Hereditary Spherocytosis

hemolytic anemia, splenomegaly, jaundice, gall stones, hemolytic crisis triggered by infection

RBC cytoskeletal membrane defect

mutation in spectrin, ankryrin or protein 4.1

spheroidal RBC, unable to deform

mutation in WASP

X linked immunodeficiency

no WASP=no ARP 2/3 activation

actin unable to nucleate and form the weblike stx

thrombocytopenia, eczema, recurrent infections

actin mutation where binds to Z disk

unable to transfer force of contraction

early heart failure

develops CHF, dypsnea, weakness, fatigue, palpitations, pedal edema, m. is enlarging but unable to contract properly

high risk of PE and sudden death

mutations in myosin II tropomyosin troponin

#1 cause of sudden cardiac death in athletes

dypsnea, angina, palpitations, syncope, fatigue

increased cholsterol in RBCs

associated with chronic liver disease; alcoholism

excess cholesterol transferred to outer leaflet produces spur formations, decreasing deformibility

hemolytic anemia, increased sequenstration by spleen

absence of glycoprotein IIb, a major apatelet specific integrin

failure of platelet aggregation

excessive bleeding and bruising

Plasmodium falciparum

infected RBCs express adhesive glycoproteins, will attach to capillaries

inflamatory bowel disease

IBD

down regulation of epithelial tight junction protein occludin

enhanced paracellular permeability,

allows neutrophils to excessively migrate causing inflamation

Pemphigus

pemphigus vulgaris

autoimmune disorder,

anti-desmogelin autoantibodies

blistering raw sores on skin and mucous membranes, abnormal movement of fluid within skin, skin pulls apart

mutation of Connexin 32

progressive degeneration of PNS, mm. weakness and atrophy, impairment of deep tendon reflexes

foot drop, high stepping gait, high arched foot, hammertoes

vitamin C deficiency for 20-40 days

fewer H bonds formed in collagen triple alpha helix, makes weak CT

s/s  swollen gums, loose teeth, pinpoint hemmorrhages around hair follicles, gums and nails, slow wound healing, anemia and fatigue

high risk are infants, elderly, smokers, alcoholics and Davey Jones arrggg

OI

Osteogenesis Imperfecta

mutation of type I collagen

gly substitution

predisposed to fractures

range of severities

blue slera, bone fragility, possible deformities, short stature,

mutation in type I, III and V

hyperextensible skin, hypermobile joints

at risk for ruptred colon and large aa., corneal fragility and diaphragmatic hernia

also can have a mutation in lys hydroxylase, or in the conversion of procollagen to collagen

mutation in type IV collagen

affects basal lamina,

causes nephritis, and deafness, hematuria, proteinuria, HTN

autoimmune disease, autoantibodies to Type IV collagen

inflamatory destruction of basal lamina in kidney glomerulus and lung alveoli

progressive renal failure

mutaiton in keratin 5 and 14

extremely fragile skin, minor mechanical friction or trauma results in significant blistering

mutation in lamins, integrins, hemidesmosomal proteins

extremely fragile skin, minor mechanical friction or trauma results in significant blistering

mutation in collagen VII

extremely fragile skin, minor mechanical friction or trauma results in significant blistering

mutation of type II collagen

includes Spondyloepiphyseal dysplasia

type II collagen mutation

drawrfism, enlarged joints

type II or type XI collagen mutation

flat facial appearance secondary to underdeveloped facial bones,

mutation of transcription factor SOX9

decrease in type II collagen results in bent bones, small chest and is often lethal

can also see XY sex reversal

mutation in FGFR3 tyrosine

restriction of bone growth through excessive inhibition of chondrocytes

constitutive activation of tyrosine kinase receptor

drawfism

weak elastic tissue

mutation in fibrillin

aortic root dilation, lens subluxation, retinal detachment,

tall thin stature, arachnodactyly and pectus excavatum

autosomal recessive disease, amplified by smokers

dyspnea, hyperventilation, barrel chest secondary to hyperinflation

downregualtion of HSPG

causes glomerulus basement membrane to thicken, increased collagen and decreased HSPG

proteinuria, fluid retention, HTN, renal failure

dialysis pts.

inhalation and phagocytosis by alveolar macrophages, microbe can survive for decades and be transported to regional lymph nodes

