Patho Unit 4

Serum Calcium Homeostasis

-maintained at 8.5-10.5mg/dL low concentrations= hypocalcemia -stimulates PTH to increase synthesis of calcitrol by stimulating 1-hydroxylase Opposing Endocrine Organs and Hormones regulate the Serum Calcium Concentration Calcitonin (thyroid) is secreted into the blood in response to increasingCa2+ levels Parathyroid hormone or PTH (parathyroid) is secreted into the blood in response to decreasing Ca2+ levels (1) Calcium is ingested in the diet, broken down by HCL in the stomach, and absorbed into the bloodstream via the intestine with facilitation by vitamin D. (2) When calcium levels are decreased in the blood, the parathyroid glands are stimulated to release PTH. (3) PTH acts at bone to activate osteoclasts to break down bone and release calcium, which raises the calcium level in the blood. When calcium levels normalize, the parathyroid receives feedback and shuts off. (4) Alternatively, high calcium levels in the blood stimulate the thyroid gland to release calcitonin. (5) Calcitonin activates osteoblasts to build bone.

osseous cells

Osteoclasts (klastos, broken) Remove and remodels bone matrix Secretes acids and enzymes to dissolve bone matrix (releases Ca2+) Osteoblasts (blast, precursor) Secretes new bone matrix (ossification) Deposits Ca2+ salts to produce mineralized bone Osteocytes Osteoblasts that have surrounded themselves with bone matrix Maintains surrounding bone matrix

compact v spongy bone

Osteon - functional unit of compact bone Central canal containing nerves and vessels Circular arrangement of osteocytes in lacuna surrounding the central canal Provides strength to bone Spongy (Trabecular) Bone Thin, branches of bone form a open network called trabeculae Red marrow is located between trabeculae

response to low serum calcium

Parathyroid gland cells detect low serum (blood) Ca2+ Parathyroid gland secretes parathyroid hormone which has 3 effects on target organs: Kidney: Stimulates Ca2+ absorption from forming urine; stimulates Calcitriol (hormone) secretion GI Tract: Calcitriol stimulates increased Ca2+ absorption from diet Osteoclasts: PTH stimulates osteoclast digestion of bone matrix releasing Ca2+ into the blood PTH increases serum Ca2+

gout pathophysiology

Pathophysiology •Excessive uric acid accumulation from cellular purine metabolism •Renal injury, renal insufficiency or excessive accumulation of uric acid elevates uric acid levels •High uric acid levels in the tissues may precipitate and accumulate in soft tissues including the kidneys and the synovial cavity of joints •Urate crystal aggregates within the synovial joints initiate an inflammatory response, local tissue necrosis, and soft tissue hyperplasia

response to high serum calcium

Thyroid gland cells detect high serum (blood) Ca2+ Thyroid gland secretes calcitonin (a hormone) that has the effects on target following organs: Kidney: Inhibits Ca2+ absorption from forming urine; inhibits Calcitriolsecretion Osteoclasts: Calcitonin inhibits bone matrix digestion by osteoclasts allowing osteoblast to synthesize bone matrix (decrease serum Ca2+) Calcitonin decreases serum Ca2+

collagen fibers

allow for bone flexibility to resist fracture

Paget disease

•(also known as osteitis deformans) is the second most common metabolic bone disease after osteoporosis •can be described as a state of high bone turnover with abnormal bone production •A progressive disorder of the adult skeletal system characterized by abnormal bone remodeling due to: •Increased bone resorption by osteoclasts •Excessive, unorganized new bone formation by osteoblasts •Abnormal bone remodeling eventually replaces normal bone marrow and trabecular bone with vascular and fibrous tissue •The excessive, abnormally structured bone of Paget disease lacks the structural stability of normal bone, leading to complications such as: •Deformity •Fracture •Arthritis Pain •Incidence •Paget disease is a common disease of the aging population: •Rarely manifesting before age 35 •Increasing prevalence among adults older than age 50 (3% to 4% may be affected of the population older than age 50) •Both men and women are affected •Paget disease is often familial and has an unusual geographic distribution •Populations of the British Isles and countries where migration from Britain occurred have a greater incidence •Etiology •The cause of Paget disease is unknown: •Genetics of the disease is poorly understood •Paget disease is often inherited in an autosomal dominant pattern •No clear genetic susceptibility for the majority of cases •Environmental factors may also be responsible •Chronic viral infection

osteoporosis

•(literally "porous bones") is disorder of decreased bone mass and microscopic injury/degeneration of bone microanatomy •Loss of both bone mass, bone strength, and bone structure! •Osteoporosis is classified based upon underlying etiology: •Primary osteoporosis (most common form) has an unknown etiology, but is associated with negative calcium balance due to activity levels or endocrine dysfunction •Can occur in both genders at all ages, but often: 1) follows menopause in women and 2) occurs later in life in men •Primary osteoporosis has two subtypes 1) postmenopausal/estrogen-deficient (type 1) and Age-related/senile (type 2) •Secondary osteoporosis is associated with medications, other conditions, or diseases •Endocrine disorders, malabsorption, nutritional deficiency, etc. •Incidence •Osteoporosis is more common in women, especially postmenopausal women who are estrogen deficient •One in every two women older than age 50 will experience fragility fractures secondary to osteoporosis •One in four men will experience an osteoporosis-related fragility fracture during their lifetime •Etiology •Primary osteoporosis occurs due to many contributory factors •Mild and prolonged negative calcium balance •Declining gonadal and adrenal function •Relative or progressive estrogen deficiency •Sedentary lifestyle •Secondary osteoporosis is associated with long-term medication treatment, other conditions, or diseases •Prolonged therapy with corticosteroids, heparin, anticonvulsants, and other medications •Alcoholism, malnutrition, malabsorption, or lactose intolerance •Endocrine disorders •Risk factors •Peak bone mass occurs between age 25 and 35 years followed by increasing bone resorption and a reduced rate of bone formation •Many factors contribute to risk for osteoporosis: •Aging is characterized by multifactorial bone mass loss: declining adrenal and gonad hormone production; endocrine dysfunction; reduced physical activity •Genetics: Ethnic differences in bone mass and individual variation in bone mass •Immobility or physical inactivity: lack of weight-bearing exercise (disuse osteopenia) •Long-care facility residents have a 5 to 10-fold greater fracture risk •Nutrition: poor dietary habits; lack of calcium and vitamin D; GI tract disorders and disease •Lifestyle: tobacco use and chronic alcoholism •Medications: corticosteroid-use impairs osteoblast activity, intestinal calcium absorption, and increases osteoblast activity

osteomyelitis clinical presentation

•Adults: back pain is typically the chief complaint, but if infection spreads systemically, a low-grade fever may be present •Spinal osteomyelitis can produce intermittent or constant back pain •Radiculopathy, myelopathy, or complete paralysis can occur with neural compression as a result of abscess •Children: present with acute, severe complaints: •High fever and intense pain •Local manifestations predominate in some cases: such as edema, erythema, and tenderness. •Initial phases of osteomyelitis: pain may not be present due to lack of pain fibers in trabecular bone •Complicates diagnosis and allows the rapid spread of the pathogen making intervention difficult •Later phases of osteomyelitis: pain may be described as deep and constant, increasing with weight bearing when the infection is anywhere in the lower extremity •Chronic osteomyelitis presents with complaints of local pain and swelling, but otherwise are often asymptomatic

