLU(-/-)) in mice on the force production capabilities, contractile mass, oxidative capacity, energy status, morphology, and desmin content of skeletal muscle. Muscle function was assessed in halothane-anesthetized animals, using a recently designed murine isometric dynamometer. Maximal torque production during single tetanic contraction was 50% lower in the knockout mice than in wild type. Loss of developed torque was found to be disproportionate to the 20% loss in muscle mass. During a series of supramaximal contraction, fatigue, expressed as percentile decline of developed torque, did not differ between AGLU(-/-) mice and age-matched controls. Muscle oxidative capacity, energy status, and protein content (normalized to either dry or wet weight) were not changed in knockout mice compared to control. Alterations in muscle cell morphology were clearly visible. Desmin content was increased, whereas alpha-actinin was not. As the decline in muscle mass is insufficient to explain the degree in decline of mechanical performance, we hypothesize that the large clusters of noncontractile material present in the cytoplasm hamper longitudinal force transmission, and hence muscle contractile function. The increase in muscular desmin content is most likely reflecting adaptations to altered intracellular force transmission.

Altered aquaporin-4 expression in human muscular dystrophies: a common feature?

Duchenne Muscular Dystrophy (DMD) is a progressive lethal muscle disease that affects young boys. Dystrophin, absent in DMD and reduced in the milder form Becker Muscular Dystrophy (BMD), binds to several membrane-associated proteins known as dystrophin-associated proteins (DAPs). Once this critical structural link is disrupted, muscle fibers become more vulnerable to mechanical and osmotic stress. Recently, we have reported that the expression of aquaporin-4 (AQP4), a water-selective channel expressed in the sarcolemma of fast-twitch fibers and astrocyte end-feet, is drastically reduced in the muscle and brain of the mdx mouse, the animal model of DMD. In the present study, we analyzed the expression of AQP4 in several DMD/BMD patients of different ages with different mutations in the dystrophin gene. Immunofluorescence results indicate that, compared with healthy control children, AQP4 is reduced severely in all the DMD muscular biopsies analyzed and in 50% of the analyzed BMD. Western blot analysis revealed that the deficiency in sarcolemma AQP4 staining is due to a reduction in total AQP4 muscle protein content rather than to changes in immunoreactivity. Double-immunostaining experiments indicate that AQP4 reduction is independent of changes in the fiber myosin heavy chain composition. AQP4 and a-syntrophin analysis of BMD muscular biopsies revealed that the expression and stability of AQP4 in the sarcolemma does not always decrease when a-syntrophin is strongly reduced. Finally, limb-girdle muscular dystrophy biopsies and facioscapulohumeral muscular dystrophy revealed that AQP4 expression was not altered in these forms of muscular dystrophy. These experiments provide the first evidence of AQP4 reduction in a human pathology and show that this deficiency is an important feature of DMD/BMD.

Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis

Sporadic inclusion-body myositis (IBM) is the most common, progressive muscle disease of older individuals. We investigated the presence of BACE1 and BACE2-two beta secretases that cleave amyloid-beta-precursor protein-in muscle-biopsy samples from patients with IBM and from controls. On immunofluorescence, BACE1 and BACE2 co-localised with amyloid beta in IBM vacuolated muscle fibres, but were not found in controls. Immunoblotting showed increased BACE2 but not BACE1 in patients with IBM compared with controls. Our study suggests that both of these proteases might participate in processing of amyloid-beta-precursor protein in IBM muscle fibres.

Novel cytoplasmic immunolocalization of RNA polymerase II in inclusion-body myositis muscle.

Sporadic inclusion-body myositis (IBM) is a progressive degenerative muscle disease of older persons. Abnormalities of gene-expression and RNA metabolism have recently been proposed to contribute to the IBM pathogenic cascade. We now demonstrate, using well characterized, epitope-specific antibodies, that the largest subunit of RNA polymerase II is abnormally accumulated in the cytoplasm of IBM muscle fibers, where it is co-localized with phosphorylated tau on IBM paired helical filaments. Since RNA polymerase II is a crucial nuclear factor involved in both transcription and mRNA processing, our results support the hypothesis that abnormality of either or both of those processes might be caused, in part, by pathological trafficking of RNA polymerase II, and that abnormal trafficking might be an important factor in the IBM pathogenic cascade.