#1 infectious disease killer worldwide

s/s--prroductive cough, chest pain, hemoptysis, fever, weight loss, fatigue, night sweats

spread by aerosal

microbe found in water via infected amoeba

multiply in the alveolar macrophages

Hyperlipidemia Type IIa

Familial Hypercholesterolemia

mutation in LDL receptor

increased plasma cholesterol, increased synthesis of LDL, result of innefective endocytosis

increased risk factor of CAD, CVA, present with Xanthomata, Xanthelasmata and corneal arcus

inhibition of acetylcholine release at the neuromuscular junction

cleaves synaptobrevin (v-snare)

s/s--flaccid paralysis, constipation, loss of head control, hypotonia and hyporeflexia, resp. difficulties, "floppy baby syndrome"

cleaves synaptobrevin (v-snare)

prevents vesicle fusion and release of GABA and glycine (the inhibitory neruotransmitters of motor neurons)

s/s--prolonged contraction of skeletal mm., trismus(lock jaw), violent spastic paralysis, pt bites down on spatula when touchinng uvulua

mutation of desmin, creating aggregates that interfere with the other filament stx. in the cell

misaligned sarcomeres causes m. cell apoptosis and necrosis

s/s--progessive m. weakness and atrophy, intestinal obstruction, cardiac failure, resp. failure

altered lamin A results in an unstable nuclear envelope

causes nuclear pore clustering, progressive nuclear damage and premature cell death

s/s--failure to thrive, prominent eyes, alopecia, loss of subcutaneous fat, aged looking skin, joint stiffness, arteriosclerosis by 5 y/o, life expectancy of 13 y/o

most common laminopathy

mutation of lamin A/C or Emerin

contractures of elbows, ankles, neck, m. weakness and atrophy, conduction defects and arrhythmias

skeletal, abnormalities, coarse features, restricted joint movements, psychomotor retardation, enlarged liver, spleen and heart valves, life expectancy of 10 y/o

absense of M6P tag, causing lysosome deficiency

pseudo-hurler polydystrophy

(mucolipidosis III)

most common lysosmal stroage disease

accumulation of glucocerebroside b/c of an enzyme deficiency

progressive organomegaly with marrow and CNS infiltration, hypersplenism results in anemia, convulsions, dementia, MR, apnea

most severe MPS

accumulation of GAGs dermatan sulphate and heparin sulphate because of a deficency in alpha L iduronidase

physical and mental retardation, organomegaly, deafness, hirsutism, corneal clouding, death by 10 y/o

residual enzyme activity alpha L iduronidase

milder than hurlers

X linked

deficiency of iduronodate sulphatase

deafness, decreased IQ, short stature, chronic diarrhea, joint stiffness, hepatosplenomegaly, no corneal clouding, onset at 2-4 y/o, survival to 30s

Sanflippo syndrome

defect in heprain sulphate degradation

progressive MR and behavioral problems (aggressive and destructive), hyperactivity, sleep distrubance, hearing loss

defective degradaion of keratan sulphate

keratan sulphate in urine, short stature, kyphoscoliosis, pectus carinatum, deafness, weakness, aortic regurgitaion, normal IQ

dermatan sulfate build up

deficiency of arylsulphatase B

s/s are similar to Hurler's but pts have a normal IQ

deficiency of Beta glucoronidase

many different mutations and variable severity

autosomal disease, rare

mutation in CHS1/LYST lysosomal trafficking regulatory protein

results in delayed fusion of phagosome with lysosome in leucocytes, autophagocytosis of melanosomes, granular defects in natural killer cells and platelets

s/s--albinism, recurrent life threatening infections, mild coagulation defects, variable neruro problems

progressive external opthalmoplegia

(PEO)

bilateral ptosis, progressive weakening of external eye mm., proximal mm. weakness and wasting

mtDNA deletion or multiple large deletions in mtDNA

mutation of pol gamma

can be from mutations in TWINKLE, the gene for mt helicase

AR disease of childhood

progressive cerebral degeneration

s/s--seizures, cortical blindness, deafness, liver failure and eventual death

mt DNA reduced to 30% with no detectable pol gamma

mtDNA deletions in muscle

ragged red fibers secondary to 80% mutated mtDNA

s/s--severe progressive external opthalmoplegia, retinopathy, cerebellar ataxia, heart block

bone marrow is involved

all tissue has mtDNA with deletions

s/s--sideroblastic anemia, exocrine pancreatic failure

(sideroblasteic anemia is the abnormal production of RBCs, but body can't put Fe into hemoglobin)

MELAS

(mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes)

short stature, vomiting, headaches, visual disturbances (stroke like episodes), sensorinerual hearing loss

base sub. for leucine mutates tRNA gene

always heteroplasmic

maternally transmitted

MERRF

(myoclonus epilepsy and ragged red fibers)

progressive myoclonic epilepsy and seizures

mutated tRNA gene

always heteroplasmic

LHON

(leber's hereditary optic neuropathy)

subacute painless bilateral visual failure

missense mutations in subunits of mt complex 1 (the NADH dehydrogenase)

optic n. is the only affected tissue

may be homplasmic

maternally transmitted

NARP

(Neruogenic muscle weakness, Ataxia, and Retinitis Pigmentosa

late childhood or adult onset, ataxia, pigmentary retinopathy

mutation in mt complex V (ATP syntahse)

always heteroplasmic

maternally inherited

leigh syndrome is more severe form

Shingles

Varicella Zoster Virus

dermatomal distribution of paiful vesicular lesions

reactivation of latent viral infestation in dorsal root ganglia

viral infection that ascends to CNS along the PNS via dynein

s/s--encephalitis, malaise, fever, headache, confusion, agitition, delirium, hallucination, hydrophobia, photophobia, coma, death