DDD clinical presentation

•Although DDD can cause disk herniation, DDD is a separate pathological entity from disc herniation •Signs and assessments are used to differentiate the disorders •DDD usually affects the lumbar spine, but can involve cervical spine as well: •Cervical DDD presents with neck pain, weakness, or numbness of the upper extremities •Lumbar DDD presents with back pain, weakness, or numbness in a lower extremity •Can involve gait abnormality, sciatica, and bladder/bowel dysfunction •Most patients experience the gradual onset of increasing severe midline lower back pain •Often intermittent and reoccurring •Diagnosis: •Physical examination with musculoskeletal and neurological evaluation of the back and extremities •Muscle strength •Deep tendon reflexes •Sensory dermatomes (sensory deficits due to nerve impingement or spinal cord injury) •MRI imaging of the spine allows assessment of degenerating bone, disks, soft tissues, and joints •CT scan imaging assessment of spondylolisthesis

MD clinical management

•Clinical Management •Prenatal diagnosis requires chorionic villi sampling or amniocentesis to perform genetic testing on fetal DNA •Postnatal diagnosis is based on clinical presentation, family history, and diagnostic testing (muscle imaging and biopsy, genetic testing, serum test for skeletal muscle enzymes and electromyography) •Important note: new, sporadic mutations cause 30% of cases of DMD (family history of DMD may not exist) •Treatment •DMD and other MD are progressive muscular degenerative diseases and no cure exists; primary treatment is supportive •Strength training is NOT helpful and may weaken and exacerbate the symptoms of MD •Contracture management using physical therapy (stretching, splinting, and casting) •Glucocorticoid therapy (steroidal anti-inflammatories) may slow the progression of injury, inflammation, and fibrosis/fatty tissue accumulation within the muscle

MD clinical presentation

•Clinical Presentation: all dystrophies present with muscular weakness, wasting, and hypotonia •We will focus on DMD (BMD presents similarly with a slower progression and longer life expectancy) •DMD is presents as a child with: •Difficulty getting up off the floor (Gower sign) •Falling frequently •Difficulty climbing stairs •Develops a waddling gait and increased lumbar lordosis •Gait changes continue as muscle weaken and fibrotic changes are induced •The child begins to walk on the toes because of contracture of the posterior calf musculature and weakness of the anterior tibial, peroneal, and proximal muscles •Ambulation continues to deteriorate up to age 10 to 12 years; at this time, most individuals with DMD are no longer able to walk •Other musculoskeletal abnormalities occur: •Shoulder girdle becomes involved with excessive scapular winging and shoulder and limb weakness •Lordosis and scoliosis develop •Restrictive respiratory impairment progresses to reduced ventilation and respiratory tract stasis leading to pneumonia or other respiratory infections and death by the third decade

osteoarthritis clinical management

•Clinical management •Prognosis: OA is a major contributor to functional limitations, disability, and immobility in adults older than 65; in addition to OA treatments, prevention and risk reduction is key •Diagnosis •OA is diagnosed by: history, physical examination, radiologic findings, and laboratory findings to exclude rheumatoid arthritis •Primary criteria used is specific for the affected joint (other joint possess similar criteria) •Knee OA is diagnosed by the presence of knee pain with at least 3 of the following: •Older than age 50 years •Morning stiffness lasting less than 30 minutes •Crepitus on motion •Bony tenderness •Bony enlargement •No palpable warmth over the knee joint •Kellgren and Lawrence criteria is used to classify stages of OA and the progression of the disease MRI findings are utilized to identify skeletal, articular cartilage, and soft connective tissue changes

ankylosing spondylosis clinical management

•Clinical management •Prognosis: disability of AS patient varies; fewer than 1% experience complete remission and the majority experiences periods of exacerbations and remissions •Onset of hip disease at a young age is a major prognostic marker for chronic severe disease •Treatment involves: •Mobility and posture management •Pain and anti-inflammatory medications •Immunosuppressive medications to reduce inflammation and progression to disability •Pharmaceutical management involves similar treatment modalities for RA

DDD clinical management

•Clinical management •Treatment •Conservative care involves: •NSAIDS and mild analgesics for pain control, physical therapy, physical activity, and lifestyle changes •Surgical intervention may be necessary, if conservative care is unsuccessful and/or neurological symptoms persist •Glucocorticoid and anesthetic injection to the injured area or spinal canal to reduce inflammation and edema •Surgical interventions: discectomy, laminectomy, and/or spinal fusion to remove tissue causing nerve tissue compression and support the vertebral column

gout clinical management

•Clinical management •Treatment goals are to: •1) Prevent recurrent gout attacks •2) Correct hyperuricemia •Dietary and lifestyle modifications •Weight loss •Reduced purine intake (meat) and alcohol consumption •Pharmacological treatments are a key treatment modality •Xanthine oxidase inhibitors (allopurinol) to reduce uric acid levels •NSAIDS reduce pain and inflammation of an acute attack •Colchicine, a potent anti-inflammatory medication, can be useto reduce the severity of acute attacks

ankylosing spondylosis clinical presentation

•Clinical presentation •AS initial presents as insidious onset of low back, buttock, or hip pain and stiffness lasting for at least 3 months •Early onset of back pain, stiffness, and fatigue during childhood •Pain is described as a dull ache that is poorly localized, but it can be intermittently sharp •Onset of symptoms leads to diagnosis during early adulthood •Pain can become severe and constant, increased by prolonged rest or immobility and decreased by active movement •Significant morning stiffness lasting more than 1 hour is often present •Tenderness, pain, and/or stiffness within the joints and bone process of the axial skeleton (especially sacroiliitis: inflammation of the sacroiliac joints) •Clinical presentation •Diagnosis involves history, physical examination, and radiologic imaging (MRI imaging or x-ray) of the vertebral column identifying calcification and ossification •Several diagnostic classification exists based upon laboratory findings, clinical presentation, and symptoms