Autologous stem cell transplantation for rapidly progressive jo‐1‐positive polymyositis with long‐term follow‐up

We read with interest the case report of a patient with Jo-1-positive polymyositis treated effectively with autologous stem cell transplantation (ASCT) (Baron et al, 2000) and would like to report our experience of ASCT in polymyositis. After an initial period of inflammatory polyarthritis, our patient (a 38-year-old woman) developed Jo-1-positive polymyositis [creatine kinase (CK) level 5754 IU/l (0–140)] with restrictive lung disease. Her disease progressed rapidly and was resistant to therapy with prednisolone (60 mg), azathioprine (150 mg), intravenous cyclophosphamide pulses (total 15 g), intravenous immunoglobulin, cyclosporine (150 mg) and plasmapheresis. In July 1997, stem cells were mobilized with cyclophosphamide (Cy) 2 g/m2 and granulocyte colony-stimulating factor (GCSF) 5 μg, and the graft underwent CD34-positive selection. After 6 g/m2 of Cy, 3·7 × 106 of CD34+ cells/kg and 4·04 × 104 of CD3+ cells/kg were reinfused. The transplant proceeded without any serious complications. During the first 3 weeks the patient felt much better with increased muscle strength and stamina; however, relapse occurred on d 21 (CK 241 IU/l). Despite recommencing methotrexate and cyclosporine and increasing prednisolone to 35 mg, her muscle strength deteriorated (CK 110–780 IU/l) and she required plasmapheresis in January 1998. In early 1999 she developed two subcutaneous abscesses and aspiration revealed Mycobacterium avium complex. Peripheral blood FACS analysis revealed that CD3, CD4 and CD8 T-cell levels, and NK and B-cell levels were all low (0·06 × 109/l, 0·03 × 109/l, 0·05 × 109/l, 0·10 × 109/l and 0·01 × 109/l respectively). Her disease stabilized for the next few months; methotrexate and cyclosporine were discontinued and prednisolone reduced to 12·5 mg/d. Lung function tests showed no progression over the preceding 12 months. For the last year, her CK has remained stable (250 IU/l) but there has been a mild clinical deterioration. This patient underwent ASCT for aggressive polymyositis with rapidly progressive lung and muscle disease and, although she felt clinically better for only 3 weeks, the rate of progression of her disease has clearly slowed. She has subsequently responded to previously ineffective medication, suggesting an immunomodulatory effect. However, our patient did not respond as dramatically as the patient reported by Baron et al, 2000 and unfortunately suffered an opportunistic infection 2 years post transplant. Some variation in outcome may be caused by differences in the method of ASCT used in these two patients. Our patient received a less intensive conditioning regime, which may account for her reduced response. Both patients received manipulated grafts and our patient received a smaller number of CD3+ cells back. The case reported by Baron et al (2000) was shown to have peripheral lymphocyte depletion for the first 6 months post ASCT, but our patient continued to have impaired reconstitution at 20 months. This probably contributed to opportunistic infection. Our patient had also received a large amount of immunosuppression before the transplant, which may have impaired her ability to reconstitute. The use of ASCT in autoimmune disease is still in its exploratory phase (Bingham et al, 2000). A balance must be struck between the wish to give patients a large amount of conditioning in order to achieve complete myeloablation and the need to minimize transplant-related toxicity. This point is borne out by the lack of serious toxicity seen in six patients with rheumatoid arthritis (RA) transplanted in our unit (conditioned with Cy 200 mg/kg) (Bingham et al, 2001) and the fact that the only patient with RA who died after ASCT had received BuCy (Durez et al, 1998, 1999; Tyndall et al, 1999).

