Bones and joints. Markéta Hermanová osteoklast Inherited diseases nAchondroplasia -AD, single gene disorder (gene for fibroblast growth factor receptor) -short stature,rhizomelic shortening of the limbs, frontal bossing, midface deficiency - nOsteopetrosis -reduced osteoclast bone resorption, diffuse symmetric skeletal sclerosis -bones abnormaly brittle (osteosclerosis fragilis generalisata) -AR malignant type and AD benign type -Anemia (reduced bone marrow space), extramedullar hemopoiesis – hepatosplenomegaly, repeated infections, fractures, cranial nerves problems – the result of nerve compression (optic atrophy, deafness, facial paralysis) - nMucopolysacharidoses -enzymes (acid hydrolases) degrading dermatan, heparan, and keratan sulphates deficiences -chondrocytes (playing a role in the metabolism of extracellular matrix mucopolysacharides) most severly affected; also bones, skin, connective tissues and corneas affected -abnormalities of hyaline cartilage result in short stature, chest wall abnormalitites, malformed bones -type I (Hurler disease) and IV n - - n Inherited diseases - ntype 1 collagen disease (osteogenesis imperfecta types 1-4) -phenotypically related disorders; variable severity of the disease within the types -clinically: bone fragility, hearing loss, blue sclerae, dentinogenesis imperfecta; variable severity of the disease within the types - ntype 2, 10, and 11 collagen diseases -achondrogenesis (short trunk, severely shortened extremities, relatively enlarged cranium, flattened face) -hypochondrogenesis (similar phenotype) -multiple epiphyseal dysplasia (short or normal stature, small epiphyses, early onset osteoarthritis) -metaphyseal chondrodysplasia (coxa vara, bowing of lower extremitites, metaphyseal flaring) - n Regulation of calcium metabolism nParathyroid hormone (PTH) nVitamin D -to stimulate bone calcium mobilisation (PTH) -to increase renal reabsorption of calcium in the distal tubule (PTH, vitamin D) -to stimulate intestinal calcium and phosphate absorption (vitamin D) - nCalcitonin -produced by parafollicular cells of the thyroid -to lower serum calcium, if elevated n Hyperparathyreoidism: fibrous osteodystrophy, osteitis cystica fibrosa, von Recklinghausen disease of bones nHyperparathyreoidism (↑PTH): causes increased osteoclastic breakdown of bone -primary: hyperplasia, tumor (adenoma) -secondary: in hypocalcemia resulting in increased secretion of PTH n (e.g. in renal failure: renal osteodystrophy (combination of n osteomalacia and ↑PTH) -secretion of PTH related peptide by malignant tumor n nentire skeleton affected, osteitis fibrosa cystica now very rare n nthin cortex, osteopenia, fibrovascular tissue within bone marrow spaces, hemorrhages, organisation of hematoms, pseudocysts, brown tumors (mass of reactive tissue) n - n Pathologic fracture and brown tumor WHO-Bone Tumours_03 WHO-Bone Tumours_04 Renal osteodystrophy nhigh turnover osteodystrophy (high osteoclastic and osteoblastic activity) nlow turnover osteodystrophy (low activity; adynamic, aplastic disease) nosteomalacia nmixed picture of the renal osteodystrophy n n nchronic renal diseases: -phosphate retention and hyperphosphatemia -hypocalcemia (avitaminosis D) -secondary hyperparathyreoidism -metabolic acidosis stimulating also bone resorption -aluminium deposition at the site of mineralization (dialysis solution); Al interferes with the deposition of calcium hydroxyapatite promoting osteomamacia -amyloid deposition in bones and periarticular structures (β2 mikroglobulin) in patients on long-term dialysis n Rickets and osteomalacia nDue to deficient mineralisation of organic bone matrix n nIn sites of enchondral, endostal and periostal ossification; results in excess of unmineralized matrix n nDue to lack of active metabolites of vitamin D n nHypovitaminosis D due to dietary deficiency of vitamin D, lack of sunlight, intestinal malabsroption, failure to metabolise vitamin D (in renal and liver diseases, in congenital enzyme deficiences) n n n n Rickets and osteomalacia nRickets occurs in growing children and causes bone deformities; inadequate provisional calcification of epiphyseal cartilage, persisted masses of cartilage, osteoid matrix on inadequately mineralized cartilaginous remnants, abnormal overgrowth of capillaries and fibroblasts in the disorganized zones because of microfractures, deformation of skeleton (caput quadratum, pigeon breast deformity, rachitic rosary, lumbar