OI Clinical presentation

•Clinical presentation •Presentation varies depending on type and severity of OI: •Normal bone appearance with occasional fractures (Type I) •Repeated fractures upon walking is an indication of mild OI •The tendency to fracture declines after puberty as cortical bone density increases •Severe OI can be readily identified at birth from presence of abnormal skeletal structure and fracture (Type III) •After birth, severe OI patients continue to exhibit skeletal growth retardation, fractures, and spinal deformities Short stature is common in children with OI •Lower extremities tend to be more involved than upper extremities •Diagnosis •Diagnosis of OI is based on clinical manifestations and collagen structure evaluation from a skin biopsy •Skeletal imaging demonstrates evidence of multiple old fractures and skeletal deformities •Skull radiographs show wide sutures with small, irregularly shaped islands of bone called wormian bones

gout clinical presentation

•Clinical presentation •The development of gout is multifactorial: many people with elevated uric acid levels for a prolonged period of time never develop signs or symptoms of gout •Gout progresses in four stages: 1.Asymptomatic hyperuricemia (serum urate levels > 7 mg/dL) 2.Acute gouty arthritis 3.Intercritical gout: intermittent periods of gout attacks and exacerbation followed by asymptomatic periods 4.Chronic tophaceous gout: development of tophi (nodular masses of urate crystals) •The most common clinical presentation is acute, monarticular, inflammatory arthritis manifested by exquisite joint pain occurring suddenly at night •Metatarsophalangeal joint (i.e., the big toe) is a common site of pain, however the ankle, instep, knee, wrist, elbow (olecranon bursa), and fingers can also be the site of an attack •Rapid onset of erythema, warmth, and tenderness is also present •Gout attacks can be precipitated by trauma, excessive alcohol consumption, or excessive consumption of high-purine content foods

osteoarthritis clinical presentation

•Clinical presentation •The most common symptoms of OA presents as: •Bony enlargement •Limited range of motion •Crepitus (audible cracking or grating in a joint) on motion •Tenderness on pressure •Joint effusion (fluid accumulation in synovial space) •Malalignment •Joint deformity •The most common joints involved are the weight-bearing joints: •First most common: the hip and knee •Next most common: shoulder, lumbar and cervical spine, and the first carpometacarpal and metatarsophalangeal joints (next slide) •Soft tissue inflammation is a prominent sign of early OA •Acute exacerbation result with joint inflammation and edema •Pain complaint progresses slowly and gradually until degeneration involves ligaments, tendons, and bones •Stiffness of short duration (less than 30 minutes) after period of inactivity (siting and sleeping); short period of morning stiffness that resolves after movement and activity •Note: rheumatoid arthritis symptoms are greatly extended compared to OA •Chronic inflammation causes joint enlargement (Heberden and Bouchard nodes) and/or bone spurs (osteophytes)

MD physiology

•DMD and BMD pathophysiology •Dysfunctional or absent dystrophin render the muscle cell susceptible to damage during contraction-relaxation phases •Dystrophin exists in a protein complex that: •Provides structural stability to the skeletal muscle cell •Regulates cell signaling •Protects the muscle cell from injury •Dysfunctional/absent dystrophin causes: •Abnormal Ca2+ influx •Muscle cell injury followed by necrosis, inflammation, and fatty and fibrous tissue scarring •DMD biopsy pathology: muscle tissue has significant inflammation, skeletal muscle degeneration with fatty tissue replacement, fibrous tissue, and a mix of normal diameter unaffected and atrophying skeletal muscle cells (images below) •DMD is caused by undetectable or absent levels of dystrophin •Age of ambulation (walking) loss < 13 years old •BMD is caused by abnormal dystrophin structure or reduced dystrophin levels •Age of ambulation loss > 16 years

degenerative intervertebral disk disease (DDD)

•Degenerative intervertebral disk disease (DDD) is a degenerative disease of the vertebral column commonly affecting the lower lumbar segments •Estimated that 50% of all American older than 40 years are affected •Lumbar disk degeneration begins early in life with macroscopic changes occurring from age 30 onwards •Risk factors •Genetic inheritance and family history of back pain or DDD •Aging •Excessive body weight •Occupational physical demands •Etiology and pathophysiology •Disk degeneration follows a predictable pattern: 1.Nucleus pulposus (gelatinous center surrounded by the annulus fibrosus) loses the ability to hold water 2.Intervertebral disk then dehydrates 3.Nucleus pulposus becomes thick and fibrous losing shock resistance 4.Spinal cord and nerves (radiculopathy) are compressed as: •Annulus tears form •Nucleus pulposus ruptures (disk herniation) •Intervertebral disk collapses compressing vertebra •Vertebrae misalignment occurs (spondylolisthesis) •Osteophyte development occurs (spinal stenosis) •Degenerative spondylolisthesis: anterior slippage of one vertebra over another to disk degeneration and degenerative changes of the posterior facet joint

RA clinical management

•Diagnosis •Early stages are difficult due to subtle waxing and waning symptoms •Diagnosis criteria (right) includes a combination of: •History and physical examination •Imaging studies: MRI imaging of joint degeneration •Laboratory findings of rheumatoid factor and inflammatory markers •Most individuals are asymptomatic before reporting to a physician •Clinical management •Prognosis: RA-induced joint changes are irreversible: early diagnosis can help prevent or reduce erosive and reduce morbidity and mortality •RA remission is the goal of treatment: absence or minimal symptoms and signs •Pharmacological management is challenging because of the balance between minimizing RA progression and drug toxicity and side effects •Treatment involves a combination of pain relieving and anti-inflammatory medications to reduce RA progression: •Analgesics to reduce pain •Anti-inflammatories •NSAIDs and corticosteroids •DMARDs (disease modifying antirheumatic drugs) which are effective immunosuppressants •Methotrexate is the standard medication •Immunosuppressants •Orthopedic surgery is recommended when pain or joint damage becomes severe

gout clinical presentation (2)

•Diagnosis •Gout is described as "the great imitator" that masquerades as RA, septic arthritis, or musculoskeletal neoplasm •Serum uric acid levels may or may not elevated in gout patients, therefore: •Definitive diagnosis occurs when urate crystals (tophi) are identified in synovial fluid, cartilages, or soft tissues •Diagnosis usually requires a triad of findings: •Acute monoarticular arthritis •Hyperuricemia •Prompt response to pharmaceutical therapy •Radiographic imaging or ultrasonography may identify bone abnormalities in the affected joint

