Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Desmin-related myopathy is characterised by skeletal muscle weakness often combined with cardiac involvement. Mutations in the desmin gene have been described as a cause of desmin-related myopathy (OMIM 601419). We report here on two distantly related Dutch families with autosomal dominant inheritance of desmin-related myopathy affecting 15 family members. A highly heterogeneous clinical picture is apparent, varying from isolated dilated cardiomyopathy to a more generalised skeletal myopathy and mild respiratory problems. Morphological analysis of muscle biopsies revealed intracytoplasmic desmin aggregates (desmin and p62 staining). In both families we identified an identical novel pathogenic heterozygous missense mutation, S13F, in the 'head' domain of the desmin gene which cosegregates with the disease phenotype. This is the 5th reported missense mutation located at the 'head' domain of the desmin gene and the first reported Dutch family with desmin-related myopathy. This article illustrates the importance of analysing the desmin gene in patients with (familial) cardiac conduction disease, dilated cardiomyopathy and/or a progressive skeletal myopathy resembling limb-girdle muscular dystrophy.
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PMID:Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene. 1772 Jun 47

While both neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD) show frontotemporal lobar degeneration and/or motor neuron disease, it remains unclear whether, and how, these diseases differ from each other. Here, we compared the clinicopathological characteristics of four BIBD and two NIFID cases. Atypical initial symptoms included weakness, dysarthria, and memory impairment in BIBD, and dysarthria in NIFID. Dementia developed more than 1 year after the onset in some BIBD and NIFID cases. Upper and lower motor neuron signs, parkinsonism, and parietal symptoms were noted in both diseases, and involuntary movements in BIBD. Pathologically, severe caudate atrophy was consistently found in both diseases. Cerebral atrophy was distributed in the convexity of the fronto-parietal region in NIFID cases. In both BIBD and NIFID, the frontotemporal cortex including the precentral gyrus, caudate nucleus, putamen, globus pallidus, thalamus, amygdala, hippocampus including the dentate gyrus, substantia nigra, and pyramidal tract were severely affected, whereas lower motor neuron degeneration was minimal. While alpha-internexin-positive inclusions without cores were found in both NIFID cases, one NIFID case also had alpha-internexin- and neurofilament-negative, but p62-positive, cytoplasmic spherical inclusions with eosinophilic p62-negative cores. These two types of inclusions frequently coexisted in the same neuron. In three BIBD cases, inclusions were tau-, alpha-synuclein-, alpha-internexin-, and neurofilament-negative, but occasionally p62-positive. These findings suggest that: (1) the clinical features and distribution of neuronal loss are similar in BIBD and NIFID, and (2) an unknown protein besides alpha-internexin and neurofilament may play a pivotal pathogenetic role in at least some NIFID cases.
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PMID:Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. 1808 Jan 29

Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2+/-8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.
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PMID:Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. 1996 41

How are biological structures maintained in a cellular environment that constantly threatens protein integrity? Here we elucidate proteostasis mechanisms affecting the Z disk, a protein assembly essential for actin anchoring in striated muscles, which is subjected to mechanical, thermal, and oxidative stress during contraction [1]. Based on the characterization of the Drosophila melanogaster cochaperone Starvin (Stv), we define a conserved chaperone machinery required for Z disk maintenance. Instead of keeping Z disk proteins in a folded conformation, this machinery facilitates the degradation of damaged components, such as filamin, through chaperone-assisted selective autophagy (CASA). Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62. CASA is thus distinct from chaperone-mediated autophagy, previously shown to facilitate the ubiquitin-independent, direct translocation of a client across the lysosomal membrane [2]. Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men. Our findings reveal the importance of chaperone-assisted degradation for the preservation of cellular structures and identify muscle as a tissue that highly relies on an intact proteostasis network, thereby shedding light on diverse myopathies and aging.
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PMID:Chaperone-assisted selective autophagy is essential for muscle maintenance. 2006 Feb 97