lordosis, bowing of the legs,…) n nOsteomalacia occurs in adults, causes susceptibility to fracture but few deformities; inadequate mineralization of newly formed osteoid matrix – weak and vulnerable bones (bone trabecules rimmmed by unmineralized osteoid) n nVitamin D resistent rickets and osteomalacia -hypophosphatemic osteomalacia -inhibition of mineralization by fluor, aluminium, diphosphonates -oncogenic osteomalacia (small cell carcinoma produces phosphaturic substance) n n Moller-Barlow disease – avitaminosis C nvitamin C – hydroxylation of molecules of procollagen n ndecreased secretion of collagen by fibroblasts and osteoblasts n nhemorrhages, subperiostal hematomas, bleeding into joint spaces n ndecreased production of osteoid and proliferation of cartilage (mineralization normal) – infractions, fractures, lysis epiphyseos, periostitis ossificans n Paget disease (osteitis deformans) 1.osteolytic stage 2.osteoclastic-osteoblastic stage 3.osteosclerotic stage 4. nEtiology?? nslow virus infection (paramyxovirus) – viral particles seen in osteoclasts nhereditary component (linked to locus on 18q) n nPagetic bone enlarged with thick, coarsened cortices and cancellous bone nClinically pain, deformities, fractures, nerve compression nMonoostotic – Polyostotic (15 %) nHigher incidence of tumors and tumor-like lesions n n paget Osteoporosis nReduction of bone mass in the presence of normal mineralisation; due to increased bone resorption, decreased bone formation, or both n nCommon in elderly, particularly in females, follows any form of immobility n nComplication of steroid therapy and Cushing´s syndrome n nAssociated with alcoholism, diabetes, livers disease and smoking n nCommon predisposing factor of fractures, particularly neck of femur, causes skeletal deformities and bone pain (due to compression fractures) n Osteoporosis: increased porosity of the skeleton resulting from reduced bone mass nPrimary -postmenopausal -Senile n nSecondary n1. Endocrinopathies -hyperparathyreoidism -hypo-hyperthyreoidism -hypogonadism -pituitary tumors -type I diabetes mellitus -Addison disease n2. Neoplasia (multiple myeloma, carcinomatosis) n3. GIT disorders (malnutrition, malabsorption, hepatic insufficiency, vit. C,D deficiencies) n4. Rheumatologic diseases n5. Drugs (anticoagulans, chemotherapy, corticosteroids, alcohol, anticonvulsants) n6. Miscellaneous (osteogenesis imperfecta, immobilisation, pulmonary diseases, homocystinuria, anemia) - n Osteomyelitis nInflammatory lesion due to bacterial infection of bone nBacteria enter bone either from blood or directly through skin wound over a compound fracture nNecrotic bone forms inner sequestrum nReactive new bone forms outer involcurum nMost common in children (most usual Staphylococcus aureus infection) nA complication of advanced tuberculosis nMay complicate the use of internal fracture fixation divices n Osteomyelitis Infections - osteomyelitis nPyogenic osteomyelitis -Staphylococcus a., E. coli, Pseudomonas, Klebsiella, Haemophilus i., Salmonella,… -acute, subacute, chronic -acute inflammatory reaction, subperiostal abscess, necrosis (sequestrum), draining sinus -chronic osteomyelitis: reactive periostitis ossificans (involcurum) - nTuberculous osteomyelitis -hematogenous spread of BK into bones (rarely direct extension or lymphogenous spread) -Pott disease in the spine n nSkeletal syphilis -STD, Treponema pallidum -congenital syphilis (spirochetes localized in areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis) -acquired syphilis (tertiary stage; reactive periostitis: nose, palate, skull, extremities – tibia – saber shin) - Avascular necrosis: osteonecrosis nIdiopathic (m. Perthes – femur, m. Kohler – os naviculare) nTraumatic (mechanical vascular interruption, fracture) nCorticosteroids nInfections nDysbarism (nitrogen bubbles) nRadiation therapy (vessel injury) nConnective tissue disorders (vasculitis, vessel injury) nPregnancy nGaucher disease nSickle cells and other anemias nAlcohol abuse nChronic pancreatitis nTumors nEpiphyseal disorders Bone tumors and tumor-like lesions nBone-forming tumors n nCartilage-forming tumors n nFibrous and fibro-osseous tumors n nEwing sarcoma and primitive neuroectodermal tumor (PNET) n nGiant cell tumor (osteoclastoma) Secondary – metastatic tumours nMetastases in adults: -carcinomas of prostate, breast, kidney, lung,…. n nMetastases in children: -neuroblastoma, Wilms