DS diagnosis & management

•Diagnosis •Invasive and noninvasive assessments are utilized for prenatal genetic screening •Invasive screening of fetal tissue and cells: chorionic villus Screening (biopsy of the fetal placenta), percutaneous umbilical cord sampling, and amniocentesis (removal of amniotic fluid surrounding the embryo; contains fetal cells) •Noninvasive screening methods: •Maternal serum screening: measurement of α-fetoprotein, human chorionic gonadotropin, and unconjugated estrogen in maternal serum (triple screen test) allows detection of an estimated 60% to 70% of fetuses with Down syndrome •Ultrasound identification of nuchal translucency is used to assess a fetus for Down syndrome: carries a 6% false-positive rate and identifies only 77% of affected fetuses •Postnatal diagnosis begins with suspected physical findings followed by genetic studies to confirm the chromosomal abnormality •Clinical Management •Down syndrome treatment is directed toward specific medical problems that affect the patient and usually involves a multi-disciplinary approach •The life span of people with Down syndrome has increased significantly: In 1968, the average age of death was 2 years; by 1997 it had increased to 50 years •The presence of congenital malformations, especially of the heart and gastrointestinal tract, can result in high mortality rates

osteomalacia clinical presentation

•Diagnosis of osteomalacia is difficult and often delayed: •Patients initially present with diffuse, generalized aching and fatigue with anorexia and weight loss •Combination of muscle weakness and softening of bone contributes to postural deformities and abnormal gait due to the bowing of the femurs and tibias •Diagnosis requires history and physical examination, laboratory testing, and imaging studies •Osteomalacia is accompanied by hypocalcemia (low serum Ca2+levels) causing latent tetany, paresthesia of the hands, and muscle cramps •Imaging studies identify osteopenia, similar to osteoporosis •Serum evaluation of calcium, vitamin D, phosphate, parathyroid hormone, etc. •Bone biopsy can evaluate the calcification of the bone matrix •Clinical management •Treatment of osteomalacia depends on the cause: •If inadequate nutrition is the problem, the treatment is dietary modification with calcium and vitamin D supplementation •If intestinal malabsorption is the problem, the treatment is directed toward improving or correcting progression of the disease

RA

•Finger deformities associated with RA are caused by: •Joint laxity •Tendon rupture •Tendon hyperextension ulnar deviation

osteoarthritis treatment

•Goal is to relieve pain, maintain mobility, and minimize disability •Lifestyle modification and low impact exercise; walking, swimming •Supportive measures to reduce stress on the affected joint •Pharmacotherapy is utilized to reduce pain, inflammation, and OA progression •Nonsteroidal anti-inflammatory drugs (NSAIDs) are a first line treatment, such as ibuprofen which are nonspecific cyclooxygenase (COX) inhibitors •Long-term use of NSAID therapy should be avoided •COX-2 inhibitors should be utilized if NSAID treatment is ineffective •Intra-articular injection of glucocorticoids (hydrocortisone) •Bisphosphonates to prevent bone degeneration •Dietary supplements such as chondroitin sulfate and glucosamine may help •Orthopedic surgery to remove osteophytes, clear fibrosis scar tissues, or stabilize joints, such as arthroplasty or articular fusion

osteomyelitis clinical management

•Infection prevention •Chronic osteomyelitis is recognized as a complication of open fractures •Patient with biomaterial implants has an increased risk of infection, especially in the immediate postoperative period •Diagnosis •Osteomyelitis diagnosis is often complicated by lack of symptoms and signs which are masked by systemic infection or musculoskeletal disorder •Laboratory findings: elevated WBC count, elevated erythrocyte sedimentation rate (ESR), and positive blood cultures •Radiologic imaging (x-ray, MRI, CT scan, and ultrasonography) can identify lesions of the skeletal area with caveats •Early phases of the infection are unremarkable •Lytic lesions may be identified within 2 weeks of onset •Treatment •Immediate treatment is necessary utilizing sequential IV and high-dose antibiotic therapy based on pathogen and patient health history •Established infections are difficult to manage due to reduce blood flow to bone and loss of circulation to the necrotic area •Orthopedic surgery is required if infection has spread to the joint or if excessive injury has occurred •Involves the debridement of the bone and soft tissue and purulent exudate drainage •Without immediate treatment, skeletal structure, bone, and soft tissue will likely suffer permanent damage

osteoarthritis pathophysiology

•OA is a disorder of the whole synovial joint, not just "wear and tear" on the articular cartilage: OA is an active disease process with joint tissue destruction, inflammation, and abnormal repair •Articular cartilage provides a smooth, reduced friction surface for bone end movements •Articular cartilage damage and wear may be the by-product of a pathological mechanism located in the deeper bone below the joint surfaces •Underlying bone metabolic changes may proceed with loss of cartilage, hypertrophic bone growth, synovial inflammation, and degenerative changes to the ligaments and tendons •Articular cartilage wear may be the final end-point of the disease process •Inflammation is a key contributor to early OA pathophysiology and progression •Key inflammatory markers are elevated in early knee OA •Cytokines (IL-1beta and TNF-alpha): may contribute to articular cartilage and bone catabolic events in the joint •Serum C-reactive protein levels are also increased •Progressive articular cartilage loss causes further inflammation and: •Ligament laxity •Narrowing of the joint space •Abnormal bone growths or abnormal surface markings characterized by hypertrophy and overgrowth due to sclerosis of bone and new bone growth •Progressive muscle weakness and atrophy

OI management

•Orthopedic management is central to the overall care of clients with symptomatic OI primarily to control and prevent fractures •Intramedullary rod implantation to restore bone strength is recommend when: •Indications for this procedure include more than two fractures in the same long bone within a 6-month period •Lower extremity bone angles greater than 40 degrees •Very unstable lower extremities in a child who appears ready to walk •Pharmaceutical management includes the use of bisphosphonates •A class of medications that inhibit osteoclast function, improve bone mineral density, and decrease the incidence of fractures. •Individuals with OI types I and IV have a milder course and a relatively normal life span. •In type III OI, mortality is associated with cardiorespiratory failure stemming from kyphoscolioticdeformity

osteoporosis clinical presentation

•Osteoporosis can present as: •Loss of overall body height and postural changes •Change in vertebral column curvatures •Change in abdominal musculature and shoulder positioning •Back pain and/or bone fracture •Order of most common fracture sites: •Vertebral bodies, hip, ribs, radius, and femur •Vertebral compression fractures are common osteoporosis-related spinal fractures causing back pain •Vertebra compact and trabecular bone become too porous to resist compression