Post-polio syndrome (PPS) develops in approximately 30% of polio survivors several decades after the acute attack of paralytic poliomyelitis. Some of these patients develop post-poliomyelitis muscular atrophy (PPMA) which is characterized by a slowly progressive muscle weakness. Due to its clinicopathological features, investigators have often studied PPS and PPMA in association with amyotrophic lateral sclerosis (ALS), the underlying hypothesis being an increased risk of developing ALS from a prior acute paralytic poliomyelitis. Various studies, however, have indicated that de novo ALS cases in patients with prior acute paralytic poliomyelitis are rare. Herein, we describe a rare case of a 75-year-old woman who at post-mortem examination presented a combination of a PPS with proven histopathological sporadic ALS features. Furthermore, neuropathology of this case also revealed several other histopathological findings reminiscent of a tauopathy, synucleinopathy and amyloid angiopathy and a large pituitary cyst. To our knowledge, this is the first reported case of PPS with clear pathological hallmarks of sporadic ALS, including ubiquitin-, TDP-43, phosphorylated TDP-43- and p62-positive inclusions, with accompanying features compatible with Alzheimer's and Parkinson's disease.
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PMID:Concomitant CNS pathology in a patient with amyotropic lateral sclerosis following poliomyelitis in childhood. 2154 74

The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.
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PMID:An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. 2239 26

Inclusion body myositis is an inflammatory myopathy characterized pathologically by rimmed vacuoles and the accumulation of amyloid-related proteins. Autopsy studies in these patients, including histochemical examinations of multiple skeletal muscles, have not yet been published. In this paper, we describe the autopsy findings of a patient with inclusion body myositis and hypertrophic cardiomyopathy. A 69-year-old man, who was a human T lymphotropic virus type 1 carrier, exhibited slowly progressive muscle weakness and atrophy, predominantly affecting the scapular, quadriceps femoris, and forearm flexor muscles. His disease course was more rapidly progressive than that typically observed; the patient died suddenly of arrhythmia 5 years after diagnosis. Autopsy findings revealed that multiple muscles, including the respiratory muscles, were involved. Longitudinal studies revealed an increased frequency of rimmed vacuoles and p62/sequestosome 1- and/or TAR DNA-binding protein 43-positive deposits in autopsied muscles, although the amount of inflammatory infiltrate appeared to be decreased. We speculated that muscle degeneration may be more closely involved in disease progression compared with autoimmunity. Genetic analysis revealed a myosin binding protein C3 mutation, which is reportedly responsible for familial hypertrophic cardiomyopathy. This mutation and human T lymphotropic virus type 1 infection may have affected the skeletal muscles of this patient.
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PMID:Inclusion body myositis coexisting with hypertrophic cardiomyopathy: an autopsy study. 2256 May 14

Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.
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PMID:mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. 2325 Sep 13

A large Italo-Spanish kindred with autosomal-dominant inheritance has been reported with proximal limb and axial muscle weakness. Clinical, histological and genetic features have been described. A limb girdle muscular dystrophy 1F (LGMD1F) disease locus at chromosome 7q32.1-32.2 has been previously identified. We report a muscle pathological study of two patients (mother and daughter) from this family. Muscle morphologic findings showed increased fiber size variability, fiber atrophy, and acid-phosphatase-positive vacuoles. Immunofluorescence against desmin, myotilin, p62 and LC3 showed accumulation of myofibrils, ubiquitin binding protein aggregates and autophagosomes. The ultrastructural study confirmed autophagosomal vacuoles. Many alterations of myofibrillar component were detected, such as prominent disarray, rod-like structures with granular aspect, and occasionally, cytoplasmic bodies. Our ultrastructural data and muscle pathological features are peculiar to LGMD1F and support the hypothesis that the genetic defect leads to a myopathy phenotype associated with disarrangement of the cytoskeletal network.
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PMID:Ultrastructural changes in LGMD1F. 2398 Dec 53

The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresome-autophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation.
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PMID:Aggresome-Autophagy Involvement in a Sarcopenic Patient with Rigid Spine Syndrome and a p.C150R Mutation in FHL1 Gene. 2519 Dec 66


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