Arrhythmogenic Right Ventricular Cardiomyopathy as a Cause of Sudden Unexplained Death

Objective:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive cardiac muscle disease characterized as a progressive fibrofatty replacement of the right ventricle, severe ventricular arrhythmia, and sudden death. However, there is has been no report reports of ARVC as a cause of sudden death in Korea. Methods and Results:Postmortem studies were done to on 115 cases of sudden unexplained death at the department Department of legal Legal medicineMedicine, school School of medicineMedicine, Kyungpook national National university University in year 1999. We identified 7 cases (6%) of typical ARVC with no other identifiable cause of sudden death. The subjects included 5 males and 2 females, ranging in age from 19 to 41 years (mean 29.7 years). All were found dead at in bed (5 cases) or in the workshop (2 cases). Five cases were fibrofatty types and two cases were fatty types. Right ventricular aneurysm, inflammatory infiltrates and left ventricular involvement were found in 4, 2 and 1 cases, repectivelyrespectively. Two cases had a family history of sudden death before age 40. No one was None were suspected of having cardiovascular disease or ARVC before death. Conclusion:These findings indicate that ARVC in the Taegu-Kyungpook area may be more frequent than previously thought. ARVC may be a major cause of sudden unexplained death. (Korean Circulation J 2001;31(3):335-340)

Novel immunolocalization of alpha-synuclein in human muscle of inclusion-body myositis, regenerating and necrotic muscle fibers, and at neuromuscular junctions.

Alpha-synuclein (alpha-syn) is an important component of neuronal and glial inclusions in brains of patients with several neurodegenerative disorders. Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older patients. Its muscle phenotype shows several similarities with Alzheimer disease brain. A distinct feature of s-IBM pathology is specific vacuolar degeneration of muscle fibers characterized by intracellular amyloid inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies of s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn was strongly immunoreactive at the postsynaptic region of the neuromuscular junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots. Our study provides the first demonstration that alpha-syn participates in normal and pathologic processes of human muscle. Therefore. its function is not exclusive to the brain and neurodegenerative diseases.

Paired Helical Filaments of Inclusion-Body Myositis Muscle Contain RNA and Survival Motor Neuron Protein

Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older persons. Pathologically, the muscle biopsy manifests various degrees of inflammation and specific vacuolar degeneration of muscle fibers characterized by paired helical filaments (PHFs) composed of phosphorylated tau. IBM vacuolated fibers also contain accumulations of several other Alzheimer-characteristic proteins. Molecular mechanisms leading to formation of the PHFs and accumulations of proteins in IBM muscle are not known. We report that the abnormal muscle fibers of IBM contained (i) acridine-orange-positive RNA inclusions that colocalized with the immunoreactivity of phosphorylated tau and (ii) survival motor neuron protein immunoreactive inclusions, which by immuno-electron microscopy were confined to paired helical filaments. This study demonstrates two novel components of the IBM paired helical filaments, which may lead to better understanding of their pathogenesis.

Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies.

Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibres containing paired helical filaments. We immunostained muscle biopsy specimens from quadriceps-sparing autosomal-recessive and autosomal-dominant inclusion-body myopathy subjects, disease-control subjects and normal patients, utilizing isoform-specific antibodies against the neuronal and inducible forms of nitric oxide synthase, and antibodies against nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all recessive and dominant inclusion-body myopathy patients contained inclusions strongly immunoreactive with antibodies against neuronal and inducible nitric oxide synthase which, by immunoelectron microscopy, were colocalized to clusters of tubulofilaments (previously shown, by us, to be paired helical filaments). Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large granular patches, which ultrastructurally did not immunolocalize to tubulofilaments. Excess intracellular nitric oxide can combine with superoxide to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins. The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative stress. Our data suggest that oxidative stress plays a role in the pathogenic cascade of hereditary inclusion-body myopathies.