Paget disease pathophysiology

•Paget disease involves both osteoblast and osteoclast dysfunction that occurs in stages: •Initial resorptive stage: abnormal osteoclasts proliferation and excessive bone resorption outpacing osteoblast function •Fibrous tissue replaces bone creating lytic areas that are sharply defined and wedge/flamed shaped •Osteoblastic sclerotic phase: normal trabecular bone is replaced by coarse, thick struts; normal compact bone is irregularly thickened, rough, and pitted •Normal highly-organized lamellar structure is lost producing aenlarged bone with a chaotic pattern •Example: imaging of vertebral bodies identifies a "picture-framing" appearance: cortical shell and endplates are greatly exaggerated

Paget disease clinical presentation

•Paget disease is a slow and insidious chronic disease •Mild cases may present as only a few symptoms: bone pain and minor skeletal deformities •Severe case present as skeletal pain and deformities with hypercalcemia due to excessive calcium secretion into the blood •Fatigue, weakness, loss of appetite, abdominal pain, and constipation •Progressive demineralization weakens bone in the axial skeleton, but can also affect other sites •Fracture can occur in any bone, but are especially found in the femur, pelvis, and lumbar spine •Postural deformities affecting vertebral curvatures •Bowing of the femurs and tibia •Neurological presentation: Paget disease of the skull and spine can cause nerve impingement, compression, or ischemia •Cardiovascular presentation: rarely involved, but Paget diseased bone can cause heart failure

Paget disease clinical presentation (2)

•Paget disease progresses slowly, and the severity of the disease varies, therefore, the disease may be misdiagnosed until symptoms worsen •Diagnosis requires laboratory findings and radiologic imaging studies •Serum bone markers are an important screening tool: •Serum alkaline phosphatase is a key enzyme secreted by bone cells which is excessively secreted in Paget bone •Radiologic findings are a key diagnostic for Paget disease •Diagnosis is based on the characteristic bone deformities and changes observed in the disease •Bone biopsy

ankylosing spondylosis pathophysiology

•Pathophysiology •AS fundamental lesion of chronic inflammation and vertebral fusion occurs at sites of cartilage, tendons, ligaments, and synovial membrane to bone •Inflammation of the cartilage and bone stimulates reactive bone formation and progressive inflammation causing: •Bamboo spine: fused, rigid, vertebrate characteristics of the end-stage of the disease •Neurological disorders caused by compression of the spinal cord and/or spinal nerves •Musculoskeletal degenerative disorders including shoulder and hip loss of mobility •AS is a systemic disease with widespread effects involving other joints and other tissue and organs, especially cardiopulmonary disorders and inflammatory bowel disease

osteoporosis pathophysiology

•Pathophysiology •Bone is composed of: •Osteocytes •Collagen fibers •Calcium phosphate-forming hydroxyapatite •Bone strength is determined by: •Bone density: number of cells and bone matrix components in a given volume of bone •Bone quality: bone thickness, bone structure, and quality of the collagen •Bone Remodeling •Bone renews itself in a constant remodeling process: a repeating cycle of 1) osteoclasts breaking down the existing bone bit by bit (resorption) and 2) osteoblasts laying down new cells (formation) for mineralization •Osteoporosis begins when new bone production decreases below bone breakdown (resorption) during bone remodeling which characterizes age-related bone mass decline •Small defects in bone accumulate during these remodeling processes •Osteoblast populations are reduced •Other factors also contribute to defective bone remodeling •Bone demineralization occurs (osteopenia) occurs when deficits in endocrine function, physical activity, and/or nutrition occur •Mechanical and load stimulation (physical activity) is critical for bone mineral density

osteomyelitis pathophysiology

•Pathophysiology •Healthy adults are normally resistant to osteomyelitis due to reduced bone vascularity compare to children •Dense vascularization of the epiphyseal growth plates increase the likelihood of infection •Osteomyelitis is initiated by the invasion of the skeletal tissue via the surrounding tissues or bloodstream •Bacterial colonization of an area of bone initiates a necrosis and abscess formation •Usually involves the colonization of blood vessels draining into the medullary cavity •Abscess formation is followed by a spreading infection, inflammatory response, and necrosis •Inflammation and necrosis destabilizes bone and joint tissue increasing risk of soft tissue injury and fracture

OI pathophysiology

•Pathophysiology •The majority of OI cases is caused by over a 150 different mutations of the Type I collagen genes, while a minority of cases involve other genes that may regulate collagen synthesis or collagen fiber organization •Type I collagen is found in the extracellular matrix of bone, skin, and tendon and is the major structural protein (scaffolding) •Abnormal or lack of necessary amounts of type I collagen prevents the triple helix formation of type I collagen fibers which destabilizes bone and connective tissues •Bone modeling in OI is defective: •A smaller cross-sectional area is observed with thinner cortex noted in the long bones leading to diminished bone strength •Reduced growth and thickening of bone during childhood

osteoporosis clinical management

•Prevention and early intervention is crucial for everyone, especially those at risk •Physical activity •Regular exercise and physical activity is necessary throughout life to encourage bone remodeling •Nutrition •Adequate calcium: childhood and adolescence calcium intake is essential to increase bone mineral density (1300 mg daily for 9-18 y; 1000 mg for males; 1000 mg for females (1200 mg females >50 y) •Adequate Vitamin D: required for intestinal absorption of calcium from the diet; adequate sun exposure is necessary for vitamin D synthesis, but is supplemented in many foods •Healthy diet •Screening •National Osteoporosis Foundation (NOF) guide for physicians suggests a bone density test for every woman age 65 years and older and men age 70 and older •Diagnosis of osteoporosis requires history and physical examination, laboratory testing, and imaging studies •Imaging studies: Bone mineral density (BMD) comprises the majority of bone strength, therefore a DXA scan is often used as a proxy measure •Dual-energy x-ray absorptiometry (DXA) is the preferred procedure •Measures bone density at the femoral neck and lumbar spine which are the primary areas of rapid bone loss •BMD is a measurement of the mineral content of bone in grams/square centimeter (g/cm2) for the area •WHO classification: BMD is compared to normal values matched to a young adult of the same sex (T score) and those of the same age (Z Score) •X-rays can be useful, but can only identify gross abnormalities when 30% or greater BMD is lost •Laboratory testing for serum metabolic bone markers •Calcium, vitamin D, and parathyroid hormone •Introduction •Early prevention and detection is key for osteoporosis treatment; as well as fracture risk assessment •Treatment of secondary cause of osteoporosis is necessary if associated with another disorder •Lifestyle changes: •Fall prevention •Bone loss prevention: high calcium intake, smoking cessation, reduced alcohol consumption, physical activity, and exercise •Daily calcium intake: >1000 mg for premenopausal women •Daily calcium intake: >1200 mg for premenopausal women •Vitamin D (800 units/day) •Pharmaceutical treatment for osteoporosis ts initiated when the T-score is: < −2 in the absence of risk factors or < −1.5 if other risk factors are present •Bisphosphonates: inhibit bone resorption reversing bone loss •Postmenopausal women: estrogen replacement using selective estrogen receptor modulators (SERMs) •Selectively stimulate estrogen activity within the bone without stimulating the reproductive system •SERMs and bisphosphonates have been shown to increase BMD and decrease fracture risk