tumor, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma,… n nMetastases: -lytic – secrets (PG, IL, PTHRP,…) stimulating ostaeoclastic bone resorption (e.g. carcinomas of kidney, lung, GIT, melanoma,…) -osteoblastic (prostatic cancer) -mixed lytic and osteoblastic n Bone forming tumors - benign nOsteoma -facial and skull bones -solitary or multiple (Gardner syndrome: osteomas, intestinal polyps, benign STT) -bosselated round to oval sessile tumors -waven and lamelar bone in a cortical patterns with haverian-like systém - nOsteoid osteoma -< 2 cm, painful (excess of PG E2 produced by proliferating osteoblasts) -teenagers -appendicular skeleton (femur, tibia,…), cortex>medulla; M:F=2:1 -centrally nidus (trabeculae of woven bone rimmed by osteoblasts); rimmed by reactive sclerotic bone n nOsteoblastoma -> 2 cm -no rim of sclerotic bone -locally aggressive -spine and long bones -pain no responsive to salicylates n Bone forming tumors – malignant nOsteosarcoma -malignant mesenchymal tumors with neoplastic cells producing bone matrix -75 % in patients under 20 -in older patients often associated with Paget´s disease, bone infarcts and prior irradiation (secondary tumors) -metaphyses of long bones (60 % knee) -intramedullary, intracortical or surface -abnormalities of RB gene, p16, p53, p21, cyclinD1, mdm2, CDK4,… -osteoblastic, chondroblastic, fibroblastic, teleangiectatic, small cell, giant cell -clinically painful, enlarging masss, pathologic fracture -destruction of cortex, soft tissue masses, periostal bone formation (Codman triangle) -hematogeneous spreading (metastases in lungs, bones, brain,…) - - - Osteosarcoma WHO-Bone Tumours_08 WHO-Bone Tumours_07 Cartilage-forming tumors nOsteochondroma (exostosis osteocartilaginea) -metaphysis of long bones (knee) near the growth plate -solitary or multiple (hereditary exostosis-AD) -mushroom shaped covered by benign hyaline cartilage and perichondrium, 1-20 cm, growth based on enchondral ossification -rarely giving rise to chondrosarcoma n nChondroma -enchondroma (within medullar cavity) or juxtacortical chondromas n (subperiostal) -Ollier disease - multiple enchondromas with a risk of malignization -Maffucci syndrome – multiple enchondromas with a risk of malignization + soft tissue hemangiomas -Nodules of hyaline cartilage surrounded by a thin layer of reactive bone nChondroblastoma -young patients, teens, M:F=2:1 -epiphyses (knee), pelvis, ribs -sheets of compact polygonal chondroblast, hyaline matrix (if calcified – chicken-wire pattern of hyalinization) , nodules of hyaline cartilage, osteoclast-type giant cells, hemorrhagic cystic degeneration n nChondromyxoid fibroma -teens and twenties, M>F -metaphysis of long tubular bones, 3-8 cm, lobular, chondromyxoid tissue with spindle or stellate cells; more cellular at the periphery of lobules, often with osteoclast-type cells - nChondrosarcoma -patients more than 20, usually more than 40 -pelvis, shoulder, ribs -de novo or malignization of enchondromas, osteochondromas, chondroblastomas, fibrous dysplasia, or setting in Paget´s disease -painful, progressively enlarging mass, thickening of the cortex, destruction of the cortex and soft tissue mass; metastatic spread into lungs and skeleton (often late metastatic spread) -malignant hyaline and myxoid cartilage, nodular arrangement; variants: juxtacortical, dedifferentiated, clear cell n Chondrosarcoma and chondroma WHO-Bone Tumours_13 Fibrous and fibro-osseous tumors nFibrous cortical defect and non-ossifying fibroma (metaphysal fibrous defect) -distal femur and proximal tibia, also bilateral and multiple -lytic lesions -self-limited FCD; progressively growing NOF -proliferation of fibroblasts (often storiform pattern), histiocytes (multinucleated giant cells, clusters of foamy macrophages) nFibrous dysplasia -monoostotic, polyostotic, McCune-Albright syndrome (polyostotic FD, café au lait sin pigmentation, endocrinopathies) -circumscribed, intramedullary -curvilinear trabeculae of woven bone and moderately cellular fibroblastic proliferation, sometimes nodules of hyaline cartilage; cystic degeneration, hemorrhages, foamy macrophages nFibrosarcoma -older people, long bones -malignant fibroblast in a herringbone pattern nMalignant fibrous histiocytoma -older patients, long bones -spindle fibroblasts, storiform pattern admixed with bizarre, large, multinucleated tumor giant cells Miscellaneous tumors nEwing sarcoma and primitive neuroectodermal tumor (PNET) -small round cell tumors of the bones and soft tissues -6-10 % of primary bone tumors -80 % patients under 20, M>F -translocations (t(11;22), t(7;22), t(21;22)); fusion of EWS gene with a member of ETS family of transcription factor; result in chimeric protein which acts as a constitutively active transcription factor stimulating cell proliferation -diaphyses of long tubulary bones and pelvis; arising in medullary cavity invading the cortex, periostium and soft tissues -lytic lesion, periostal reaction – reactive bone in an onion-like fashion -neural differentiation, Homer-Wright rosettes - nGiant cell tumor (osteoclastoma) -locally agressive, osteolytic, large, red brown, often cystically degenerated; high recurrence rate, potentially malignant (5 %) -proliferating mononuclear cells, osteoclast-type giant cells, necrosis, hemorrhage, hemosiderin deposits, reactive bone formation -epiphyses of long bones -between 20 and 40 -differential diagnosis: brown tumor in hyperparathyreoidism, giant cell reparative granuloma, pigmented villonodular synovitis, chondroblastoma - n Giant cell tumor - osteoclastoma WHO-Bone Tumours_05 WHO-Bone Tumours_06 Malignant tumours of the bone Tumor % Usual age M:F Sites affected Behaviour Treatment, prognosis Osteosarcoma 30 Adolescents 2:1 Long bones, distal femur, proximal tibia Rapid growth, pain, swelling, lung metastases Surgery and chemotherapy 40% + cure rate Chondrosarcoma 15 35-60 2:1 Pelvis, ribs, spine, long bones Slow enlargement, lung metastases Surgery 75% cure rate Fibrosarcoma 20 Any age, peak 30-40 3:2 Femur, tibia, humerus, pelvis Local growth, vascular invasion Surgery 40% cure rate Ewing´s sarcoma 7 Children and teenagers 2:1 Long bones, pelvis, ribs Widespread metastases Surgery and chemotherapy 50% + cure rate + secondary, metastatic tumors: breast, lung, prostate, kidney, thyroid cancer,….. + osteolytic lesions in myeloma (plasmocytoma) Pathology of the Joints Osteoarthritis (osteoarthrosis) nCommon painful, disabling degenerative joint disease n nPrimarily affects cartilage of weight-bearing joints (e.g. hips, knees) n nErosion of cartilage leads to secondary changes in underlying bone n nOnly limited inflammatory changes in synovial membrane n nOsteoarthritis of hip and knee can be treated surgically by joint replacement Osteoarthritis (degenerative joint disease) nnon-inflammatory degenerative disease; progressive erosion of cartilage; secondary changes: inflammatory and reactive changes in synovial membranes and the adjacent bones n naging and mechanical defects, genetic factors n ndeep achy pain, morning stiffness, crepitus and limitation of range of movement n nproliferation of chondrocytes, biochemical changes of matrix, vertical and horizontal fibrillation and cracking of the matrix, degradation of superficial layers of cartilage, bone eburnation, sclerosis of underlying bone, formation of loose bodies, synovial fluid in subchondral regions – pseudocysts, osteophytes at the margins of the articular surface n n Rheumatoid arthritis na chronic systemic inflammatory disorder affecting also joints n na nonsuppurative proliferative, inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints n nautoimmune disease, in a genetically susceptible host; 95 % RA patients have positivity of rheumatoid factor (IgM against Fc fragment of IgG – immunocomplexes); F>M n nsmall bones of the hands, wrist, ankels, elbows, knees, cervical spine, hips affected; lumbosacral region spared n n Rheumatoid arthritis nsystemic features include: subcutaneous rheumatoid nodules, anaemia, lymphadenopathy and splenomegaly, serositis (e.g. pericarditis), Sjögren syndrome, uveitis, vasculitis,…. njuvenile rheumatoid arthritis: children can be also affected n RA pannus Seronegative spondylarthropathies: spondylarthropaties assoc. with HLA-B27 haplotype nAnkylosing spondylitis -Inflammatory disorder of spinal joints -Chronic synovitis, destruction of cartilage, bony ankylosis (sacroiliac and apohyseal joints), ossification of tendinoligamentous insertion -Fusion of vertebral bodies inhibits flexion and rotation, especially in cervical segment, some patients develop fixed spinal deformities -90 % of cases have the HLA-B27 haplotype -Systemic feature include peripheral arthritis, uveitis, chronic inflammatory bowel disease - nReiter´s disease -arthritis + conjuctivitis + urethritis -80 % HLA-B27+; autoimmune reaction initiated by prior infection -infections of genitourinary (Chlamydia) and GIT (Shigella, Salmonella, Yersinia, Campylobacter) n n+ arthritis in psoriasis (distal interphalangeal joints); in IBD (inflammatory bowel disease) - - Ankylosing spondylitis nBacterial arthritis -Staphylococcus aureus -Staphylococcus albus (prosthetic joints) -Streptococcus pyogenes -Haemophilus influenzae -Diplococcus pneumoniae -Neisseria gonorrhoeae n ntbc arthritis -complication of tbc osteomyelitis or hematogenous dissemination from a visceral site of infection n nLyme arthritis -Borrelia burgdorferi (transmitted by ticks) n nVirus-associated arthritis -parvovirus B19, rubella, HCV n nInfective discitis -Staphylococcus aureus, Mycobacterium tuberculosis, Brucella abortus n - Infective arthritis Rheumatic arthritis – rheumatic fever nan acute immunologically mediated multisystem inflammatory disease occuring a few weeks after an episode of group A streptococcal pharyngitis n nmigratory polyarthritis of large joints npancarditis n n !!! Rheumatic fever: immunologically mediated post-streptococcal illness affecting heart and joints Rheumatoid disease: autoimmune disorder causing arthritis, completely unrelated to rheumatic fever Gout dna -Painful acute inflammatory response to tissue deposition of urate crystals -Most commonly affects metatarsopahlangeal joint of first toe -Much more common in males than females, onset 40-60 years, familial tendency -Serum auric acid levels are raised -May be associated with chronic renal disease Pathogenesis: -Idiopathic -Impaired uric acid excretion secondary to chronic renal failure, thiazide diuretics -Increased uric acid production (in increased cell turnover, in specific enzyme defects) -High dietary purine intake Tumor-like lesions of the joints nGanglion -near a joint capsule, wrist, pea-sized nodule -result of cystic and myxoid degeneration of connective tisuue n nSynovial cysts -herniation of synovium or enlargement of a bursa -poplitesal space – Baker cyst - nOsteochondral loose bodies -in degenerative joint disease n Tumors of the joints nPigmented villonodular synovitis -benign neoplasm -one or more joints, diffusely involved (knee) -red brown folds, finger-like projections, nodules, synovialocytes, hemosiderin deposits, foamy macrophages, multinucleated gint cells, zones of sclerosis; erosion of the bone - nGiant cell tumor of tendom sheat -localised nodular tendosynovitis, disrete nodule on a tendon sheath n nSynovial chondromatosis n- multiple intrasynovial chondromas or ossifying chondromas n nSynovial sarcoma -soft tissue tumor -dual line of differentiation (epithelial-like and spindle cells); rarely monophasic -t(X;18) -metastases into lungs - n Connective tissue diseases, systemic nMultisystem disorders, often affecting joints, skin, subcutaneous tissues n nFemales preferentially affected (except polyartheritis nodosa ans ankylosing spondylitis), weak genetic tendency n nChronic clinical course, may respond to antiinfalmmatory drugs, immunosuppressive drugs (e.g. steroids) n nFirst presentation may be during adolescence or early adult life n nImmunological abnormalities often present (circulating auto-antibodies or evidence of immune complexes) Clinical and pathological features of the major connective tissue diseases Disease F:M Age (onset) Clinical features Immune abnormality Pathology Rheumatoid arthritis 3:1 Young and middle aged adults, also children Chronic polyarthritis Subcutaneous nodules Splenomegaly autoAb against native Ig (rheumatoid factor) Chronic synovitis Granuomas in subcutaneous tissues Fibrinous pericarditis Systemic lupus erythematosus 8:1 Young and middle aged adults Erytematous (butterfly) skin rash Renal disease, glomerular damage Light sensitivity Arthritis, arthralgia. Anaemia, leukopenia autoAb against nuclear and cytoplasmic proteins and other cellular component Synovitis, glomerulonephritis, erytematous skin rashes Polyarteritis nodosa 3:1 Any age, chiefly middle aged adults Arthralgia Abdominal pain Ischaemic lesions in many organs, neuropathy, renal damage Fever, Leukocytosis, eosinofilia Some antinuclear antibodies and rheumatoid factor Necrotising vasculitis of medium-sized arteries Ankylosing spondylitis 2:1 Young adults Back pain Arthritis Uveitis Most HLA-B27+ Spondylitis, bony fusion of spine and SI joints Clinical and pathological features of the major connective tissue diseases Disease F:M Age at onset Clinical features Immune abnormality