Sporadic Inclusion-body Myositis and Its Similarities to Alzheimer Disease Brain: Recent Approaches to Diagnosis and Pathogenesis, and Relation to Aging

Sporadic inclusion-body myositis (s-IBM) is the most common, debilitating and progressive muscle disease beginning at the age 50 or later. The most characteristic pathologic feature is vacuolar degeneration of muscle fibers accompanied by intrafiber congophilia and clusters ("tangles") of paired-helical filaments, containing phosphorylated tau. An unusual feature of sporadic inclusion-body myositis is accumulation within its abnormal muscle fibers of several proteins that are characteristic of Alzheimer disease brain, including epitopes of beta-amyloid precursor protein (betaAPP), phosphorylated tau, alpha-1-antichymotrypsin, apolipoprotein E, and presenilin-1. Indicators of oxidative stress are also present within abnormal s-IBM muscle fibers. In this review, we describe new advances seeking the pathogenic mechanism of sporadic inclusion-body myositis. We hypothesize on the possible pathogenic role of abnormally accumulated proteins, and we propose that important contributory factors leading to inclusion-body myositis are the milieu of muscle-fiber aging and oxidative stress. In addition, we present evidence that overexpression of adenovirus-transferred betaAPP gene in cultured human muscle fibers induces aspects of the inclusion-body myositis phenotype, and suggest that betaAPP-overexpression is an early event in the pathogenic cascade causing inclusion-body myositis.

Spectrum of Clinicopathologic Manifestations of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: A Multicenter Study

Objectives. The aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement.Background. Long-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure.Methods. Forty-two patients (27 male, 15 female; 9 to 65 years old, mean [±SD] age 29.6 ± 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol.Results. Thirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 ± 15 years vs. 20 ± 8.8 and 25 ± 9.7 years, respectively), had significantly longer clinical follow-up (9.3 ± 7.3 years vs. 1.2 ± 2.1 and 3.4 ± 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 ± 150 g vs. 328 ± 40 and 380 ± 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients.Conclusions. LV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.

Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies.

Sporadic inclusion body myositis and the hereditary inclusion body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired helical filaments. We immunostained muscle biopsy specimens from sporadic inclusion body myositis, hereditary inclusion body myopathy, disease control, and normal patients with several antibodies against apolipoprotein E (ApoE). Approximately 80 to 90% of the vacuolated muscle fibers of sporadic inclusion body myositis contained well-defined, strongly immunoreactive ApoE inclusions. In hereditary inclusion body myopathy, only rare vacuolated fibers had immunoreactive inclusions, whereas most had diffuse cytoplasmic ApoE immunoreactivity. Ultrastructurally, ApoE immunoreactivity in sporadic myositis was localized mainly to the paired helical filaments. By contrast, in the hereditary form, ApoE immunoreactivity occurred on material in close proximity to the paired helical filaments, but never was on the paired helical filaments. In both muscle diseases, ApoE was also on the 6- to 10-nm filaments and amorphous material. In the sporadic form, ApoE-immunoreactive deposits colocalized with Congo red-positive deposits; however, in muscle fibers from patients with hereditary disease there was no congophilia. ApoE messenger RNA was not detectable in muscle fibers from patients with hereditary or sporadic disease but was expressed abundantly in muscle macrophages. In all control and inclusion body myositis or myopathy biopsy specimens, ApoE immunoreactivity was strong at the postsynaptic domain of neuromuscular junctions; nonjunctional regions of normal fibers were negative for ApoE. ApoE immunoreactivity occurred diffusely in regenerating muscle fibers, a subset of which had detectable ApoE messenger RNA.

Reduced levels of dystrophin associated proteins in the brains of mice deficient for Dp71.

Duchenne muscular dystrophy (DMD) is a progressive degenerative lethal muscle disease. A significant proportion of DMD affected children suffer also from mental retardation. The rod shaped protein, dystrophin, which is absent from or defective in the muscle of DMD patients, binds to a number of membrane associated proteins (known collectively as dystrophin associated proteins [DAPs]). The levels of DAPs is greatly reduced in the muscle of DMD patients and mdx mice, which lack dystrophin. In addition to dystrophin isoforms, the DMD gene codes also for several smaller proteins. One of the small proteins, Dp71, is expressed in most or all non-muscle tissues and is the major DMD gene product in the brain. The function of the small DMD gene products is unknown. Here we show that mutant mice which do not express the smaller non-muscle products of the DMD gene have a reduced level of DAPs in their brain. This suggests that Dp71 is important for the formation and/or stabilization of a DAPs complex in brain.