Paget disease clinical management

•Prognosis: disease course varies widely from stable to asymptomatic, to rapid progression of the clinical signs •Remission of metabolic bone destruction is possible in a majority of cases by using bisphosphonates •Treatment: bisphosphonates (inhibitors of bone resorption) are the first line treatments decreasing bone turnover •Successful treatment is monitored using serum alkaline phosphatase (increased excessive serum AP is released by excessive osteoclast activity) •Pain and pathological bone changes are treated accordingly: •Nonsteroidal and steroidal anti-inflammatory medication; orthopedic surgical intervention to treat fractures and bone degeneration

RA clinical presentation

•RA is a systemic disease presenting with articular and extraarticular complaints •RA usually presents insidiously and progresses slowly from: •Cartilage degradation •Ligamentous laxity •Synovial hyperplasia and joint erosion •Common complaints: •Fatigue, weight loss, weakness, and diffuse musculoskeletal pain •Multiple joints are involved with symmetric bilateral presentation involving the: •Wrist, knee, and joints of the fingers, hands, and feet •Metacarpophalangeal and proximal interphalangeal joints of the hand are involved early •Joints presents edematous, warm, painful, and stiff •Progressive RA is characterized by a variety of musculoskeletal disorders and deformities: •Finger deformities: ulnar deviation, swan-neck deformity, and boutonnière deformity •Soft tissue disorders: synovitis, bursitis, tendinitis, etc. •Spine: early involvement of the cervical spine causing deep, aching neck pain and possible cervical instability (atlantoaxial instability) with neurological symptoms and signs •Cutaneous: rheumatoid nodules in 25% of cases: granulomatous lesion appearing in areas of repeated pressure •Progressive RA manifest in chronic inflammatory disorders in other tissues and organs, some which are life threatening (see box on next slide)

RA pathophysiology

•RA is an autoimmune disease affecting both the joint capsule and other tissues and organ of the body •80% of RA patients are rheumatoid factor positive •Rheumatoid factors are autoantibodies that react with other antibodies in the bloodstream and trigger inflammatory action •RA pathogenesis •An RA autoimmune reaction attacks the joint within the synovial cavity •Synovial cells undergo hyperplasia •Leukocytes are recruited to the synovial membrane initiating inflammation and edema •Synovial membrane thickens causing clinical synovitis •Synovitis results with a destructive vascular granulation tissue called pannus •The RA-affected synovial membrane can no longer lubricate and nourish the articular cartilage •As pannus tissue proliferates, the tissue dissolves surrounding connective tissue (collagen, cartilage, and bone) •The inflammatory cytokines (TNF-alpha and IL-1) play a major role in inflammation, tissue destruction, and synovial hyperplasia •As RA progresses, the joint degenerates creating irreversible: •Joint instability and laxity •Joint deformity •Ankylosis (fibrous adhesion or bony fusion of a joint)

soft tissue healing

•Skeletal muscle •Muscle regeneration depends on the severity of the injury •Mild injury can result with near complete muscle regeneration •Moderate injury will result with less muscle regeneration and increasing replacement of necrotic tissue with fibrous scar tissue •Muscle satellite cells can proliferate and regenerate some muscle •Severe injury is characterized by scar tissue replacement of muscle tissue and contractures •Tendons and ligaments •Healing and repair of the dense regular connective tissue depends on the severity of the injury •Mild to moderate injury proceeds through an inflammatory phase and proliferative phase creating granulation tissue •Maturation consists of deposition of scar tissue and remodeling of collagen fibers leaving the connective tissue weaker

soft tissue trauma

•Skeletal muscle •Strains: overuse or overstretching of muscle •Muscle contusion: injury and hemorrhage of skeletal muscle tissues (myofibers and connective tissues) due to trauma •Tendons and ligaments •Sprains: over-stretching, tearing, and/or swelling •Tendinitis: injury and inflammation of the tendon, tendon sheath, and associated connective tissues •Tendon rupture: complete tearing of the tendon •Neurovascular bundles •Hemorrhage within a muscle or muscle compartment, hematoma, can inflammation with edema can compress nerve and vascular components leading to ischemia and infarction causing compartment syndrome

ankylosing spondylosis

•Spondyloarthropathies is a group of disorders characterized by vertebral joint inflammation •Ankylosing Spondylitis (AS, sometimes referred to as Marie-Strümpell disease) is an inflammatory arthropathy of the axial skeleton, including the sacroiliac joints, apophyseal joints, costovertebral joints, and intervertebral disk articulations. •One third of AS patients have asymmetric involvement of the large peripheral joints, including the hip, knee, and shoulder •AS ultimately can lead to fibrosis, calcification, and ossification with fusion of the involved joints •Etiology and risk factors •AS typical affects young people between the ages of 15 and 30 years •AS differs from back pain of mechanical origin, which is much more likely to develop between 30 and 65 years of age •Men are affected two to three times more often •Evidence points to a genetic and environmental factors •Genetic inheritance of the HLA-B27 allele increases the likelihood of AS development •Environmental factors, such as bacterial pathogens, may contribute to AS development

osseous tissue

•Structural components: •Bone matrix •Osteocytes in lacunae •Types •Compact bone: organized into osteons •Trabecular bone: organized into trabeculae •Also called spongy bone or cancellous bone •Function •Protects organs, levers for movement, calcium/phosphate ion sink, and houses hematopoietic cells Composed of: •Bone Matrix •Hardened calcium phosphate mineral deposits •Flexible collagen (protein fibers) •Around 1/3 of a bone's mass •Bone (osseous) cells

metabolic skeletal disorders

•The skeletal undergoes continuous remodeling throughout life •10% of the adult skeleton is turned over each year •Remodeling is necessary to maintain structural integrity •Skeletal metabolism provides storage for calcium and phosphorus ions •Metabolic skeletal disorders are characterized by excessive bone destruction or excessive bone production •Excessive bone metabolism (either destruction or production) directly affect calcium and phosphorus levels