Pathology Poly- and dermatomyositis 3:1 Adults (DM also in children) Muscle weakness, pain, tenderness, skin rashes in DM Myositis assoc. autoAb Inflammatory myositis, in some cases paraneoplastic Polymyalgia rheumatica 2:1 Elderly Malaise, weakness, muscle aching, esp. shoulders, pelvis, hips No consistent changes Raised ESR Non specific muscle biopsy changes, some overlap with temporal arteritis Temporal, giant cell arteriis 2:1 Elderly Headache Visual loss Tender scalp No consistent changes Raised ESR Chornic granulomatous arteritis, head and neck arteries Systemic sclerosis (scleroderma) 3:1 30-50 years Raynaud´s phenomenon Thick skin Polyarthritis Dysphagia. Dyspnoe. Hypertension RF (25 %) Antinuclear Ab (50 %) Fibrosis of subcutaneous and submucosal tissue, fibrosis of muscular arteries Skeletal muscle pathology: Neuromuscular disorders Muscle biopsy nSpecialized laboratories in departments of pathology (FN Motol) nGuided using imaging and results of clinical assessment nOpen versus needle biopsy nStandard histological techniques, enzyme histochemistry nImmunohistochemistry and immunoblotting -panel of antibodies -evaluation of primary and secondary changes on immunoanalysis nDirection of reasonable mutational analysis n n n sval-herm-10772-03-20x-nadh-2 sval-herm-16368-03-20x-he-1 Lobulated fibers in LGMD2A Dystrophic features in biopsy Neuromuscular disorders nNeurogenic disorders – neurogenic atrophy n nDisorders of neuromuscular transmission n nMyogenic disorders -Muscular dystrophies -Congenital structural myopathies n nInflammatory myopathies – myositis n nMyopathies associated with metabolic diseases -Glycogenosis (glycogen storage diseases) -Carnitine deficiency -Mitochondrial disorders n nOthers -myopathies in endocrinopathies (thyreotoxic and hypothyreoid myopathy, steroid myopathy,… ) -drug induced myopathy (steroid myopathy, myopathy in patients treated with hydrochloroquine,…) -ethanol myopathy - n n - - Myopathies associated with inborn errors of metabolism (1) nGlycogen storage disease n nType IIa ; AR, Pompe´s disease; acid maltase deficiency nTyp IIb; XR, X linked vacuolar cardiomyopathy and myopathy ; Danon´s disease, LAMP 2 deficiency (lysosome associated membrane protein) nTyp IV; AR, Andersen´s disease; brancher enzyme deficiency nTyp V; AR, McArdle´s disease; muscle phosphorylase deficiency nTyp III (debrancher deficiency), Typ VII (phosphofruktokinase deficiency) Storage of glycogen in muscles in glycogenosis (inherited; AR) nPAS+ (glycogen) n 52-b22b PAS Myopathies associated with inborn errors of metabolism (2) nLipid myopathies -carnitine palmitoyl-transpherase deficiency -carnitine deficiency n nMitochondrial myopathies (oxidative phosphorylation diseases) n (mt DNA, nuclear DNA) n n n n n n n 53-b23a 54-b23b 55-b26 06-04-27-1 Carnitine palmitoyl-transpherase deficiency: accumulation of neutral lipids Mitochondrial myopathy: lamelar mitochondrial inclusion Ragged red fiber in mitochondrial myopathy Neurogenic disorders (denervation atrophy) nMotor neuron diseases -Amyotrophic lateral sclerosis -Spinal muscular atrophy - nRadiculopathies -discopathies -extramedullar tumors -polyradiculoneuropathy-immune mediated-Guillain-Barré syndrome – demyelinating disorder n nDamage of peripheral nerves/peripheral neuropathies n inflammatory, traumatic, metabolic (diabetic), toxic, genetic (hereditary motor and sensory neuropathies), neoplastic n n n n Motor neuron tract Upper motoneuron Lower motoneuron Types of muscle fibers reaction 1 (SO) Slow oxidative 2A (FOG) Fast oxidative glycolytic 2B (FG) Fast glycolytic mATPasa (pH 9,4) - + + mATPasa (pH 4,6) + - + mATPasa (pH 4,3) + +/- - NADH-TR and SDH + +/- - 09-f02 12-e12 15-e04 13-b07b Group atrophy of muscle fibers in neurogenic lesion 14-b07c Type I group atrophy of muscle fibers Motor neuron diseases -Amyotrophic lateral sclerosis n (both upper and lower motorneurons affected, distal and proximal muscle weakness and wasting spasticity) n -Progressive muscular atrophy n (lower motor neuron involvement, weakness an wasting of distal muscles, fasciculations and absent reflexes) n -Progressive bulbar pulsy n (cranial nerves involvement results in weakness of the tongue, palate, pharyngeal muscles) n Amyotrophic lateral sclerosis n90 % sporadic ALS nM:F – 1,7:1 nolder people, survival 3-4 years, first symptoms in 56-63 years, upper extremities preferentially affected, bulbar symtomatology n n10 % hereditary