AD disease

N terminus CAG repeat expansion

causes microtubule destabilizatoin, proteolysis, neuronal cell death

s/s--chorea, loss of coordination, unsteady gait, dementia, forgetfullness, death w/in 15 years of onset

progressive neuro disorder

destruciton of lower motor neurons, m. atrophy and weakness

destruction of upper motor neurons, hyperreflexia, spasticity

progressive paralysis, aphasia, aphagia, resp. failure

hyperphosphorylated tau

accumulation of NFTs (neurofibrillary tangles) in beta amyloid plaques

decreased funcional microtubules

pts will have increased tau in CSF

progressive degeneration of cerebral cortex causing dementia

AR with variable penetrance

immotile cilia and sperm

s/s--retention of lung secretions, recurrent infection, infertility

bronchiectasis, situs inversus, chronic paranasal sinusitis, infertility

caused by immotile cilia, total lack of dynein arms or a defect of inner dynein arms

50% of pts with primary ciliary dyskinesia have this syndrome

X linked

framshift insertion/deletions dystophin mutation

no detectable dystrophin in mm.

gower's maneuver, calf pseudohypertrophy, lordosis, scoliosis,

aberrant but partially functional dystrophin protein

inframe insertions/deletions of dystrophin

X linked

autosomal dominant

triplet repeat disorder of CTG, with anticipation of repeat expansion

affects myotonin protein kinase, idiopathic

s/s--cataracts, frontal balding, atrophy of facial mm., ptosis, weakness in hands, legs, SCMs

LGMD

limb girdle muscular dystrophy

autosomal recessive laminopathy

mutation of any of the sarcoglycans, makes disrupted interacion with dystroglycan protein

s/s--similar to DMD, no calf pseudohypertrophy or cognitive impairment, weakness of proximal musculature

pectoral folds with severe shoulder weakness, resp. insufficiency, contractures, seizures, MR

mutation in laminin,

imparied myogenesis, synaptogenesis and mechanical stability

defect in lamin A/C

impaired adipocyte differentation

accumulation of adipose tissue in face and neck, peripheral m. prominence, defecive lipid metabolism

autosomal dominant leukodystrophy

ADLD

Lamin B duplicaiton

phenotypically similar to MS, slow progressive symmetrical demyelination in CNS

mutation of survival of motor neruon proteins that are found in the Gems of the nucleus

causes defective snRNP assembly and defective pre-mRNA splicing resulting in loss of motor neurons, spinal cord and brainstem

s/s--mm. weakness and atrophy, hypotonia, dysphagia,

degradaion of purines into uric acid

s/s--hyperuricemia, joint inflamation

autosomal recessive

peroxins don't recognize SKL ser-lys-leu, can't import peroxisomal enzymes, causing VLCFAs to build up in blood and tissue

s/s--hepatomegaly, liver failure, m. weakness, hypotonia, hyporeflexia, siezures, MR, dysphagia, prominnet forehead, hypertelorism, large fontanelles death by 12 months

XALD

X linked Adrenoleukodystrophy

most common peroximal disorder

myelin breakdown b/c of a defect in transport of VLCFAs into peroxisomes

s/s--spasticity, ataxia, visual loss

deletion of chr 15, only maternal copy acitve in the brain

s/s--hyperactivity, epilepsy, affectionate nature, frequent laughter, severe learning disabilities

autosomal recessive

mutation of CFTR, protein degraded after ejection from ER

s/s--chronic cough, dyspnea, irreversible bronchial dilation, dilated central bronchi, hyperexpansion, mucoid impaction

failure of peptidase cleavage of proinsulin to C peptide

causes increased serum proinsulin, resembles NIDDM

Sjorgren's syndrome

autoimmune destruction of lacrimal and salivary glands, anti RNP and anti Golgi antiboidies

s/s--dry mouth (Xerstomia), dry eyes (Keratoconjunctivites sicca)

anti centromere and anti golgi antibodies

Calcinosis, Raynaud's phenomenon (spasms of blood vessels in response to cold or stress), Esophageal dysfunction, Sclerodactyly, (thickening and tightening of skin on hands), Telangiectasias (dilation of capillaries causing red maks on skin)

C.R.E.S.T.