Down syndrome pathophysiology

•Trisomy 21 causes Down syndrome, however the genetics of the disease are not well understood •Inheritance of a third chromosome may occur due to: •Faulty meiosis of the ovum or, sometimes, the sperm (moderate to severe Down syndrome) •Genetic mosaicism: faulty cell division in the early embryo with only a portion of the cells affected (mild to moderate Down syndrome) •Unknown internal or environmental factors may contribute chromosome abnormality •Abnormal elevated gene dosage (increased production of chromosome 21 gene products) is presumed to be a contributor to Down syndrome •Downstream effects of elevated gene dosage may disrupt other regulatory pathways •Several genes are abnormally elevated or reduced in Down syndrome are associated with: •Neuropathologies •Alzheimer disease (beta-amyloid deposition) •Immune dysfunction

down syndrome

•a chromosomal abnormality resulting with three copies of chromosome 21 (trisomy 21) and is characterized by multiple congenital and developmental abnormalities: •Cognitive delay and/or intellectual impairment and other neurological disorders •80% of children have an IQ of 25 to 50; remaining 20% have normal or near normal intelligence •Alzheimer disease is prevalent by age 40 •Musculoskeletal deformities: dysmorphic facial features, muscle hypotonia, and secondary musculoskeletal and orthopedic problems due to hypotonia •Organ system abnormalities: immunodeficiency, congenital heart disease, digestive, and renal disease •40% of children have congenital heart disease and esophageal and intestinal malformation •Down syndrome is the most common inherited chromosomal disorder: occurring once in every 700 live births •The incidence of Down syndrome increases with maternal age •Incidence before maternal age 30 is 1 in 2000 births •Incidence for mothers 35 to 39 is 1 in 50 births •Incidence for mothers older than 40 is 1 in 20 births •Other factors •5% to 10% of cases correlates with advanced paternal age •There is a 2% risk of recurrence for a couple who have had a child with Down syndrome clinical presentation: •Children with Down syndrome are readily identified by characteristic facial features: •Flat facial profile, oblique eyes, and epicanthic folds •Children with Down syndrome predictably present with feeding difficulties and delayed acquisition of motor skills •Secondary disorders often develop after age 30 or 35 •Alzheimer disease, obesity, diabetes mellitus, and cardiovascular disease •Children with Down syndrome frequently present with various musculoskeletal or orthopedic problems due soft tissue laxity and muscle hypotonia •Hypotonia and decreased muscle strength destabilize and weaken joints •Atlantoaxial instability (AAI) of the cervical spine (subluxation between C1 and C2) is a characteristic in some Down syndrome children •Progressive spinal cord compression due to joint laxity produces associated symptoms (refer to Unit 3) •More common findings include recurrent patellar dislocation, excessive foot pronation, scoliosis, slipped capital femoral epiphysis, and late hip dislocation

gout

•a heterogeneous group of metabolic disorders characterized by elevated levels of serum uric acid (hyperuricemia) and urate crystals deposited within the: •Joints •Soft tissues •Kidneys (renal stones or nephrolithiasis) •Hyperuricemia and gout are generally classified into one of three groups. •Primary hyperuricemia: inherited genetic disorder of uric acid metabolism •Secondary hyperuricemia: result of another metabolic problem, such as chronic renal disease or reduced uric acid excretion •Idiopathic hyperuricemia: unknown etiology of hyperuricemia and gout •Additionally, other organic or mineral salt crystals can form inside joints presenting similar to gout •Etiology •Prevalence of gout increases with increasing serum urate concentration and age •Patients receiving chemotherapy for hematological disorder are at increased risk of gout •Heavy alcohol consumption, obesity, and endocrine disorders (thyroid, parathyroid, etc.) can all lead to decreased excretion of uric acid •Purine-rich diet consisting of meat and high protein content increase risk of gout and increase the severity of gout attacks

osteomalacia

•a progressive disease characterized as lack of mineralization decreasing the strength of the bone matrix without bone matrix reduction •Newly synthesized bone matrix lacks mineralization softening the bone matrix •Caused by calcium, vitamin D, or phosphate deficiency •Referred as the adult form of rickets • Etiology •Two primary causes of osteomalacia are: •Insufficient intestinal calcium absorption (lack of calcium, vitamin D, or resistance to vitamin D) •Increased renal phosphorus losses (renal failure; long-term use of antacids, etc.) •Incidence and risk factors •Osteomalacia primarily occurs in malnourished aging adults who may not receive adequate sunlight •Osteomalacia is seen with greater frequency in cultures where the population has increased skin pigmentation and vitamin D dietary deficiency •e.g. northern China, Japan, and northern India •Other risk factors include that conditions adversely affect absorption of calcium and the action of vitamin D: •Digestive or GI tract disorders: small intestine, cholestatic disorders of the liver, biliary obstruction, and chronic pancreatic insufficiency

osteogenesis imperfecta

•also known as brittle bone disease), is a rare congenital collagen synthesis disorder affecting bones and connective tissue •Four primary types exist: Type I, II, III, and IV •Type I is the mildest form of OI causing mild to moderate skeletal fragility without deformity •Type II is the most severe form usually resulting with perinatal death •Type III is moderately severe consisting of progressive deformities, including vertebral column deformation, limb deformation, osteoporosis and disability •Etiology •OI is usually an autosomal dominant disorder that is inherited from a parent •Parental genetic mosaicism of germ cells •Approximately 25% of OI children have no family history of the disorder suggesting spontaneous mutation

bone remodeling

•continuous process of bone resorption by osteoclasts, followed by a period of repair during which new bone tissue is synthesized by osteoblasts controlled by: •Repair microscopic structural damage •Bone anabolism or catabolism to modify blood calcium levels •Response to weight-bearing stress •Circulatory factors •Bone degeneration occurs when bone catabolism overtakes bone anabolism due to: •Inadequate calcium intake/absorption •Increased osteoclast activity •Increased parathyroid activity and PTH secretion

osteomalacia pathophysiology

•develops due to lack of calcium ion deposition into the growing or remodeling bone matrix •Bone structure and microanatomy is unchanged, but is greatly weakened from lack of calcium minerals •Radiographic imaging can identify demineralization of the bone identifying loss interface sharpness between compact and trabecular bone •Imaging can also identify pseudofractures and other mineralization abnormalities