ALS n4th decade, juvenile forms, F:M – 1:1 Spinal muscular atrophy nInherited; AR; homozygous loss of SMN1 (survival motor neuron gene) n noccuring in 1/6000-10000 births; 2-3 % of populations are carriers n n2nd most common inherited disorder after cystic fibrosis (mucoviscidosis) n n n n Allelic variants of SMA nType 1 (Werdnig-Hoffmann disease) -Rapidly progressive, onset before 3 months of age, death before the age of 18 months - nType 2 -Onset between 6-12 months of age, more slowly progressive with variable life expectancy - nType 3 (Kugelberg-Welander disease) -Onset between 2-15 years of age, slowly progressive - nType 4 -Affects adults, very slow course causing mild disability n n 19-f04 Spinal muscular atrophy Type I fiber hypertrophy Peripheral neuropathy: peripheral nerve disorders nMononeuropathy -a single nerve involved -e.g. carpal tunnel syndrome - nMononeuritis multiplex -several isolated nerves involved -e.g. polyarteritis nodosa, sarcoidosis n nPolyneuropathy: multiple nerve involvement nMainly motor: e.g. Guillain-Barre sy (autoimmune polyradiculoneuritis) nMainly sensory: carcinomatous neuropathy nSensorimotor: e.g. alcoholism nAutonomic: e.g. diabetes Intervertebral disc prolapse Disorders of neuromuscular transmission nMyasthenia gravis -autoimmune disease, loss of acetylcholine receptor due to production of autoAb -fluctuating progressive muscle weakness (ocular, bulbar and proximal limb muscles preferentially affected) -females more often affected -thymic hyperplasia or thymoma in many patients -immunosuppressive treatment and thymectomy n nLambert-Eaton myasthenia syndrome -paraneoplastic, complication of malignancy (e.g. lung cancer – small cell carcinoma) -limb girdle and proximal muscle weakness -autoimmunity to calcium channels??? n Muscular dystrophies nheterogeneous group of inherited disorders of muscles n nprogressive muscle weakness and wasting n n„dystrophic“ muscle biopsy changes and replacement of muscle by fibrofatty tissue n ndefects in muscle proteins n nclinical and genetic heterogeneity n nsome are associated with multisystem involvement (including cardiac (arrhytmias, both dilated and hypertrophic cardiomyopathies) and CNS) n 26-g04 Muscular dystrophies nDystrophinopathies (X-linked) nLimb-girdle muscular dystrophies; LGMDs (AR, AD) nEmery-Dreifuss muscular dystrophy (X-linked, AD) nFacioscapulohumeral muscular dystrophy (AD) nCongenital muscular dystrophy (AR) nOculopharyngeal muscular dystrophy (AD) nDistal myopathy (AR, AD) nBethlem´s myopathy (AD) nBarth´s syndrome (X-linked) nMyotonic dystrophy (AD) n Diagnosis of muscular dystrophies nClinical assessment -general neurological examination -serum creatine kinase (CK) level -neurophysiology – electromyography (exclusion of neuropathy) -muscle imaging (MRI, CT) n nMuscle biopsy (2/3 genetically defined LGMD are suggested by biopsy) -histopathology -immunohistochemistry (IH), immunofluorescence (IMF) -immunoblotting n nMolecular genetic testing – mutational analysis (the gold standard for diagnosis) -DNA -mRNA -NGS Duchenne muscular dystrophy (DMD) nDue to severe mutations in dystrophin gene n nX-linked; female carriers n nMedian age of presentation: 3.5 years; progressive course; life expectancy 20 years; calf pseudohypertrophy n nMyogenic lesion in muscle biopsy, loss of dystrophin 29-b11a immunofluorescence, loss of dystrofin in DMD nBecker muscular dystrophy (BMD) nDue to in-frame deletion in dystrophin gene nMilder allelic variant of DMD nTruncated protein dystrophin is produced n nFemale carriers of DMD/BMD nSymptomatic nAsymptomatic n Limb-girdle muscular dystrophies nGenetically and clinically heterogeneous group of progressive muscular dystrophies n nMuscles of the pelvic and shoulder girdle are preferentially affected n n25 forms autosomal recessive (at least) n8 forms autosomal dominant n + AR, AD and X-linked muscular dystrophies with LGMD phenotype n fa-lgmd01 Classification of autosomal recessive LGMD (14) Disease Protein Gene Relative prevalence LGMD2A Calpain 3 CAPN3 worldwide (WW); eastern Europeans LGMD2B Dysferlin DYSF southern>northern Europe; Australia LGMD2C γ-Sarcoglycan SGCG WW, most frequent in Tunisia LGMD2D α-Sarcoglycan SGCA WW; most frequent sarcoglycanopathy LGMD2E β-Sarcoglycan SGCB northern and southern Indiana Amish LGMD2F δ-Sarcoglycan SGCD common in African-Brazilian LGMD2G Telethonin TCAP rarely outside Brasil LGMD2H TRIM32 TRIM32 Hutterite population