osteomyelitis

•inflammation of a bone caused by infectious microorganisms •Mostly commonly bacteria, specifically staphylococcus aureus •Fungi, parasites, and viruses can also colonize and infect bone •Primary skeletal areas affected: spine, pelvis, and limbs •Etiology and risk factors •Acute osteomyelitis describes a new bone infection that can develop into a chronic infection and inflammatory reaction without proper treatment •Acute osteomyelitis is a rapidly destructive pyogenic infectionthat enters the body through an open wound or gastrointestinal tract •High risk for septicemia or a septic infectious joint: an acute bone infection has the capability to spread quickly through the bloodstream •Commonly found in children, older adults, and IV drug users •Chronic osteomyelitis is the result of persistent bone infection, failed treatment, or untreated acute disease •Commonly identified in adults and immunocompromised patients •Necrotic bone tissue lacking blood supply is susceptible to gangrene •Exogenous (contiguous) osteomyelitis •Bone infection acquired by invasion of the bone by direct extension from the environment •Penetrating or puncture trauma •Extension from infected or injured soft tissue overlying the bone •Open fracture •Hematogenous osteomyelitis •Bone infection acquired from the spread of infectious organisms (usually bacterial) via the bloodstream from preexisting infections: •Such as, but not limited to the paranasal sinuses, ear, dental, soft tissue, respiratory, and genitourinary infections •85% of hematogenous osteomyelitis occurs in children younger than 17 •Any risk factors compromise immunity and make the patient susceptible to bone infection •Nutritional deficiency •Comorbid diseases such as diabetes mellitus or HIV •The prevalence of osteomyelitis in diabetic patients is 16%; after a foot wound, the risk increases to 30% to 40% •Immunosuppressive medications such as corticosteroids, methotrexate, or tumor necrosis factor (TNF) inhibitors •Implanted synthetic or allograft prosthetic material increase the incidence of Staphylococcus aureus (S. aureus) infections •Incidence of prosthetic joint infection among all prosthesis recipients ranges from 2% to 10%.

osteoarthritis

•is slowly evolving degenerative joint disease that appears to originate in the cartilage and affects the underlying bone, soft tissues, and synovial fluid •Primary OA is of unknown etiology, but may be related to a series of joint degeneration events associated with defective articular cartilage •Secondary OA associated with a known injury or disorder, such as trauma, infection, hemarthrosis, osteonecrosis, or some other condition •OA consists of a heterogenous groups of conditions cause slow, progressive degeneration of the articular cartilage with underlying soft tissue and bone structural changes •OA is the most common joint disease, with an estimated prevalence of 60% in men and 70% in women after the age of 65 years. •Etiology •OA is multifactorial consisting of both biomechanical and pathological contributors •Major factors and likely factors that contribute to OA: •Genetic predisposition •Poor nutrition and excessive body weight •Bone density •Local biomechanical factors •Immobilization of a joint •Serious joint or skeletal trauma and an inherited genetic predisposition accounts for 50% of all cases of OA in the hands, hips, and knees

rheumatoid arthritis

•major sub-classification of rheumatoid diseases; rheumatoid diseases can affect many body systems and have the following characteristics: •Onset of joint pain and loss of function accompanied with fever, rash, neuritis, and other inflammatory conditions •Not typically associated with joint or muscle conditions caused by overuse or trauma •Often marked by periods of exacerbation and remission •Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that manifests with a wide range of: •Articular findings: chronic polyarthritis, which perpetuates a gradual destruction of joint tissues, can result in severe deformity and disability •Extraarticular findings: cardiovascular, pulmonary, and gastrointestinal systems •Risk factors and etiology •RA is the most prevalent form of arthritis after OA •The peak onset is usually between 20 and 50 years, but onset of RA can occur at any age •Women are affected two to three times more frequently than men •Little is known about the exact causes of RA which may involve a combination of genetic predisposition, environmental triggers, and immune hypersensitivity

Gower sign (MD)

•sign of lumbar and gluteal weakness as a child stands from a prone position Note the excessive lordosis of the patient

neuromuscular junction

•site of excitation-contraction coupling •A motor neuron depolarizes to an action potential •Axon terminal of the neuron releases Acetylcholine (ACh) into the synaptic cleft •ACh stimulates receptors of the motor end plate depolarizing the sarcolemma •The action potential travels along the entire sarcolemma •The action potential stimulates Ca2+ release from the sarcoplasmic reticulum •Ca2+ concentration of the sarcoplasm rapidly increases •Ca2+ binding to the Troponin-Tropomyosin complex allows cross-bridge interactions •Sarcomere shortens; contraction force (tension) increases

skeletal muscle

•surrounded by connective tissue at multiple levels •Epimysium is the thick layer of fibrous tissue that surrounds an entire muscle •Perimysium is the layer of fibrous tissue that surrounds a fascicle •A fascicle is bundle of skeletal muscle fibers (muscle cells) •Endomysium is a thin layer of areolar tissue surrounding a single muscle fiber •The -mysium layers terminate into connective tissue forming: •Tendons - a cord-like structure that attaches a muscle to a bone •Aponeurosis - a broad, sheet-like structure that attaches a muscle to other muscles and/or bones •Tendons and aponeuroses transmit force to bones, muscles, and other tissues to generate tension and force

muscular dystrophy

•the most common group of inherited progressive neuromuscularchildhood disorders •MD is characterized by ongoing, typically symmetric muscle wastingcausing increased musculoskeletal deformity and disability •The etiology of all forms of MD are inherited genetic disorders •Clinical sign of MD can occur at any point in the life span of the patient; usually appear by late adolescence •Six major types of MD are: •Duchenne muscular dystrophy (DMD) is the most common form of MD •The incidence of DMD is ~1 in 3500 live births •Becker muscular dystrophy (BMD) is a milder form of MD •Facioscapulohumeral (Landouzy-Dejerine) dystrophy (FSHD) •Limb-girdle muscular dystrophy (LGMD) •Myotonic dystrophy •Muscular dystrophy congenita (MDC), also known as congenital muscular dystrophy Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) •DMD and BMD pathophysiology •The dystrophin gene locus is located on the X chromosome: therefore DMD/BMD is a sex-linked inherited genetic disorder •Human males have only one X chromosome; the Y chromosome is much shorter and lacks a majority of X chromosome genes. •Another way to think about this is that a female genotype (XX or double X) has a backup X chromosome to restore gene function •Females are usually carriers for DMD/BMD; although spontaneous mutations can occur •DMD and BMD pathophysiology •The affected gene in DMD and BMD is dystrophin •The dystrophin gene encodes a protein localized to the plasma membrane of skeletal muscle cells which interconnects the contractile proteins to the plasma membrane