of Canada LGMD2I Fukutin-related protein FKRP Northern Europe (826C>A) LGMD2J Titin TTN Only in Finland LGMD2K O-Mannosyl transferase-1 POMT1 Few cases in Turkey and England LGMD2L Anoctamin 5 ANO5 French-Canadian family LGMD2M Fukutin FKTN 5 families LGMD2N O-Mannosyl transferase-2 POMT2 Few reported + 13 recently described AR LGMD….. Classification of autosomal dominant LGMD (8) Disease Protein Gene Relative prevalence LGMD1A Myotilin MYOT 5q22-q34 > 15 families described LGMD1B LaminA/C LMNA 1q11-q21 Clinical syndromes: Emery-Dreifuss MD, LGMD1B, CMD with rigid spine, neuropathy (AR-CMT2A), quadriceps myopathy with dilated cardiomyopathy, Familial partial lipodystrophy, Mandibuloacral dysplasia, premature aging, lethal phenotype. LGMD1C Caveolin-3 CAV3 3p25 Clinical syndromes: LGMD1C, rippling muscle disease, idiopathic hyperCKaemia, distal myopathy LGMD1D ? 7q 2 families described LGMD1E ? 6q23 1 large family described: French Canadian descent LGMD1F ? 7q32 1 large family described: Spanish LGMD1G ? 4p21 1 family described: Brazilian-Caucasian LGMD1H ? 3p23 1 family described: Southern Italian family Sarcomere associated proteins 1134815-1170911-1344 Telethonin: LGMD2G Myotilin: LGMD1A Titin: LGMD2J Sarcolemmal proteins. Nuclear lamina structural complex. Glycosyltransferases. Sarcoglycans: LGMD2C-2F Caveolin-3: LGMD1C Dysferlin: LGMD2B Lamin A/C: LGMD1B FKRP: LGMD2I POMT1: LGMD2K POMT2: LGMD2N Fukutin: LGMD2M vertebratedevelopment_DGC2 Emery-Dreifuss muscular dystrophy ncontractures nslight progressive myopathy preferentially in humeroperoneal localisation narrthytmias nmild myogenic lesion in muscle biopsy nX-EDMD (Xq28): emerin nAD (resp. AR)-EDMD (11q11-23): lamin A a C 42-b14a IHC, normální exprese emerinu na jaderné membráně Congenital muscular dystrophies (CMD) nCongenital, presented at birth, progressive n nInherited, AR, genetically and phenotypically heterogeneous n nMuscle weakness, hypotonia, contractures; in some subtypes structural lesions of CNS and retina n n40 % of CMD: merosin deficient form (MDC1A); mutations in LAMA2 gene (a2 chain of merosin) n na-dystroglycanopathies – mutations in genes encoding glycosyltranspherases of a-dystroglycan (FCMD, MDC1C, MEB, WWS, MDC1D) n nmuscle biopsy: myogenic lesion, often degeneration, regeneration, and also inflammatory pattern in muscle biopsy Congenital structural myopathies nA distinctive abnormality in skeletal muscle fibres on the cellular level; observable via light microscope n nSymptoms of muscle weakness and hypotonia. n nIs a congenital disorder, meaning it occurs during development and symptoms present themselves at birth or in early life. n nIs a genetic disorder n nClinically and genetically heterogeneous n Congenital structural myopathies nCentral core disease nMulti and minicore disease nNemaline myopathy nCentronuclear myopathy nCongenital fibre type disproportion n n 47-b18 50-b21c Inflammatory myopathies -myositis nPolymyositis -females, autoimmune disease, ofted associated with other autoimmune diseases (anti-Jo-1 protilátky) -Endomysial inflammatory infiltration n nDermatomyositis -Juvenile and adult, more in females, dermatitis and myopathy -Perivascular inflammatory infiltration (CD20+, CD4+, MAC+) -Perifascicular atrophy - nMyositis/myopathy with inclusion bodies -Sporadic and hereditry -Resistent to imunosupresive therapy n 60-f07 Polymyositis: endomysial lymhocytic inflammatory infiltration Myotonia: the sustained involuntary contraction of a group of muscles; patients complain of stiffness, difficulties in releasing their grip n1. Myotonia congenita (reduction of functional chloride channels) -Becker type (AR) -Thomsen type (AD) - n2. Myotonic dystrophy -DM1 (AD; 19q13.3, myotonin proteinkinase) n congenital (dementia, hypotonia), classic (myotonia, muscle weakness, atrophy, cataract, endocrinopathies), milder form -DM2 (AD; 3q21; zinc finger protein)- PROMM – proximal myothonic dystrophy Malignant hyperpyrexia nInherited disorder; AD; diagnostic in vitro contraction test n nMutation in ryanodin receptor gene; association with central core disease n nHypermetabolic state triggered by the induction of anesthesia, usually with halogenated inhalational agents and succinylcholine n nTachycardia, tachypnoe, muscle spasms, hyperpyrexia; without intensive treatment fatal clinical outcome n nChannelopathy; increased levels of free calcium in sarcoplasms of myofibers Thank you for your attention….